General Medicine Update

1. General Medicine Update Minnesota ACP November 7, 2008 Steve Hillson Hennepin County Medical Center University of Minnesota s_hill2@msn.com

2. 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

3. 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.

4. 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.

5. 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

6. 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

7. 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

8. 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

9. #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

10. #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

11. #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

12. Findings - Achieved A1C

13. Findings - Primary Outcomes * * *

14. Findings - Death * * *

15. Limitations • ACCORD used a lot of rosiglitazone • Neither ACCORD nor ADVANCE achieved target A1C on most patients • UKPDS “usual care” isn’t

16. 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

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

18. 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

19. 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

20. Findings - Detectable Venous Thromboembolism

21. 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

22. 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

23. The Infected Respiratory Tract • Two studies of antibiotics • BMJ, October 2008 • JAMA, December 2007

24. 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

25. #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

26. Findings - Complications of Respiratory Infections (Elderly Patients Only)

27. #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

28. Findings - Resolution of Sinusitis

29. 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

30. 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

31. 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

32. 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

33. #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

34. #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

35. Findings - Cohort Study *

36. 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

37. 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

38. 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

39. After the Fall • Prevention after a hip fracture • NEJM, November 2007 • KW Lyles et al.

40. 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

41. 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

42. Findings

43. Limitations • Mortality benefit unexpected and unexplained • Industry-funded research has many opportunities for misleading reports

44. 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

45. 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

46. 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

47. 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

48. Findings

49. 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

50. 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…)