Me, Active in Health Policy? Why? Campbell et al....Me, Active in Health Policy? Why? Norm Campbell...

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Volume 5, Issue 4 • December 2010

Me, Active in Health Policy? Why?Campbell et al.

CanMEDS Health AdvocacyCurriculum for ResidentsSohi et al.

NOW INDICATED FOR THE PREVENTION OF STROKE AND SYSTEMIC EMBOLISM IN PATIENTS WITH ATRIAL FIBRILLATION, IN WHOM ANTICOAGULATION IS APPROPRIATE.1

NEW PrPRADAX™ 150 mg BID

PRADAX (dabigatran etexilate) is indicated for the prevention of stroke and systemic embolism in patients with atrial fi brillation, in whom anticoagulation is appropriate. PRADAX is contraindicated in patients with: severe renal impairment (CrCL <30 mL/min); hemorrhagic manifestations, bleeding diathesis, or patients with spontaneous or pharmacological impairment of hemostasis; lesions at risk of clinically significant bleeding, e.g. extensive cerebral infarction (hemorrhagic or ischemic) within the last 6 months, active peptic ulcer disease with recent bleeding; concomitant treatment with the strong P-glycoprotein (P-gp) inhibitors, i.e. oral ketoconazole, and with known hypersensitivity to dabigatran, dabigatran etexilate or to any ingredient in the formulation or component of the container. Bleeding is the most relevant side effect of PRADAX; bleeding of any type or severity occurred in long-term treatment in 16.5% of patients with atrial fi brillation treated for the prevention of stroke and systemic embolism. As with all anticoagulants, PRADAX should be used with caution in circumstances associated with an increased risk of bleeding. Bleeding can occur at any site during therapy with PRADAX. An unexplained fall in hemoglobin and/or hematocrit or blood pressure should lead to a search for a bleeding site. Patients at high risk of bleeding should not be prescribed PRADAX. Close clinical surveillance (looking for signs of bleeding or anemia) is recommended throughout the treatment period, especially if risk factors are combined. Should severe bleeding occur, treatment with PRADAX must be discontinued and the source of bleeding investigated promptly. Patients who develop acute renal failure must discontinue PRADAX. In patients who are bleeding, an aPTT test may be useful to assist in determining an excess of anticoagulant activity, despite its limited sensitivity. An aPTT >80 sec at trough, i.e. when the next dose is due, is associated with a higher risk of bleeding. Agents that may enhance the risk of hemorrhage should not be administered concomitantly with PRADAX, or, if necessary, should only be administered with caution. Treatments that should NOT be administered concomitantly with PRADAX due to increase in bleeding risk include: unfractionated heparin and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, bivalirudin, thrombolytic agents, GPIIb/IIIa receptor antagonists, ticlopidine, sulfi npyrazone and vitamin K antagonists such as warfarin. The concomitant use of PRADAX with the following treatments has not been studied and may increase the risk of bleeding: rivaroxaban, prasugrel and the strong P-gp inhibitors itraconazole, tacrolimus, cyclosporine, ritonavir, tipranavir, nelfi navir and saquinavir. Unfractionated heparin may be administered at doses necessary to maintain a patent central venous or arterial catheter. In patients with atrial fi brillation treated for the prevention of stroke and systemic embolism, the co-administration of oral anti-platelet (including ASA and clopidogrel) and NSAID therapies increases the risk of bleeding by about two-fold (see ACTION and CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions). If necessary, co-administration of low-dose ASA, i.e. 100 mg daily with PRADAX may be considered for other indications than stroke prevention in atrial fi brillation. The concomitant use of PRADAX with the strong P-gp inducer, rifampicin, reduces dabigatran plasma concentrations. Other P-gp inducers such as St. John’s Wort or carbamazepine are also expected to reduce dabigatran plasma concentrations, and should be co-administered with caution. The most common adverse events observed in 1% of PRADAX 150 mg BID patients and 110 mg BID patients was anemia (1.6%, 1.2%), epistaxis (1.1%, 1.1%), gastrointestinal hemorrhage (4.6%, 3.3%), urogenital hemorrhage (1.4%, 1.1%), abdominal pain (2.2%, 2.3%), diarrhea (1.2%, 1.3%), dyspepsia (3.9%, 4.2%) and nausea (1.2%, 1.0%), respectively. Gastrointestinal adverse reactions occurred more often with dabigatran etexilate than warfarin. These were related to dyspepsia (including upper abdominal pain, abdominal pain, abdominal discomfort, epigastric discomfort) or gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis and gastrointestinal ulcer). Gastrointestinal hemorrhage occurred at a higher frequency with PRADAX 150 mg BID and 110 mg BID (4.6%, 3.3%, respectively) compared to warfarin (2.6%). The underlying mechanism of the increased rate of GI bleeding has not been established. Allergic reactions or drug hypersensitivity including urticaria, bronchospasm, rash and pruritus have been reported in patients who received dabigatran etexilate. Rare cases of anaphylactic reactions have also been reported. For complete prescribing information, please refer to the Product Monograph.Reference: 1. Pradax Product Monograph. Boehringer Ingelheim (Canada) Ltd., 11/08/2010

Pradax™ is a trademark used under license by Boehringer Ingelheim (Canada) Ltd.

bigatran etexilate) is indicated for the prevention of stroke and systemic embolism in patients with atrial fi brillation, in whom anticoagulation is appropriate.contraindicated in patients with: severe renal impairment (CrCL <30 mL/min); hemorrhagic manifestations bleeding diathesis or patients with spo

See prescribing summary on page xxx178

Message from the President • Message du président

In Search of Shakespeareans Finlay McAlister MD

En quête d’émules de ShakespeareFinlay McAlister MD

Congratulations

Me, Active in Health Policy? Why?Norm Campbell MD, Bert Govig MD, Don Echenberg MD, on behalf of the CSIM Health Promotion Committee

Moi, agir à l’échelon de la politique de la santé? Pourquoi?Norm Campbell MD, Bert Govig MD, Don Echenberg MD, au nom du Comité de promotion de la santé de la Société canadienne de médecine interne

Something Less from Something More, Part 2George Veenhuyzen MD

Carotid Atherosclerosis: TechnologicalEvolution of Ultrasonic ImagingStella S. Daskalopoulou MD, Marios E. Daskalopoulos MD

Genetics & GIM

C O N T E N T S

ABOUT THE COVER

Volume 5, Issue 42010

Volume 5, Issue 4 • 2010

E D I T O R - I N - C H I E FHector Baillie

E D I T O R I A L B O A R D

Ranjani Aiyar, Simona Bar, Pat Bergin Peter Brindley, Benjamin Chen, Kaberi Dasgupta

Don Echenberg, Don FarquharBert Govig, Luc Lanthier, Alex Leung

Suzanne Morin, Jock MurrayKathryn Myers, Glen Pearson, Louise PiloteColin Powell, Margot Roach, Linda Snell Matthieu Touchette, George Veenhuyzen

C S I M S TA F FMs. Domenica Utano

Ms. Katie BealM A N A G I N G E D I T O R

Susan HarrisonA R T D I R E C T O RAndrea Brierley

P R O O F R E A D E RScott Bryant

T R A N S L AT O RMarie Dumont

A D V E R T I S I N GJohn Birkby

(905) [email protected]

C I R C U L AT I O N C O O R D I N AT O RBrenda Robinson

[email protected] C C O U N T I N GSusan McClung

G R O U P P U B L I S H E RJohn D. Birkby

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Research

This photo was taken by Rene Ehrhardt, a freelance photographer based in London, United Kingdom, who specializes in wedding, portraiture, and event photography (www.ehrhardt-photography.com). In his spare time, he is a keen traveller and photographs land, sea and city scapes, architecture, interiors, and exteriors. He captured this photo of Notre-Dame Basilica in 2008 while on vacation in Montreal, Quebec.

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Misrepresentation by Trainees: A Serious Threat to ProfessionalismAlexander A.C. Leung MD

Dronedarone: Current Evidence and Place in Our Anti-arrhythmic ArmamentariumSally Man PharmD, Glen J. Pearson PharmD

Achieving a Peaceful Death: The Internist’s Role In Advance Care PlanningJohn J. You MD

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C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 5 , I s s u e 4 , D e c e m b e r 2 0 1 0 147

NOW INDICATED FOR THE PREVENTION OF MAJOR CARDIOVASCULAR EVENTS1

In adult patients without documented history of cardiovascular or cerebrovascular events, but with at least two conventional risk factors for cardiovascular disease, CRESTOR is indicated to:

▪ Reduce the risk of nonfatal myocardial infarction▪ Reduce the risk of nonfatal stroke▪ Reduce the risk of coronary artery revascularization

COUNT ON

CRESTOR is also indicated as an adjunct to diet, at least equivalent to the Adult Treatment Panel III (ATP III TLC diet), for the reduction of elevated total cholesterol (Total-C), LDL-C, ApoB, the Total-C/HDL-C ratio and triglycerides (TG) and for increasing HDL-C; in hyperlipidemic and dyslipidemic conditions, when response to diet and exercise alone has been inadequate, including: primary hypercholesterolemia (Type IIa including heterozygous familial hypercholesterolemia and severe nonfamilial hypercholesterolemia); combined (mixed) dyslipidemia (Type IIb); or homozygous familial hypercholesterolemia where CRESTOR is used either alone or as an adjunct to diet and other lipid-lowering treatment such as apheresis.In the JUPITER trial, there were no statistically significant treatment differences between the CRESTOR and placebo groups for death due to cardiovascular causes or hospitalizations for unstable angina.The majority of patients are controlled at the 10 mg dose.A dose of 20 mg once daily has been found to reduce the risk of major cardiovascular events.CRESTOR is contraindicated in patients who are hypersensitive to any component of this medication; in patients with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal; in pregnant and nursing mothers and in patients using concomitant cyclosporine. CRESTOR 40 mg is contraindicated in patients with predisposing factors for myopathy/rhabdomyolysis and in Asian patients.

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with CRESTOR and with other HMG-CoA reductase inhibitors.CRESTOR, as well as other HMG-CoA reductase inhibitors, should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. CRESTOR therapy should be discontinued if markedly elevated CK levels (> 10 x ULN) are measured or myopathy is diagnosed or suspected.In the JUPITER trial, CRESTOR 20 mg was observed to increase plasma glucose levels, which were sufficient to shift some prediabetic subjects to the diabetes mellitus status.Most commonly reported adverse events in hypercholesterolemia vs. placebo were headache (1.4% vs. 2.2%), abdominal pain (1.7% vs. 2.2%), flatulence (1.8% vs. 2.7%) and nausea (2.2% vs. 1.6%).Most commonly reported adverse events in prevention of major cardiovascular events vs. placebo were urinary tract infection (8.7% vs. 8.6%), nasopharyngitis (7.6% vs. 7.2%), back pain (7.6% vs. 6.9%) and myalgia (7.6% vs. 6.6%). See the Product Monograph for full contraindications, warnings, precautions, dosing and administration.Reference: 1. CRESTOR® Product Monograph. AstraZeneca Canada Inc. April 28, 2010.

CRESTOR® and the AstraZeneca logo are trade-marks of the AstraZeneca group of companies. Licensed from Shionogi & Co Ltd, Osaka, Japan. © AstraZeneca 2010

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183


Me s s age f r om t h e P r e s i d e n t

In Search of Shakespeareans

Finlay McAlister MD

CSIM Members of Council

The Royal College Committee on Specialtiesapproved the motion to recognize general

internal medicine (GIM) as a subspecialty ofmedicine on October 29, 2010. This was a majorhurdle on the path to recognition, but we still needthe approval of the Royal College EducationCommittee, the Executive of Council, andultimately the Royal College Council. All goingwell, I hope we will thus have Royal Collegerecognition of GIM by late February 2011. Recognition by the Royal College will mark onlythe start of our journey. The onus will then be onall of us to attract trainees into careers in GIM. Atour Annual Scientific Meeting in Vancouver, Dr. Bill Coke pointed out that whereas 2% ofmedical subspecialists are older than 65 years, 23%of general internists in the Canadian MedicalAssociation 2009 Masterfile are older than 65 years.Clearly, if we want our specialty to continue toexist, we need to attract trainees to follow in ourfootsteps! We also heard from both community- anduniversity-based general internists at the ProvincialRoundtable, and the message was the same fromboth groups: we are desperately short of generalinternists. In the coming months, there will bediscussion of the issues surrounding 4 and 5 yearsof training in GIM. But we should not lose ourfocus – we need to train both community anduniversity internists. The flexibility proposed byDr. Brian O’Brien and the GIM Program directorsfor a 2-year GIM training program will meet thegoals of both of our key constituencies – academicGIM trainees will have more time to pursue MScdegrees in research or education, and communityGIM trainees will obtain clinical, procedural, andmanagement skills appropriate to their chosencommunity of practice.Although the popularity of GIM training hasincreased recently, we are still training only abouthalf of the number of general internists requiredto maintain the status quo. Dr. Coke presenteddata, drawn from the CMA Masterfile and CAPER,that showed the scope of the problem. Assumingan average retirement age of 70 years, we need toproduce 463 new general internists by 2013 just tomaintain the current GIM workforce. Weanticipate graduating only 239 GIM specialists bythat date. In fact, GIM and geriatrics are the onlytwo medical specialties that have fewer traineesthan needed to replace anticipated retirements.Thus, unless we can drive a rapid upswing in GIMtraining positions, the situation, both forcommunity and academic GIM, is going to get

worse in the short term.How can we increase the popularity of GIM as acareer choice? While the traditional role modellingand mentoring of trainees will clearly remain thefoundations of our recruitment efforts, better payfor general internists will help too. As many readersknow, several provinces have modified fee codes toenhance remuneration for comprehensive care ofpatients with multi-system disease. Many of thesebilling codes benefit those of us in GIMpreferentially and reflect government recognitionof the need for more general internists. We shouldexplicitly acknowledge that economics does play arole in career choice, particularly as our traineesare now graduating with higher levels of debt thanat any time in the past. As the pendulum swings toreimbursing cognitive skills as much (or more)than procedural skills, I think we will see a declinein the popularity of some of the more procedurallybased subspecialties in medicine. Another important factor working in our favour isthe increasing prevalence of multi-system diseaseand co-morbidities in the Canadian population. A2003 study from the Saguenay region of Quebecfound that the average number of chronicconditions in patients aged 45–64 was 4.1 (men)and 4.8 (women), and in patients aged over 65 itwas 6.3 (men) and 6.6 (women). In the words ofthe authors of that report, “Patients withmultimorbidity … represent the rule rather thanthe exception.”1 Surely internists, specialists incomplex adult medicine, will be best suited to helpour primary care colleagues deal with theseincreasingly challenging patients.Finally, the strongest factor working in our favourfor recruitment is the sheer diversity of patients we,as general internists, meet. In an earlier message(April 2010), I had opined that no 2 days, and notwo patients, are ever the same for generalinternists and that that was what drove me tochoose GIM. Dr. Tinsley Harrison said it better inhis introduction to the first edition of his Principlesof Internal Medicine, when he stated that the bestphysicians must have “a Shakespearean breadth ofinterest.”2 The task for all of us is to continue tofind the budding Shakespeareans among ourtrainees.

References1. Fortin M, Bravo G, Hudon C, et al. Prevalence

of multimorbidity among adults seen in family practice. Ann Fam Med 2005;3:223–8.

2. Harrison T. Principles of Internal Medicine, 1st edition. 1950.

About the AuthorFinlay McAlister is a member of the Division of General Internal Medicine atthe University of Alberta, in Edmonton, Alberta. Correspondence may be directed to [email protected].

Dr. Finlay McAlisterPresident, Vice-President, Research/Awards Committee

Edmonton, AB

Dr. Maria BacchusPresident-Elect, Vice-President, Education Committee

Western Region RepresentativeCalgary, AB

Dr. Stephen HwangSecretary-Treasurer, Ontario Region Representative

Toronto, ON

Dr. Hector BaillieEditor-in-Chief, Canadian Journal of General Internal Medicine

Nanaimo, BC

Dr. David SimpsonChair, 2011 Annual Meeting Committee

Halifax, NS

Dr. Patrick BerginEastern Region Representative and Executive

Charlottetown, PEI

Dr. Mahesh K. RajuEastern Region Representative

Saint John, NB

Dr. Bert GovigVice-President, Health Promotion Committee

Quebec Region RepresentativeAmos, QC

Dr. Donald EchenbergQuebec Region Representative

Chair, CPD Sub-Committee, CMA RepresentativeSherbrooke, QC

Dr. Lucie OpatrnyQuébec Region Representative

Montreal, QC

Dr. Nadine LahoudQuébec Region Representative

LaSalle, QC

Dr. Benjamin ChenOntario Region Representative

Napanee, ON

Dr. William CokeOntario Region Representative

Toronto, ON

Dr. Ameen PatelOntario Region Representative

Hamilton, ON

Dr. Jim Nishikawa Representative, RCPSC Specialty Committee in Internal Medicine

Ottawa, ON

Dr. Gary VictorVice-President, Membership Affairs

Kelowna, BC

Dr. Neil GibsonWestern Region Representative and Executive

St. Albert, AB

Dr. Amy HendricksWestern Region Representative

Yellowknife, NT

Dr. Anne Marie PausJenssenWestern Region Representative

Saskatoon, SK

Dr. Ranjani AiyarResident Representative

Calgary, AB

To contact a member of CSIM Council, please e-mail [email protected].

C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e150 V o l u m e 5 , I s s u e 4 , D e c e m b e r 2 0 1 0

Mes s age d u p r é s i d e n t

En quête d’émules de Shakespeare

Finlay McAlister MD

Au sujet de l’auteurFinlay McAlister est membre de la Division de médecine interne générale de l’Université de l’Alberta à Edmonton. Prièred’adresser la correspondance à [email protected].

Le 29 octobre 2010, le Comité des spécialités du Collège royal a adoptéla motion voulant que la médecine interne générale soit reconnue au

titre de surspécialité médicale. Voici que nous venons de franchir une haiede taille dans ce parcours de la reconnaissance, mais il nous faut encoreobtenir l’approbation du Comité de l’éducation, du Comité de directiondu Conseil et, au bout du compte, du Conseil d’administration du Collègeroyal. Si tout se déroule sans heurts, j’espère bien que le Collège royaldonnera son aval à la reconnaissance de la médecine interne générale à lafin de février 2011. Cette reconnaissance du Collège royal marquera le début de l’aventure. Ilnous incombera alors d’attirer des médecins résidents vers notresurspécialité. Au dernier congrès scientifique à Vancouver, le docteur BillCoke a fait remarquer que 2 % des médecins surspécialistes sont âgés deplus de 65 ans, tandis que 23 % des internistes généralistes dont le nomfigure dans le fichier central de l’Association médicale canadienne (AMC)en 2009 ont plus de 65 ans. À l’évidence, nous devons recruter desmédecins résidents pour assurer la viabilité de notre spécialité. Des internistes généralistes des milieux communautaires comme desmilieux universitaires ont exprimé leur opinion lors de la table rondeprovinciale, et les deux groupes ont transmis le même message : la pénuried’internistes généralistes est criante. Dans les prochains mois, la discussions’attardera aux questions ayant trait aux 4e et 5e années de la formationen médecine interne générale. Mais gardons-nous de perdre de vue notrebut, celui de former des internistes de pratique communautaire et desinternistes de pratique universitaire. Grâce à sa souplesse, la propositiondu docteur Brian O’Brien et des directeurs de programme de formationde se doter d’un programme de formation de deux ans saura répondreaux besoins des deux milieux de pratique : les médecins résidents qui sedestinent au milieu universitaire auront amplement le loisird’entreprendre une maîtrise en recherche ou en éducation et les médecinsrésidents qui s’orientent vers la pratique communautaire acquerront lesaptitudes cliniques et techniques et les compétences en gestion nécessairesà leur mode de pratique.Bien que la formation en médecine interne générale ait gagné enpopularité dernièrement, nous ne formons que la moitié environ desinternistes généralistes qu’il faudrait pour que la situation reste telle quelle.Le docteur Coke a illustré l’ampleur du problème par des données issuesdu ficher central de l’AMC et du Système informatisé sur les stagiairespost-M.D. en formation clinique (CAPER). En supposant que l’âge moyende la retraite est de 70 ans, nous devrions former 463 nouveaux internistesgénéralistes d’ici 2013 juste pour compenser les départs à la retraite etmaintenir l’effectif tel qu’il est en ce moment. Cependant, nous prévoyonsque seulement 239 internistes généralistes frais émoulus seront entrés enfonction d’ici là. De fait, la médecine interne générale et la gériatrie sontles deux seules spécialités médicales où les résidents ne sont pas asseznombreux pour remplacer les médecins qui prendront leur retraite. Aussi,à moins que nous puissions faire grimper rapidement le nombre de postesde formation en médecine interne générale, la situation, tant en pratique

communautaire qu’en pratique universitaire, ira de mal en pis à brèveéchéance.Que faire pour que la médecine interne générale devienne un choix decarrière prisé? Manifestement, l’exercice du modèle de rôle et du mentoratdemeurera l’assise du recrutement, mais celui-ci s’en trouverait facilité sil’on haussait la rémunération de l’interniste généraliste. Vous êtesnombreux à savoir que plusieurs provinces ont modifié leur barèmed’honoraires pour rehausser la rémunération des médecins quiprodiguent des soins globaux aux patients atteints d’une maladiemultisystémique. Nombre de ces nouveaux codes de facturation sontavantageux d’abord pour nous autres en médecine interne générale, sanscompter qu’ils traduisent le fait que les administrations publiques serendent compte de la nécessité d’augmenter le nombre d’internistesgénéralistes. Nous devrions admettre en toute franchise que les aspectsfinanciers entrent en jeu dans le choix d’une carrière, d’autant plus queles médecins résidents terminent leur formation à un niveaud’endettement plus élevé que jamais auparavant. Au moment où lependule se dirige vers la rétribution des compétences cognitives et deshabiletés techniques à égale mesure (si ce n’est plus pour les premières),je prévois que certaines surspécialités médicales à forte composanteopératoire deviendront de moins en moins attrayantes. La prévalence croissante des troubles multisystémiques et de lacomorbidité dans la population canadienne est un autre facteur importantqui nous est favorable. Une étude effectuée en 2003 au Saguenay (Québec)révèle que le nombre moyen d’affections chroniques chez les patients âgésde 45 à 64 ans était de 4,1 chez les hommes et de 4,8 chez les femmes à cemoment-là et qu’il était de 6,3 chez les hommes et de 6,6 chez les femmesdans le groupe de patients de plus de 65 ans. Pour reprendre le mot del’un des auteurs du rapport : « Les patients présentant unemultimorbidité…sont la règle, non pas l’exception »1. Dans un telcontexte, l’interniste, spécialiste de la médecine complexe de l’adulte, estcertes le mieux placé pour prêter main-forte à ses collègues de premièreligne dans la prise en charge de ces cas de plus en plus difficiles.Enfin, la diversité des cas qui sont le lot de la médecine interne généraleest sans doute l’argument le plus convaincant aux fins de recrutement. J’aidéjà dit qu’il n’y a pas deux jours ni deux patients pareils dans la vie del’interniste généraliste et que c’est ce qui m’a motivé dans le choix de cettecarrière. Le docteur Tinsley Harrison le dit avec plus d’élégance dans sonintroduction à la première édition de ses Principles of Internal Medicinelorsqu’il affirme que le meilleur médecin est celui qui a un « champd’intérêt shakespearien »2. La tâche qui nous attend est d’identifier cesémules de Shakespeare parmi les médecins résidents.

Références1. Fortin M, Bravo G, Hudon C, et al. Prevalence of multimorbidity

among adults seen in family practice. Ann Fam Med 2005;3:223–8. 2. Harrison T. Principles of Internal Medicine, 1st edition. 1950.


C S IM News

Congratulations

Osler Awards Dr. Howard Abrams, Toronto, OntarioDr. Donald Echenberg, Sherbrooke, Quebec

CSIM/Royal College Osler LectureDr. Samuel Benaroya,Montreal, Quebec

“Great Expectations: Challenges and Leadership in Canadian Medical

Faculties”

Hui Lee Health Promotion Scholarship Dr. Andrea Kermack, McGill University

Ted Giles Clinical VignettesFirst Place – Dr. Samantha Halman, University of Ottawa“A Modern Case of Scurvy: Gastrointestinal Hemorrhage in a

Hemodialysis Patient”

Second Place – Dr. Lindsay Crabbe,McMaster University

“A Breathtaking Presentation of Metastatic Renal Cell Carcinoma”

Third Place – Dr. Erin Kelly, University of Ottawa“Master of Disguises – An Interesting Case of CNS Pseudovasculitis”

CSIM/CAPM Awards for Post-Graduate Research

Research Oral CompetitionFirst Place – Dr. Karmon Helmle, University of Calgary “Basal Bolus Insulin Therapy: A ‘BBIT’ of Change in Hospital Diabetes

Management”

Second Place – Dr. Leena Amin, University of Toronto“Impact of Gender and Socioeconomic Status on Lower Extremity

Amputation Rates in Individuals with Diabetes”

Third Place – Dr. Ngan Lam, University of Western Ontario

“Hospital Admissions for Hyperkalemia with Trimethoprim-

Sulfamethoxazole”

Research Poster CompetitionFirst Place – Dr. Geneviève Beaulieu-Boire, Sherbrooke University“MUSIC Project: Musicotherapy at the Intensive Care Unit”

Second Place – Dr. Alexandre Lafleur, Université Laval“Atorvastatin Increases Intestinal Expression of NPC1L1 in

Hyperlipidemic Men”

Third Place – Dr. Ben John Wilson, University of Calgary“Pulse Oximeter Accuracy in Intensive Care Unit Patients with Severe

Sepsis: A Retrospective Cohort Study”

Dr. David Sackett Senior Investigator AwardDr. Jack Tu, Toronto, Ontario “Canadian Cardiovascular Outcomes Research Team: Lessons Learned”

(to appear in Volume 6, Issue 1)

New Investigator AwardDr. John You,McMaster University

“Achieving a Peaceful Death: The Internist’s Role in Advance Care

Planning” (see p. 174)

The Canadian Society of Internal Medicine congratulates the following winners andpresenters from its Annual Scientific Meeting, held on October 27–30, 2010, in Vancouver.

P l e a s e wa t c h f o r t h e c a l l f o r a b s t r a c t s a n d awa r d s u bm i s s i o n s .

CSIM Annual Scientific MeetingOctober 12–15, 2011Halifax, Nova Scotia

Information: [email protected]/613-730-6244


Hea l t h P r omo t i o n

Me, Active in Health Policy? Why?

Norm Campbell MD, Bert Govig MD, Don Echenberg MD, on behalf of the CSIM Health Promotion Committee

Most Canadians are physically inactive and eat an unhealthy diet. The

consequences are hypertension, obesity, diabetes mellitus (type 2),

dyslipidemia, cardiovascular disease, and several types of cancer. These

changes are occurring throughout the industrialized world and, sadly, it

has been predicted that the next generation after ours will be the first since

industrialization where the life expectancy is anticipated to be shorter than

the previous one. Note that the greatest impact of these chronic non-

communicable diseases is in the developing world. As internists, a large

proportion of our patients have these health risks and diseases. However,

it is important to note that much of the death and disability caused by

health risks are below the thresholds we traditionally use in clinical

medicine. For example, about 50% of blood pressure–related disease

occurs in individuals who are considered to have normal blood pressure.

Population-based approaches to lower risk can prevent disease in those

with clinical risk as well as those who we perceive are not at risk: for

example, lowering blood pressure on a population-wide basis reduces the

risk of stroke in both hypertensive and normotensive groups. Improved

population health often requires strategic implementation of health policy

initiatives.

Internists can play an important role in advocating for policy changes to

reduce risk and prevent disease. In recent years, Canadian health care

professionals have helped by advocating for health policy changes to

reduce smoking and intake of dietary trans fats and sodium, which have

the potential to markedly improve the well-being of Canadians.

Hypertension, like most other prevalent health risks, is largely preventable.

Unhealthy diets high in sodium and saturated fats and low in fresh fruits

and vegetables; physical inactivity and weight gain; coupled with excess

alcohol consumption and smoking cause many of our current health risks.

In Canada, more than 70% of the adult population have at least one or

more traditional health risk factor. It is estimated that about 95% of those

living an average lifespan will become hypertensive: almost half of

Canadians over the age of 60 are on medications for hypertension.

Changing lifestyle is very difficult in our social environment where an

unhealthy diet is easy, fast, and inexpensive. Nearly all of our communities

encourage driving, rather than an alternative mode of transport that

involves some degree of daily physical activity.

The government policies required to facilitate healthy choices have been

outlined by many public health organizations and expert groups – but

rarely implemented. This lack of political action is likely a consequence

of a failure of health care professionals (and their representative

organizations) to engage public opinion. On some health issues (tobacco

use, dietary trans fats, and sodium intake), there has been modest success

in modifying outcomes.

Our government does not intervene to limit the provision of unhealthy

food in many of our schools, to our military, or to patients and visitors in

our hospitals. Municipal, provincial, and federal buildings are often

sources of unhealthy foods. Even if our food is labelled accurately, the

average Canadian cannot determine if its nutrient content is likely to be

unhealthy. The food industry, which claims to be self-regulating, continues

to heavily market unhealthy food items to children. As a result, childhood

obesity is on the rise. Physicians have sat on the sidelines, waiting for some

other group or person to act.

In New York City, a food procurement policy is being developed to ensure

that government buildings buy and sell only healthy food.1 The Quebec

provincial government, in response to health advocates, has banned

advertizing of foods that might contribute to childhood obesity. In

Finland, warning food labels alert consumers to high sodium content. In

the United Kingdom, colour-coded packaging labels have been developed

to indicate which foods to avoid (red), be cautious of (orange), or consider

safe to eat (green) – based on their sodium, saturated fat, and simple sugar

contents. When this easy-to-understand food label was considered for use

in Europe, the food sector reportedly spent $1 billion in a successful lobby

to block its use – while the health sector was largely silent.

The Canadian Society for Internal Medicine’s Health Promotion

Committee will endorse policies and actions that promote health and

prevent disease. Every internist in Canada has a potential role and

responsibility to engage in public advocacy, and we encourage your active

participation. By aligning health care professionals, their organizations,

and various levels of government to work on a common policy agenda,

we can make substantive progress toward improving the health of

Canadians, now and in the future.

Reference/Référence1. New York City. City agency food standards – requirements and

recommendations. Washington, DC: Center for Science in the

Public Interest, 2008; ttp://www.cspinet.org/new/pdf/nyc_agency_

food_standards.pdf. Accessed December 8, 2010.

About the AuthorsNorm Campbell (far left) is a professor of medicine in community health sciencesand physiology and pharmacology at the University of Calgary, in Calgary, Alberta.Bert Govig (middle) is with the Departments of Internal Medicine at CSSS LesEskers de L’Abitibi, Amos, and at McGill University, Montréal, Québec, and isphysician in chief with Coalition pour L’Acquisition de Saines Habitudes. DonaldEchenberg practises and teaches general internal medicine at the UniversityHospital, in Sherbrooke, Quebec.


P romo t i o n d e l a s a n t é

Moi, agir à l’échelon de la politique de la santé? Pourquoi?

Norm Campbell MD, Bert Govig MD, Don Echenberg MD, au nom du Comité de promotion de la santé de la Société canadienne demédecine interne

La majeure partie de la population du pays est inactive et ne mange pas

de façon équilibrée. Un tel mode de vie a des conséquences :

hypertension, obésité, diabète de type 2, dyslipidémie, maladie

cardiovasculaire et cancers de toute sorte. Cette situation se répand dans

tout le monde industrialisé, et l’on prévoit, hélas, que la génération qui

nous suit sera la première depuis l’industrialisation dont l’espérance de

vie sera moindre que celle de la précédente. À souligner que ces maladies

chroniques non transmissibles ont un effet dévastateur dans les pays

développés surtout. Un grand nombre de nos patients, à nous internistes,

sont aux prises avec ces risques pour la santé et ces maladies. Il faut savoir

toutefois que la mortalité et l’incapacité découlant de ces risques pour la

santé se produisent pour beaucoup en deçà des seuils généralement admis

en pratique clinique. Ainsi, dans près de 50 % des cas de maladie liée à la

pression artérielle, celle-ci se situe dans les valeurs normales. La stratégie

de masse destinée à réduire ces risques aurait le potentiel de prévenir la

maladie tant dans les groupes présentant un risque clinique que dans les

groupes qui ne sont pas à risque apparemment : par exemple, la campagne

de diminution de la pression artérielle à l’échelle de la population aurait

pour effet de réduire le risque d’accident vasculaire cérébral dans les

groupes hypertendus comme dans les groupes normotendus.

L’amélioration de la santé de la population repose souvent sur la mise en

œuvre d’initiatives stratégiques en matière de politiques de santé.

L’interniste est en mesure d’exercer de l’influence dans ce domaine en

militant pour des changements de fond dans le but de réduire les risques

pour la santé et de prévenir la maladie. Les dernières années ont vu des

professionnels de la santé du pays promouvoir de tels changements dans

les politiques de la santé afin de favoriser l’abandon du tabac et la

diminution de l’apport alimentaire en gras trans et en sodium, des

mesures qui pourraient améliorer grandement le bien-être des Canadiens

et des Canadiennes.

L’hypertension, à l’instar de la plupart des autres risques pour la santé

courants, est essentiellement évitable. Le régime alimentaire riche en

sodium et en graisses saturées et pauvre en fruits et légumes frais,

l’inactivité physique et le gain de poids, couplés à la consommation

d’alcool excessive et au tabagisme, sont à l’origine de nombre des risques

pour la santé actuels. Au Canada, plus de 70 % de la population adulte

présente au moins un facteur de risque connu. Les estimations veulent

qu’environ 95 % des personnes de longévité moyenne deviennent

hypertendues : presque la moitié de la population de plus de 60 ans prend

un médicament antihypertenseur. Modifier son mode de vie est très

difficile dans une société où le prêt-à-manger a la cote : c’est facile, rapide

et bon marché. Les collectivités ont tendance à encourager l’usage de la

voiture plutôt qu’un mode de transport incitant à un certain degré

d’activité physique.

De nombreux organismes de santé publique et groupes d’experts ont

proposé des politiques publiques qui faciliteraient l’adoption d’un mode

de vie saine, mais qui n’ont jamais vu le jour pour ainsi dire. Cette inaction

politique est probablement due à l’échec des professionnels de la santé (et

des associations qui les représentent) à convaincre le public. Néanmoins,

certains dossiers (tabagisme, gras trans dans les aliments et apport de

sodium) ont évolué pour le mieux quoique dans une proportion modeste.

Notre gouvernement n’intervient pas pour limiter l’offre d’aliments creux

aux élèves, aux militaires et aux patients ou aux visiteurs dans les hôpitaux.

De tels aliments se retrouvent dans bien des immeubles des

administrations publiques municipales, provinciales et fédérale. Même si

les aliments sont étiquetés avec exactitude, le consommateur est bien peu

en mesure de déterminer leur valeur nutritive. L’industrie alimentaire, qui

prétend s’autoréglementer, inonde le marché d’aliments à calories vides

destinés aux enfants. Et c’est ainsi que l’obésité est à la hausse dans ce

groupe de la population. Les médecins se sont tenus en retrait, attendant

que d’autres groupes ou personnes agissent.

La Ville de New York prépare une directive sur l’approvisionnement

alimentaire qui fera en sorte que les immeubles gouvernementaux

n’achèteront et ne vendront que des aliments sains1 . Le gouvernement du

Québec a banni la publicité d’aliments susceptibles de contribuer à

l’obésité chez les enfants en réaction aux pressions exercées par des

promoteurs de la santé. En Finlande, les aliments riches en sodium portent

une étiquette mettant en garde le consommateur. Le Royaume-Uni a

conçu un code de couleurs pour l’étiquetage des aliments selon leur

contenu en sodium, en graisses saturées et en sucre simple; le rouge

désigne les aliments à éviter, l’orange commande la circonspection et le

vert s’applique aux aliments sûrs. Lorsque l’Europe a envisagé d’adopter

ce système d’étiquetage simple, le secteur alimentaire a investi un milliard

de dollars dans une campagne de lobbying pour bloquer sa mise en œuvre,

tandis que le secteur de la santé se tenait coi.

Le Comité de promotion de la santé de la Société canadienne de médecine

interne appuiera les politiques et les actions destinées à promouvoir la

santé et à prévenir la maladie. L’interniste est bien placé pour exercer de

l’influence dans ce sens et défendre les intérêts publics, et je souhaite qu’il

s’engage activement dans cette voie. En mobilisant les professionnels de

la santé, les associations qui les représentent et les divers ordres de

gouvernement dans le cadre d’un programme d’action commun, nous

pouvons réussir à améliorer la santé des Canadiens et des Canadiens,

aujourd’hui et à l’avenir.

Les auteursNorm Campbell (à gauche) est un médecin enseignant les matières des sciences dela santé communautaire, de la physiologie et de la pharmacologie à l’Université deCalgary à Calgary (Alberta); Bert Govig (au milieu) œuvre au sein du Service demédecine interne au centre de santé et de services sociaux (CSSS) Les Eskers del’Abitibi à Amos (Québec), il enseigne à l’Université McGill à Montréal (Québec)et il est le médecin en chef de la Coalition pour l’acquisition de saines habitudes;Donald Echenberg exerce et enseigne la médecine interne générale au Centrehospitalier de l’Université de Sherbrooke (CHUS) à Sherbrooke (Québec).

The CSIM is a society of volunteers and encourages members to become involved.

Volunteering on one of CSIM’s many committees (Membership, Education, and Annual Meeting Committees) is a great opportunity to contribute to your specialty and to meet new colleagues and contacts from across the country.

If you are interested in becoming more involved in the CSIM, please speak to a member of CSIM Council. Or you may contact the CSIM Office at [email protected] / 613-730-6244.

MARK YOUR CALENDARS!

October 12–15, 2011Halifax, Nova Scotia

October 17–20, 2012Quebec City, Quebec

Société canadiennede médecine interne

Canadian Societyof Internal

Medicine

Canadian Society of Internal Medicine

Annual Scientific Meetings

Canyon Ste-AnneQuebec

Halifax, Nova Scotia

Peggy’s CoveHalifax, Nova Scotia

Fontaine de TournyQuebec


EKG & U

Something Less from Something More, Part 2

George Veenhuyzen MD

In the last issue (Volume 5, Issue 3), we reviewed the EKGs shown in

Figures 1 and 2, recorded in an 80-year-old woman with a history of

rapid palpitations. She has sinus rhythm with non-conducted atrial

bigeminy (see Figure 1), and sinus rhythm with conducted atrial bigeminy

(see Figure 2). No abnormalities of sinus node function are apparent on

these EKGs, and she had no symptoms of bradycardia, even though her

effective ventricular rate during non-conducted atrial bigeminy was only

40 bpm, so there is no obvious indication for a pacemaker. A pacemaker

could still be indicated if she had asymptomatic advanced His-Purkinje

disease. In this regard, when atrial bigeminal beats conduct, they do so

with right bundle branch block (RBBB; see Figure 2), so the question left

dangling at the end of this column in the preceding edition was, does this

patient have asymptomatic advanced His-Purkinje disease that might

require a pacemaker?

About the AuthorGeorge Veenhuyzen is an adult cardiac electrophysiologist at the Libin Cardiovascular Institute of Alberta in Calgary, Alberta.Correspondence may be directed to [email protected].

Figure 1. Sinus bradycardia with non-conducted atrial bigeminy. The premature atrial contractions are marked with black arrows on the rhythm strip.


S ome t h i n g L e s s f r om S ome t h i n g Mo r e

Figure 2. Sinus bradycardia with atrial bigeminy. The premature atrial contractions (PACs) are marked with black arrows on the rhythm strip. Why do the PACsconduct with right bundle branch block? Is this a sign of His-Purkinje disease?

Figure 3. As the ladder diagram shows, the rate at which the His-Purkinje (HP) network is stimulated alternates during atrial bigeminy with long (green arrows)and short (brown arrows) sequences. When the premature atrial contraction (PAC) occurs, the preceding long sequence lengthens the refractory period of theHP network so that the right bundle (which usually has a slightly longer refractory period than the left bundle) hasn’t completely recovered. Accordingly, thepremature atrial beat conducts aberrantly with right bundle branch block: a classic case of Ashman’s phenomenon, which is purely physiological. AVN = atrioventricular node; SN = sinus node.


Ve e n h u y z e n

DiscussionAs mentioned above, the rhythm on display in the EKG shown in Figure

2 is sinus rhythm with atrial bigeminy. That is, after every sinus beat, there

is a premature atrial contraction (PAC) that conducts through the AV

conduction system. In contrast, in the EKG shown in Figure 1, the PACs

that occur after every sinus beat are so premature that they cannot

conduct through the AV conduction system. In Figure 1, the PACs block

in the AV conduction system for purely physiological reasons: the AV

conduction system simply hasn’t had sufficient time to recover from

having just conducted the preceding sinus beat.

The refractory period of the His-Purkinje network is rate dependent. As

the rate at which the His-Purkinje network is stimulated increases, the

refractory period of the His-Purkinje network decreases. This makes good

physiological sense: at fast heart rates, one would want the His-Purkinje

network to recover more quickly to ensure, as much as physiologically

possible, that it will be ready to be depolarized when the next heartbeat

occurs. Changes in His-Purkinje network refractoriness occur quickly, on

a beat-to-beat basis. Accordingly, the refractory period of the His-Purkinje

network is proportional to the duration of the preceding R–R interval. If

the preceding R–R interval is short, the refractory period of the His-

Purkinje network is relatively short; whereas if the preceding R–R interval

is relatively long, the refractory period of the His-Purkinje network is

longer.

At the time that a PAC occurs and conducts to the AV conduction system,

the refractory period of the His-Purkinje will have been determined by

the preceding, comparatively slower rate. Accordingly, at the time that the

PAC occurs, the His-Purkinje network has a relatively long refractory

period. In addition, the refractory period of the right bundle is usually

slightly longer than that of the left bundle. Thus, when the PAC occurs,

the right bundle simply hasn’t had enough time to recover for purely

physiological reasons. This phenomenon, aberrant His-Purkinje conduction

associated with a premature beat (usually RBBB but can be left bundle

branch block too), is known as Ashman’s phenomenon (Figure 3).

Gouaux and Ashman first described this phenomenon in 1947,1 noting

the variable R–R intervals that can be seen during conducted atrial

fibrillation. They noticed that after a long R–R, interval, when the next

beat has a relatively short R–R interval, that QRS complex often has the

typical morphology of RBBB. These beats are frequently confused with

premature ventricular contractions because they are wide complex.

With no apparent abnormalities of sinus node or AV conduction system

function, and no symptomatic bradycardia, this patient has no obvious

indication for a pacemaker.

Reference1. Gouaux JL, Ashman R. Auricular fibrillation with aberration

simulating ventricular paroxysmal tachycardia. Am Heart J

1947;34:366.

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About the AuthorsStella S. Daskalopoulou is a member of the Department of Medicine, Faculty of Medicine, McGill University, in Montreal, Quebec,and Marios Daskalopoulos is a member of the Department of Vascular Surgery, Medical School, National and KapodistrianUniversity of Athens, in Athens, Greece. Correspondence may be directed to [email protected] .


Re s e a r c h

Carotid Atherosclerosis: Technological Evolution of Ultrasonic Imaging

Stella S. Daskalopoulou MD, Marios E. Daskalopoulos MD

Stroke represents a major health problem and is an important cause of

death and long-term disability in several developed countries.1 In

Canada, 15,000 deaths are attributed to stroke each year. In the United

States, at least 500,000 persons suffer new or recurrent stroke annually,

and stroke is a contributing factor in 150,000 deaths each year. Mortality

from stroke ranges between 10 and 30%, and its survivors remain at a high

annual risk of recurrent ischemic events and mortality, both from

myocardial infarction and recurrent stroke.1

Internal carotid artery (ICA) stenosis due to the formation of

atherosclerotic plaques is one of the main etiological factors known to

cause cerebrovascular events – stroke, transient ischemic attack (TIA), and

amaurosis fugax.2 The atherosclerotic plaque is a dynamic structure that

undergoes continuous remodelling of the extracellular matrix on which

its structural integrity depends. Unstable atherosclerotic plaques (also

known as high-risk or vulnerable plaques) are at high risk of rupture,

which might lead to severe and potentially life-threatening cerebrovascular

events. Scientific efforts to identify patients at high risk of cerebrovascular

events early are numerous, but applications ready for implementation in

clinical practice are few.

Imaging and Image AnalysisSeveral invasive and non-invasive imaging techniques have been used to

identify arterial atherosclerosis (e.g., high-resolution ultrasonography,

computed tomography angiography [CTA], and magnetic resonance

angiography [MRA]).3 Among these techniques, high-resolution

ultrasonography has been the most widely used method to assess

atherosclerotic disease.4 For the diagnosis of high-grade stenosis,

ultrasonography has a pooled sensitivity and specificity of 86% and 87%,

respectively, when compared with digital subtraction angiography (the

“gold standard”), while for occlusion its sensitivity and specificity is 96%

and 100%, respectively.5 Moreover, ultrasonography allows for real-time

in vivo imaging, and it is a non-invasive, reliable, safe, and relatively

inexpensive modality that in experienced hands can facilitate the study

not only of the lumen (as digital subtraction angiography does) but also

of the intima-media thickness and atherosclerotic plaques, both

hemodynamically and morphologically.4

The degree of carotid stenosis is a well-established risk factor of plaque

instability and rupture.6 Natural history studies have demonstrated that

the risk of developing ipsilateral hemispheric symptoms grows with

increasing severity of ICA stenosis. Specifically, the risk of stroke in

asymptomatic patients is low (0.1–1.6%/y) for stenosis <75–80% (North

American Symptomatic Carotid Endarterectomy Trial [NASCET] criteria)

and higher (2.0–3.3%/y) with greater degrees of stenosis.6

However, many high-grade stenoses remain stable and asymptomatic,

whereas other plaques that cause moderate stenoses rupture and induce

symptoms. It is increasingly recognized that, in addition to the degree of

stenosis, plaque morphology and surface characteristics play an important

role in plaque instability. In fact, Saam et al.7 evaluating the American

Heart Association (AHA) histological lesion type in patients who

underwent carotid endarterectomy noted that 29.8% of AHA type VI

lesions (most advanced type) occurred in patients who had ≤50% carotid

stenosis. This indicates that a large proportion of vulnerable plaques

produce low-grade stenoses. Therefore, it is critical to identify unstable

plaques based not only on the degree of stenosis but also on plaque

morphology using advanced technology and imaging modalities that are

simple, reliable, and non-invasive, such as ultrasonography.

Visual ClassificationSeveral visual classifications have been proposed to characterize the

morphology of ultrasonic plaques; the most widely used consists of five

plaque types (Geroulakos classification): type 1, completely echolucent

(homogeneous, appears black on ultrasonograms); type 2, predominantly

echolucent (heterogeneous, mostly black); type 3, predominantly echogenic

(heterogeneous, mostly white on ultrasonograms); type 4, completely

echogenic (homogeneous, white ); and type 5, calcified plaque with acoustic

shadow.8 Numerous studies have demonstrated that unstable plaques are

typically characterized on ultrasonograms by high-grade stenosis,

ulceration, and intraplaque hemorrhage, appearing echolucent with

irregular borders (types 1 and 2).8 There is evidence suggesting that plaque

echolucency is associated with histologically advanced atherosclerosis.6,9

Furthermore, plaque echolucency is associated with hemispheric

symptomatology. In a study of symptomatic patients, the relative risk (RR)

of ipsilateral ischemic stroke for echolucent versus echogenic plaques was

3.1 (95% confidence interval [CI] 1.3–7.3), whereas for 80–99% versus

50–79% stenosis, the RR was only 1.4 (95% CI 0.7–3.0).10 The

Asymptomatic Carotid Stenosis and Risk of Stroke (ACSRS) study, a

natural history, multi-centre prospective study of asymptomatic patients

designed by the authors’ group in the United Kingdom, showed that for

stenosis 50–99% (North American Symptomatic Carotid Endarterectomy

Trial [NASCET] criteria), the RR for those with echolucent plaques versus

those with echogenic plaques was 11.7 (95% CI 1.63–84.5).6 This shows

that plaque echolucency is an important determinant for the risk of stroke

and has additional prognostic value when added to stenosis. Although it

is well known that echolucent plaques are more unstable than echogenic

plaques, visual classification is a qualitative, subjective method with low

reproducibility; for example, a wide variability in the classification of type


Da s k a l o p o u l o u a n d D a s k a l o p o u l o s

2 plaques has been noted, which can range from nearly type 1 to type 3.6

Computer-Assisted Methods of Plaque MorphologyThe need for a quantitative assessment of ultrasonic images led to

computer-assisted methods to characterize plaque morphology. In this

process, the median of the frequency distribution of grey values of the

pixels within the plaque (grey-scale median [GSM] ranges from 0 to 255;

0 = black and 255 = white) was used to quantify echodensity (the overall

brightness of the plaque). Echolucent plaques are characterized by a lower

GSM than echogenic plaques, and they are unstable on histology with a

large necrotic core volume.11 It was shown that the lower the GSM, the

higher the macrophage infiltration on histological examination of carotid

specimens.12 Furthermore, a low GSM is strongly associated with

hemispheric symptomatology6; for example, it was shown that echolucent

plaques with a GSM <32 had a fivefold increase in the prevalence of silent

brain infarctions on CT brain scans.13 It quickly became apparent that

ultrasonic image normalization was necessary, so that images captured

under different instrument settings, from different scanners, by different

operators, and through different peripherals, such as digital video disc

(DVD), video, and magneto-optical disc could be compared.14 Images of

plaques are normalized according to two reference points, the blood

(GSM = 0) and adventitia (GSM = 190), using commercially available

software.6 Image normalization in the ACSRS study resulted in 60% of

plaques being reclassified.6

The Need for Further Technological AdvancementThere is controversy about the role of heterogeneity in plaque instability;

some studies suggest that plaques with a heterogeneous texture (mixture

of echolucent and echogenic areas) are more unstable, while others suggest

that homogeneous (predominantly echolucent) plaques are more

unstable.6 However, assessments of heterogeneity have been performed

visually.

Although previous studies advanced our knowledge on plaque

echomorphology, they have limitations. Either they are subjective (visual

classification) or they only assess the overall brightness of a plaque

(median of the grey tone values), failing to provide important information

about its heterogeneity. For example, a plaque with a GSM of 40 can be

heterogeneous (median value 40 of black parts with a low GSM and white

parts with a high GSM) or homogeneous (with all parts having a GSM of

approximately 40). These limitations stimulated research to generate more

sophisticated computer-assisted methods of plaque characterization, such

as digital image analysis.

Digital Image Analysis Digital image analysis can provide an accurate measurement of the

morphology of a plaque, including not only the echodensity (the overall

brightness of the plaque, measured by GSM) but also the texture

(heterogeneity, measured by texture analysis) of the plaque.6 Measuring

plaque texture provides quantitative information about its morphology,

that is, if the plaque is homogeneous or heterogeneous.

Digital image analysis is a well-established method initially developed by

electrical and electronic engineers. Past studies have confirmed reliability,

reproducibility, and validity of the digital image analysis method in

ultrasonic studies of solid organs. In the ACSRS study, the combination

of measures of heterogeneity with GSM significantly (p = .02) improved

the value of GSM alone in distinguishing embolic from non-embolic CT

brain infarctions; the area under the curve increased from 0.62 (GSM) to

0.81 (combination).15 Not only can texture analysis discriminate between

symptomatic and asymptomatic carotid plaques, it can further

discriminate between carotid plaques obtained from patients with

different hemispheric symptomatology, significantly improving the

diagnostic value of GSM alone. Furthermore, in the ACSRS study,

heterogeneous plaques carried a significantly higher risk (odds ratio [OR]

5, p = .0001) of stroke in comparison with homogeneous plaques during

a mean follow-up of 37 months. Furthermore, heterogeneous plaques

were at a particularly increased risk of progression (OR 5.2, p = .0001).

Three-Dimensional ReconstructionThree-dimensional reconstruction of ultrasonic plaques is another recent

advancement that enables more accurate and reproducible quantification

of plaque volume/size and plaque surface characteristics (e.g., ulceration)

when compared with two-dimensional ultrasonography or angiography.16

Expected ContributionsWith more than 70,000 myocardial infarctions, 50,000 strokes, and 15,000

TIAs in Canada each year, atherosclerosis causes a deep burden on the

Canadian health care system; $22.2 billion per year is spent as a result of

these life-threatening events. Additionally, the impact of stroke is

devastating: 20% of stroke patients die, 11% go to long-term care, and

even many people who are able to return home have functional

limitations, severely compromising quality of life. Early identification of

plaque instability will result in appropriate management of carotid

atherosclerosis and prevention of stroke, with direct benefit at the

individual and the health services levels.

Advanced imaging technologies are now available and can be used to

monitor patients with carotid atherosclerotic plaques and identify early

when plaques become unstable and at risk to rupture (when prevention

is still possible). These advanced technologies will challenge the current

paradigm of managing carotid atherosclerotic disease in clinical practice.

Currently, recommendations for surgical interventions are based on only

the degree of carotid stenosis. Using these novel methods of plaque

characterization could lead to the refining of guidelines for carotid

atherosclerosis beyond carotid stenosis to include plaque morphology. In

this context, carotid intervention will be reserved for patients with high-

risk plaques, while those at low risk will be spared an unnecessary,

potentially dangerous, and expensive intervention.

Furthermore, currently pharmacological treatments focus on target

therapeutic values (e.g., blood pressure, glucose, cholesterol levels) as

evidence of therapeutic efficacy. These advanced methods of plaque

characterization will stimulate future research aimed at expanding the

focus to include not only target values but also the target tissue, namely

the stabilization of atherosclerotic plaques. In this concept, old and new

anti-atherosclerotic medication will have to prove their efficacy in

stabilization or even the reversal of the progression of atherosclerosis.

Medicine needs to take advantage of the extensive technological advances

that are already available, and implement them in the everyday clinical

practice in order to achieve more accurate diagnosis, better monitoring,

improved treatment, and more effective prevention of atherosclerosis.


C a r o t i d A t h e r o s c l e r o s i s : Te c h n o l o g i c a l E v o l u t i o n o f U l t r a s o n i c I m a g i n g

References1. Mayo NE, Nadeau L, Daskalopoulou SS, Cote R. The evolution of

stroke in Quebec: a 15-year perspective. Neurology 2007;68:1122–7.

2. Golledge J, Greenhalgh RM, Davies AH. The symptomatic carotid

plaque. Stroke 2000;31:774–81.

3. Romero JM, Ackerman RH, Dault NA, Lev MH. Noninvasive

evaluation of carotid artery stenosis: indications, strategies, and

accuracy. Neuroimaging Clin N Am 2005;15:351–65, xi.

4. Daskalopoulou SS, Daskalopoulos ME, Perrea D, et al. Carotid artery

atherosclerosis: what is the evidence for drug action? Curr Pharm

Des 2007;13:1141–59.

5. Nederkoorn PJ, van der GY, Hunink MG. Duplex ultrasound and

magnetic resonance angiography compared with digital subtraction

angiography in carotid artery stenosis: a systematic review. Stroke

2003;34:1324–32.

6. Nicolaides A, Griffin M, Kakkos S, et al. Ultrasonic characterization

of carotid plaques. In: AbuRahma AF, Bergan JJ, eds. Noninvasive

Vascular Diagnosis: A Practical Guide to Therapy, 2nd edition.

London: Springer Verlag; 2006: 127–48.

7. Saam T, Underhill HR, Chu B, et al. Prevalence of American Heart

Association type VI carotid atherosclerotic lesions identified by

magnetic resonance imaging for different levels of stenosis as

measured by duplex ultrasound. J Am Coll Cardiol

2008;51:1014–21.

8. Geroulakos G, Ramaswami G, Nicolaides A, et al. Characterization

of symptomatic and asymptomatic carotid plaques using high-

resolution real-time ultrasonography. Br J Surg 1993;80:1274–7.

9. Nordestgaard BG, Gronholdt ML, Sillesen H. Echolucent rupture-

prone plaques. Curr Opin Lipidol 2003;14:505–12.

10. Gronholdt ML, Nordestgaard BG, Schroeder TV, et al. Ultrasonic

echolucent carotid plaques predict future strokes. Circulation

2001;104(1):68–73.

11. Sabetai MM, Coker J, Sheppard M, Nicolaides AN. The association

of carotid plaque necrotic core volume and echogenicity with

ipsilateral hemispheric symptoms [abstract]. Circulation 2001;104

Suppl 2:671.

12. Gronholdt ML, Nordestgaard BG, Bentzon J, et al. Macrophages are

associated with lipid-rich carotid artery plaques, echolucency on B-

mode imaging, and elevated plasma lipid levels. J Vasc Surg

2002;35(1):137–45.

13. el-Barghouty N, Nicolaides A, Bahal V, et al. The identification of the

high risk carotid plaque. Eur J Vasc Endovasc Surg 1996;11:470–8.

14. Elatrozy T, Nicolaides A, Tegos T, et al. The effect of B-mode

ultrasonic image standardisation on the echodensity of symptomatic

and asymptomatic carotid bifurcation plaques. Int Angiol

1998;17:179–86.

15. Kakkos SK, Stevens JM, Nicolaides AN, et al. Texture analysis of

ultrasonic images of symptomatic carotid plaques can identify those

plaques associated with ipsilateral embolic brain infarction. Eur J

Vasc Endovasc Surg 2007;33:422–9.

16. Fenster A, Blake C, Gyacskov I, et al. 3D ultrasound analysis of

carotid plaque volume and surface morphology. Ultrasonics 2006;44

Suppl 1:e153–7.

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Gene t i c s & G IM

Tumour in the Kidneys: Have You Considered a Genetic Syndrome?

Dawna M. Gilchrist MD

Case ReportA 48-year-old female presented to her family doctor complaining of flank

discomfort. An abdominal ultrasonogram showed multiple bilateral

tumours of the kidneys without other abnormality. A referral to urology

was made, and surgery followed. Frozen section showed the tumours were

oncocytomas, and limited resection was done to preserve kidney function.

Post-surgical pathology confirmed the findings with no evidence of

malignancy. The patient has normal kidney function post-operatively.

The patient was referred to genetics. There was no contributory personal

or family history. A detailed physical examination was unremarkable.

Based on the pathology of oncocytomas, genetic testing was requested for

succinate dehydrogenase B (SDHB) and Birt-Hogg-Dubé (BHD)

syndrome. The test for SDHB was negative, but a mutation was found in

the BHD gene. At-risk family members have been offered testing for the

BHD mutation.

When to Consider a Genetic Cause for Tumour of theKidneyApproximately 2% of cancer is kidney cancer, with 80–85% of that being

renal cell (also known as clear cell) cancer,1 followed by transitional cell

cancer at 8%. The contribution of genetic factors to kidney cancer is still

undetermined but is likely higher than the traditionally quoted 5–10%. A

hereditary syndrome2 should be particularly considered when the

following are present:

• Young age of onset <40 years

• Bilateral tumours

• Personal or family history of manifestations of a genetic syndrome

known to include kidney tumours

• Pathological type (Table 1)

In patients with an onset of kidney tumour under the age of 40, there is a

1,800% increased risk3 for development of bilateral tumours.

The genetic syndromes2 associated with kidney cancers are all inherited

as autosomal dominant conditions. These syndromes exhibit incomplete

penetrance, that is, not all individuals with a mutation have

manifestations. There is also variable expressivity, meaning that

individuals with the same mutation do not always present with the same

manifestations or at the same age, or have the same response to therapy.

Von Hippel–Lindau DiseaseVon Hippel–Lindau disease (VHL) is a multisystem disorder with both

central nervous system and visceral manifestations. The best known of

these are cerebellar hemangioblastoma, retinal angiodysplasia, and

pheochromocytoma. Clear cell kidney cancers occur in approximately 35–

45% of patients with VHL. Kidney cysts and cancers are usually multifocal

and often bilateral. Mutation analysis of the VHL gene has a sensitivity of

99%.

Lynch SyndromeLynch syndrome, also known as hereditary non-polyposis colon cancer

(HNPCC), accounts for approximately 5% of colon cancer. Cancer can

potentially occur in most organs in the abdomino-pelvic cavity, with

urinary collection system cancer in approximately 10% of patients. The

pathological type is transitional cell. These tumours are likely to be

unifocal and unilateral. There are four genes known to be associated with

Lynch syndrome. Most genetic laboratories test for mutations in MLH1

and MSH2, which account for about 80% of Lynch syndrome cases.

Mutations in MSH6 account for 10% of Lynch syndrome cases. Mutation

analysis of these genes has a sensitivity of 96–98%.

Tuberous SclerosisTuberous sclerosis (TS) is a multisystem disorder that has a wide variety

of presentations. Severe cases are likely due to sporadic new mutations;

mild TS is underdiagnosed in the population and often familial. The

common renal manifestations are cysts and angiolipomas. Approximately

1% of patients with TS have oncocytomas of the kidney and 3% have renal

cell cancer. Genetic testing in TSC1 and TSC2 reveals the mutation in 70–

About the AuthorDawna Gilchrist is a professor and clinical geneticist in the Department of Medical Genetics, Faculty of Medicine and Dentistry,University of Alberta, Edmonton, Alberta. Correspondence may be directed to [email protected].

Table 1. Correlations of Pathological Type to SyndromePathological Type SyndromeRenal cell VHL, BHD, TS, SDHB, HRCCPapillary cell HPCC, HL+PCC, SDHBOncocytoma BHD, SDHB, TSChromophobe BHD, SDHBHybrid BHDAngiolipoma TSTransitional cell LynchCysts VHL, BHD, HL+PCC, TS/polycystic kidney disease

overlapBHD = Birt-Hogg-Dubé; HL+PCC = hereditary leiomyomatosis (skin and uterus) and papillary

cell carcinoma of the kidney; HPCC = hereditary papillary cell carcinoma of the kidney; HRCC

= hereditary renal cell carcinoma; SDHB = succinate dehydrogenase B; TS = tuberous sclerosis;

VHL = Von Hippel–Lindau disease.

Source: Adapted from Linehan.5


Tumou r i n t h e K i d n e y s : H a v e Yo u C o n s i d e r e d a G e n e t i c S y n d r ome ?

75% of cases. The diagnosis is better made on clinical grounds following

published criteria.4

Birt-Hogg-Dubé SyndromeBHD is a syndrome with manifestations of skin, kidneys, and lung. Of the

multiple skin findings, fibrofolliculomas are the most specific;

dermatological pathology is usually necessary. Lung cysts are similar to

those produced by emphysema and are usually multiple and bilateral.

They may lead to spontaneous pneumothorax. The kidney tumours are

bilateral and usually slow growing, with an unusual pathology of

oncocytoma, chromophobe, or a hybrid of the two. There is a single gene

associated with BHD called FLCN, and current testing has 88% sensitivity.

Other SyndromesThere are other rare syndromes of kidney cell tumours that are defined

by their pathology and genetic etiology:

• Hereditary papillary cell carcinoma of the kidney (HPCC) – MET

gene

• Hereditary leiomyomatosis (skin and uterus) and papillary cell

carcinoma of the kidney – (HL+PCC) – FH gene

• SDHB – more usually associated with paragangliomas and

pheochromocytomas

• Hereditary renal cell carcinoma (HRCC) – gene(s) unknown

Identifying Kidney Tumour SyndromesA genetic cause for kidney tumour should always be considered but

especially when the patient is young, the pathology is unusual, and/or the

tumours are multifocal or bilateral. A thorough exploration of the

patient’s personal and family histories is necessary, and attention should

be paid to potential manifestations outside of the urinary tract. Physical

examination may be helpful in terms of the skin manifestations of BHD

and TS (for the latter, a black light may be necessary). Pathology of the

tumour can be extremely helpful, and correlations are found in Table 1.5

Should suspicion for a genetic cause be significantly raised, referral of the

affected individual to a medical genetics clinic is recommended.

Identification of a specific syndrome will offer better prognostic

information and monitoring recommendations for the patient. If a

specific gene mutation is found, pre-symptomatic predictive testing

should be offered to at-risk individuals, that is, all first-degree adult

relatives of the affected individuals. In some instances, testing of children

is also recommended (for VHL, SDHB, and possibly TS).

SummaryPatients with kidney tumour(s) are common in internal medicine

practices. It is worthwhile to consider potential genetic syndromes as their

diagnosis can be to the benefit of the patients and their family.

References1. UpToDate. Waltham (MA): Author;

http://www.uptodate.com/home/index.html.

2. Sudarshan S, Linehan WM. Genetic basis of cancer of the kidney.

Semin Oncol 2006;33:544–51.

3. Wiklund F, Tretli S, Choueiri TK, et al. Risk of bilateral renal cell

cancer. J Clin Oncol 2009;27:3737–41.

4. GeneTests. Seattle (WA): University of Washington;

www.genetests.org.

5. Linehan WM. Genetic basis of bilateral renal cancer: implications for

evaluation and management. J Clin Oncol 2009;27:3731–3.

Now available!

All trademarks are owned by Novo Nordisk A/S and used under license by Novo Nordisk Canada Inc.

About the AuthorsDavedeep Sohi (far left) is a resident in the University of British ColumbiaDepartment of Medicine, Anson Li (middle) is chief resident in the UBC Divisionof Geriatric Medicine, and Roger Wong is a clinical professor in the UBC Divisionof Geriatric Medicine, Department of Medicine, in Vancouver, British Columbia.Correspondence may be directed to [email protected].



Development and Implementation of CanMEDS Health Advocacy Curriculum for Internal Medicine Residents

Davedeep Sohi MD, Anson Li MD, Roger Y. Wong MD

The health advocate role and the related competencies are part of the

formal educational and assessment requirements in Canadian

residency training within the CanMEDS framework (Table 1).1,2 Since the

adoption of CanMEDS by residency programs nationwide, it has become

apparent that the role of health advocate is one of the most difficult to

teach and assess.3 A 2006 survey of Canadian general internal medicine

graduates identified the role of health advocate as being an area of

particular weakness.4 Although this role has been highlighted as an area

of deficiency in residency training, there is a paucity of data in the

literature to explore this issue. The broad scope of health advocacy,

insufficient resident and staff time, an inadequate definition of advocacy,

a lack of remuneration, a lack of resident awareness, and the absence of a

structured curriculum are some of the barriers identified in the literature

explaining the difficulty in teaching the role of health advocate.5–7

In this article, we address some of these obstacles by providing an outline

of our innovative health advocacy curriculum at the University of British

Columbia (UBC) internal medicine residency program. The curriculum

is resident driven, experiential, flexible, and community responsive, and

it includes an assessment tool. To our knowledge, this is the first report of

a structured health advocacy curriculum in a Canadian internal medicine

residency program.

Curriculum DevelopmentSettingThe UBC internal medicine residency program is based in Vancouver and

consists of three core years of internal medicine training. The total

number of residents as of 2010 is 134.

ComponentsDevelopment of our health advocacy curriculum was a collaborative effort

between dedicated faculty members and residents. The Residency

Program Committee (RPC) approved the curriculum. In addition to input

from the perceived needs of our faculty, we conducted a comprehensive

literature review to identify our curriculum goals, objectives and

content.2,8–10 Previous work showed that role modelling alone is

insufficient in teaching health advocacy and that clear objectives need to

be established ahead of time to evaluate understanding and learning.

The UBC health advocacy curriculum consists of two pillars: an

interactive, lecture-based curriculum and a longitudinal, experiential

component. This approach is modelled after successful advocacy

programs in other disciplines. The didactic component can be based on

lectures, workshops, or even Internet-based training. The experiential

component helps to nurture and maintain continual interest.11

The lecture-based curriculum was deployed first in 2008 within our

annual resident retreat, which is a 3-day extracurricular event. A second

phase of the didactic curriculum was distributed throughout the year

within our academic half-day lectures. The objective of the didactic

component was to provide residents with a foundation in core health

advocacy topics, while focusing on local issues at the community and

population levels (Table 2).

Table 1. Definition and Competencies of the CanMEDSHealth Advocate Role

Definition of the Health Advocate RoleAs health advocates, physicians responsibly use their expertise and influenceto advance the health and well-being of individual patients, communities, andpopulations.

CompetenciesPhysicians will:• respond to individual patient health needs and issues as part of

patient care;• respond to the health needs of the communities that they serve;• identify the determinants of health of the populations that they serve;

and• promote the health of individual patients, communities, and

populations.

Source: Adapted from Frank.2

Table 2. Advocacy Topics Covered in Interactive LectureFormat during Academic Half-Days and Annual RetreatSessions

Health disparities and advocacyEmergency preparedness for natural disasterInternational health advocacy initiativesAdvocacy issues in patient careLocal community health resourcesInsights on advocacy from local internistsInfectious diseases and health advocacy


S o h i e t a l .

The bulk of the UBC health advocacy curriculum involves experiential

learning whereby residents are required to participate in at least one self-

selected, applied advocacy activity during their 3 years of training. To

create opportunities for residents, we began by identifying faculty

members who are active in health advocacy activities. These faculty

members have spearheaded a variety of projects including dementia

awareness sessions with culturally sensitive lectures and blood pressure

checks targeting the local Chinese immigrant population. Another faculty-

led project is an international health initiative that sends teams of faculty

and residents to a resource-poor area of South Africa to not only care for

patients but also educate local healthcare providers.

Creating a culture among faculty that nurtures health advocacy led to a

number of resident-driven projects. Since 2008, residents used their

medical expertise to promote health and well-being throughout the

greater Vancouver area via a number of initiatives (Table 3). These

individual initiatives have evolved into a Health Advocacy Network

(HAN). The HAN is a partnership between community-based health

advocacy groups and UBC internal medicine residents. It uses existing

community channels to advertise the availability and interest of our

residents to work with local groups on health promotion. The HAN

streamlines the ability of our residents to provide educational talks on a

variety of topics for local groups that represent a diversity of ethnicities,

languages, and lifestyle choices.

The curriculum also includes two assessment and feedback tools. The first

is a reflection survey that residents fill in after participating in health

advocacy events. This not only gives residents a chance to reflect on the

health advocate role but also provides feedback on the event itself. For

example, one resident remarked, “Based on the experience of this

advocacy event, I am motivated to actively identify and participate in

outreach projects in the community in the future.” Essentially, such

reflections become part of the residents’ learning portfolios. An additional

tool we have used is an online photo blog. This is a password-protected,

online forum where residents can post pictures from advocacy events.

Residents can also add in their online reflections, which again become

part of their portfolios. These tools are added to a log of advocacy events

in which residents participated; when combined with other relevant letters

or media exposure, residents have constructed their individual health

advocacy portfolios.

DiscussionThe UBC health advocacy curriculum is an innovative approach to

teaching the CanMEDS role of health advocate. This is the first reported

curriculum of its kind in Canada that targets internal medicine residents.

We have combined a small number of classroom-based sessions with a

greater emphasis on practical, community-based, health advocacy

experiences. Throughout the development process, we have adhered to

the five principles outlined below that make our curriculum unique:

experiential, resident driven, community networking, flexibility, and

assessment.

ExperientialOur advocacy curriculum is predominantly experiential. Hands-on health

advocacy is challenging because it demands competency in many of the

CanMEDS roles.9 Although being inherently demanding, or perhaps

because it is so demanding, experience in health advocacy is also highly

educational and richly rewarding. Experience-based learning equips

residents with the motivation and the skill set to be highly effective health

advocates as practising internists.

Resident DrivenWe strived to involve our residents in curriculum development and

implementation. Supported by faculty role models, residents have

demonstrated a keen interest in both the process of curriculum

development and in health advocacy itself. In addition, collaborating with

staff on advocacy initiatives gave residents another opportunity to seek

out mentors within our faculty.

Community NetworkingOne particularly unique aspect of the curriculum is community

networking. Work done in the pediatric population has shown that

community-driven advocacy events lead to increased positive attitude and

higher self-perceived competency for residents.12 The need to partner with

established community groups that serve as a voice for marginalized,

underserved populations has also been endorsed by other authors as an

effective means of practising health advocacy.5,7 The emergence of the

HAN allows our residents to be truly community responsive in their

activities by targeting populations most in need of health promotion. In

addition, community groups share the work involved in organizing health

promotion events. This helps overcome resident time constraints, which

has been reported as being a barrier to involvement in health advocacy.6

FlexibilityWe have encouraged residents to be creative in their health advocacy

endeavours and embrace their subspecialty interests within internal

medicine. Although we do have a mandatory community-based activity

for all residents, the target population, topic, and form of involvement are

entirely flexible. By giving residents choice in their advocacy training, we

encourage greater involvement and a more rewarding experience. This is

reflected in the diversity of topics chosen by residents (see Table 3).

Assessment In order to assess learning of health advocacy, an assessment tool is

required. Other Canadian schools have incorporated in-training

evaluation records for documentation as well as self-evaluation methods

in the form of logs, portfolios, or essays.8

Here at UBC, an individualized resident advocacy portfolio is composed

of feedback surveys, photo blogs, and a record of advocacy activities. This

form of assessment allows for residents to reflect on their progress in

mastering the CanMEDS competencies for the health advocate role. In

addition, it gives our faculty the opportunity to track each resident’s

development with respect to health advocacy.

Barriers and LimitationsThere were a number of obstacles in the development and

implementation of this curriculum. First, there is a paucity of peer-

reviewed literature to guide health advocacy training at the resident level.

Therefore, we often relied on faculty and resident opinion to design the

curriculum. Second, it was difficult to identify and recruit faculty to


C a nMED S H e a l t h A d v o c a c y C u r r i c u l um

Table 3. Summary of Community-Based Health Advocacy Initiatives

Topic Description Led by F or R AddictionsSmoking Cessation Strategies* Residents talk to the public to increase awareness R

on smoking cessationTours of Community Resources Residents are oriented to health facilities in Vancouver’s F

downtown east side to better understand barriers to health faced by marginalized population

Cardiology Residents give educational sessions to ambulatory patientsOptimizing Cardiovascular Health* regarding cardiac health and risk factor modification, the RSubstance Abuse and Heart Disease* deleterious effects of substance abuse, and gender-specific RWomen and Heart Disease* heart health REndocrinologyDiabetes Education* Residents give educational sessions to diabetic outpatients R

regarding diabetes mellitusGeriatricsDementia Awareness Workshop for Caregivers Residents participate in this annual outreach program F

targeting at-risk Asian seniors in Chinatown, and they check blood pressure for seniors and advise them of the benefits of blood pressure control in preventing dementia

Osteoporosis* Residents give educational sessions to the public Rregarding osteoporosis

Immigrant/Language IssuesMedical Cantonese Lessons for Health Providers Residents participate in several peer-teaching sessions to R

learn the basics of medical Cantonese, which help residents to more effectively communicate with their Cantonese-speaking patients

Medical Punjabi Lessons for Health Providers Residents participate in several peer-teaching sessions to R learn the basics of medical Punjabi, which help residents to more effectively communicate with their Punjabi-speaking patients

Visit to Refugee Shelter Residents are oriented to refugee shelter to better understand Rhealth challenges faced by marginalized population

Infectious Diseases Residents give educational sessions to the public regardingHIV/Hepatitis C Education* common infections and their prevention RInfluenza Education* RInternational FocusEstablishment of South Africa Medical Residents spend 1 month in a community hospital in South Africa, F Elective for Residents which helps them gain insight into marginalized population and

challenges in system changes to improve overall health delivery Oncology Residents attend informal barbeque to promote cancer awareness Cancer Screening* and screening; residents give educational sessions to the public RLeukemia Education* regarding common cancers and their prevention RPancreatic Cancer Education* ROrgan DonationPublic Awareness Initiative This initiative is organized by BC Transplant and aims to educate R

the public about the importance of organ donation; residents aretrained in a short session and then paired with a transplant recipient to hold public education sessions in the community

F = faculty members; HIV = human immunodeficiency virus; R = residents.

*Health promotion talks delivered in the community via the Health Advocacy Network.


S o h i e t a l .

mentor residents and serve as local champions for health advocacy. The

reasons for this are numerous and include those identified in the

literature, such as lack of time, a perception of advocacy as charity work,

and inadequate training.6 Overcoming these obstacles requires a sustained

effort at both the local and national levels to change the perception of

health advocacy and equip faculty with the tools necessary to teach

residents. Finally, residents often felt burdened from existing educational

obligations and thus were hesitant to engage in formal health advocacy

training. We feel that our curriculum is community driven and yet

minimizes the time requirements of the residents.

There are also notable limitations to this descriptive report. Foremost is

the fact that this curriculum was deployed at a single institution and it

therefore requires tailoring when implemented at other institutions,

although we believe the curriculum is generalizable. Also, it would be ideal

to develop additional measures of objective learning outcomes to augment

our current assessment tools. To remedy this problem, we are currently

developing tools to enable web-based, multi-source feedback of resident

community health promotion activities.

ConclusionThere is a need to improve teaching of the health advocate role among

residency programs nationwide. We believe the UBC health advocacy

curriculum is an engaging, structured curriculum that empowers residents

to learn health advocacy through participating in community-based

health promotion initiatives.

References1. Frank JR, Jabbour M, Tugwell P, et al. Skills for the new millennium:

report of the societal needs working group, CanMEDS 2000 Project.

Ann R Coll Physicians Surg Can 1996;29:206–16.

2. Frank JR, ed. The CanMEDS 2005 Physician Competency

Framework. Better Standards. Better Physicians. Better Care. Ottawa

(ON): The Royal College of Physicians and Surgeons of Canada;

2005.

3. Frank JR, Cole G, Lee C, et al. Progress in paradigm shift: the RCPSC

CanMEDS Implementation Survey. Office of Education, Royal

College of Physicians and Surgeons of Canada, University of Ottawa,

Ottawa, Canada. Presented at the Annual Meeting of the Association

of Canadian Medical Colleges, Quebec City (QC), 2003.

4. Card SE, Snell L, O’Brien B. Are Canadian general internal medicine

training program graduates well prepared for their future careers?

BMC Med Educ 2006;6:56.

5. Oandasan IF. Health advocacy: bringing clarity to educators through

the voices of physician health advocates. Acad Med 2005;80(10):S38–

41.

6. Verma S, Flynn L, Seguin R. Faculty’s and residents’ perceptions of

teaching and evaluating the role of health advocate: a study at one

Canadian university. Acad Med 2005;80(1):103–5.

7. Earnest MA, Wong SL, Federico SG. Perspective: physician advocacy:

what is it and how do we do it? Acad Med 2010;85(1):63–7.

8. Bandiera G. Emergency medicine health advocacy: foundations for

training and practice. Can J Emerg Med 2003;5(5):336–42.

9. Flynn L, Verma S. Fundamental components of a curriculum for

residents in health advocacy. Med Teach 2008;30(7):e178–83.

10. Chamberlain LJ, Sanders LM, Takayama JI. Child advocacy training

curriculum outcomes and resident satisfaction. Arch Pediatr Adolesc

Med 2005;159:842–7.

11. Pottie K, Hostland S. Health advocacy for refugees. Can Fam

Physician 2007;53:1923–6.

12. Hufford L, West DC, Paterniti DA, Pan RJ. Community-based

advocacy training: applying asset-based community development in

resident education. Acad Med 2009;84:765–70.


Re s i d e n t G IM

Misrepresentation by Trainees: A Serious Threat to Professionalism

Alexander A.C. Leung MD

BackgroundIt has been suggested that the medical culture, which rewards clinicalachievements and academic scholarship, may ironically promote dishonestbehaviour among trainees who may choose to lie and deceive in order toexcel, produce, publish, and gain recognition.1 Although honesty is a valuedand essential component of the medical profession, deceit andmisrepresentation may be alarmingly more common than previouslythought. However, deceptive practices can jeopardize trust and irreparablytarnish the credibility of the medical profession.

Misrepresentation on Multiple LevelsThe iterative and competitive selection process to enter medical schools,post-graduate training programs, and even positions of faculty appointmentmay reward candidates who embellish their achievements. Consequently,identifying dishonest practices during these particular milestones has beena subject of considerable interest.1,2

The application to medical schools and most residency training programsis perceived to be a competitive process. Deans of admission and programdirectors typically look at many factors when selecting students andresidents, which may include academic records, research experience,scientific publications, extracurricular involvement, volunteer experience,advanced degrees, and letters of reference. Many of these areas are providedby self-report and the accuracy based solely on the “honour system.”Unfortunately, to gain a competitive advantage, some applicants may betempted to falsify credentials or exaggerate their accomplishments. The fabrication of academic accomplishments appears to be more commonthan most would believe. The Association of American Medical Collegesreported that over a period of a decade, nearly a thousand irregular caseswere investigated, and fraudulent transcripts, unauthentic letters ofrecommendation, inaccurate and incomplete credentials, applications underassumed identities, and irregular examination behaviour were exposedamong applicants to medical schools.2

Erroneous claims of authorship by medical students applying for residencytraining have been well documented in various fields including medical,3,4

psychiatric,5 surgical,6 and diagnostic imaging specialties.7 Estimates ofpublication misrepresentation are consistently between 10 and 30% acrossstudies, mostly involving the reporting of non-existent articles or non-existent journals.3–8

Furthermore, the falsification of credentials, inaccurate reporting ofadvanced degrees, and fabrication of previous employment history arecommon, estimated to occur in as many as a quarter to half of applications.3–4,8

Shockingly, case reports exist of individuals entering residency programswithout successful completion of medical school, and even con artists whonever attended medical school at all.9

One study of applicants to family medicine residency across 150 programsin the United States estimated that deception (defined as “the activemisrepresentation or omission of facts about one’s qualifications,background, or abilities”) may occur in up to half of all applications.9 Ofthese, acts of deception relating to personal statements accounted for 56%of cases, and inaccurate reporting of graduation status from a qualifiedmedical school accounted for 13%. Other acts of deception includedcandidates misrepresenting their specialty choice, the purposeful omissionof information from application materials, misrepresentation of pastexperiences, and the submission of falsified documents. Very rarely, someapplicants were discovered to have undisclosed criminal backgrounds orprevious positive drug screens.9

Interestingly, the pattern of misrepresentation is not unique to medicaltrainees but has also been noted in physicians in practice. A study of eightacademic institutions in the United States (with specialty representationfrom emergency medicine, internal medicine, ophthalmology, pediatrics,radiology, and surgery) found that 15.6% of applicants to faculty positionshad misrepresented their bibliographies, with journal citations being themost frequent source of misrepresentation.10 Many of these discrepancieswere likely intentional, with rearrangement of authorship order withadvancements, claiming authorship for another’s material, and outrightfabrication of non-existent articles.10 Physicians may also falsify credentials.An audit of physicians listed in the Yellow Pages found that 12% of thoseadvertising as “specialists” were not board certified in any specialty.11

Another audit found that 5% of physicians provided false clinical credentialswhen applying for ambulatory staff privileges.12

Reinforcing Dishonest Behaviour Dishonesty may have become institutionalized into our medical training.1

Despite an apparently careful admission process to medical schools,education in medical ethics, and professional mentoring, trainees stillappear to misrepresent themselves to gain a competitive edge. Whenselecting applicants for medical schools, residency programs, and facultypositions, we should reconsider the value of solely using academic merit todiscriminate between candidates. Although it is unrealistic to completelyeliminate conventional selection criteria (i.e., academic transcripts,educational experience, scientific contributions, publications, and awards),perhaps greater emphasis can be placed on other important qualities suchas compassion, integrity, honesty, humanity, collaboration, and altruism,which may be presently undervalued. Moreover, academic success is often measured by publications, resulting inunfortunate adages like “publish or perish.” Given these expectations andthe competitive academic climate, it is not surprising that some people givein to the temptation to embellish their achievements, even among physicians

About the AuthorAlex Leung is a clinical scholar in the Division of General Internal Medicine, at the University of Calgary, Calgary, Alberta.Correspondence may be directed to [email protected].


L e u n g

in practice and those applying for academic and clinical appointments.It is disturbing that societal acceptance of lying and deceit may also beshifting. For example, a faculty member at the University of Chicagosuggested that “a limited form of resumé embellishment is morallypermissible (and perhaps required)” on the basis of relativity, arguing thatas it is certain that some resumés are embellished, it is better that all resumésare embellished for fair comparison.13 Disappointingly, if these ideas alsofairly represent changing societal norms, intentional misrepresentation islikely to become more rampant over time.

Possible SolutionsDishonesty is a serious threat to our medical profession, and those whodemonstrate a pattern of deceit during their training may go on to bedishonest in their dealings with colleagues and patients in the future. Assuch, it is paramount to identify solutions to deter the widespread use ofdeceptive practices. One possible strategy is to educate trainees, increasesurveillance to detect dishonest behaviour, instate a common standard forthe reporting of achievements and activities, and enforce strict disciplinarymeasures for those who are caught breeching the rules.First, the purpose of education should be to educate trainees on ethicalstandards and principles, and to promote accurate documentation practices.While it is impossible to know with certainty if some inaccuracies aredeliberate (as that is a question of motivation), some discrepancies such aserroneous authorship claims or factitious declarations of certification aremost likely intentional fabrications, whereas other errors are likely the resultof unintentional mistake (i.e., typographical errors). Consequently, it is quitepossible that some of the “misrepresentation” reported by existing studiesmay be a result of “sloppy referencing,” thus resulting in the reporting ofpublications or activities that could not be confirmed by reviewers. Teachingbetter documentation practices is a simple remedy. Second, there is evidence that deceptive practices are more likely to bedetected when formal verification processes are instituted to reviewapplications.9 Complete verification of all claims made on applications tomedical schools, residency programs, faculty appointments, and hospitalpositions will likely never be instituted because this would be a prohibitivelycostly and time-consuming endeavour. Nonetheless, with the wideaccessibility of electronic databases, primary verification of publications (asa surrogate marker of application accuracy) can be a simple tool that canbe employed universally. Random audits by confirming the authenticity ofletters of reference or employment can also be considered on a case-by-casebasis.Third, addressing the common finding of misrepresentation of authorship,some authorities have proposed that all cited publications should beaccompanied by photocopies or reprints of cover pages; articles listed as “inpress” should be accompanied by a letter of acceptance from the journal’seditor; and the listing of articles “in preparation/in progress” or “inreview/submitted for publication” should be discourraged.14 Instatingspecific citation guidelines may help reduce innocent errors and dissuadeintentional misrepresentation. Finally, upholding high ethical standards should be a criterion foremployment. When misrepresentation is found, it must be treated seriously.If intentional, the applicant breeches the professional code of ethics andbreaks the rules that govern the formal application process to medicaltraining programs. A concerted effort is required by training institutionsand professional regulatory bodies to discipline those found guilty. Forexample, the American Board of Internal Medicine has developed a

standard method of handling confirmed cases of misrepresentationinvolving revocation of board eligibility and certification, and notificationof state disciplinary boards.15 A similar formalized process does not yet existin Canada but should be considered.

ConclusionsThe profession of medicine is held to a high standard. The physician-patientand physician-physician relationships are built on trust and honesty.Lamentably, ethical compromises and deceit appear to be disturbinglycommon among trainees and even among physicians in practice.Falsification of credentials or self-misrepresentation is clearly undesirablein our profession. Promoting awareness of this problem and creatingsystematic checks to dissuade deceit are necessary to prevent unscrupulousbehaviour from those who are in positions of trust and authority.

References1. Young TA. Teaching medical students to lie. The disturbing

contradiction: medical ideals and the resident-selection process. Can Med Assoc J 1997;156:219–22.

2. Petersdorf RG. A matter of integrity. Acad Med 1989;64:119–23.3. Katz ED, Shockley L, Kass L, et al. Identifying inaccuracies on

emergency medicine residency applications. BMC Med Educ 2005;5:30.

4. Sekas G, Hutson WR. Misrepresentation of academic accomplishments by applicants for gastroenterology fellowships. AnnIntern Med 1995;123:38–41.

5. Caplan JP, Borus JF, Chang G, et al. Poor intentions or poor attention:misrepresentation by applicants to psychiatry residency. Acad Psychiatry 2008;32:225–9.

6. Konstantakos EK, Laughlin RT, Markert RJ, et al. Follow-up on misrepresentation of research activity by orthopaedic residency applicants: has anything changed? J Bone Joint Surg Am 2007;89:2084–8.

7. Panicek DM, Schwartz LH, Dershaw DD, et al. Misrepresentation of publications by applicants for radiology fellowships: is it a problem? AJR Am J Roentgenol 1998;170:577–81.

8. Roellig MS, Katz ED. Inaccuracies on applications for emergency medicine residency training. Acad Emerg Med 2004;11:992–4.

9. Grover M, Dharamshi F, Goveia C. Deception by applicants to familypractice residencies. Fam Med 2001;33:441–6.

10. Goe LC, Herrera AM, Mower WR. Misrepresentation of research citations among medical school faculty applicants. Acad Med 1998;73:1183–6.

11. Reade JM, Ratzan RM. Yellow professionalism. Advertising by physicians in the Yellow Pages. N Engl J Med 1987;316:1315–9.

12. Schaffer WA, Rollo FD, Holt CA. Falsification of clinical credentials 0by physicians applying for ambulatory-staff privileges. N Engl J Med1988;318:356–8.

13. Marcoux AM. A counterintuitive argument for résumé embellishment.J Bus Ethics 2006;63:183–94.

14. Boyd AS, Hook M, King LE, Jr. An evaluation of the accuracy of residency applicants’ curricula vitae: are the claims of publications erroneous? J Am Acad Dermatol 1996;35:606–8.

15. Kimball HR. Credentials misrepresentation: another challenge to professionalism. Ann Intern Med 1995;123:58–9.

About the AuthorsSally Man was a doctor of pharmacy student at the University of British Columbia, Vancouver, British Columbia, at the time ofthis writing. Glen Pearson is an associate professor in the Faculty of Medicine, and co-director of the Cardiac Transplant Clinic,University of Alberta, Edmonton, Alberta. Correspondence may be directed to [email protected].


Pha rm -G IM

Dronedarone: Current Evidence and Place in Our Anti-arrhythmic Armamentarium

Sally Man PharmD, Glen J. Pearson PharmD

Atrial fibrillation (AF) is the most common form of sustained cardiac

arrhythmia, especially among older adults, and contributes to

significant morbidity and mortality.1 Between the years 2000 and 2005,

deaths reported as resulting from AF or atrial flutter totalled 7,911 in

Canada.1

Two treatment strategies currently exist for the management of AF – rate

control and rhythm control. In the AFFIRM study (expansion provided

in Appendix 1), neither method was found to be superior in reducing all-

cause mortality in patients at risk for recurrent AF.2 The decision to pursue

rate versus rhythm control should therefore be individualized according

to patient symptoms and preference. The rhythm control strategy may be

preferred in patients who present with their first AF episode, those with

disabling symptoms of AF, or those remaining symptomatic despite rate

control therapy. The most recent American College of

Cardiology/American Heart Association/European Society of Cardiology

(ACC/AHA/ESC) guidelines recommend class Ic and class III anti-

arrhythmic agents as first-line therapy for the maintenance of sinus

rhythm in AF patients.3

While amiodarone is one of the most commonly prescribed anti-

arrhythmic agents, it is associated with significant potential long-term,

multi-organ toxicity, including skin photosensitivity and discoloration

(blue-grey), pulmonary fibrosis, hypothyroidism (common),

hyperthyroidism (rare), corneal micro-deposits, and non-alcoholic

steatohepatitis.4 Dronedarone is a non-iodinated benzofuran derivative

of amiodarone that has been developed to retain the efficacy of

amiodarone while improving its safety profile.5 This review evaluates the

current evidence regarding the efficacy and safety of dronedarone in the

chronic management of AF.

Rationale for the Use of DronedaroneIn August 2009, Health Canada approved dronedarone for the treatment

of patients with a history of or current AF to reduce the risk of

cardiovascular (CV)-related hospitalization. Like amiodarone,

dronedarone exhibits electrophysiological properties that span all four

Vaughan-Williams classes.5 However, the deletion of the iodine moiety

from this new agent is thought to eliminate harmful effects on the thyroid

gland, and the addition of a methane sulphonyl group renders the

compound less lipophilic. These pharmacological modifications decrease

the elimination half-life of dronedarone to 24–31 hours (compared with

58 days for amiodarone), thereby reducing the total tissue drug

accumulation and potentially long-term drug toxicities.4,5 In addition, the

shorter half-life negates the need for the use of a loading dose during the

initiation of therapy.

Efficacy of DronedaroneTo date, there are published six placebo-controlled trials and one trial that

directly compared dronedarone to amiodarone in the chronic

management of AF (see Appendix 1).6–11 A detailed summary of these

clinical trials is presented in Table 1. No clinical trials have yet evaluated

dronedarone for acute pharmacological cardioversion.

Recurrent AF Recurrent AF constitutes the majority of cases of AF in clinical practice

and is defined by the ACC/AHA as the occurrence of two or more AF

episodes.5 Three large, multi-national randomized controlled trials

(EURIDIS,6 ADONIS,6 and ATHENA7) were conducted to compare the

efficacy and safety of dronedarone versus placebo in patients with

recurrent AF. All patients were in sinus rhythm at the time of

randomization. In the ATHENA trial, treatment with dronedarone

significantly reduced the primary composite end point of first CV-related

hospitalization and all-cause mortality compared with placebo (HR 0.76,

95% confidence interval [CI] 0.69–0.84).7 Notably, this result was

primarily driven by a reduction in CV-related hospitalization since the

end point of all-cause mortality alone demonstrated a non-significant

reduction. In post hoc analyses, both the EURIDIS and ADONIS studies

showed a similar reduction in the composite outcome of first CV-related

hospitalization and all-cause mortality (HR 0.73, 95% CI 0.57–0.93).6

In the EURIDIS and ADONIS studies, patients treated with dronedarone

were also observed to have derived other benefits: (1) a longer time to

their first recurrence of AF (median time of 116 days compared with 53

days in the placebo group); (2) an 8.3% reduction in the symptomatic

recurrence of AF at 12 months (HR 0.71, 95% CI 0.60–0.86); and (3) a

decrease in their mean ventricular response rate of 13.7 beats per minute

(bpm).6 In comparison, previous trials have shown that amiodarone

reduced recurrent AF episodes by 40.7% but did not demonstrate a

mortality benefit relative to placebo.12

Persistent AFIt is estimated that approximately 10% of patients with AF progress to

persistent AF.3While a rate control strategy may suffice for many of these

patients in reducing symptoms, some will remain symptomatic despite

heart rate control. There are two placebo-controlled trials (ATHENA7 and

DAFNE8) and one comparator-controlled trial (DIONYSOS9) with

amiodarone that evaluated patients with persistent AF. These studies

defined persistent AF as episodes lasting longer than 72 hours. This

definition deviates from the ACC/AHA clinical definition for persistent

AF, which is AF lasting longer than 7 days.3


Man a n d Pe a r s o n

Table 1. Summary of Results of Dronedarone Clinical Trials

Study* N Patient Characteristics Treatment ResultsEURIDIS6 612 ≥21 yo, recurrent AF Placebo (n = 201) Mean time to first AF recurrence: 41 d (P) vs. 96 d (D)

Excluded: Dronedarone 400 mg PO bid (n = 411) AF recurrence rate at 12 mo: 77.5% (P) vs. 67.1% (D)Use of class I or III anti-arrhythmics, (p = .01)CHF NYHA class III–IV, SCr >150 µmol/L Mean ventricular rate at first AF recurrence: 117.5 ±

29.1 bpm (P) vs. 102.3 ± 24.7 (D) (p < .001)Hospitalization or death: 32.0% (P) vs. 21.2% (D) (p = .02)

ADONIS6 625 See EURIDIS Placebo (n = 208) Mean time to first AF recurrence: 59 d (P) vs. 158 d (D)Dronedarone 400 mg PO bid (n = 417) AF recurrence rate at 12 mo: 72.8% (P) vs. 61.1% (D)

(p = .002)Mean ventricular rate at first AF recurrence: 116.6 ± 31.9 bpm (P) vs. 104.6 ± 27.1 (D) (p < .001)Hospitalization or death: 29.8% (P) vs. 24.5% (D) (p = .22)

ATHENA7 4,628 ≥70 yo, paroxysmal or Placebo (n = 2,327) Composite of first CV hospitalization/all-cause persistent AF, LVEF <40% Dronedarone 400 mg PO bid (n = 2,301) mortality: 39.4% (P) vs. 31.9% (D) (p < .001)Excluded: First CV hospitalization: 36.9% (P) vs. 29.3% (D) Permanent AF or AFL, CHF NYHA (p < .001)class IV, GFR <10 mL/min All-cause mortality: 6.0% (P) vs. 5.0% (D) (p = .18)

Any serious treatment-emergent adverse events: 21.1% (P) vs. 19.9% (D) (p = .31)Discontinuation of drug due to adverse events: 8.1% (P) vs. 12.7% (D) (p < .001)

DAFNE8 199 21-85 yo, persistent AF scheduled Placebo (n = 48) Median time to first AF recurrence: 5.3 d (P) vs. 60 d for elective cardioversion Dronedarone 400 mg PO bid (n = 54) (D400 bid) (p = .001)Excluded: Dronedarone 600 mg PO bid (n = 54) NSD between placebo and dronedarone 600 mg bid >2 cardioversions in last 6 mo, AFL, Dronedarone 800 mg PO bid (n = 43) and 800 mg bidWPW syndrome, UA, recent MI, LVEF <35%, Spontaneous cardioversion rates: 3.1% (P) vs. 5.8% AICD, concomitant anti-arrhythmics (D400 bid) vs. 8.2% (D600 bid) vs. 14.8% (D800 bid)

Adverse event: 0% (P) vs. 3.9% (D400 bid) vs. 7.6% (D600 bid) vs. 22.6% (D800 bid)

DIONYSUS9 504 Persistent AF Amiodarone 600 mg PO daily × 28 d, Composite (AF recurrence or premature study Amiodarone naive then 200 mg PO daily thereafter discontinuation): 58.8% (A) vs. 75.1% (D) (p < .001)

Dronedarone 400 mg PO bid AF recurrence after electrical cardioversion: 24.3% (A) vs. 36.5% (D) Premature drug discontinuation: 34 patients (A) vs. 26 patients (D)Adverse events: 107 patients (A) vs. 83 patients (D) (p = .13)Bradycardia: 22 patients (A) vs. 8 patients (D)Pronounced QTc prolongation: 52 patients (A) vs. 27 patients (D)

ERATO10 174 ≥21 yo, symptomatic permanent Placebo (n = 89) Mean 24 h ∆ in ventricular rate at 4 mo: –1.3 bpm AF for which cardioversion was not Dronedarone 400 mg PO bid (n = 85) (P) vs. –10.1 bpm (D) (p < .001); results remained an option significant after adjusting for concomitant rate-Excluded: controlling agentsCHF NYHA class III–IV, UA, diabetes Mean 24 h ∆ in ventricular rate during sub-maximal Concurrent rate-controlling agents permitted exercise: –2.2 bpm (P) vs. –25.6 bpm (D) (p < .0001)

Mean 24 h ∆ in ventricular rate during maximal exercise: –2.9 bpm (P) vs. –27.4 bpm (D) (p < .0001)Treatment-emergent adverse events: 60% (P) vs. 77% (D)Discontinuation of drug due to adverse events: 10% (P) vs. 15% (D)

ANDROMEDA11 627 > 18 yo, hospitalized for symptomatic Placebo (n = 310) Composite of all-cause mortality/hospitalization for CHF NYHA class III–IV, LVEF ≤35% Dronedarone 400 mg PO bid (n = 317) worsening HF: 12.6% (P) vs. 17.1% (D) (p = .12)Excluded: Mortality at median of 2 mo: 3.8% (P) vs. 8.1% (D) (p = .03)MI within 7 d, use of class I or III Hospitalization for worsening HF: 60.0% (P) vs. 49.3% (D) anti-arrhythmic agents (p = not reported)

A = amiodarone; AF – atrial fibrillation; AFL = atrial flutter; AICD = automated implantable cardioverter defibrillator; bpm = beats per minute; CHF = congestive heart failure; D = dronedarone; GFR =glomerular filtration rate; LVEF = left ventricular ejection fraction; MI = myocardial infarction; NSD = no significant difference; NSR = normal sinus rhythm; NYHA = New York Heart Association; P =placebo; QTc = QT interval corrected for heart rate; SCr = serum creatinine; UA = unstable angina; WPW – Wolff-Parkinson-White; yo = years old. *See Appendix 1 for study acronym expansions.


D r o n e d a r o n e : C u r r e n t E v i d e n c e

Results for the ATHENA trial are presented above. The DAFNE trial was

the first randomized controlled trial to exclusively evaluate patients with

persistent AF where cardioversion was indicated.8 In this placebo-

controlled trial, patients treated with dronedarone had a significantly

longer time to first AF recurrence (median 60 days versus 5.3 days). At

6 months, 35% of patients on dronedarone remained in normal sinus

rhythm (NSR) compared with only 10% with placebo. All patients who

did not return to NSR after 5–7 days underwent electrical cardioversion.

DAFNE was also a dose-finding study, and it evaluated dronedarone

400 mg bid, 600 mg bid, 800 mg bid, and placebo. Of note, only

dronedarone 400 mg bid dosing was superior to placebo in delaying time

to first AF recurrence. Higher doses failed to demonstrate significant

benefit but resulted in significantly higher rates of study discontinuation

due to adverse drug effects (3.9% with 400 mg bid versus 7.6% with

600 mg bid versus 22.6% with 800 mg bid).

The DIONYSOS trial was the first randomized controlled trial to compare

dronedarone against an active comparator, amiodarone, in the

management of AF.9 Patients were randomized to dronedarone 400 mg

bid and amiodarone 600 mg daily for 28 days, followed by 200 mg daily.

Dronedarone was shown to be inferior to amiodarone in reducing the

composite end point of AF recurrence or premature study discontinuation

at 12 months (75.1 versus 58.8%; HR 1.59, 95% CI 1.28–1.98; p < .0001).

This result was driven by the increased rate of AF recurrence in patients

treated with dronedarone (63.5 versus 42.0%). The main safety end point,

defined as the occurrence of thyroid, hepatic, pulmonary, neurological,

skin, eye, or gastrointestinal specific event, or premature study drug

discontinuation following an adverse event, showed a non-significant

reduction among patients treated with dronedarone (39.3 versus 44.5%

at 12 months; HR = 0.80, 95% CI 0.60–1.07; p = .129).

Permanent AFThe ERATO study was the only double-blind randomized controlled trial that

exclusively enrolled patients with symptomatic permanent AF.10 Permanent

AF was defined as AF persisting for more than 6 months where electrical

cardioversion was not indicated. The primary outcome in this study was the

mean change in ventricular heart rate at 14 days. Secondary outcomes

included reduction in heart rate during exercise, exercise duration, and adverse

effects. Although more than 50% of the study population were prescribed

concomitant negative chronotropic agents (i.e., beta-blockers, calcium

channel blockers, digoxin), the primary outcome of mean change in

ventricular heart rate at 14 days was superior in the dronedarone group (mean

decrease of 11 bpm versus mean increase by 0.7 bpm in the placebo group).

This benefit was sustained at 4 months. Dronedarone also significantly

reduced heart rate during exercise compared with placebo but failed to

significantly increase patients’ ability to exercise for a longer duration.

Unfortunately, the ERATO study enrolled only 174 patients and was not

adequately powered to evaluate clinically meaningful end points, such as all-

cause mortality, CV mortality, and CV-related hospitalization.10 Although

previous studies (EURIDIS, ADONIS, and ATHENA) evaluated these end

points, patients with permanent AF were excluded from enrollment.6,7

Therefore, it is not possible to extrapolate these trial results to patients with

permanent AF. Another limitation to the ERATO trial was that it failed to

address whether further heart rate reduction resulted in decreased patient

symptoms.

AF Associated with Heart FailureHeart failure (HF) is a common comorbidity and often a direct

complication of AF. Historically, only HF patients with mild to moderate

symptoms have been included in AF clinical trials while those with severe

disease have often been excluded. Therefore, efficacy data in this

population were largely derived from post hoc analyses. Similarly, the

majority of studies evaluating dronedarone excluded patients with severe

HF. ANDROMEDA was the only clinical trial that included patients with

class III and IV HF (57% and 4.1%, respectively).11 Importantly, this trial

was terminated prematurely due to increased mortality in the

dronedarone-treated group compared with the placebo-treated group. At

7 months, patients randomized to dronedarone had a significantly higher

rate of all-cause mortality (8.1% versus 3.8%; HR = 2.13; 95% CI 1.07–

4.25; p = .03) and more hospitalizations for acute CV causes (22.9% versus

15.8%, p = .02). Progressive HF accounted for much of the excess in all-

cause mortality (3.2 versus 0.6%) and rate of hospitalization for CV causes

(11.3 versus 9.5%) attributed to dronedarone. In a subgroup analysis, the

risk of death associated with dronedarone was shown to be increased

among patients who had a lower wall-motion index. The unexpected

findings in the ANDROMEDA trial remain the subject of significant

debate and speculation. Nevertheless, this study has caused dronedarone

to receive a “black box warning,” with a contraindication for use in

patients with New York Heart Association (NYHA) class IV HF, or NYHA

class II–III HF with a recent decompensation requiring hospitalization or

referral to a specialized HF clinic.13

Safety and Tolerability of Dronedarone Common adverse effects reported for dronedarone include

gastrointestinal symptoms (i.e., nausea, vomiting, and diarrhea), a rise in

serum creatinine, bradycardia, and QT prolongation.6–11 Serum creatinine

generally increased but does not appear to correlate with a reduction in

the glomerular filtration rate. In the DIONYSOS trial, significantly fewer

patients randomized to dronedarone discontinued the study medication

secondary to adverse effects as compared with amiodarone.9 Although

more patients on dronedarone complained of gastrointestinal symptoms,

fewer patients reported thyroid, neurological, bradycardic, and QT

prolonging effects.

Place in TherapyDronedarone is the first novel anti-arrhythmic agent to reach the market

in over a decade. As a structurally modified version of amiodarone, it

holds the potential to retain the favourable efficacy characteristics of

amiodarone while minimizing the long-term toxicities that may

contribute to significant morbidity. Clinical trials have shown that

dronedarone delays the time to first AF recurrence and reduces overall

recurrences compared with placebo in patients with recurrent, persistent,

and permanent AF. It also exerts negative chronotropic effects and lowers

CV-related hospitalization, but has not yet demonstrated any mortality

benefits. In direct comparison to amiodarone, dronedarone demonstrated

inferior efficacy but superior short-term tolerability. It is important to

keep in mind that the current studies are too short in duration to evaluate

dronedarone’s long-term toxicity profile – a property that will likely

determine its future place in the management of AF. Therefore, ongoing

post-marketing surveillance will be critical to evaluate the long-term safety


Man a n d Pe a r s o n

of dronedarone. Until long-term safety data are ascertained, it is

premature to conclude whether dronedarone is a safer alternative to

amiodarone. Since there are currently a number of anti-arrhythmic agents

indicated for the maintenance of sinus rhythm in patients with AF, it may

be more prudent to select these agents for patients at risk for amiodarone-

induced toxicity when a rhythm control strategy is being pursued. When

clinicians are considering dronedarone in appropriately selected patients,

they must consider the fact that there are no cost-effectiveness data that

compare it to other marketed anti-arrhythmic agents, such as amiodarone,

which is available as a generic. Recently, the Canadian Expert Drug

Advisory Committee completed the common drug review of dronedarone

and concluded that it should not be listed for coverage in participating

provincial and other drug plans across Canada.14 This decision was based

on the clinical trial evidence available for dronedarone to date and its

excess (~fourfold) cost over the most appropriate comparator,

amiodarone.

ConclusionCurrent evidence with dronedarone demonstrates that is a reasonable

option for the management of AF in select patients. It appears to have an

improved tolerability in the short term, at the expense of decreased

efficacy when compared with amiodarone. Dronedarone is not

appropriate for use in patients with NYHA class IV HF or class II–III HF

with a recent decompensation. The lack of cost-effectiveness data and

potential of non-coverage by provincial formulary programs may limit

the clinical use of this new agent.

Appendix 1. Clinical Trial Acronym DefinitionsBelow are the expansions for trial acronyms discussed in this article:

ADONIS6 - American–Australian–African trial with DrONedarone In

atrial fibrillation or flutter patients for the maintenance of Sinus rhythm

AFFIRM2 - Atrial Fibrillation Follow-up Investigation of Rhythm

Management

ANDROMEDA11 - ANtiarrhythmic trial with DROnedarone in Moderate

to severe CHF Evaluating morbidity DecreAse

ATHENA7 - A placebo-controlled, double-blind, parallel arm Trial to

assess the efficacy of dronedarone 400 mg bid for the prevention of

cardiovascular Hospitalization or death from any cause in patiENts with

Atrial fibrillation/atrial flutter

DAFNE8 - Dronedarone Atrial FibrillatioN study after Electrical

cardioversion

DIONYSOS9 - randomized, Double-blind trIal to evaluate the efficacy and

safety of drOnedarone [400 mg bid] versus amiodaroNe [600 mg qd for

28 daYS, then 200 mg qd thereafter] for at least 6 mOnths for the

maintenance of Sinus rhythm in patients with AF

ERATO10 - Efficacy and safety of dRonedArone for The cOntrol of

ventricular rate during atrial fibrillation

EURIDIS6 - EURopean trial In atrial fibrillation or flutter patients

receiving Dronedarone for the maIntenance of Sinus rhythm

References1. Statistics Canada. CANSIM: Deaths, By Cause, Chapter IX: Diseases

of the Circulatory System (I00 To I99), Age Group and Sex, Canada,

Annual. Ottawa (ON): Statistics Canada;

http://cansim2.statcan.gc.ca/cgi-win/cnsmcgi.pgm. Accessed

November 22, 2009.

2. AFFIRM Investigators. A comparison of rate control and rhythm

control in patients with atrial fibrillation. N Engl J Med

2002;347:1825–33.

3. American College of Cardiology/American Heart

Association/European Society of Cardiology. ACC/AHA/ESC 2006

guidelines for the management of patients with atrial fibrillation.

Circulation 2006;114:e257–354.

4. Zimetbaum P. Amiodarone for atrial fibrillation. N Engl J Med

2007;356:935–41.

5. Dale KM, White CM. Dronedarone: an amiodarone analog for the

treatment of atrial fibrillation and atrial flutter. Ann Pharmacother

2007;41:599–605.

6. Singh BN, Connolly SJ, Crijn HJ, et al. Dronedarone for maintenance

of sinus rhythm in atrial fibrillation or flutter. N Engl J Med

2007;357:987–99.

7. Hohnloser SH, Crijns HJ, van Eickels G, et al. Effect of dronedarone

on cardiovascular events in atrial fibrillation. N Engl J Med

2009;360:668–78.

8. Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention

of atrial fibrillation: a dose-ranging study. Eur Heart J

2003;24:1481–7.

9. Heuzey JY, De Ferrari GM, Radzik D, et al. A short-term,

randomized, double-blind, parallel-group study to evaluate the

efficacy and safety of dronedarone versus amiodarone in patients

with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc

Electrophysiol 2010;21:597–605.

10. Davy J, Herold M, Hoglund C, et al. Dronedarone for the control of

ventricular rate in permanent atrial fibrillation: the Efficacy and

safety of dRondeArone for The cOntrol of ventricular rate during

atrial fibrillation (ERATO) study. Am Hear J 2008:156:527.e1–527.e9

11. Kober L, Torp-Pedersen C, McMurray JJV, et al. Increased mortality

after dronedarone therapy for severe heart failure. N Engl J Med

2008;358:2678–87.

12. Piccini JP, Hasselblad V, Peterson ED, et al. Comparative efficacy of

dronedarone and amiodarone for the maintenance of sinus rhythm

in patients with atrial fibrillation. J Am Coll Cardiol

2009;54:1089–95.

13. US Food and Drug Administration. Multaq (Dronedarone) Briefing

Document to the Advisory Committee Meeting of the

Cardiovascular and Renal Drugs Division of the US Food and Drug

Administration. Silver Spring (MD): The Administration, 2009;

http://www.fda.gov/downloads/AdvisoryCommittees/Committees

MeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisory

Committee/UCM134981.pdf. Accessed July 18, 2010.

14. Canadian Agency for Drugs and Technology in Health. Canadian

Expert Drug Advisory Committee (CEDAC) Final Recommendation

for Dronedarone (Multaq). Ottawa (ON): The Agency, 2010;

http://www.cadth.ca/media/cdr/complete/cdr_complete_

Multaq_May-31-2010.pdf. Accessed July 18, 2010.


New I n v e s t i g a t o r Awa rd W i nne r

Achieving a Peaceful Death: The Internist’s Role In Advance Care Planning

John J. You MD

Do not go gentle into that good night,

Old age should burn and rage at close of day;

Rage, rage against the dying of the light.

– Dylan Thomas

Written for his dying father, these words evoke helplessness, the fear

of losing a loved one, and a desperate plea for his father to fight

on. The will, courage, and audacity to survive and the refusal to let go of

life comprise a visceral human instinct. Expressions such as, “He was a

real fighter,” or, “I’m a cancer survivor,” glorify the struggle to stay alive.

Medical science has given us the tools to push the frontiers of human

survival to new limits and has increased our ability to rescue ourselves

from deeper and deeper out of the jaws of death. We celebrate these

innovations and modern miracles, and rightly so. But, as Atul Gawande

aptly puts it, how should our patients decide “when to switch from

fighting for time to fighting for the other things that people value?”1

A general internist colleague of mine once told me, “Everyone comes to

visit me before they die.” Those of us who practise in-patient general

internal medicine agree that we regularly come face to face with death.

The reality of death in Canada is that over 250,000 individuals die each

year, projected to reach nearly half a million individuals per year by 2035,

and that 70% of these deaths occur in hospital.2,3 There is also evidence

suggesting that the general medical ward is home to the highest number

of deaths compared with any other service in hospital.4

My own experiences on the clinical teaching unit confirm that death on

the medical ward is common. But more importantly, my experiences

indicate that there are a much larger number of patients who actually do

not die in hospital but who are reaching the end of the road. For these

people, who are at the end stages of chronic illness, there is often little that

we can do to change the overall trajectory of their disease. Should we

throw up our hands in despair? Ironically, I think that it is among this

group of patients where we as internists have an opportunity to make a

huge difference in their life and in the lives of their families.

Some might argue that we should fight until the very end. That would be

no problem if that is the experience that patients truly desired. However,

when directly asked, many patients and their families identify the

following elements as important aspects of high-quality end-of-life care:

feelings of peace, assessment and treatment of emotional problems, trust

in the doctors looking after them, avoidance of life support when there is

little hope for a meaningful recovery, honest communication of

information about their disease, and preparation for life’s end.5,6 Each

time I attend on the general medicine teaching unit, there is at least one

and usually more patients who die while under my care. Unfortunately,

“peaceful” is not one of the words I would typically use to describe their

death. Instead, a slow deterioration punctuated by invasive procedures,

life support, multiple tests, innumerable complications of their underlying

disease and their treatments, and overworked health care staff with little

time to attend to the basic needs of patients describes a commonplace

scenario for many of my patients at the end of life. The family members,

thrust unprepared into their role as substitute decision makers, are forced

into the uncomfortable situation of making decisions about treatment for

their loved one without any prior knowledge of their values or preferences

for care at the end of life.

In these situations, it is too late. We are left to struggle through and to do

our best to guide the family through the series of decisions that lie ahead.

However, for the much larger group of patients we care for on the medical

ward who do not die during their hospital stay but who are at high risk of

dying in the coming year, there is a captive moment. The hospitalization

can be an opportune time for us to start conversations about advance care

planning for many reasons: the acute change in the patient’s condition

may increase the relevance of having these kinds of conversations; family

members, who will typically become the surrogate decision makers, are

often present; a multidisciplinary health care team is present; and the

target population – the patient at high risk of dying – are concentrated in

one physical location (the in-patient medical ward).

There are, however, important barriers to initiating advance care planning

in this setting. First, talking about death can be uncomfortable, and with

more pressing demands for our time it is all too easy to push these

discussions to the bottom of our priority list. Second, many of us do not

follow up with these patients in the community after discharge, creating

problems for continuity of any discussions that might get started in

hospital. Third, some of us may feel inadequately trained to have these

conversations or may believe that it is simply not our job to address these

issues and that the physicians who know the patients the best (i.e., the

primary care physicians or specialists who provide longitudinal care) are

the most appropriate care providers to be starting these conversations.

Finally, difficulties in estimating survival may be an important barrier. In

contrast to the patient with newly diagnosed metastatic cancer, many of

our patients have non-malignant disease, and it can be harder to define a

group of patients who are at high risk of dying within the coming 6–12

months. Although prognostic scores have been published, none are simple

to use at the bedside.7,8 Also, these scoring systems only provide estimates

of survival at a given point in time, for example, the proportion of patients

alive at 6 months, when median life expectancy (or 90th percentile life

expectancy – the time within which 90% of similar patients would be

dead) would likely be more meaningful and understandable for most

About the AuthorJohn You is the winner of the CSIM New Investigator Award 2010. He is a member of the Departments of Medicine, and ClinicalEpidemiology and Biostatistics, at McMaster University, in Hamilton, and the Institute for Clinical Evaluative Sciences, in Toronto,Ontario. Correspondence may be directed to [email protected].


Yo u

patients. Heyland et al. have used what may be a more practical approach

in their work in end-of-life care to define patients at high risk of dying in,

and their criteria appear to identify a group of patients with an average

mortality of 50% at 6 months (patients age 55 years or older with end-

stage congestive heart failure, chronic obstructive pulmonary disease,

cirrhosis, metastatic cancer, or dementia, or any patients age 80 years or

older admitted to hospital from the community for an acute medical

condition).5,6

Even if we were to overcome these barriers, is there any evidence that

advance care planning actually works? SUPPORT (the Study to

Understand Prognoses and Preferences for Outcomes and Risks of

Treatments) was a landmark randomized clinical trial to improve end-of-

life care and advance care planning in critically ill patients, but the

intensive intervention failed to make any meaningful difference in

important outcomes, including the timing of a written do not resuscitate

order before death, patient and physician agreement on preferences to

withhold resuscitation, days spent in an intensive care unit before death,

frequency or severity of pain, and hospital resource use before death.9

Despite these sobering results, there is still reason for optimism. A recent

randomized clinical trial of an advance care planning intervention

delivered by a trained facilitator versus usual care in medical in-patients

aged 80 years or more showed that, of the participants who died during

follow-up, end-of-life wishes were much more likely to be known and

followed in patients who received the study intervention.10

As internists, we can each get involved and make a difference. We each

invest our time differently into research, education, and patient care. For

those of us who do research, there are huge opportunities to conduct

research that aims to improve care in this area. For those of us who are

educators, there are tremendous opportunities to develop educational

interventions, curricula, and programs that provide our undergraduate

and postgraduate trainees and our colleagues (through continuing

medical education) with the skills they need to provide high-quality end-

of-life care. For all of us who see patients, we are called by our profession

not to treat disease entities and normalize aberrant physiology, but to heal

people. Patients want to be heard, to receive honest information about

their disease and prognosis, and to have their spiritual and emotional

needs addressed. We either need to develop the skills to do these ourselves

or to work out practical and innovative ways to deliver care in a way that

can meet these needs. This is what our patients want. I think we can stand

to do a whole lot better, so what are we waiting for?

References1. Gawande A. Letting go. What should medicine do when it can’t save

your life? The New Yorker 2010 August 2.

2. Statistics Canada. Population Projections for Canada, Provinces and

Territories – 2000–2026 (Catalogue No. 91-520). Ottawa (ON):

Statistics Canada.

3. Heyland DK, Lavery JV, Tranmer JE, et al. Dying in Canada: is it an

institutionalized, technologically supported experience? J Palliat Care

2000;16 Suppl:S10–6.

4. Workman S, Mann OE. ‘No control whatsoever’: end-of-life care on

a medical teaching unit from the perspective of family members. Q

J Med 2007;100:433–40.

5. Heyland DK, Dodek P, Rocker G, et al., for the Canadian Researchers,

End-of-Life Network (CARENET). What matters most in end-of-

life care: perceptions of seriously ill patients and their family

members. Can Med Assoc J 2006;174:627–33.

6. Heyland DK, Cook DJ, Rocker GM, et al., for the Canadian

Researchers, End-of-Life Network (CARENET). Defining priorities

for improving end-of-life care in Canada. Can Med Assoc J

2010;182:E747–52.

7. Knaus WA, Harrell FE Jr, Lynn J, et al. The SUPPORT prognostic

model. Objective estimates of survival for seriously ill hospitalized

adults. Ann Intern Med 1995;122:191–203.

8. Walter LC, Brand RJ, Counsell SR, et al. Development and validation

of a prognostic index for 1-year mortality in older adults after

hospitalization. JAMA 2001;285:2987–94.

9. The SUPPORT Principal Investigators. A controlled trial to improve

care for seriously ill hospitalized patients. JAMA 1995;274:1591–8.

10. Detering KM, Hancock AD, Reade MC, Silvester W. The impact of

advance care planning on end of life care in elderly patients:

randomized controlled trial. BMJ 2010;340:c1345.



The Forest among the Trees: Which Ubiquitous Risk Factor Are We Ignoring?How to integrate nutrition screening in your clinical practice

Bert Govig MD, MPH

Abalanced and nutritive diet has long been recognized as the

cornerstone of health. Hippocrates observed, “Our food should be

our medicine and our medicine should be our food.” Maimonides echoed

this, and advised, “Let nothing which can be treated by diet be treated by

other means.” More recently Thomas Edison predicted that “the doctor

of the future will give no medications, but will interest his patients in the

care of the human frame, diet and in the cause and prevention of disease.”

His contemporary, Abraham Flexner, a major architect of modern medical

education, concurred – “the physician’s function is fast becoming social

and preventative, rather than individual and curative.” Despite a strong

narrative that runs throughout 2,000 years of healing traditions, modern

clinicians fail to routinely diagnose and address their patients’ nutrition

needs. In the twentieth century explosion of medical sub-specialization

and technological advances in pharmacology, immunology, genetics,

medical devices, etc., nutrition issues seem to have been pushed to the

back burner.

Clinical neglect aside, healthy nutrition is threatened by a multitude of

cultural and societal developments within the past half-century. These

include changes in school lunch programs, a general decline of traditional

family meals, and transformations in the agricultural and food-processing

industries. The link between the land (in theory where food comes from)

and what we put on our table has become hard to trace, and in some cases

it is difficult to identify at the most basic levels the origins of “food” items,

that is, animal, mineral, vegetable, or … chemical?

On a positive note, nutritional epidemiologists have made tremendous

strides toward understanding the relationships between diet and health.

A growing body of epidemiological literature supports the conclusion that

a plant-based diet rich in fruits, vegetables, legumes, and whole grains is

associated with positive health outcomes.1–6 Dietary analysis of the

INTERHEART study observed that patients observing a “prudent” diet,

largely as defined above, had half the risk of myocardial infarction as did

“less prudent” patients (odds ratio comparing extreme quartiles = 1.92;

95% confidence interval [CI] 1.74–2.11),7 and estimated that 30% of the

myocardial infarction in the studied population was attributable to diet.

From a therapeutic perspective, the DASH diet trials demonstrated that a

diet rich in fruits, vegetables, and low-fat dairy products, as well as reduced

saturated and total fats, was associated with a 5.5 and 3.0 mm Hg

reduction in systolic and diastolic blood pressures8 – similar or greater

than would be expected with many antihypertensive drugs.

Whom to ScreenIn today’s evidence-driven medical culture, addressing nutrition is no

longer an option. The first clinical dilemma is whom do we screen? Survey

studies from the United States suggest that 77% of Americans eat less than

five fruits and vegetables per day.9 Canadian practices may be marginally

different, but among lifestyle-related risk factors, nutrition ranks high.

The HOPER study,10 published in this journal, observed the following

risk-related behaviours in a sample of emergency room outpatients:

smoking 27%, overweight 51%, sedentary behaviour 65%, and unhealthy

nutrition 83%. Such data are alarming, and yet the screen that was used

to identify unhealthy nutrition was extremely simple – less than five fruits

and vegetables per day – and is likely to underestimate the incidence of

“at risk” nutrition. A decade ago, one might have been tempted to limit

nutrition screening to the population with overt nutrition-related

complications, such as obesity, cachexia, or frank vascular disease. Yet,

ignoring nutrition-related risk because a patient has normal body weight

is the equivalent of ignoring smoking because pulmonary function is

preserved. The clear, albeit somewhat depressing, conclusion is that almost

all of our patients with a life expectancy of a decade or more merit

consideration for nutrition screening.

How to ScreenThe second and more challenging clinical dilemma is how to screen this

large segment of the population. Over the past 30 years, epidemiologists

have developed and standardized methods to identify nutrient-related

risk, and much of our understanding of nutrition-related risk comes from

the use of these food frequency questionnaires (FFQs). Unfortunately,

they are unwieldy to use in clinical practice, and many of the lessons culled

from the epidemiological research are not easily translated into clinical

practice. For example, a recommendation to eat more selenium is not very

useful to most patients. Nutrition researchers recognize that people buy,

cook, and eat food not nutrients, and over the past decade food-based

patterns of healthy nutrition have been identified. It is no surprise that

there are many eating patterns that are associated with health, and some

of the mainstream ones that are becoming a part of the nutrition

vernacular are the Mediterranean Diet, the DASH Diet, and the Prudent

Diet.

These dietary patterns are the intellectual offspring of epidemiological

studies, and some of them still require the use of FFQs for

implementation. This relegates them to the research arena, and there is

an ongoing need for clinical screening tools that can be implemented at

the bedside, in the clinics, or, even better, by patients in their own homes.

In 2008, a group, of which I was part, published one such tool – the Eating

Assessment Table (EAT).11 This is a self-administered nutrition screening

About the AuthorBert Govig is with the Departments of Internal Medicine at CSSS Les Eskers de L’Abitibi, Amos, and at McGill University, Montréal,Québec, and is physician in chief with Coalition pour L’Acquisition de Saines Habitudes. Correspondence may be directed [email protected].

C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e

G o v i g

tool that can be completed by most patients in 15

minutes or less. This was well received by the research

community and by many clinicians who were quick

to recognize that they did not have 15 minutes to

administer a screening questionnaire to even a

fraction of their patients. Two years of experience

with this tool have taught us that busy clinicians also

lack the time to correct, tabulate, and score even this

simple questionnaire; therefore, we built an online

version that validates data entry, tabulates the data,

creates a score on a scale of 0–100, creates a

computer-generated report based on the patient data,

and makes recommendations seeking to guide

patients toward a change process. This online tool,

currently in a Beta version, is freely available to

patients and clinicians and can be accessed under the

tools tab of the website www.soundhabits.org.

Readers of this journal are invited to use this tool and

submit any feedback through the website.

ConclusionThe links between nutrition and health constitute

nothing less than ancient knowledge, and nutrition’s

role in today’s health problems is probably even

greater than in the past. The evidence base for this

conclusion grows stronger by the year, and yet,

paradoxically, it has become perhaps the most

prevalent and at the same time the most neglected

risk factor for chronic disease. Arguably, almost all

patients should be screened for nutrition issues in the

same way that we screen for blood pressure and ask

about tobacco use. Until recently, such screening was

labour and resource intensive and simply not

achievable on a large-scale basis. However, emerging

Internet-based technologies promise to dramatically

reduce the barriers to nutrition screening and to shift

the burden of work to patients who are most likely to

benefit from the procedure. As with tobacco use,

clinicians can exert great influence on their patients’

nutrition through the use of focused, time-limited

interventions. Our job is not to conduct the screen,

but to promote it. Health care workers who believe in

the links between lifestyles and health can make

critical contributions to healthy lifestyle promotion,

and collectively we may achieve Abraham Flexner’s

100-year-old vision of clinician-led, population-

based medicine.

References1. Keys A. Coronary heart disease in seven

countries, XVII. The diet. Circulation.

1970;41 Suppl 4:I162–83.

2. Phillips RL. Role of life-style and dietary

habits in risk of cancer among seventh-day

Adventists. Cancer Res 1975;35(11 Pt 2):

3513–22.

3. Belanger CF, Hennekens CH, Rosner B, et al.

The nurses’ health study. Am J Nurs

1978;78:1039–40.

4. Lowenstein FW. Major nutritional findings

from the First Health and Nutrition

Examination Survey in the United States of

America, 1971–1974. Bibl Nutr Dieta

1981;30:1–16.

5. Ascherio A, Rimm EB, Giovannucci EL, et al. A

prospective study of nutritional factors

and hypertension among US men.

Circulation 1992;86:1475–84.

6. Hu FB, Rimm EB, Stampfer MJ, et al.

Prospective study of major dietary patterns

and risk of coronary heart disease in men.

Am J Clin Nutr 2000;72:912–21.

7. Iqbal R, Anand S, Ounpuu S, et al. Dietary

patterns and the risk of acute myocardial

infarction in 52 countries: results of the

INTERHEART study. Circulation

2008;118:1929–37.

8. Appel LJ, Moore TJ, Obarzanek E, et al. A

clinical trial of the effects of dietary patterns

on blood pressure. DASH Collaborative

Research Group. N Engl J Med 1997;336:1117–24.

9. MMWR 2001;September 7.

10. Laliberté TC, Hofmann A, Govig B. Hidden

Opportunities for Promotion in the

Emergency Room: The HOPER Study. Can J

Gen Intern Med 2007;2(1):22–3.

11. Govig B, de Souza R, Levitan EB. The Eating

Assessment Table – an evidence-based

nutrition tool for clinicians. Crit Pathw Cardiol

2009;8:55–62.

3rd McMaster University Review Course in

March 30th – April 2nd, 2011

HAMILTON CONVENTION CENTRE1 Summers Lane, Hamilton ON

MARK YOUR CALENDAR!

OBJECTIVESTo learn practical approaches to medical

problems from different disciplines of internal medicine encountered by hospital based medicine

practitioners. To learn practical approaches to medical

problems from different disciplines of medicine encountered in ambulatory settings.

To appreciate the breadth of internal medicine problems faced by clinicians.

To learn about controversies in internal medicine. Update your knowledge in problems encountered

in internal medicine.

TARGET AUDIENCE

General Internists | Subspecialists | ER Physicians Hospitalists | Community Physicians

Family Physicians | General Practitioners Interns and Residents in Training Programs for Internal

Medicine and its Subspecialties

For further information contact: Angela Silla, Event Coordinator,

Continuing Health Sciences Education, McMaster University, MDCL 3510,

1200 Main Street West, Hamilton ON L8N 3Z5Phone: 905-525-9140 ext. 26327 Fax:

905-572-7099 Email: [email protected] or visit the CHSE Website at

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Dabigatran Etexilate 110mg and 150mg Capsules

Prescribing Summary

This is a condensed version of the Product Monograph. For complete information please refer to the Product Monograph available at www.boehringer-ingelheim.ca or by contacting Boehringer Ingelheim (Canada) Ltd., 5180 South Service Road, Burlington, Ontario, L7L 5H4.

Patient Selection Criteria

THERAPEUTIC CLASSIFICATION: AnticoagulantINDICATIONS AND CLINICAL USE• Prevention of stroke and systemic embolism

in patients with atrial fi brillation, in whom anticoagulation is appropriate.

Geriatrics (>65 years of age): Clinical studies have been conducted in patients with a mean age >65 years. Safety and effi cacy data are available (see CLINICAL TRIALS). Pharmacokinetic studies in older subjects demonstrate an increase in exposure to dabigatran in most of those patients, usually in association with age-related decline of renal function (see WARNINGS AND PRECAUTIONS, Renal, and DOSAGE AND ADMINISTRATION, Renal Impairment).Pediatrics (<18 years of age): The safety and effi cacy of PRADAX have not been established in children less than 18 years of age. Therefore, PRADAX is not recommended in this patient population.

CONTRAINDICATIONS• Severe renal impairment (CrCl <30mL/min)• Hemorrhagic manifestations, bleeding

diathesis, or patients with spontaneous or pharmacological impairment of hemostasis

• Lesions at risk of clinically signifi cant bleeding, e.g., extensive cerebral infarction (hemorrhagic or ischemic) within the last 6 months, or active peptic ulcer disease with recent bleeding

• Concomitant treatment with strong P-glycoprotein (P-gp) inhibitors, i.e., oral ketoconazole (see DRUG INTERACTIONS)

• Known hypersensitivity to dabigatran or dabigatran etexilate or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

Safety Information

WARNINGS AND PRECAUTIONSThe following Warnings and Precautions are listed in alphabetical order.

BleedingAs with all anticoagulants, PRADAX should be used with caution in circumstances associated with an increased risk of bleeding. Bleeding can occur at any site during therapy with PRADAX. An unexplained fall in hemoglobin and/or hematocrit or blood pressure should lead to a search for a bleeding site. Patients at high risk of bleeding should not be prescribed PRADAX (see CONTRAINDICATIONS).Close clinical surveillance (looking for signs of bleeding or anemia) is recommended throughout the treatment period, especially if risk factors are combined.Table 1: Factors which increase hemorrhagic risk, as identifi ed in clinical studies

Factors increasing dabigatran plasma levels

Moderate renal impairment (30-50 mL/min CrCl)

P-glycoprotein-inhibitor comedication

Pharmacodynamic interactions

Acetylsalicylic acid

NSAID

Clopidogrel

Diseases/procedures with special hemorrhagic risks

Congenital or acquired coagulation disorders

Thrombocytopenia or functional platelet defects

Active ulcerative gastrointestinal disease

Recent gastro-intestinal bleeding

Recent biopsy or major trauma

Recent intracranial hemorrhage

Brain, spinal or ophthalmic surgery

Bacterial endocarditis

Others Age 75 years The measurement of dabigatran-related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors.In patients who are bleeding, an aPTT test may be useful to assist in determining an excess of anticoagulant activity, despite its limited sensitivity. An aPTT >80 sec at trough, i.e., when the next dose is due, is associated with a higher risk of bleeding (see Monitoring and Laboratory Tests).Should severe bleeding occur, treatment with PRADAX must be discontinued and the source of bleeding investigated promptly.Agents that may enhance the risk of hemorrhage should not be administered concomitantly with PRADAX, or, if necessary, should only be administered with caution (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetic Interactions in the Product Monograph).Treatments that should NOT be administered concomitantly with PRADAX due to increase in bleeding risk include: unfractionated heparin and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, bivalirudin, thrombolytic agents, GPIIb/IIIa receptor antagonists, ticlopidine, sulfi npyrazone, and vitamin K antagonists such as warfarin. The concomitant use of PRADAX with the following treatments has not been studied and may increase the risk of bleeding:

rivaroxaban, prasugrel, and the strong P-gp inhibitors itraconazole, tacrolimus, cyclosporine, ritonavir, tipranavir, nelfi navir and saquinavir. Unfractionated heparin may be administered at doses necessary to maintain a patent central venous or arterial catheter. In patients with atrial fi brillation treated for the prevention of stroke and systemic embolism, the co-administration of oral anti-platelet (including aspirin and clopidogrel) and NSAID therapies increases the risk of bleeding by about two-fold (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions). If necessary, co-administration of low-dose ASA, i.e.,

100 mg daily with PRADAX may be considered for other indications than stroke prevention in atrial fi brillation. Note that in the RELY trial, there is no evidence that the addition of ASA or clopidogrel to dabigatran, or its comparator warfarin, improved outcomes in respect to stroke (see CLINICAL TRIALS, Stroke Prevention in Atrial Fibrillation).Treatment initiation with verapamil should be avoided in patients following orthopedic surgery who are already treated with PRADAX. Simultaneous initiation of treatment with PRADAX and verapamil should also be avoided at any time (see DRUG INTERACTIONS, P-glycoprotein inhibitors).

Interaction with P-gp inducersThe concomitant use of PRADAX with the strong P-gp inducer, rifampicin, reduces dabigatran plasma concentrations. Other P-gp inducers such as St. John’s Wort or carbamazepine are also expected to reduce dabigatran plasma concentrations, and should be co-administered with caution (see DRUG INTERACTIONS and Special Populations).

Surgery/Procedural InterventionsPatients on PRADAX who undergo surgery or invasive procedures are at increased risk for bleeding. In these circumstances, temporary discontinuation of PRADAX may be required.

Pre-operative PhaseIn advance of invasive or surgical procedures PRADAX should be stopped temporarily due to an increased risk of bleeding. If possible, PRADAX should be discontinued at least 24 hours before invasive or surgical procedures. In patients at higher risk of bleeding (see DOSAGE AND ADMINISTRATION) or in major surgery where complete hemostasis may be required, consider stopping PRADAX 2-4 days before surgery. Clearance of dabigatran in patients with renal insuffi ciency may take longer (see DOSAGE AND ADMINISTRATION, Renal). This should be considered in advance of any procedures.PRADAX is contraindicated in patients with


severe renal dysfunction (CrCl <30 mL/min). Should acute renal failure occur before surgery is required, PRADAX should generally be stopped at least 5 days before major surgery.If acute intervention is required, PRADAX should be temporarily discontinued, due to increased risk of bleeding. Surgery or procedural interventions should be delayed if possible until at least 12 hours after the last dose of PRADAX, with risk of bleeding weighed against the urgency of the needed intervention.

Peri-Operative Spinal/Epidural Anesthesia, Lumbar PunctureProcedures such as spinal anesthesia may require complete hemostatic function.In patients treated with PRADAX for VTE prevention following major orthopedic surgery and who undergo spinal or epidural anesthesia, or in whom lumbar puncture is performed in follow-up to surgery, the formation of spinal or epidural hematomas that may result in long-term or permanent paralysis cannot be excluded. In the case of these peri-spinal procedures, administration of the fi rst dose of PRADAX should occur after hemostasis has been obtained and no sooner than 2 hours following puncture or removal of catheters related to these procedures.The risk of these rare events may be higher with post-operative use of indwelling epidural catheters or the concomitant use of other products affecting hemostasis. Accordingly, the use of PRADAX is not recommended in patients undergoing anesthesia with post-operative indwelling epidural catheters.Post-Procedural PeriodResume treatment with PRADAX as soon as complete hemostasis is achieved.

RenalPRADAX is contraindicated in cases of severe renal impairment (CrCl <30 mL/min). Patients who develop acute renal failure while on PRADAX should discontinue such treatment. • Patients with atrial fi brillation treated for

prevention of stroke and systemic embolism: Since no dose adjustment is necessary for most atrial fi brillation patients with moderate renal impairment (CrCl 30-50 mL/min), a standard daily dose of 300 mg, taken orally as one 150 mg capsule twice daily is recommended (see DOSAGE AND ADMINISTRATION, Renal Impairment).

Special PopulationsPregnant Women: Since there are no studies of PRADAX in pregnant women, the potential risk in these patients is unknown. Animal reproductive studies did not show any adverse effects on fertility or postnatal development of the neonate.

Women of child-bearing potential should avoid pregnancy during treatment with PRADAX and when pregnant, women should not be treated with PRADAX unless the expected benefi t is greater than the risk.Nursing Women: Breast-feeding during treatment with PRADAX is not recommended. There are no clinical data available on the excretion of dabigatran into breast milk.Geriatrics (>65 years of age): Pharmacokinetic studies in older subjects demonstrate an increase in drug exposure; especially in those patients with age-related decline of renal function (see WARNINGS AND PRECAUTIONS, Renal, and DOSAGE AND ADMINISTRATION, Renal Impairment). • Patients with atrial fi brillation treated for

prevention of stroke and systemic embolism: Patients aged 80 years and above should be treated with a daily dose of 220 mg taken orally as one 110 mg capsule twice daily. This alternate dosing may also be considered for other geriatric patients (see DOSAGE AND ADMINISTRATION, Elderly). Use with caution.

Pediatrics (<18 years of age): The safety and effi cacy of PRADAX have not been established in children less than 18 years of age. Therefore, PRADAX is not recommended in this patient population.Patients of low body weight (<50 kg): Since limited data are available in these patients, PRADAX should be used with caution.

Monitoring and Laboratory Tests At recommended doses of PRADAX, dabigatran prolongs coagulation time as measured by the activated partial thromboplastin time (aPTT), thrombin time (TT) and ecarin clotting time (ECT). In patients who are bleeding due to excess activity of dabigatran, these coagulation tests would be expected to be elevated and may be helpful in assessing anticoagulant activity of dabigatran, if necessary (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics). The aPTT is generally less sensitive to anticoagulant activity than either TT or ECT (see DRUG INTERACTIONS, Drug-Laboratory Interactions). However, the aPTT test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. In patients who are bleeding, the aPTT test may be useful to assist in determining an excess of anticoagulant activity, despite its limited sensitivity. An aPTT greater than 80 sec at trough (when the next dose is due) is associated with a higher risk of bleeding. In circumstances where there is no excess of anticoagulant activity, the utility of aPTT is limited in monitoring anticoagulant status of patients taking PRADAX.

ADVERSE REACTIONSThe safety of PRADAX has been evaluated overall in 22,126 patients.A total of 10,084 patients were exposed to at least one dose of dabigatran as study medication in four active-controlled clinical trials conducted to evaluate the safety and effectiveness of dabigatran etexilate in the prevention of venous thromboembolic events (VTE) following major elective orthopedic surgery. Of these, 5,419 were treated with 150 mg or 220 mg daily of PRADAX, while 389 received doses of less than 150 mg daily, and 1,168 received doses in excess of 220 mg daily. In the RELY trial investigating the prevention of stroke and systemic embolism in patients with atrial fi brillation, a total of 12,042 patients were exposed to PRADAX. Of these, 6,059 were treated with 150 mg twice daily of dabigatran etexilate, while 5,983 received doses of 110 mg twice daily. About 21% of patients with atrial fi brillation treated with dabigatran and about 16% of patients treated with warfarin for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years) experienced adverse events considered related to treatment.

BleedingBleeding is the most relevant side effect of PRADAX. Bleeding of any type or severity occurred in approximately 14% of patients treated short-term for elective hip or knee replacement surgery and in long-term treatment in 16.5% of patients with atrial fi brillation treated for the prevention of stroke and systemic embolism. Although rare in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes. A summary description of major and total bleeding is provided in Table 2.Table 2 shows the number of patients experiencing major and total bleeding event rates during the treatment period in the RELY study, conducted in patients with atrial fi brillation. In Table 2, the category of major bleeds includes both life-threatening and non-life threatening bleeds. Within life-threatening, intracranial bleeds is a subcategory of life-threatening bleeds. Intracranial bleeds include intracerebral (hemorrhagic stroke), subarachnoid and subdural bleeds. For this reason, these events may be counted in multiple categories.


Table 2: Frequency and annualized event rate (%) of bleeding events from the RELY trial

Dabigatran etexilate 110 mg bid

N (%)

Dabigatran etexilate 150 mg bid

N (%)

Warfarin**N (%)

Patients randomized 6,015 6,076 6,022

Patient-years 11,899 12,033 11,794

Major bleeding event (MBE)* 342 (2.9) 399 (3.3) 421 (3.6)

Hazard ratio vs. warfarin (95% CI)

0.80 (0.70, 0.93) 0.93 (0.81, 1.07)

p-value 0.0026 0.3146

Life threatening MBE 147 (1.2) 179 (1.5) 218 (1.9)


0.67 (0.54, 0.82) 0.80 (0.66, 0.98)

p-value 0.0001 0.0305

Intra-cranial hemorrhage (ICH)+ 27 (0.2) 38 (0.3) 90 (0.8)


0.30 (0.19, 0.45) 0.41 (0.28, 0.60)

p-value < 0.0001 < 0.0001

Any bleeding eventa 1,754 (14.7) 1,993 (16.6) 2,166 (18.4)


0.78 (0.73, 0.83) 0.91 (0.85, 0.96)

p-value < 0.0001 0.0016

*Adjudicated bleeds**Dose-adjusted warfarin to an INR of 2.0 – 3.0 + ICH consists of adjudicated hemorrhagic stroke and subdural and/or subarachnoid hemorrhage.

aInvestigator-reported bleeding events

Major bleeding fulfi lled one or more of the following criteria:• Bleeding associated with a reduction in

hemoglobin of at least 20 grams per litre or leading to a transfusion of at least 2 units of blood or packed cells;

• Symptomatic bleeding in a critical area or organ: intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding or pericardial bleeding.

Major bleeds were classifi ed as life-threatening if they fulfi lled one or more of the following criteria:• Fatal bleed; symptomatic intracranial

bleed; reduction in hemoglobin of at least 50 grams per litre; transfusion of at least 4 units of blood or packed cells; a bleed associated with hypotension requiring the use of intravenous inotropic agents; a bleed that necessitated surgical intervention.

Clinical Trial Adverse Drug Reactions:Because clinical trials are conducted under very specifi c conditions, the adverse reaction rates observed in the clinical trials may not refl ect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 3: Common Adverse Reactions observed in 1% of dabigatran-treated patients with atrial fi brillation in the active- controlled trial, RELY

Dabigatran etexilate 110 mg N (%)

Dabigatran etexilate 150 mg N (%)

Warfarin N (%)

5,983 (100) 6,059 (100) 5,998 (100)

Bleeding and anemia* 599 (10.0) 747 (12.3) 825 (13.8)

Anemia 73 (1.2) 97 (1.6) 74 (1.2)

Epistaxis 66 (1.1) 67 (1.1) 107 (1.8)

Gastrointestinal hemorrhage

196 (3.3) 277 (4.6) 155 (2.6)

Urogenital hemorrhage 66 (1.1) 84 (1.4) 96 (1.6)

Gastrointestinal disorders* 735 (12.3) 772 (12.7) 220 (3.7)

Abdominal pain 135 (2.3) 134 (2.2) 15 (0.3)

Diarrhea 75 (1.3) 71 (1.2) 11 (0.2)

Dyspepsia 250 (4.2) 234 (3.9) 13 (0.2)

Nausea 58 (1.0) 73 (1.2) 12 (0.2)

* Aggregate incidence presented for all adverse reactions within the body system, including those reactions occurring <1% and not listed in the Table above.Gastrointestinal adverse reactions occurred more often with dabigatran etexilate than warfarin. These were related to dyspepsia (including upper abdominal pain, abdominal pain, abdominal discomfort, epigastric discomfort), or gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, gastrointestinal ulcer). Gastrointestinal (GI) hemorrhage occurred at a higher frequency with PRADAX compared to warfarin (see Table 3). GI adjudicated major bleeds were reported at 1.1%, 1.6%, and 1.1% (annualized rates) in the DE 110 mg, DE 150 mg and warfarin groups, respectively. GI life-threatening bleeds occurred with a frequency of 0.6%, 0.8% and 0.5% in the DE 110 mg, DE 150 mg and warfarin groups, respectively. Any GI bleeds occurred with a frequency of 5.4%, 6.1% and 4.0% in the DE 110 mg, DE 150 mg and warfarin groups, respectively. The underlying mechanism of the increased rate of GI bleeding has not been established (see CLINICAL TRIALS, Prevention of stroke and systemic embolism in patients with atrial fi brillation). Allergic reactions or drug hypersensitivity including urticaria, bronchospasm, rash and pruritus have been reported in patients who received dabigatran etexilate. Rare cases of anaphylactic reactions have also been reported.

Less Common Clinical Trial Adverse Drug Reactions (<1%)Observed with exposure to dabigatran 110 mg bid and 150 mg bid during the RELY trial, an active-controlled clinical trial for the prevention of stroke and systemic embolism in patients with atrial fi brillation:

Blood and lymphatic system disorders: thrombocytopeniaVascular disorders: hematoma, hemorrhageGastrointestinal disorders: gastrointestinal ulcer, gastroesophagitis, gastro-esophageal refl ux disease, vomiting, dysphagiaHepatobiliary disorders: hepatic function abnormal/liver function test abnormal, hepatic enzyme increasedSkin and subcutaneous tissue disorders: skin hemorrhage, urticaria, rash, pruritusMusculoskeletal and connective tissue and bone disorders: hemarthrosisRenal and urinary disorders: hematuriaGeneral disorders and administration site conditions: injection site hemorrhage, catheter site hemorrhageInjury, poisoning and procedural complications: incision site hematoma, traumatic hematoma, incision site hemorrhageImmune system disorder: drug hypersensitivityRespiratory disorders: hemoptysis, bronchospasmNervous system disorders: intracranial hemorrhage

For abnormal liver function tests reported in the RE-LY trial, please see Table 5.To report an adverse event, contact your Regional Adverse Reaction Monitoring Offi ce

at 1-866-234-2345, or contact: Boehringer Ingelheim (Canada) Ltd., 5180 South Service Rd., Burlington, ON L7L 5H4.

DRUG INTERACTIONSBased on in vitro evaluation, neither dabigatran etexilate nor its active moiety, dabigatran, have been shown to be metabolized by the human cytochrome P450 system, nor did they exhibit effects on human CYP P450 isozymes.Concomitant use of PRADAX with treatments that interfere with hemostasis or coagulation increases bleeding risk (see WARNINGS AND PRECAUTIONS, Bleeding). Co-administration of PRADAX with other anticoagulants has not been adequately studied and is not recommended. In the RELY trial, conducted in patients with atrial fi brillation, a two-fold increase in major bleeding was seen in both dabigatran study treatment arms, as well as that of the comparator, warfarin, when ASA was administered concomitantly (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions in the Product Monograph; CLINICAL TRIALS, Stroke Prevention in Atrial Fibrillation; and DOSAGE AND ADMINISTRATION).

Drug-Drug InteractionsTransporter interactions: Dabigatran etexilate, but not dabigatran, is a substrate with moderate affi nity for the effl ux P-glycoprotein (P-gp) transporter. Therefore, potent P-glycoprotein inducers or inhibitors may be expected to impact exposure to dabigatran.P-glycoprotein inhibitors: P-gp inhibitors like verapamil, quinidine and amiodarone may be expected to increase systemic exposure to dabigatran, see Table 4 below. The strong P-glycoprotein inhibitor ketoconazole, when administered orally, is contraindicated (see CONTRAINDICATIONS). If not otherwise specifi cally described, close clinical surveillance (looking for signs of bleeding or anemia), along with a sense of caution is required when dabigatran is co-administered with strong P-glycoprotein inhibitors.P-glycoprotein inducers: The concomitant use of PRADAX with the strong P-gp inducer rifampicin, reduces dabigatran plasma concentration. Other P-gp inducers such as carbamazepine and St John’s Wort are also expected to reduce the systemic exposure of dabigatran. Less potent inducers such as tenofovir can potentially reduce systemic exposure. Caution is advised when co-administering these drug products. P-glycoprotein substrates: Dabigatran etexilate is not expected to have a clinically meaningful interaction with P-glycoprotein substrates that do not also act as inhibitors or inducers of P-gp.


Table 4: Summary of Drug-Drug InteractionsProper name Ref* Effect Clinical comment

Amiodarone CT Dabigatran exposure in healthy subjects was increased by 60% in the presence of amiodarone (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions).

Adjust dosing for patients treated for prevention of VTE after hip- or knee-replacement surgery to 150 mg daily PRADAX with amiodarone. Caution should be exercised.

No dose adjustment is generally recommended for AF patients. Use with caution. Occasional testing of aPTT may be considered to rule out excessive anticoagulant effect.

Antacids (aluminium compounds, sodium bicarbonate, calcium and/or magnesium compounds, or combinations of these)

CT In population PK analyses, a reduction in dabigatran exposure by 35% was seen over the fi rst 24 hours following surgery. Thereafter, (>24 hours after surgery), a reduction of about 11% was observed.

Diminished clinical effect may occur, as may be expected for any drug resulting in an increase in gastric pH during PRADAX administration. PRADAX should be administered at least 2 hours before taking an antacid. Co-administration with PRADAX should be avoided within 24 hours after orthopedic surgery.

Atorvastatin CT When dabigatran etexilate was co-administered with atorvastatin, exposure of atorvastatin, and atorvastatin metabolites were not signifi cantly changed. Dabigatran concentrations were decreased about 20%.

No dose adjustment is recommended.

Clarithromycin CT Dabigatran exposure in healthy subjects was increased by about 15% in the presence of clarithromycin (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions).

No dose adjustment is recommended. Caution should be exercised.

Diclofenac CT When dabigatran etexilate was co-administered with diclofenac, pharmacokinetics of both drugs appeared unchanged.

No dose adjustment is recommended.Use with caution (see WARNINGS AND PRECAUTIONS, Bleeding, Table 2.)

Digoxin CT When dabigatran etexilate was co-administered with digoxin, no PK-interaction was observed.

No dose adjustment isrecommended.

Ketoconazole CT Dabigatran exposure was increased 150% after single and multiple doses of ketoconazole (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions).

Co-administration with PRADAX is contraindicated.(see CONTRAINDICATIONS).

Pantoprazole CT When dabigatran etexilate was co-administered with pantoprazole, a decrease in dabigatran AUC of about 30 % was observed. In the Phase III study, RELY, PPI co-medication did not result in lower trough levels and on average only slightly reduced post-dose concentrations (-11%) (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions).

No dose adjustment is recommended. Diminished clinical effect may occur, as may be expected for any drug resulting in an increase in gastric pH during PRADAX administration.

Rifampicin CT After 7 days of treatment with 600 mg rifampicin qd total dabigatran AUC0- and Cmax were reduced by 67% and 66% compared to the reference treatment, respectively (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions).

Concomitant use of PRADAX with rifampicin should, in general, be avoided. Concomitant use would be expected to result in substantially diminished anticoagulant effect of PRADAX.

Verapamil CT When dabigatran etexilate, given at 150 mg once daily, was co-administered with moderate doses of oral verapamil, the Cmax and AUC of dabigatran were increased, but the magnitude of this change varied depending on the timing of administration and the formulation of verapamil used (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic Interactions)

Dosing should be reduced to 150 mg PRADAX daily in patients treated for prevention of VTE after hip- or knee-replacement surgery who concomitantly receive dabigatran etexilate and verapamil. To minimize potential for interaction, PRADAX should be given at least two hours before verapamil.Caution should be exercised.

Although no dose adjustment is recommended for AF patients, to minimize potential for interaction, PRADAX should be given at least two hours before verapamil.Caution should be exercised.

Quinidine CT Dabigatran exposure in healthy subjects was increased by 53 % in the presence of quinidine.

Adjust dosing for patients treated for prevention of VTE after hip- or knee-replacement surgery to 150 mg daily PRADAX.Caution should be exercised.

Although no dose adjustment is recommended for AF patients, to minimize potential for interac-tion, PRADAX should be given at least two hours before quinidine, if possible.Caution should be exercised.

*C = Case Study; CT = Clinical Trial; T = Theoretical

Drug-Food InteractionsFood does not affect the bioavailability of PRADAX but delays the time-to-peak plasma concentrations by 2 hours.

Drug-Herb InteractionsDrug-herb interactions have not been investigated. Potent P-gp inducers such as St. John’s Wort (Hypericum perforatum) may be expected to affect systemic exposure of dabigatran. Co-administration of these products is not recommended.

Drug-Laboratory InteractionsNo single test (aPTT, TT, ECT) is adequate to reliably assess the anticoagulant activity of dabigatran following PRADAX administration. At therapeutic levels of dabigatran, thrombin time (TT) is the best measure of the pharmacodynamic effect of dabigatran because of its linear and sensitive relationship with dabigatran exposure (WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests; ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, in the Product Monograph).The aPTT test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. In patients who are bleeding, the aPTT test may be useful to assist in determining an excess of anticoagulant activity, despite its limited sensitivity. An aPTT greater than 80 sec at trough (when the next dose is due) is associated with a higher risk of bleeding. Note that a PT (INR) test is not useful to assess the anticoagulant activity of PRADAX.

Drug-Lifestyle InteractionsNo direct interaction between dabigatran etexilate and alcohol was demonstrated in animal models or has been hypothesized. The effect of PRADAX on the ability to drive and use machines has not been investigated. However, no such interaction is to be expected.

v Administration

DOSAGE AND ADMINISTRATIONPRADAX should be taken orally, with the entire capsule to be swallowed whole. The capsule should not be chewed, broken, or opened.PRADAX should be taken regularly, as prescribed, to ensure optimal effectiveness. All temporary discontinuations should be avoided, unless medically indicated.

Recommended Dose and Dosage Adjustment• Prevention of stroke and systemic embolism

in patients with atrial fi brillation: The recommended dose of PRADAX is 300 mg daily, taken orally as one 150 mg capsule twice a day.

Elderly:• Prevention of stroke and systemic embolism

in patients with atrial fi brillation: Patients aged 80 years and above should be treated with a dose of 220 mg of PRADAX daily, taken orally as one 110 mg capsule twice a day (see WARNINGS AND PRECAUTIONS, Geriatrics, and CLINICAL TRIALS, Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation, Tables 24 and 25, in the Product Monograph).

• The usual recommended dose for most geriatric patients under the age of 80 years is 300 mg daily, taken orally as one 150 mg

capsule twice a day (see CLINICAL TRIALS, Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation, Tables 24 and 25, in the Product Monograph). However, in geriatric patients, especially those over the age of 75 with at least one other risk factor for bleeding (see WARNINGS AND PRECAUTIONS, Bleeding, Table 2), the administration of a dose of 220 mg of PRADAX daily, taken orally as one 110 mg capsule twice a day, may be considered. It should be noted, however, that the effectiveness of stroke prevention may be expected to be lessened with this dosage regimen, compared to that of the usual one of 300 mg of PRADAX daily. As with any anticoagulant, caution is required when prescribing PRADAX to the elderly (see CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS, Bleeding).

Patients at risk of bleeding: Prevention of stroke and systemic embolism in patients with atrial fi brillation: Patients with an increased risk of bleeding (see WARNINGS AND PRECAUTIONS, Bleeding, Table 1), should be closely monitored clinically (looking for signs of bleeding or anemia). In such patients, a dose of 220 mg, given as 110 mg twice daily may be considered. A coagulation test, such as aPTT (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests), may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure. As for any anticoagulant, PRADAX is NOT indicated in patients at excessive risk of bleeding (see CONTRAINDICATIONS).Renal impairment: Following oral dosing with dabigatran etexilate, there is a direct correlation of systemic exposure to dabigatran with degree of renal impairment (see WARNINGS AND PRECAUTIONS, Renal). The kidneys account for 85% of dabigatran clearance.There are no data to support use in patients with severe renal impairment (CrCl <30 mL /min). Given the substantial increase in dabigatran exposure observed in this patient population, treatment with PRADAX is not recommended (see CONTRA-INDICATIONS, and ACTION AND CLINICAL PHARMACOLOGY, Renal Insuffi ciency). • Patients with atrial fi brillation treated for

prevention of stroke and systemic embolism having moderate renal impairment (CrCl 30-50 mL/min): No dose adjustment is recommended (see CLINICAL TRIALS, Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation, Renal Impairment). Patients with moderate renal impairment (CrCl 30-50 mL/min) should be treated with a daily dose of PRADAX at 300 mg taken orally as one 150 mg capsule twice daily, with


caution. Regular assessment of renal status is required in these patients (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Renal). A coagulation test, such as aPTT (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests), may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure.

Creatinine clearance can be estimated using the Cockroft-Gault formula as follows:Creatinine clearance (mL/min) =

Males: (140-age (years)) x weight (kg) 72 x serum creatinine (mg/100mL)

Females: 0.85 x (140-age (years)) x weight (kg) 72 x serum creatinine (mg/100mL)

P-glycoprotein inhibitors: P-gp inhibitors like verapamil, quinidine, and amiodarone may be expected to increase systemic exposure to dabigatran. Combination use with oral ketoconazole is contraindicated (see CONTRAINDICATIONS).• Patients with atrial fi brillation treated for

prevention of stroke and systemic embolism: No dose adjustment is recommended in patients concomitantly receiving amiodarone, quinidine or verapamil (see DRUG INTERACTIONS, Table 4, Summary of Drug-Drug Interactions; and ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic interactions in the Product Monograph). Patients should be treated with a daily dose of 300 mg PRADAX taken orally as one 150 mg capsule twice daily. To minimize potential for interaction, PRADAX should be given at least two hours before verapamil (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations, Pharmacokinetic interactions in the Product Monograph). Caution should be exercised. Close clinical surveillance is recommended.

Drugs that increase gastric pH, such as antacids, protein pump inhibitors (PPI): Diminished clinical effect for antacids may occur (see DRUG INTERACTIONS, Table 4, Summary of Drug-Drug Interactions). Although no dosage adjustment is generally necessary, administer PRADAX at least two hours before antacids, if possible, to minimize interaction potential. No dose adjustment is required for pantoprazole or other PPIs.Concomitant antithrombotic use:Concomitant use of ASA or clopidogrel with PRADAX in patients with atrial fi brillation approximately doubled the risk of major bleed, irrespective of dose of PRADAX used. A similar increase was noted with such concomitant use with the study comparator, warfarin. These observations contrasted with little apparent additional improvement in stroke and systemic embolic events with combined

antithrombotic use and PRADAX (or warfarin). Concomitant use of PRADAX with an antithrombotic is not recommended for prevention of cardiogenic thromboembolic stroke in patients with atrial fi brillation. Concomitant use of ASA or other antiplatelet agents based on medical need to prevent myocardial infarction should be undertaken with caution. Close clinical surveillance is recommended.Acute myocardial infarction (AMI):Consideration should be given to discontinuing PRADAX in the setting of acute myocardial infarction should the treatment of myocardial infarction involve invasive procedures, such as percutaneous coronary revascularization, or coronary artery bypass surgery. Similar consideration should be given if thrombolytic therapy is to be initiated, because bleeding risk may increase. Patients with AMI should be treated according to current clinical guidelines for that disorder. In this setting, PRADAX may be resumed for the prevention of stroke and systemic embolism upon completion of these revascularization procedures.Children: Since PRADAX has not been investigated in patients <18 years of age, treatment is not recommended.Patient Body Weight: Population PK modelling shows that patients with a body weight of about 120 kg have about 20% lower drug exposure. Patients with a body weight of about 48 kg have about 25% higher drug exposure compared to patients with average weight. No dose adjustment deemed necessary.Switching from PRADAX treatment to parenteral anticoagulant: • In patients with atrial fi brillation treated

for prevention of stroke and systemic embolism: wait 12 hours after the last dose of PRADAX before switching to a parenteral anticoagulant.

Switching from parenteral anticoagulants treatment to PRADAX: If deemed medically appropriate, treatment with PRADAX should be initiated 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g., intravenous unfractionated heparin, [UFH]).Switching from Vitamin K antagonists to PRADAX: If deemed medically appropriate, PRADAX should only be started after Vitamin K antagonists have been discontinued, and the patient’s INR is found to be below 2.0.Cardioversion: Patients can be maintained on PRADAX while being cardioverted.

Missed Dose: Prevention of stroke and systemic embolism in patients with atrial fi brillation: If the prescribed dose of PRADAX is not taken at the scheduled time, the dose should be taken as soon as possible on the

same day. A forgotten PRADAX dose may still be taken up to 6 hours prior to the next scheduled dose. From 6 hours prior to the next scheduled dose on, the missed dose should be omitted. Patients should not take a double dose to make up for missed individual doses. For optimal effect and safety, it is important to take PRADAX regularly twice a day, at approximately 12-hour intervals.

AdministrationPRADAX may be taken with food, or on an empty stomach with water.The capsule should be swallowed intact. It should not be opened, broken, or chewed (see ACTION AND CLINICAL PHARMACOLOGY in the full Product Monograph, Pharmacokinetics).

SUPPLEMENTAL PRODUCT INFORMATIONAdverse Reactions:Liver Function Tests: In the long-term RELY study, observed abnormalities of liver function tests (LFT) are presented below in Table 5.

Table 5: Liver Function Tests in the RELY trialDabigatran etexilate 110 mg twice daily

N (%)

Dabigatran etexilate 150 mg twice daily

N (%)

Warfarin N (%)

Total treated 5,983 (100.0) 6,059 (100.0) 5,999 (100.0)

ALT or AST >3xULN 118 (2.0) 106 (1.7) 125 (2.1)

ALT or AST >5xULN 36 (0.7) 45 (0.7) 50 (0.8)

ALT or AST >3xULN + Bilirubin >2xULN

11 (0.2) 14 (0.2) 21 (0.4)

OVERDOSAGEThere is no antidote to dabigatran etexilate or dabigatran. Doses of PRADAX beyond those recommended expose the patient to increased risk of bleeding. Excessive anticoagulation may require discontinuation of PRADAX. In the event of hemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. Since dabigatran is excreted predominantly by the renal route, adequate diuresis must be maintained. Appropriate standard treatment, e.g., surgical hemostasis as indicated and blood volume replacement, should be undertaken. In addition, consideration may be given to the use of fresh whole blood or the transfusion of fresh frozen plasma.As protein binding is low, dabigatran can be dialysed, although there is limited clinical experience in using dialysis in this setting.Activated prothrombin complex concentrates (e.g., FEIBA) or recombinant Factor VIIa or concentrates of coagulation factors II, IX or X, may be considered. There is some experimental evidence to support the role of these agents in reversing the anticoagulant effect of dabigatran but their usefulness in clinical settings has not yet been clearly demonstrated. Consideration should also be given to administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used. All symptomatic treatment should be given according to the physician’s judgement.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Product Monograph is available upon request or at www.boehringer-ingelheim.ca

Boehringer Ingelheim (Canada) Ltd.5180 South Service RoadBurlington, ON L7L 5H4

PRADAX™ is a trademark of Boehringer Ingelheim Pharma GmnH & Co. KG, used under license by Boehringer Ingelheim (Canada) Ltd.

November 8, 2010


Prescribing Summary

Patient Selection Criteria

THERAPEUTIC CLASSIFICATION: Lipid Metabolism Regulator INDICATIONS AND CLINICAL USE: Hypercholesterolemia: CRESTOR (rosuvastatin calcium) is indicated as an adjunct to diet, at least equivalent to the Adult Treatment Panel III (ATP III TLC diet), for the reduction of elevated total cholesterol (Total-C), LDL-C, ApoB, the Total-C/HDL-C ratio and triglycerides (TG) and for increasing HDL-C; in hyperlipidemic and dyslipidemic conditions, when response to diet and exercise alone has been inadequate including:• Primary hypercholesterolemia (Type IIa including heterozygous familial hypercholesterolemia and

severe nonfamilial hypercholesterolemia)• Combined (mixed) dyslipidemia (Type IIb)• Homozygous familial hypercholesterolemia where CRESTOR is used either alone or as an adjunct to

diet and other lipid-lowering treatment such as apheresisPrevention of Major Cardiovascular Events: In adult patients without documented history of cardiovascular or cerebrovascular events, but with at least two conventional risk factors for cardiovascular disease (see CLINICAL TRIALS), CRESTOR is indicated to:• Reduce the risk of nonfatal myocardial infarction• Reduce the risk of nonfatal stroke• Reduce the risk of coronary artery revascularizationCONTRAINDICATIONS: CRESTOR (rosuvastatin calcium) is contraindicated:• In patients who are hypersensitive to any component of this medication• In patients with active liver disease or unexplained persistent elevations of serum transaminases

exceeding 3 times the upper limit of normal (see WARNINGS AND PRECAUTIONS)• In pregnant and nursing mothers (see SUPPLEMENTAL PRODUCT INFORMATION)• In patients using concomitant cyclosporine (see DRUG INTERACTIONS)CRESTOR 40 mg is contraindicated in:• Asian patients• Patients with predisposing factors for myopathy/rhabdomyolysis such as: • Personal or family history of hereditary muscular disorders • Previous history of muscle toxicity with another HMG-CoA reductase inhibitor • Concomitant use of a fibrate or niacin • Severe hepatic impairment • Severe renal impairment (CrCl < 30 mL/min/1.73 m2) (see ADMINISTRATION,

Patients with Renal Impairment) • Hypothyroidism • Alcohol abuse • Situations where an increase in rosuvastatin plasma levels may occur

Safety Information

WARNINGS AND PRECAUTIONS: Before instituting therapy with CRESTOR (rosuvastatin calcium), an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in overweight patients, and to treat other underlying medical problems and associated cardiovascular risk factors. The patient should be advised to inform subsequent physicians of the prior use of CRESTOR or any other lipid-lowering agent.Co-enzyme Q10 (ubiquinone): Ubiquinone levels were not measured in CRESTOR clinical trials. Significant decreases in circulating ubiquinone levels in patients treated with other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure.Endocrine Function: HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Rosuvastatin demonstrated no effect upon nonstimulated cortisol levels and no effect on thyroid metabolism as assessed by TSH plasma concentration. In CRESTOR-treated patients, there was no impairment of adrenocortical reserve and no reduction in plasma cortisol concentrations. Clinical studies with other HMG-CoA reductase inhibitors have suggested that these agents do not reduce plasma testosterone concentration. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Patients treated with rosuvastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g., ketoconazole, spironolactone or cimetidine) that may decrease the levels of endogenous steroid hormones.Plasma Glucose: In the JUPITER trial, rosuvastatin 20 mg was observed to increase plasma glucose

levels, which were sufficient to shift some prediabetic subjects to the diabetes mellitus status (see ADVERSE REACTIONS).Lipoprotein(a): In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in the Lipoprotein(a) [LP(a)] concentrations. Present knowledge suggests the importance of high LP(a) levels as an emerging risk factor for coronary heart disease. It is thus desirable to maintain and reinforce lifestyle changes in high-risk patients placed on rosuvastatin therapy.Hepatic Effects: CRESTOR is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal.As with other HMG-CoA reductase inhibitors, it is recommended that a liver function test be carried out prior to, and 3 months following, the initiation of CRESTOR or if the patient is titrated to the dose of 40 mg. CRESTOR should be discontinued or the dose reduced if the level of transaminases is greater than 3 times the upper limit of normal.CRESTOR, as well as other HMG-CoA reductase inhibitors, should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin (< 0.5%); the majority of cases were mild, asymptomatic and transient.Hepatic Impairment: In subjects with varying degrees of hepatic impairment there was no evidence of increased exposure to rosuvastatin other than in 2 subjects with the most severe liver disease (Child-Pugh scores of 8 and 9). In these subjects, systemic exposure was increased by at least 2-fold compared to subjects with lower Child-Pugh scores (see ADMINISTRATION, Patients with Hepatic Impairment).Muscle Effects: Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with CRESTOR and with other HMG-CoA reductase inhibitors.Effects on skeletal muscle such as myalgia, myopathy and, rarely, rhabdomyolysis have been reported in patients treated with CRESTOR at all doses and in particular with the 40 mg dose.Myopathy, defined as muscle pain or muscle weakness in conjunction with increases in creatine kinase (CK) values to greater than ten times the upper limit of normal, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CK. Patients should be advised to report promptly any unexplained muscle pain, tenderness or weakness, particularly if associated with malaise or fever. Patients who develop any signs or symptoms suggestive of myopathy should have their CK levels measured. CRESTOR therapy should be discontinued if markedly elevated CK levels (> 10 x ULN) are measured or myopathy is diagnosed or suspected.Predisposing Factors for Myopathy/RhabdomyolysisCRESTOR, as with other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with predisposing factors for myopathy/rhabdomyolysis. Such factors include:• Personal or family history of • Age > 70 years hereditary muscular disorders • Renal impairment• Previous history of muscular • Hepatic impairment toxicity with another HMG-CoA • Diabetes with hepatic reductase inhibitor fatty change• Concomitant use of a fibrate • Surgery and trauma or niacin • Frailty• Hypothyroidism • Situations where an increase• Alcohol abuse in plasma levels of rosuvastatin• Excessive physical exercise may occurIn CRESTOR trials there was no evidence of increased skeletal muscle effects when CRESTOR was dosed with concomitant therapy such as fibric acid derivatives (including fenofibrate and gemfibrozil), nicotinic acid, azole antifungals and macrolide antibiotics. However, an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with these medicines.CRESTOR therapy should be temporarily withheld or discontinued in any patient with an acute serious condition suggestive of myopathy or predisposing to the development of rhabdomyolysis (e.g., sepsis, hypotension, major surgery, trauma, severe metabolic endocrine and electrolyte disorders, or uncontrolled seizures).Renal Impairment: Subjects with severe renal impairment (CrCl < 30 mL/min/1.73 m2) had a 3-fold increase in plasma concentration of rosuvastatin compared to healthy volunteers and, therefore, CRESTOR 40 mg is contraindicated in these patients (see CONTRAINDICATIONS and ADMINISTRATION, Patients with Renal Impairment). In subjects with varying degrees of renal impairment, mild to moderate renal disease had little influence on plasma concentrations of rosuvastatin.During the clinical development program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin-treated patients, predominantly in patients dosed above the recommended dose range (i.e., 80 mg). Abnormal urinalysis testing (dipstick-positive proteinuria) has been seen in patients taking CRESTOR and other HMG-CoA reductase inhibitors. This finding was more frequent in patients taking 40 mg when compared to lower doses of rosuvastatin or comparator statins. Shifts in urine protein from none or trace to ++ (dipstick) or more were seen in < 1% of patients at some time during treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg. The protein detected was mostly tubular in origin. In most cases, proteinuria was


generally transient and it decreased or disappeared spontaneously on continued therapy. It has not been shown to be predictive of acute or progressive renal disease.Nevertheless, a dose reduction may be considered for patients with unexplained persistent proteinuria during routine testing.Hypersensitivity: An apparent hypersensitivity syndrome has been reported rarely with other HMG-CoA reductase inhibitors. This has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive antinuclear antibody (ANA), erythrocyte sedimentation rate (ESR) increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme including Stevens-Johnson syndrome. Treatment should be discontinued if hypersensitivity is suspected (see CONTRAINDICATIONS).Special PopulationsPregnant Women: CRESTOR is contraindicated during pregnancy (see CONTRAINDICATIONS).Nursing Women: It is not known whether rosuvastatin is excreted in human milk. Because of the potential for adverse reactions in nursing infants, women taking CRESTOR should not breastfeed (see CONTRAINDICATIONS).Pediatrics (≤ 18 years of age): Treatment experience with CRESTOR in a pediatric population is limited to 8 patients with homozygous familial hypercholesterolemia. None of these patients was below 8 years of age (see ADMINISTRATION, Use in Children).Geriatrics (≥ 65 years of age): There were no clinically significant pharmacokinetic differences between young and elderly patients (≥ 65 years) (see ADMINISTRATION, Use in Elderly). However, elderly patients may be more susceptible to myopathy (see WARNINGS AND PRECAUTIONS, Muscle Effects, Predisposing Factors for Myopathy/Rhabdomyolysis).Race: Results of pharmacokinetic studies, including a large study conducted in North America, have demonstrated an approximate 2-fold elevation in median exposure in Asian subjects (having either Filipino, Chinese, Japanese, Korean, Vietnamese or Asian-Indian origin) when compared with a Caucasian control group. This increase should be considered when making rosuvastatin dosing decisions for Asian patients and the dose of 40 mg is contraindicated in these patients (see CONTRAINDICATIONS and ADMINISTRATION, Race).ADVERSE REACTION SERIOUSNESS AND INCIDENCE: CRESTOR (rosuvastatin calcium) is generally well tolerated. The adverse events seen with CRESTOR are generally mild and transient. CRESTOR clinical trial experience is extensive, involving 9800 patients treated with CRESTOR in placebo-controlled trials and 9855 patients treated with CRESTOR in active-controlled clinical trials. Discontinuation of therapy due to adverse events occurred in 2.6% of patients receiving CRESTOR and 1.8% of patients receiving placebo. The most frequently reported adverse events at an incidence of ≥ 1% and at a rate greater than placebo were arthralgia, upper abdominal pain and ALT increase. See SUPPLEMENTAL PRODUCT INFORMATION. Abnormal Hematologic and Clinical Chemistry Findings: As with other HMG-CoA reductase inhibitors, a dose-related increase in liver transaminases and CK has been observed in a small number of patients taking rosuvastatin (see WARNINGS AND PRECAUTIONS, Hepatic Effects, Muscle Effects).Abnormal urinalysis testing (dipstick-positive proteinuria) has been seen in a small number of patients taking CRESTOR and other HMG-CoA reductase inhibitors. The protein detected was mostly tubular in origin. In most cases, proteinuria decreases or disappears spontaneously on continued therapy, and is not predictive of acute or progressive renal disease (see WARNINGS AND PRECAUTIONS, Renal Impairment).In the JUPITER trial, occurrences of diabetes mellitus as a pre-specified secondary outcome were reported more frequently in the CRESTOR-treated patients (2.8%) than in placebo (2.3%) and a slight increase in the number of subjects whose fasting glucose levels increased to ≥ 5.6 mmol/L (126 mg/dL) was observed in subjects treated with CRESTOR. There was a 0.1% increase in mean HbA1c with CRESTOR compared to placebo. A causal relationship with statins and diabetes mellitus has not been definitely established.Postmarket Adverse Drug Reactions: In addition to the events reported above, the following adverse events have been reported during postmarketing experience with CRESTOR, regardless of causality assessment.• Skeletal muscle effects: Very rare: arthralgiaIt has been observed that as with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis in postmarketing use is higher at the highest marketed dose (see WARNINGS AND PRECAUTIONS, Muscle Effects).• Hepatobiliary disorders: Very rare: jaundice, hepatitis• Nervous system disorders: Very rare: memory loss• Other: Rare: pancreatitis; Very rare: gynecomastiaDRUG INTERACTIONS: In CRESTOR (rosuvastatin calcium) clinical trials, there was no evidence of increased skeletal muscle effects when rosuvastatin was dosed with any concomitant therapy. However, CRESTOR and other HMG-CoA reductase inhibitors may cause dose-related increases in serum transaminases and CK levels. An increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors with cyclosporine, fibric acid derivatives (including gemfibrozil), nicotinic acid, azole antifungals and macrolide antibiotics.Cytochrome P450 Inhibitors: In vitro and in vivo data indicate that rosuvastatin has no clinically significant cytochrome P450 interactions (as substrate, inhibitor or inducer). Consequently, there is

little potential for drug-drug interactions upon coadministration with agents that are metabolized by cytochrome P450. Rosuvastatin clearance is not dependent on metabolism by cytochrome P450 3A4 to a clinically significant extent. This has been confirmed in studies with known cytochrome P450 3A4 inhibitors (ketoconazole, erythromycin, itraconazole).Concomitant Therapy with Other Lipid Metabolism Regulators: Coadministration of fenofibrate and CRESTOR 10 mg did not lead to a clinically significant change in the plasma concentrations of either drug. In addition, neither myopathy nor marked CK elevations (> 10 x ULN) were observed in a study of 128 patients who received CRESTOR 10, 20 and 40 mg plus extended-release niacin or in a second study of 103 patients who received CRESTOR 5 and 10 mg plus fenofibrate. Based on the above data, no pharmacokinetic or pharmacodynamic interaction was observed. No data is available with other fibrates.Based on postmarketing surveillance, gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses of niacin (nicotinic acid) may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors, probably because they can produce myopathy when given alone (see WARNINGS AND PRECAUTIONS, Muscle Effects, Predisposing Factors for Myopathy/Rhabdomyolysis). Therefore, combined drug therapy should be approached with caution.Lopinavir/Ritonavir: In a pharmacokinetic study, coadministration of CRESTOR and a combination product of two protease inhibitors (400 mg lopinavir/100 mg ritonavir) in healthy volunteers was associated with an approximately 2-fold and 5-fold increase in rosuvastatin steady-state AUC(0-24) and Cmax, respectively.Increased systemic exposure to rosuvastatin has been observed in subjects receiving CRESTOR with various protease inhibitors in combination with ritonavir. Consideration should be given to both the benefit of lipid lowering by the use of CRESTOR in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up-titrating CRESTOR doses in patients treated with protease inhibitors (see WARNINGS AND PRECAUTIONS, Muscle Effects, Predisposing Factors for Myopathy/Rhabdomyolysis).Concomitant Therapies Without Clinically Significant Interactions: See SUPPLEMENTAL PRODUCT INFORMATION.Drug-Drug Interactions: See SUPPLEMENTAL PRODUCT INFORMATION.Drug-Food Interactions: CRESTOR can be taken with or without food (see ADMINISTRATION).You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways:Report online at www.healthcanada.gc.ca/medeffectCall toll-free at 1-866-234-2345Complete a Canada Vigilance Reporting Form and: Fax toll-free to 1-866-678-6789, or Mail to: Canada Vigilance Program

Health Canada Postal Locator 0701C Ottawa, ON K1A 0K9

Postage-paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect™ Canada website at www.healthcanada.gc.ca/medeffect.NOTE: Should you require information related to the management of side effects, contact your health professional. The Canada Vigilance Program does not provide medical advice.

Administration

Patients should be placed on a standard cholesterol-lowering diet (at least equivalent to the Adult Treatment Panel III (ATP III TLC diet)) before receiving CRESTOR (rosuvastatin calcium) and should continue on this diet during treatment with CRESTOR. If appropriate, a program of weight control and physical exercise should be implemented.Prior to initiating therapy with CRESTOR, secondary causes for elevations in plasma lipid levels should be excluded. A lipid profile should also be performed.CRESTOR may be taken in the morning or evening, with or without food.Recommended Dose and Dosage Adjustment Hypercholesterolemia: The dose range of CRESTOR is 5 to 40 mg orally once a day. The recommended starting dose of CRESTOR in most patients is 10 mg orally once daily. The majority of patients are controlled at the 10 mg dose. If necessary, dose adjustment can be made at 2- to 4-week intervals. The maximum response is usually achieved within 2-4 weeks and is maintained during chronic therapy.Initiation of therapy with CRESTOR 5 mg once daily may be considered for patients requiring less aggressive LDL-C reductions or who have predisposing factors for myopathy (see WARNINGS AND PRECAUTIONS, Muscle Effects). Patients who are switched to CRESTOR from treatment with another HMG-CoA reductase inhibitor should be started on 10 mg even if they were on a high dose of the previous HMG-CoA reductase inhibitor. A switch dose of 20 mg may be considered for patients with severe hypercholesterolemia.For patients with severe hypercholesterolemia (including those with familial hypercholesterolemia), a 20 mg start dose may be considered. These patients should be carefully followed.A dose of 40 mg once daily should only be used in patients with severe hypercholesterolemia who


do not achieve their target treatment on 20 mg and have no predisposing factors for myopathy/rhabdomyolysis (see CONTRAINDICATIONS). Consultation with a specialist is recommended when initiating the CRESTOR 40 mg dose.The dosage of CRESTOR should be individualized according to baseline LDL-C, Total-C/HDL-C ratio and/or TG levels to achieve the recommended desired lipid values at the lowest possible dose.Prevention of Major Cardiovascular Events: A dose of 20 mg once daily has been found to reduce the risk of major cardiovascular events (see CLINICAL TRIALS).Dosing Considerations in Special PopulationsPatients with Hepatic Impairment: The usual dose range applies in patients with mild to moderate hepatic impairment. Increased systemic exposure has been observed in patients with severe hepatic impairment and, therefore, in these patients the dose of CRESTOR should not exceed 20 mg once daily (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Hepatic Impairment).Patients with Renal Impairment: The usual dose range applies in patients with mild to moderate renal impairment. Increased systemic exposure to rosuvastatin has been observed in patients with severe renal impairment. For patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m2), the starting dose of CRESTOR should be 5 mg and not exceed 10 mg once daily (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Renal Impairment).Race: The initial dose of CRESTOR, in Asian patients, should be 5 mg once daily. The potential for increases in systemic exposure must be considered when making treatment decisions. The maximum dose should not exceed CRESTOR 20 mg once daily (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Special Populations, Race).Use in Children: Pediatric experience is limited to a very small number of children (aged 8 years and above) with homozygous familial hypercholesterolemia. Use in children should be supervised by specialists (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics).Use in Elderly: No dose adjustment is necessary in the elderly (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).Concomitant Therapy: See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS.SUPPLEMENTAL PRODUCT INFORMATIONCONTRAINDICATIONS: Pregnant and nursing mothers: Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). CRESTOR should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the possible harm. If the patient becomes pregnant while taking CRESTOR, the drug should be discontinued immediately and the patient apprised of the potential harm to the fetus. Atherosclerosis being a chronic process, discontinuation of lipid metabolism-regulating drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women, Nursing Women).ADVERSE REACTIONS: Adverse events observed or reported in short- and long-term trials are as follows.Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions, the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.Short-term Controlled Trials: Short-term controlled trials involved 1290 patients within placebo-controlled trials of 6 to 16 weeks’ duration (768 of which were treated with rosuvastatin) and 11,641 patients within placebo- and active-controlled clinical trials of 6 to 52 weeks’ duration (5319 of which were treated with rosuvastatin). In all controlled clinical trials, 3.2% of patients were withdrawn from CRESTOR therapy due to adverse events. This withdrawal rate was comparable to that reported in placebo-controlled studies.Associated adverse events occurring at an incidence ≥ 1% in patients participating in placebo-controlled clinical studies of rosuvastatin, are shown in Table 1.Table 1: Number (%) of Subjects with Associated Adverse Events Occurring with ≥ 1% Incidence in any Treatment Group: Placebo-Controlled Pool

Body system/Adverse event Placebo (%)(N=367)

Total rosuvastatin (%) (N=768)

Whole bodyAbdominal pain 2.2 1.7

Asthenia 0.5 1.3

Headache 2.2 1.4

DigestiveConstipation 1.4 1.0

Diarrhea 1.6 1.3

Dyspepsia 1.9 0.7

Flatulence 2.7 1.8

Nausea 1.6 2.2

MusculoskeletalMyalgia 0.5 1.6

Nervous systemDizziness 1.6 0.5

Insomnia 1.9 0.4

Long-term Controlled Morbidity and Mortality Trials: In the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluation Rosuvastatin (JUPITER) study involving 17,802 participants treated with CRESTOR 20 mg once daily (n=8901) or placebo (n=8901), CRESTOR 20 mg was generally well tolerated. Subjects were followed for a mean duration of 2 years.Discontinuation of therapy due to an adverse event occurred in 5.6% of subjects treated with CRESTOR and 5.5% of subjects treated with placebo. The most common adverse events that led to discontinuation from the study were: myalgia, arthralgia, abdominal pain and constipation. The associated adverse reaction reported in ≥ 1% of patients and at a rate greater than or equal to placebo was myalgia (2.4% CRESTOR, 2.0% placebo).Treatment emergent adverse events regardless of causality occurring at an incidence ≥ 1% and at a rate greater than placebo in patients participating in the JUPITER trial are shown in Table 2.

Table 2: Number (%) of Subjects with Treatment Emergent Adverse Events Regardless of Causality Occurring with ≥ 1% Incidence and > than Placebo: JUPITER


Total rosuvastatin 20 mg (%) (N=8901)

BloodAnemia 2.1 2.2

CardiacPalpitations 0.9 1.0


Total rosuvastatin 20 mg (%) (N=8901)

GastrointestinalDiarrhea 4.6 4.7

Constipation 3.0 3.3

Nausea 2.3 2.4

General disordersEdema peripheral 3.0 3.7

Fatigue 3.5 3.7

HepatobiliaryCholelithiasis 0.9 1.0

InfectionsUrinary tract 8.6 8.7

Nasopharyngitis 7.2 7.6

Bronchitis 7.1 7.2

Sinusitis 3.7 4.0

Influenza 3.6 4.0

Lower respiratory tract 2.7 2.9

Gastroenteritis 1.7 1.9

Herpes zoster 1.4 1.6

InjuryContusion 1.4 1.7

InvestigationALT increased 1.0 1.4

Blood glucose increased 0.7 1.0

MetabolismDiabetes mellitus 2.5 3.0

MusculoskeletalBack pain 6.9 7.6

Myalgia 6.6 7.6

Arthritis 5.6 5.8

Arthralgia 3.2 3.8

Muscle spasms 3.2 3.6

Osteoarthritis 1.4 1.8

Bursitis 1.3 1.5

Neck pain 1.0 1.1

Osteoporosis 0.8 1.0

NeoplasmsBasal cell carcinoma 0.9 1.0

PsychiatricInsomnia 2.3 2.5

RenalHematuria 2.0 2.4

Proteinuria 1.3 1.4

RespiratoryEpistaxis 0.8 1.0

Less Common Clinical Trial Adverse Drug Reactions (< 1%): The frequency of adverse events in all clinical trials and considered possibly, probably or definitely drug-related are as follows:• Uncommon (≥ 0.1% and < 1%): Pruritus, rash, urticaria, arthralgia, muscle weakness, arthritis, constipation, nausea, dyspepsia, gastroesophageal reflux disease, ALT increase, creatine phosphokinase increase, hepatic enzyme increase, creatinine increase, paraesthesia, tremor, general pain, proteinuria, sinusitis, insomnia, abnormal hepatic function, vertigo, diabetes mellitus

• Rare (≥ 0.01% and < 0.1%): Myopathy (including myositis), rhabdomyolysis and hypersensitivity reactions including angioedemaThe following additional adverse events were reported in controlled clinical trials, regardless of causality: Accidental injury, back and chest pain, flu syndrome, infection, urinary tract infection, diarrhea, flatulence, gastroenteritis, hypertonia, bronchitis, increased cough, rhinitis and pharyngitis.In long-term controlled clinical trials, CRESTOR was shown to have no harmful effect on the ocular lens.DRUG INTERACTIONS: Concomitant Therapies Without Clinically Significant InteractionsBile Acid Sequestrants: CRESTOR can be used in combination with bile acid sequestrants (e.g., cholestyramine).Ketoconazole: Coadministration of ketoconazole with CRESTOR resulted in no change in plasma concentrations of rosuvastatin.Erythromycin: Coadministration of erythromycin with CRESTOR resulted in small decreases in plasma concentrations of rosuvastatin. These reductions were not considered clinically significant.Itraconazole: Coadministration of itraconazole with CRESTOR resulted in a 28% increase in the AUC of rosuvastatin. This small increase was not considered clinically significant.Fluconazole: Coadministration of fluconazole with CRESTOR resulted in a 14% increase in the AUC of rosuvastatin. This small increase was not considered clinically significant.Digoxin: Coadministration of digoxin and CRESTOR did not lead to any clinically significant interactions.Other Drugs: Although specific interaction studies were not performed, CRESTOR has been studied in over 5300 patients in clinical trials. Many patients were receiving a variety of medications including antihypertensive agents (beta-adrenergic blocking agents, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and diuretics), antidiabetic agents (biguanides, sulfonylureas, alpha glucosidase inhibitors, and thiazolidinediones), and hormone replacement therapy without evidence of clinically significant adverse interactions.Drug-Drug Interactions: The drugs listed in Table 3 are based on either drug interaction case reports or studies or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 3: Established or Potential Drug-Drug Interactions

Proper name Effect Clinical comment

Gemfibrozil Coadministration of a single rosuvastatin dose (10 mg) to healthy volunteers on gemfibrozil (600 mg BID) resulted in a 2.2- and 1.9-fold increase in mean Cmax and mean AUC of rosuvastatin, respectively.

Patients taking this combination should not exceed a dose of CRESTOR 20 mg once daily and the concomitant use of CRESTOR 40 mg once daily is contraindicated.


Proper name Effect Clinical comment

Coumarinanticoagulants

As with other HMG-CoA reductase inhibitors, coadministration of CRESTOR and coumarin (e.g., warfarin) may result in a rise in International Normalized Ratio (INR) compared to coumarin alone. In healthy subjects, the coadministration of rosuvastatin 40 mg (10 days) and warfarin 25 mg (single dose) produced a higher mean maxINR and AUC-INR than achieved with warfarin alone. Coadministration of CRESTOR 10 and 80 mg to patients on stable warfarin therapy resulted in clinically significant rises in INR (> 4, baseline 2-3). The mechanism for this effect is unknown, but is likely due to a pharmacodynamicinteraction with warfarin rather than a pharmacokinetic interaction as no relevant differences in the pharmacokinetics of either drug was observed.

In patients taking coumarin, monitoring of INR is recommended at initiation or cessation of therapy with rosuvastatin or following dose adjustment. Rosuvastatin therapy has not been associated with bleeding or changes in INR in patients not taking anticoagulants.

Antacids Simultaneous dosing of CRESTOR with an antacid suspension containing aluminum and magnesium hydroxide resulted in a decrease of rosuvastatin plasma concentration by approximately 50%.

The clinical relevance of this interaction has not been studied. However, the effect was mitigated when the antacid was dosed 2 hours after CRESTOR. This interaction should not be clinically relevant in patients using this type of antacid infrequently. A frequent antacid user should be instructed to take CRESTOR at a time of day when they are less likely to need the antacid.

Oral contraceptives When CRESTOR 40 mg was coadministered with a representative oral contraceptive (ethinyl estradiol [35 µg] and norgestrel [180 µg on days 1 to 7, 215 µg on days 8 to 15, and 250 µg on days 16 to 21]), no reduction in contraceptive efficacy was observed. An increase in plasma concentrations (AUC) of ethinyl estradiol (26%) and norgestrel (34%) occurred.

These increased plasma levels should be considered when selecting oral contraceptive doses.

Immunosuppressants (including cyclosporine)

CRESTOR 10 and 20 mg were administered to cardiac transplant patients (at least 6 months post-transplant) whose concomitant medication included cyclosporine, prednisone and azathioprine. Results showed that cyclosporine pharmacokinetics were not affected by rosuvastatin. However, cyclosporine did increase the systemic exposure of rosuvastatin by 11-fold (Cmax

) and 7-fold (AUC

(0-24)) compared with historical data in

healthy individuals.

The concomitant use of CRESTOR and cyclosporine is contraindicated (see CONTRAINDICATIONS).

CLINICAL TRIALS:HypercholesterolemiaThe following reductions in total cholesterol, LDL-C, TG, Total-C/HDL-C ratio and increases in HDL-C have been observed in a dose-response study, and may serve as a guide to treatment of patients with mild to moderate hypercholesterolemia:

Table 4: Dose Response in Patients with Mild to Moderate Hypercholesterolemia (Mean Percent Change from Baseline)

CRESTORdose

(mg/day)

N Total-C LDL-C TG HDL-C Total-C/HDL-C ratio

ApoB

Placebo 13 -5 -7 -3 3 -8 -3

5 17 -33 -45 -35 13 -41 -38

10 17 -36 -52 -10 14 -43 -42

20 17 -40 -55 -23 8 -44 -46

40 18 -46 -63 -28 10 -51 -54

Prevention of Major Cardiovascular EventsIn the JUPITER study (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin), 89,846 people with no pre-existing cardiovascular disease were screened and 17,802 (19.8%) were double-blindly randomized to CRESTOR 20 mg once daily (n=8901) or placebo (n=8901). The primary endpoint was a composite consisting of the time-to-first occurrence of any of the following cardiovascular events: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, unstable angina or an arterial revascularization procedure.

Figure 1: Time to First Occurrence of Major Cardiovascular Events

Cum

ulat

ive

inci

denc

e, %

Years

Number at risk

HR 0.56 (95% CI 0.46-0.69)

p<0.001

rosuvastatin 8901 8412 3892 1352 543 1568901 8353 3872 1333 534 173placebo

placebo rosuvastatin

0

1

2

3

4

5

6

7

8

9

0 1 2 3 4 5 6

The results of the primary composite endpoint and the individual components are presented in Table 5. CRESTOR significantly reduced the risk of nonfatal myocardial infarction (p<0.0001), nonfatal stroke (p=0.004) and arterial revascularization procedures (p=0.034). There were no statistically significant treatment differences between the CRESTOR and placebo groups for death due to cardiovascular causes or hospitalizations for unstable angina.

Table 5: Number of First Events by Treatment Group for the Composite Primary Endpoint (ITT Population)

CRESTOR (N=8901) n (%)

Placebo(N=8901)n (%)

Relative risk reduction† (95% CI)

Absolute risk reduction (%)

1.9-year NNT

PRIMARY (composite) ENDPOINT

142 (1.6) 252 (2.83) 44% (31, 54) 1.23 81

COMPONENTS OF PRIMARY ENDPOINT

Cardiovascular death* 29 (0.33) 37 (0.42) 22% (-27, 52) 0.09 1112

Nonfatal stroke 30 (0.34) 57 (0.64) 48% (18, 66) 0.30 329

Nonfatal MI 21 (0.24) 61 (0.69) 66% (44, 79) 0.45 222

Unstable angina 15 (0.17) 27 (0.30) 45% (-4, 71) 0.13 741

Arterial revascularization 47 (0.53) 70 (0.79) 33% (3, 54) 0.26 387

*Cardiovascular death included fatal MI, fatal stroke, sudden death and other adjudicated causes of CV death.†Negative numbers imply a risk increase.CI: confidence interval, ITT: intent-to-treat, MI: myocardial infarction, NNT: number needed to treatSYMPTOMS AND TREATMENT OF OVERDOSE: There is no specific treatment in the event of overdosage. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted as required. Hemodialysis does not significantly enhance clearance of rosuvastatin.For the management of a suspected drug overdose, contact your regional Poison Control Centre.

Product Monograph available on request.

CRESTOR® and the AstraZeneca logo are trade-marks of the AstraZeneca group of companies. Licensed from Shionogi & Co Ltd, Osaka, Japan. © AstraZeneca 2010

AstraZeneca Canada Inc.1004 Middlegate RoadMississauga, Ontario L4Y 1M4www.astrazeneca.ca


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