General Medicine Update

Minnesota ACP

November 7, 2008

Steve Hillson

Hennepin County Medical Center

University of Minnesota

s_hill2@msn.com

Objectives

• At the end of this session you should be able to:– Describe the main results of several

important reports from the past year– Decide how you want to change your

practice in the context of these findings

Disclosure

• I have no direct financial relationships with any commercial firm having any interest in any of the reports or topics I am about to discuss.

Process• Personally reviewed title of every original research

article from 10/01/07 till 10/22/08 in:– Annals of Internal Medicine– BMJ– JAMA– Lancet– New England Journal of Medicine

• Reviewed subspecialty updates, scattered other sources

• Personally reviewed abstract of every article with “interesting” title.

Process (cont’d)

• Selected “promising” articles by initial abstract review (about 100)

• Re-reviewed all abstracts, selecting about 60 with medium or high impact potential

• Solicited abstract reviews from colleagues to select subset of greatest importance

• Critically appraised final subset for presentation

Limitations on Process

• Personal idiosyncrasies• Incomplete survey of medical literature• No claim to comprehensive context for

assessing these articles• Very simplified presentation of complex

research• Final slide set available at

– www.paralleltext.net/ppt.html

In Pursuit of the Perfect A1C

• How intensely should we be controlling type 2 diabetes?

• 3 Important Articles– ACCORD, NEJM, June 2008

• Funded by NIH, CDC, with drugs contributed by many makers

– ADVANCE, NEJM, June 2008• Funded by maker of gliclazide

– UKPDS, NEJM, October 2008• Funded initially by UK government agencies, this follow-

up funded by drug makers

Purpose

• Assess tighter vs looser glycemic control in type 2 diabetes

• Previously limited information– None showing mortality or macrovascular

benefit in type 2 DM

• But extensive promulgation of the idea that lower is better

#1 - ACCORD

• Compare target A1C <6.0 to less tight (7-7.9) for cardiovascular outcomes

• Clinical Trial, unblinded– 10,000 US/Canadian patients with DM-2,

A1C≥7.5, and CV disease or risk factor– Any standard diabetes medications– More frequent visits and medication adjustments

for intensive therapy group– Followed 3.5 years for CV death, MI, CVA

#2 - ADVANCE

• Compare target A1C (<6.5) to less tight (local guideline) for vascular outcomes

• Clinical Trial, unblinded• 11,000 patients worldwide, type 2 diabetes,

age≥55, no insulin, and pre-existing vascular disease or a risk factor

• Gliclazide, plus frequent clinic visits and other drugs as needed, OR

• Usual care, with gliclazide excluded• Followed 5 years for vascular events

#3 - UKPDS 10-year follow-up

– Compare tight glycemic control (fasting glucose 108), to less tight (fasting glucose < 270) for macro- and microvascular outcomes

– Clinical Trial, unblinded– 4000 UK patients with new DM-2, age 25-65– Received one of several drug-based strategies OR– “Usual Care” with diet alone unless FPG>270– Treated 10 years, then followed additional 10

years on community standard care, for vascular outcomes

Findings - Achieved A1C

0

1

2

3

4

5

6

7

8

ACCORD ADVANCE UKPDS*

IntensiveStandard

Findings - Primary Outcomes

0

10

20

30

40

50

60

ACCORD ADVANCE UKPDS - All UKPDS -Metformin

IntensiveStandard

*

* *

Findings - Death

0

5

10

15

20

25

30

35

ACCORD ADVANCE UKPDS All UKPDSMetformin

IntensiveStandard

*

* *

Limitations• ACCORD used a lot of rosiglitazone

• Neither ACCORD nor ADVANCE achieved target A1C on most patients

• UKPDS “usual care” isn’t

Implications

• Target A1C of 6.5 or less is at best ambiguous for macrovascular disease, possibly dangerous– May depend on drug choice– Death (NNH of 100) trumps improved

nephropathy/retinopathy (NNT of 70)

• Metformin, without a tight target A1C, is useful for survival in obese diabetics (NNT about 15 over 20 years)

• I will not seek extremely tight A1C• I will use still more metformin

Preventing the Clot

• There’s a new perioperative anticoagulant on the block - 2 studies– RECORD1, NEJM, June 2008– RECORD3, NEJM, June 2008

Purpose

• Compare rivaroxaban to enoxaparin for preventing post-op VTE– Total Hip Arthroplasty (RECORD 1)– Total Knee Arthroplasty (RECORD 3)

• Funded by makers of rivaroxaban– Orally administered, fixed dose factor Xa inhibitor– Reportedly out in January

• Related drugs– Argatroban - parenteral– Ximelagatran - oral, withdrawn due to liver toxicity– Dabigatran - oral, possibly out in 2010

Method• Clinical trials, blinded• 2500 (knee) and 4400 (hip) patients, age≥ 18

with no hepatic or renal disease• Given rivaroxaban 10 mg orally each day, OR• Enoxaparin 40 mg SC each day

– KNEE study: 10-14 total days– HIP study: 35 total days

• Followed 2-6 weeks for venographic DVT and symptomatic VTE or death

Findings - Detectable Venous Thromboembolism

02468

1012

14161820

Hip Knee Bleeding

RivaroxabanEnoxaparin

Limitations

• Symptomatic VTE was rare (about one-tenth of all VTE events)

• Industry-funded research has many opportunities to mislead

• Issue of spinal catheter management not clarified

Implications

• I’m usually a turtle, but…– I will start using perioperative rivaroxaban when it

is released• Easier for everyone• Question of pricing

– Not for frail or otherwise high-risk patients– Does not replace heparin– Watch for studies comparing it to chronic

coumadin for long term anticoagulation– Look for dabigatran

The Infected Respiratory Tract

• Two studies of antibiotics– BMJ, October 2008– JAMA, December 2007

Purpose

• Assess the value of antibiotics (and steroids) for common respiratory tract infections

• Many guidelines and some prior evidence– Largely recommend against antibiotics for

most conditions in absence of pneumonia– Acute bacterial sinusitis more equivocal

#1 - Antibiotics for common respiratory infections

• Historical cohort study• 1.1 million episodes of respiratory infection

(URI, “chest infection,” sore throat, otitis,) in UK

• Record assessed for antibiotic prescription• Followed 1 month for diagnosis-specific

complications (pneumonia, quinsy, mastoiditis)

• Funded by UK Department of Health

Findings - Complications of Respiratory Infections

0

0.51

1.52

2.53

3.54

4.5

URI SoreThroat

Otitis ChestInfection

TreatedUntreated

(Elderly Patients Only)

#2 - Antibiotics and topical steroids for maxillary sinusitis

• Clinical trial, blinded• 240 adults with < 4 weeks acute

bacterial sinusitis (purulent discharge, local pain, pus on exam), no diabetes

• Treated with amoxicillin, budesonide spray, both or neither

• Followed for clinical cure at 10 days• Funded by UK Department of Health

Findings - Resolution of Sinusitis

01020304050

60708090

100

Amoxicillin Budesonide Nothing

10 Day Cure

Limitations• The respiratory complication study was

not a trial– Many ways that treated and untreated

groups may have differed– Including getting diagnosis of complication

• The sinusitis study was small– Could have missed difference in serious

complications

Implications

• Despite limitations– Antibiotics don’t seem important for bacterial

sinusitis, otitis, sore throat, URI– BUT, may be quite useful for “Chest Infection”

• Acute bronchitis?• NNT 40 to prevent pneumonia

– I will try to use less antibiotic for sinusitis (even acute bacterial) and otitis

– I will try to distinguish “chest infection” in older patients and treat

How Do You See the Colon?

• Two studies of CT Colonography– NEJM, October 2007

• Funding not reported,investigators receive money from makers of the colonography processing software

– NEJM, September 2008• Funded by National Cancer Institute and

American College of Radiology

Purpose• Determine whether a relatively non-invasive colonic

imaging technique can approach the ability of colonoscopy to detect pre- and early malignancies

• Colonoscopy never proven to reduce colon cancer mortality, but almost certainly does (FOBT does)

• Colonoscopy is expensive, inconvenient, and not completely safe– 1-3/1,000 have serious consequences, usually

associated with biopsies

• CT Colonography uses similar prep, insufflation, plus fluid tagging

#1 - CT Colonography for advanced neoplasia

– Cohort study, sort of– 6300 adults with no bowel disorder

• Half had enrolled in a CT colonography screening program (why?), with colonoscopy follow-up for selected findings

• Half were getting ordinary colonoscopic screening

– Assessed number and pathology of lesions found

– No follow-up

#2 - Accuracy of CT colonography

• “Test of a Test”• 2600 adults over 50, asymptomatic,

referred for ordinary colonoscopic screening– First received CT colonography– Follwed by immediate colonoscopy

• Assessed concordance for important polyps

Findings - Cohort Study

0

0.5

1

1.5

2

2.5

3

3.5

Advanced Adenomas Cancers

CTScope

*

Findings - Sensitivity Study

• CT detected– 90% of advanced lesions ≥ 1 cm– 65% of advanced lesions ≥ 5 mm

• CT incorrectly called abnormalities in 14% of subjects

Limitations

• First study had no direct comparison of CT to scope in the same patient– Why the excess of cancers in colonography?

• In both studies, CT found extracolonic stuff in majority of patients– Mostly trivial, often requiring further assessment

• In practice, unlikely to get immediate colonoscopy after positive CT– Requires repeat preps, other inconvenience

Implications

• CT Colonography still not ready for prime time– Difficult prep– Lots of follow-up colonoscopies– Lots of irrelevant findings

• I won’t be doing it• Fecal Occult Blood for my patients who

don’t want colonoscopy

After the Fall

• Prevention after a hip fracture

• NEJM, November 2007

• KW Lyles et al.

Purpose

• Determine whether annual infusion of zoledronic acid reduces subsequent fracture after hip fracture repair

• Inconclusive prior evidence about bisphsphonates following hip fracture

• Funded by the maker of zoledronic acid

Method

• Clinical Trial, blinded• 2100 adults with recent “minimal trauma” hip

fracture, previously ambulatory, no kidney disease, and refusing oral bisphosphonate

• Received Calcium and Vitamin D, plus– 5 mg IV zoledronic acid or placebo infusion

annually

• Followed 2 years for new clinical fractures and survival

Findings

0

2

4

6

8

10

12

14

Hip Fx Vertebral Fx Any Fx Death

Zoledronic AcidPlacebo

Limitations

• Mortality benefit unexpected and unexplained

• Industry-funded research has many opportunities for misleading reports

Implications

• Bisphoshonates reduce subsequent fractures and possibly mortality following hip fracture repair– NNT for another hip fx = 70 over 2 years– NNT for death = 27 (!)

• If oral bisphosphonates aren’t an option, zoledronic acid can be given IV yearly– Alendronate $100/month– Zoledronic acid $1200/year

Is the Blockade Working?

• Perioperative beta blockers

• The Lancet, May 2008

• The POISE study group– Funded by governments of Canada,

Australia and Spain, with some support from maker of the study drug

Purpose

• Reassess perioperative beta-blockade for preventing cardiac complications after non-cardiac surgery

• Several prior studies indicate improved post-operative cardiac outcomes with beta-blockade

• “Standard of care” for higher risk patients for at least 5 years– Some doubts due to study limitations and some

conflicting results

Method

• Clinical trial, blinded• 8300 adults worldwide, age ≥ 45, either existing

major vascular disease or at least 3 risk factors– Age>70, TIA, DM, CRF (2.0), CHF history, emergent

or high-risk surgery

• Received metoprolol, starting 4 hours pre-op, or placebo– Held for P<45 or SBP < 100

• Followed 1 month for major vascular outcomes and death

Findings

0

1

2

3

4

5

6

7

CompositeEndoint

MI Stroke Death

MetoprololPlacebo

Limitations

• Beta-blocker started immediately pre-op

• Drug held only for “consistent” severe bradycardia or hypotension

• Excluded patients whose physicians had planned to beta-block

Implications

• Perioperative beta-blockade, at least as done in this study, may be dangerous

• I’m limiting my use– Only beta-block if otherwise indicated– Only with plenty of advance time for slow up-

titration (a month!)– Not in higher stroke risk setting

• (Sad sigh…)

All you need is…Salt?

• Saline or bicarbonate for preventing contrast nephropathy

• JAMA, September 2008

• SS Brar et al.

Purpose

• Reassess whether bicarbonate infusion reduces contrast nephropathy

• Prior evidence that contrast nephropathy is common, around 25% of high-risk patients

• A few prior reports showed reduced nephropathy with pre-procedure bicarbonate hydration

• Funded by Kaiser Permanente

Method

• Clinical Trial, unblinded• 350 adults having non-emergent cardiac

catheterization, with GFR ≤ 60 and at least 1 of:– DM, CHF, HBP, Age > 75– Received either Sodium Bicarbonate, 150 meq in

1 liter D5, OR Normal Saline.• 3 ml/kg/hour for 1 hour pre-procedure, then 1.5

ml/kg/hour during and 4 hours after

– Followed 4 days for 25% fall in GFR

Findings

0

2

4

6

8

10

12

14

16

25% Fall in GFR 0.5 Cr Rise

BicarbonateSaline

Limitations

• Relatively small study

• Only coronary angiography patients

• Relatively good baseline GFR

Implications

• Bicarbonate might not be necessary for renal protection from contrast dye– Saline hydration probably acceptable

substitute

• However– Bicarbonate is not hard or apparently

dangerous to use– Should certainly use some form of

hydration

Staying Off the Sauce

• Baclofen to maintain alcohol abstinence

• The Lancet, December 2007

Purpose

• Assess whether baclofen can help achieve and maintain alcohol abstinence in cirrhotic alcoholics

• Growing interest in several drugs to help prevent alcohol craving and relapse– Naltrexone, acamprosate, topiramate

• Limited information, particularly in cirrhotic patients

• Funded by Italian government

Method

• Clinical Trial, blinded• 84 adults, age 18-75, with alcoholic cirrhosis,

at least 14 (women) to 21 (men) weekly drinks, and no other major system disease

• Admitted, given baclofen 5-10 mg tid, for 12 weeks, or placebo– Also frequent visits with counseling

• Followed 4 months for self- and family-reported abstinence – Dropouts assumed to be relapsed

Findings - Abstinence from Alcohol

0

10

20

30

40

50

60

70

80

Total Abstinence

BaclofenPlacebo

Limitations

• Small study

• Many dropouts, assumed relapsed– But similar results if assumed abstinent

• Duration only 3 months

• Used in context of additional support for abstinence

Implications

• I will try using it– High gain, low risk (NNT 2.5)– Avoid in renal dysfunction, epilepsy– Attempt to provide broader treatment

context

• But I’m not pushing this

Also Noted

• N-3 Polyunsaturated fatty acid supplementation may reduce 3-year mortality in CHF, NNT=60.– Lancet, 10/4/2008

• Telling smokers their “lung age,” derived from FEV1, may improve quit rates, NNT=14– BMJ, 3/6/2008

• Arthroscopic debridement and lavage does not help the osteoarthritic knee more than medicine and PT– NEJM, 9/11/2008

More “Also Noted”• In new type 2 (Irish) DM on oral treatment, home

glucose monitoring did not improve A1C but did worsen depression and anxiety– BMJ, 4/17/2008

• Low-dose risperidone may improve response in depression refractory to monotherapy, NNT=7 (Industry funded)– AnnIntMed 11/6/2007

• The US Preventive Services Task Force still does not recommend prostate cancer screening, and recommends against it after age 75– AnnIntMed, 8/5/2008

And Last -

• Coffee might decrease cardiovascular and overall mortality

• At 6 cups per day, over 25 years:– Men were 20% less likely to die– Women were 17% less likely to die– Independent of caffeine

• WARNING: Brought to you by the Nurses’ Health Study– Remember HRT?

• AnnIntMed, 6/17/2008

Summary

• Reconsider the A1C goal, use more metformin

• Oral thrombin inhibitors for perioperative DVT prophylaxis look promising

• Avoid antibiotics for most non-pneumonia respiratory infections; “chest infection” in the elderly may be an exception

• CT Colonography is pretty good, not yet ready• Bisphosphonates may be important after hip

fracture

Summary, cont’d

• Perioperative beta-blockade looks more risky than helpful

• Saline may be as good as bicarbonate for IV dye renal protection

• Baclofen may help alcohol abstinence in cirrhotics

• Coffee?

Remember:

• Before acting on anything you heard here, you may wish to study the original research, and discuss with colleagues or domain experts