Pharmacovigilance || The Cardiovascular Spectrum of Adverse Drug Reactions

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The Cardiovascular Spectrum of AdverseDrug ReactionsJUDITH HSIAGeorge Washington University Medical Center, Washington, DC, USA

JINPING MOPfizer Inc., New York, NY, USA

LAURA BURLESONPfizer Inc., New London, CT, USA

ANNLOUISE R. ASSAFPfizer Inc., New London, CT, USA

Undesired sequelae of pharmacologic agents encom-pass a wide range of adverse cardiovascular effects,including proarrhythmic, atherogenic, myopathic andvalvular consequences (Table 41.1). In this chapter,we will focus on three agents, each demonstrating adifferent undesired clinical cardiovascular drug effect.The mode of identification and subsequent scientificinvestigators and regulatory steps are summarizedfor dofetilide’s proarrhythmic characteristics, cardiacvalvular effects of appetite suppressants and oestro-gen’s venous thrombogenicity.

DOFETILIDE

Dofetilide is a specific class III antiarrhythmic agentindicated for the maintenance of and conversion tonormal sinus rhythm in highly symptomatic patients

with persistent atrial fibrillation and atrial flutter(Pfizer Inc., 1999). It prolongs action potential dura-tion and refractoriness of both the atrial and theventricular myocardium (Boriani et al., 2004). Aswith most other drugs which prolong the actionpotential, dofetilide carries a risk of proarrhythmia.Following oral administration, there is a dose- andconcentration-dependent increase in the corrected QTinterval (QTc) that can lead to torsade des pointes(Boriani et al., 2004), a life-threatening arrhythmia.In the clinical development programme, the inci-dence of torsade des pointes was dramatically reducedwhen lower dosages were administered and whendosage was decreased for patients with impairedrenal function (Torp-Pederson et al., 1999). Dofetilideis the first antiarrhythmic agent for which stud-ies of overall mortality risk were conducted beforemarket approval was requested. These studies showed

Pharmacovigilance, Second Edition Edited by Ronald D. Mann and Elizabeth B. Andrews© 2007 John Wiley & Sons, Ltd. ISBN: 0-470-01803-8

508 PHARMACOVIGILANCE

Table 41.1. Examples of drug cardiotoxicity

Cardiac effect Drug

Cardiomyopathic Doxorubicin (Singal and Iliskovic, 1998)Proarrhythmic Terfenadine (Monahan et al., 1990)

Cisapride (Rampe et al., 1997)Atherothrombotic Protease inhibitors (Zhou et al., 2005)

Cyclooxygenase inhibitors (Bresalier et al., 2005; Konstantinopoulos and Lehmann, 2005)Anabolic steroids (Hartgens and Kuipers, 2004; Payne, Kotwinski and Montgomery, 2004)

Valvulopathic Appetite suppressants (MMWR, 1997)

neutral effect on death in patients taking dofetilidewho had heart failure or previous myocardial infarc-tion (Torp-Pederson et al., 1999; Kober et al. 2000),in contrast to some other antiarrhythmic agents forwhich overall mortality either has increased or hasnot been studied (Coplen et al. 1990; Teo, Yusuf andFurberg, 1993; Fuster et al., 2001). Dofetilide wasapproved by the Food and Drug Administration (FDA)in 1999. Because of the risk of torsade des pointesidentified in the clinical development programme,the FDA mandated a risk management programmewhich required in-hospital initiation of dofetilidetherapy, and restricted its availability to hospitals andprescribers who have received appropriate educationon dofetilide treatment initiation and dosing.

Shortly after dofetilide was approved for use inthe United States, the FDA also approved sotalolHCl, a new sotalol product with the same indi-cation as dofetilide (Berlex Laboratories, 2000).As with dofetilide, sotalol is also associated with adose- and concentration-dependent incidence of QT-prolongation and torsade des pointes (Wang et al.,1986). Comparable incidence of torsade de pointeshas been reported for sotalol and dofetilide (Bren-dorp, 2002). The product labelling for sotalol HClcontained detailed dosing and monitoring recommen-dations similar to the language in the product labellingfor dofetilide. However, the FDA did not request arisk management programme for sotalol as this drughad already been marketed in the United States forthe treatment of ventricular arrhythmias.s

Because of the uniqueness of the dofetilide riskmanagement programme, a series of studies wasconducted by the Duke Center for Education andResearch on Therapeutics to evaluate the acceptanceand effectiveness of the mandatory provider education

programme for the use of dofetilide (LaPointe et al.,2002, 2003a,b). One study evaluated whether themandated risk management programme for dofetilidewas effective in improving adherence to labelleddosing and monitoring recommendations at DukeUniversity Medical Center (LaPointe et al., 2003b). Itwas found that the recommended starting dose wasprescribed more frequently in the dofetilide group thanin the sotalol group and a higher number of patientsin the dofetilide group when compared with thesotalol group received the baseline tests for potassium,magnesium, serum creatinine, and an electrocardio-gram. Dofetilide was used less often than sotalolduring the study period (47 patients vs 117 patients).The investigators raised the issue that the low usageof dofetilide might reflect an unintended, negativeconsequence of the risk management programme.

Another study assessed the opinions and knowl-edge retention of practitioners after participation inthe dofetilide risk management programme at Duke(LaPointe et al., 2002). In general, practitioners feltthe risk management programme for dofetilide wasnecessary although they either disagreed or wereundecided as to whether dofetilide was potentiallymore dangerous than other antiarrhythmic agents orwhether a similar programme should be required forother antiarrhythmic agents. This study showed thatthe knowledge-retention questions were answeredcorrectly more often by the physicians and pharma-cists than by the nurses. It was noted that the other twosmaller community hospitals within the Duke HealthCare system opted not to include dofetilide in theirformularies, and thus did not complete the educationprogramme. This may indicate the perceived burdenof the programme, a lack of resources within smaller

THE CARDIOVASCULAR SPECTRUM OF ADVERSE DRUG REACTIONS 509

community hospitals to complete the risk managementprogramme, or both.

The experience of implementing the dofetilide riskmanagement programme was reported from severalother institutions with different approaches (Tranet al., 2001; Freeland, Worthy and Zolnierz, 2003).The pharmacy and therapeutics committees at mostinstitutions required that policies and procedures bedeveloped for dofetilide use prior to putting thedrug on the formulary. The dofetilide risk manage-ment programme has been successfully implementedin many institutions. However, some have beenhesitant to incorporate dofetilide into their formu-laries, as the development of procedures for thedofetilide risk management programme is time-consuming and requires multidisciplinary expertise,including pharmacists, physicians and nurses.

Very limited data on postmarketing experience withdofetilide have been published. The reported postmar-keting clinical experience suggests that the conversionof persistent atrial fibrillation with dofetilide wascomparable to the premarketing studies, and demon-strated a similar safety profile (Prystowsky et al.,2003; Guanzon and Crouch, 2004).

The experience with dofetilide illustrates oneapproach in which a postmarketing risk managementprogramme can minimize the risk identified in a clin-ical development programme. The dofetilide experi-ence has also presented challenges in implementingrisk management programmes intended to maximizebenefits and minimize medication risks.

APPETITE SUPPRESSANTS

In contrast to the experience with dofetilide, in whichan adverse drug effect was identified during productdevelopment, the consequences of appetite suppres-sants were detected serendipitously. Phentermine wasapproved by the FDA for appetite suppression in 1959,fenfluramine in 1973, and dexfenfluramine in 1996.The former two were approved for short-term use, andall three drugs were approved for use as single agents.In the 1990s, prescription of fenfluramine in combi-nation with phentermine and for periods longer thana few weeks was widespread. From 1995 to 1997,14 million prescriptions were written for fenfluramine

or dexfenfluramine, exposing an estimated 1.2–4.7million persons to these agents (MMWR, 1997).

In July 1997, physicians in Minnesota reported24 women with valvular heart disease who hadtaken fenfluramine–phentermine for 2–28 months(Connolly et al., 1997). The women were identifiedduring evaluation of conditions such as congestiveheart failure, heart murmurs, or arrhythmias. Echocar-diographic features of the dysfunctional valves resem-bled those seen in carcinoid heart disease; in five,valvular incompetence was severe enough to requirecardiac surgery. Because of the morphologic simi-larity to carcinoid valvular disease, which has beenattributed to high circulating levels of serotonin, theauthors hypothesized that the valvular damage seenwith fenfluramine might be due to its promotion ofserotonin release and inhibition of serotonin reuptake.Phentermine is a nonadrenergic agent which impedespulmonary clearance of serotonin, and which mightpotentiate the effect or concentration of circulatingserotonin.

The Minnesota report, in conjunction with an FDApublic health advisory, rapidly spawned additionalcase reports (Cannistra, Davis and Bauman, 1997;Graham and Green et al., 1997; Kurz and Van Ermen,1997). A trio of larger clinical studies, each of differ-ent design, was published in September 1998 in theNew England Journal of Medicine.

In the first study, echocardiograms were performedon 257 of 295 participants in prior appetite suppres-sant studies at Hennepin County Medical Centerand in gender, age and body mass index-matchedcontrols (Khan et al., 1998). Study participants hadtaken fenfluramine 60–120 mg + phentermine 30 mgdaily, dexfenfluramine 30 mg daily alone, or in combi-nation with phentermine 30 mg daily. Mean dura-tion of treatment was 20�5±12 months. Echocardio-graphic aortic and mitral insufficiency was scored(none, trace, mild, moderate or severe) by two blindedreaders; if they disagreed, the study was reviewed bya third reader. FDA criteria for valvular abnormal-ity were applied, that is, aortic valvular disease ofmild or greater severity and mitral valvular diseaseof moderate or greater severity (� = 0�79 for corre-lation between readers). Valvular insufficiency wasidentified in 3/233 control subjects (1.3%) and 53/233appetite suppressant consumers (22.7%). In multivari-ate analysis which included age, gender, body mass


index, blood pressure, and diabetes as covariates,and control subjects as the reference group, the oddsratios (95% confidence intervals) for valvular abnor-mality were 12.7 (2.9–56.4), 24.5 (5.9–102.2), and26.3 (7.9–87.1) for dexfenfluramine, dexfenfluramine+ phentermine, and fenfluramine + phentermine use,respectively.

The second study compared patients who hadbeen prescribed dexfenfluramine �n = 6532�, fenflu-ramine �n = 2371�, or phentermine �n = 862� withage, gender, and weight-matched controls in the UKGeneral Practice Research Database (Jick et al., 1998).During follow-up of about 4 years, the databaseidentified 22 new diagnoses of valvular abnormal-ity. Eleven patients were excluded when other causesof valvular disease, such as rheumatic heart diseaseor mitral valve prolapse, were identified by medicalrecord review. The remaining 11 subjects had beenreferred to cardiologists for recent symptom onset ornew heart murmur. In eight patients, valvular insuf-ficiency was confirmed by echocardiography and inthree by clinical examination. All 11 patients had beenprescribed dexfenfluramine or fenfluramine, a cumu-lative incidence of 14.2 per 10 000 (95% confidenceinterval 7.8–26.2). No valvular abnormalities wereidentified in untreated subjects or those prescribedphentermine.

The third study performed echocardiograms onparticipants in a randomized, double-blind trialcomparing dexfenfluramine (15 mg bd), sustained-release dexfenfluramine (30 mg daily) and placebo,which was ongoing at the time dexfenfluramine waswithdrawn from the US market (Weissman et al.,1998). Echocardiograms were performed on 1072of 1212 randomized participants and interpreted byblinded readers; mean exposure was 72 days. UsingFDA criteria for valvular abnormality (aortic insuffi-ciency of mild or greater severity and mitral insuf-ficiency of moderate or greater severity), valvulardisease was not significantly more prevalent in thecombined dexfenfluramine groups compared withplacebo. When any degree of valvular insufficiencywas compared between the treatment groups, aortic�p = 0�03� and mitral insufficiency �p = 0�01� weremore frequent in the combined dexfenfluraminegroups compared with placebo.

In November 1998, the American College of Cardi-ology and American Heart Association (ACC/AHA)

recommended evaluation of appetite suppressantusers, including history and physical examination,with echocardiography in those with signs or symp-toms of valvular disease (Bonow et al., 1998). Subse-quent meta-analyses have tempered initial estimatesof the frequency of valvular insufficiency associ-ated with appetite-suppressant use, supporting theACC/AHA statement that routine echocardiographywas not recommended for all of the millions of indi-viduals exposed.

Pooled data from six controlled cohort studiesyielded a relative risk ratio of 2.32 for aortic insuf-ficiency (95% confidence interval 1.79–3.01) and1.55 for mitral insufficiency (95% confidence interval1.06–2.25) (Loke, Derry and Pritchart-Copley, 2002).A second analysis which included ten studies found aprevalence odds ratio of 2.2 (95% confidence interval1.7–2.7) for aortic insufficiency meeting FDA crite-ria among individuals treated for at least 90 dayswith fenfluramine derivatives (Sachdev et al., 2002).The odds ratio for mitral insufficiency of moderateor greater severity was 1.6 (95% confidence interval1.05–2.3).

The experience with appetite suppressants illus-trates the role of fortuitous observation in identifyingadverse drug effects and the potential for inaccuracyof early risk estimates due to methodologic weak-nesses.

OESTROGEN AND VENOUSTHROMBOEMBOLISM

Identification and confirmation of the adverse effectsof postmenopausal hormone therapy illustrate yet athird approach to risk assessment. Oestrogen hasbeen used to treat menopausal symptoms since 1933when emmenin was introduced. Premarin, a moreeasily manufactured oestrogen, was approved in 1942(CDER, 1997; FDA, 2003). By the 1960s, 12%of women in the United States were using post-menopausal oestrogen therapy, a proportion thatincreased steadily. The National Prescription Auditand National Disease and Therapeutic Index databasestracked annual hormone therapy prescriptions risingfrom 58 million in 1995 to 90 million in 1999;prescriptions then remained stable through June 2002(Hersh, Stefanick and Stafford, 2004). Analysis of


data from a large cohort study in the United Statesshowed that 45% of postmenopausal women usedoestrogen for at least a month and more than 20% usedit for 5 or more years, either alone or in combinationwith progestin (Brett and Madans, 1997).

These rates have been shown to differ based on awoman’s hysterectomy status; in a study by Keatingand colleagues in the early 1990s, current post-menopausal hormone use was 58.7% among womenwith prior hysterectomy compared to 19.6% amongwomen with intact uteri (Keating, Manassiev andStevenson, 1999). Most women started to take ther-apy shortly after menopause; median duration ofuse was 3 years (mean 6.6 years). Postmenopausalhormone use demonstrated a secular trend; only 19%of women born before 1904 ever used postmenopausalhormones, compared to 63% of women born between1945 and 1954 (Brett and Madans, 1997).

In 1992, the American College of Physicians recom-mended hormone therapy for postmenopausal womenwho either had hysterectomy or were at risk ofcoronary heart disease (American College of Physi-cians, 1992). It quickly became standard medicalpractice to prescribe exogenous oestrogens, eitheralone or in combination with progestin, for mostmenopausal women, with the expectation that most, ifnot all of these women, would benefit from treatment.Initially, most women received unopposed oestro-gen regardless of their hysterectomy status. After theNational Heart, Lung and Blood Institute-funded Post-menopausal Oestrogen/Progestin Interventions (PEPI)trial reported an increased risk of endometrial hyper-plasia when women with intact uteri were treatedwith unopposed oestrogen in 1995, most women withintact uteri were switched to combination oestrogen–progestin therapy (The Writing Group for the PEPITrial, 1996). Indeed, when the Women’s Health Initia-tive was being planned in the early 1990s, therewas debate about the ethics of withholding post-menopausal hormone therapy from the women whowould be randomized to placebo.

A cloud was introduced to that climate of enthu-siasm for oestrogen in the 1960s when an apparentincreased risk of venous thromboembolism (VTE),that is, deep venous thrombosis and pulmonaryembolism, was associated with oral contraceptive use(Royal College of General Practitioners, 1967; Vesseyand Doll, 1968, 1969; Jick et al., 1995; Spitzer, 1997).

The relationship between VTE and exogenous oestro-gen was explored in several small case-control andcohort studies in the 1970s (BCDSP, 1974; Nachtigallet al., 1979; Petitti et al., 1979). In these analyses,VTE was more common in women taking oral contra-ceptives, but the relationship with postmenopausalhormone therapy was less clear. These epidemiologicstudies were followed by large randomized, controlledtrials.

The PEPI was a 3-year randomized, placebo-controlled trial in 875 postmenopausal womencomparing the effects of several postmenopausalhormone regimens on cardiovascular disease riskfactors. The cohort was healthy and relatively young;consequently, only ten VTE cases were identifiedamong women on active hormone therapy and noneon placebo during the 3-year follow-up (The WritingGroup for the PEPI Trial, 1995). The rate of VTE inwomen taking conjugated oestrogens (0.625 mg daily)alone was twice that of women taking any of threeoestrogen plus progestin regimens (Table 41.2), butthe overall number of cases was small.

The Heart & Oestrogen/Progestin ReplacementStudy (HERS) randomized 2763 women withdocumented coronary heart disease to placeboor conjugated equine oestrogens 0.625 mg plusmedroxyprogesterone acetate 2.5 mg daily (Hulleyet al., 1998; Grady et al., 2000). Combinationhormone therapy increased VTE risk (relative hazard2.7, 95% confidence interval 1.4–5.0); the rela-tive hazard for deep venous thrombosis was 2.8

Table 41.2. Annualized rates (%/year) of venous throm-boembolism in randomized trials of postmenopausalhormone therapy

PlaceboUnopposedoestrogen

Oestrogenplus progestin

PEPI 0 0.76 0.38HERS 0�23 0.62

Year 1 0�29 0.96Year 2 0�15 0.61Year 3 0�23 0.55Year ≥ 4 0�20 0.40

WHI OestrogenPlus Progestintrial

0�17 0.35

WHI OestrogenAlone trial

0�21 0.28


(95% confidence interval 1.3–6.0) and for pulmonaryembolism was 2.8 (95% confidence interval 0.9–8.7)with oestrogen plus progestin.

The Women’s Health Initiative (WHI) includestwo randomized, placebo-controlled hormone trials,one with unopposed conjugated oestrogens (0.625 mgdaily) in 10 739 women with prior hysterectomy, andthe other with conjugated oestrogens 0.625 mg plusmedroxyprogesterone acetate 2.5 mg daily in 16 608women with intact uteri. In the trial of unopposedoestrogen, the hazard ratio for VTE was 1.33 (95%confidence interval 0.99–1.79) (WHI Writing Group,2004). In the trial of combination oestrogen plusprogestin, the hazard ratio for VTE was 2.06 (95%confidence interval 1.57–2.70) (Cushman et al., 2004).In these predominantly healthy women, the annualizedrates of VTE were lower than in HERS (Table 41.2),but the studies demonstrated a similar pattern of riskby year of treatment. In the WHI Oestrogen PlusProgestin trial, the yearly hazard ratios were 4.01 inyear 1, 1.97 in year 2, 1.74 in year 3, 1.70 in year 4,2.90 in year 5 and 1.04 in year 6 or later.

In a Bayesian meta-analysis which included PEPIand HERS, but not the WHI, the overall relative riskof VTE with postmenopausal hormone therapy was2.14 (95% credible interval 1.64–2.81) (Miller, Chanand Nelson, 2002). This meta-analysis also supportedthe observation in HERS that the greatest risk forthromboembolic events with oestrogen was during thefirst year (relative risk 3.49, 95% credible interval2.33–5.59).

The labels for oestrogen formulations have beenrepeatedly updated to reflect new findings, includingthe risk of VTE. A major change was made in 1998,when a warning was added stating,

In some epidemiological studies, women on oestro-gen replacement therapy, given alone or in combi-nation with a progestin, have been reported to havean increased risk of thrombophlebitis, and/or throm-boembolic disease, although the evidence is conflict-ing � � � In some epidemiological studies, women onoestrogen replacement therapy, given alone or incombination with a progestin, have been reported tohave an increased risk of thrombophlebitis, and/orthromboembolic disease, although the evidence isconflicting (FDA, 1998).

Following release of the WHI results in 2002, ablack box statement pertaining to cardiovascular risks

was added to the label for oestrogen. This state-ment read, ‘The women’s health initiative (WHI)reported increased risks of myocardial infarction,stroke, invasive breast cancer, pulmonary emboli,and deep vein thrombosis in postmenopausal womenduring 5 years of treatment with conjugated equineoestrogens (0.625 mg) combined with medroxypro-gesterone acetate (2.5 mg) relative to placebo.’ Thewarning goes on to state that the FDA assumes thesefindings will hold for all HRT formulations contain-ing oestrogen and suggests that HRT drugs should beused in the lowest doses necessary for the shortestduration possible (FDA, 2003).

The WHI experience altered the way the medicalcommunity, lay public and regulatory agencies viewedthe entire issue of drug safety. Awareness of theneed for long term randomized studies of commonlyaccepted therapies has been enhanced, along withthe importance of ‘real world’ follow-up studies ofdrugs – many of which were approved long beforecurrent pharmacovigilance guidelines.

REFERENCES

American College of Physicians (1992) Guidelines for coun-seling postmenopausal women about preventive hormonetherapy. Ann Intern Med. 117:1038–41.

Berlex Laboratories (2000) Betapace AF (sotalol) packageinsert. Wayne, NJ.

Bonow RO, Carabello B, de Leon AC Jr et al. (1998) Guide-lines for the management of patients with valvular heartdisease: executive summary: a report of the AmericanCollege of Cardiology/American Heart Association TaskForce on Practice Guidelines (Committee on Managementof Patients with Valvular Heart Disease). Circulation.98:1949–84.

Boriani G, Diemberger I, Biffi M et al. (2004) Pharmacolog-ical cardioversion of atrial fibrillation: current manage-ment and treatment options. Drugs. 64:2741–62.

Boston Collaborative Drug Surveillance Program (BCDSP)Surgically confirmed gallbladder disease, venous throm-boembolism, and breast tumors in relation to post-menopausal estrogen therapy. N Eng J Med. 290:15–19.

Brendorp B, Pedersen O, Torp-Pederson C et al. (2002) Abenefit-risk assessment of class III antiarrhythmic agents.Drug Saf. 25:847–65.

Bresalier RS, Sandler RS, quan H et al. (2005) Cardio-vascular events associated with rofecoxib in a colorec-tal adenoma chemoprevention trial. N Engl J Med.352:1092–102.


Brett KM, Madans JH (1997) Use of postmenopausalhormone replacement therapy: estimates from a nationallyrepresentative cohort study. Am J Epidemiol. 145:536–45.

Cannistra LB, Davis SM, Bauman AG (1997) Valvular heartdisease associated with dexfenfluramine. N Engl J Med.337:636.

Center for Drug Evaluation and Research (CDER) (1997).Approvability of a Synthetic Generic Versionof Premarin. [Online] http://www.fda.gov/cder/news/celetterjw.htm.

Connolly HM, Carary JL, McGoon MD et al. (1997)Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 337:581–8.

Coplen SE, Antman EM, Berlin JA et al. (1990) Efficacyand safety of quinidine therapy for maintenance of sinusrhythm after cardioversion. A meta-analysis of random-ized control trials. Circulation. 82:1106–16.

Cushman M, Kuller LH, Prentice R et al. (2004) Estrogenplus progestin and risk of venous thrombosis. JAMA.292:1573–80.

Food and Drug Administration (FDA) (1998) Summary ofsafety-related labeling changes approved by FDA.Medwatch. [Online]. http://www.fda.gov/medwatch/safety/1998/may98.htm#premar.

Food and Drug Administration (FDA) (2003) Premarinlabel. [Online] http://www.fda.gov/cder/foi/label/2003/04782s129lbl.pdf.

Freeland S, Worthy C, Zolnierz M (2003) Initiation andmonitoring of class III antiarrhythmic agents. J Cardio-vasc Electrophysiol. 14(12 Suppl):S291–5.

Fuster V, Ryden LE, Asinger RW et al. (2001)ACC/AHA/ESC Guidelines for the Management ofPatients with Atrial Fibrillation: Executive Summary: AReport of the American College of Cardiology/AmericanHeart Association Task Force on Practice Guidelines andthe European Society of Cardiology Committee for Prac-tice Guidelines and Policy Conferences (Committee toDevelop Guidelines for the Management of Patients withAtrial Fibrillation) Developed in Collaboration with theNorth American Society of Pacing and Electrophysiology.Circulation. 104:2118–50.

Grady D, Wenger NK, Herrington D et al. (2000) Post-menopausal hormone therapy increases risk for venousthromboembolic disease. Ann Intern Med. 132:689–96.

Graham DJ, Green L (1997) Further cases of valvularheart disease associated with fenfluramine-phentermine.N Engl J Med. 337:635.

Guanzon AV, Crouch MA (2004) Phase IV trial valuatingthe effectiveness and safety of dofetilide. Ann Pharma-cother. 38:1142–7.

Hartgens F, Kuipers H (2004) Effects of androgenic-anabolic steroids in athletes. Sports Med. 34:513–54.

Hersh AL, Stefanick ML, Stafford RS (2004) National useof postmenopausal hormone therapy: annual trends andresponse to recent evidence. JAMA. 291:47–53.

Hulley S, Grady D, Bush T et al. Randomized trial ofestrogen plus progestin for secondary prevention of coro-nary heart disease in postmenopausal women. JAMA.280:605–13.

Jick H, Jick SS, Gurewich V et al. (1995) Risk of idiopathiccardiovascular death and nonfatal venous thromboem-bolism in women using oral contraceptives with differingprogestogen components. Lancet. 346:1589–93.

Jick H, Vasilakis C, Weinrach LA et al. (1998) Apopulation-based study of appetite-suppressant drugs andthe risk of cardiac-valve regurgitation. N Engl J Med.339:719–24.

Keating FS, Manassiev N, Stevenson JC (1999) Maximisingthe use of HRT: focus on hysterectomised women. CurrMed Res Opin. 15:290–7.

Khan MA, Herzog CA, St Peter JV et al. (1997) Theprevalence of cardiac valvular insufficiency assessedby transthoracic echocardiography in obese patientstreated with appetite-suppressant drugs. N Engl J Med.339:713–18.

Kober L, Bloch Thomsen PE, Moller M et al. (2000) Effectof dofetilide in patients with recent myocardial infarc-tion and left-ventricular dysfunction: a randomised trial.Lancet. 356:2052–8.

Konstantinopoulos PA, Lehmann DF (2005) The cardio-vascular toxicity of selective and non-selective cyclooxy-genase inhibitors. Comparisons, contrasts, and aspirinconfounding. J Clin Pharmacol. 45:742–50.

Kurz X, Van Ermen A (1997) Valvular heart disease asso-ciated with fenfluramine-phentermine. N Engl J Med.337:1172–3.

LaPointe NM, Kramer JM, Weinfurt KP et al. (2002) Prac-titioner acceptance of the dofetilide risk-managementprogram. Pharmacotherapy. 22:1041–6.

LaPointe NM, Pamer CA, Kramer JM et al. (2003a) Newantiarrhythmic agents for atrial fibrillation and atrial flut-ter: United States drug market response as an indicator ofacceptance. Pharmacotherapy. 23:1316–21.

LaPointe NM, Chen A, Hammill B et al. (2003b) Evaluationof the dofetilide risk-management program. Am Heart J.146:894–901.

Loke YK, Derry S, Pritchard-Copley A (2002) Appetitesuppressants and valvular heart disease – a systemicreview. BMC Clin Pharmacol. 2:6.

Miller J, Chan BKS, Nelson H (2002) Postmenopausalestrogen replacement and risk for venous thromboem-bolism: a systematic review and meta-analysis for theUS Preventive Services Task Force. Ann Intern Med.136:680–90.

MMWR (1997) Cardiac valvulopathy associated with expo-sure to fenfluramine or dexfenfluramine: US Departmentof Health and Human Services Interim Public HealthRecommendations, November 46:1061–5.

Monahan BP, Ferguson CL, Killeavy ES et al. (1990)Torsades de pointes occurring in association with terfe-nadine use. JAMA. 264:2788–90.

Nachtigall LE, Nachtigall RH, Nachtigall RD et al. (1979)Estrogen replacement therapy II: a prospective studyin the relationship to carcinoma and cardiovascular andmetabolic problems. Obstetr Gynecol. 54:74–9.

Payne JR, Kotwinski PJ, Montgomery HE (2004) Cardiaceffects of anabolic steroids. Heart. 90:473–5.


Petitti DB, Wingerd J, Pellegrin F et al. (1979) Risk ofvascular disease in women: smoking, oral contraceptives,noncontraceptive estrogens, and other factors. JAMA.242:1150–4.

Pfizer Inc. (1999) Tikosyn (dofetilide) package insert. NewYork, NY.

Prystowsky EN, Freeland S, Branyas NA et al. (2003) Clin-ical experience with dofetilide in the treatment of patientswith atrial fibrillation. J Cardiovasc Electrophysiol. 14(12Suppl):S287–90.

Rampe D, Roy ML, Dennis A et al. (1997) A mechanism forthe proarrhythmic effects of cisapride (Propulsid): highaffinity blockade of the human cardiac potassium channelHERG. FEBS Lett. 417:28–32.

Royal College of General Practitioners (1967) Oral contra-ception and thromboembolic disease. J R Coll Gen Pract.13:267–79.

Sachdev M, Miller WC, Ryan T et al. (2002) Effect offenfluramine-derivative diet pills on cardiac valves: ameta-analysis of observational studies. Am Heart J.144:1065–73.

Singal PK, Iliskovic N (1998) Doxorubicin-inducedcardiomyopathy. N Engl J Med. 339:900–5.

Spitzer WO (1997) The 1995 pill scare revisited: anatomyof a non-epidemic. Hum Reprod. 12:2347–57.

Teo KK, Yusuf S, Furberg CD (1993) Effects of prophy-lactic antiarrhythmic drug therapy in acute myocardialinfarction. An overview of results from randomizedcontrolled trials. JAMA. 270:1589–95.

Torp-Pederson C, Moller M, Bloch-Thomsen PE,et al. (1999) Dofetilide in patients with congestive heartfailure and left ventricular dysfunction. Danish investi-gations of arrhythmia and mortality on dofetilide studygroup. N Engl J Med. 341:857–65.

Tran A, Vichiendilokkul A, Racine E, Milad A (2001) Prac-tical approach to the use and monitoring of dofetilidetherapy. Am J Health Syst Pharm. 58:2050–9.

US Department of Health and Human Services InterimPublic Health Recommendations (1997) Cardiac valvu-lopathy associated with exposure to fenfluramine ordexfenfluramine. Nov 1997. MMWR. 46:1061–5.

Vessey MP, Doll R (1968) Investigation of relation betweenuse of oral contraceptives and thromboembolic disease.BMJ. 2:199–205.

Vessey MP, Doll R (1969) Investigation of relation betweenuse of oral contraceptives and thromboembolic disease: afurther report. BMJ. 2:651–7.

Wang T, Bergstrand RH, Thompson KA et al. (1986)Concentration-dependent pharmacologic properties ofsotalol. The American Journal of Cardiology. 57:1160–5.

Weissman NJ, Tighe JF, Gottdiener JS et al. (1998)An assessment of heart-valve abnormalities in obesepatients taking dexfenfluramine, sustained releasedexfenfluramine, or placebo. N Engl J Med. 339:725–32.

WHI Writing Group (2004) Effects of conjugated equineestrogen in postmenopausal women with hysterectomy.The women’s health initiative randomized controlled trial.JAMA. 291:1701–12.

The Writing Group for the PEPI Trial (1995) Effectsof estrogen or estrogen/progestin regimens on heartdisease risk factors in postmenopausal women. The post-menopausal estrogen/progestin interventions (PEPI) trial.JAMA. 273:199–208.

The Writing Group for the PEPI Trial (1996) Effectsof hormone replacement therapy on endometrial histol-ogy in postmenopausal women. The postmenopausalestrogen/progestin interventions trial. JAMA. 275:370–5.

Zhou H, Pandak WM Jr, Lyall V et al. (1997) HIV proteaseinhibitiors activate the unfolding protein response inmacrophages: implication for atherosclerosis and cardio-vascular disease. Mol Pharmacol. 68:690–700.

Pharmacovigilance || The Cardiovascular Spectrum of Adverse Drug Reactions

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