General Medicine Update

1. General Medicine Update Minnesota ACP November, 2010 Steve Hillson General Internal Medicine 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 10/08/09 till 10/15/10 in: • Annals of Internal Medicine • BMJ • JAMA • Lancet • New England Journal of Medicine • American 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 50 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

7. Blood Pressure • How aggressive should we be for high-risk patients? • 3 Important Articles • Effects of intensive blood-pressure control in type 2 diabetes mellitus (ACCORD), NEJM, April 2010 • Funded by the NIH, medicines contributed by various pharmaceutical companies • Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease, JAMA, July 2010 • Funded by a pharmaceutical company • Intensive blood-pressure control in hypertensive chronic kidney disease, NEJM, September 2010 • Funded by NIH and pharmaceutical companies

8. Purpose • Assess whether cardiovascular outcomes can be improved by aggressive blood pressure control • Previous information • Cardiovascular risk rises throughout the range of systolic BP’s • JNC 7 recommends medical treatment of SBP to below 130 • Some recommendations for even tighter control in especially high risk circumstances, particularly with chronic kidney disease

9. #1 – ACCORD substudy • Compare tighter (SBP<120) to looser (SBP<140) BP control in type 2 diabetes • Clinical Trial, unblinded • 4733 patients with DM-2, over age 40 with CV disease or risk factors, Creatinine <1.5, SBP 130-180 and <1 gram proteinuria • Received standard BP medications titrated to 120 OR 140 • Also were enrolled in ACCORD glycemic control study • Followed up to 8 years for MI, stroke, cardiovascular death

10. #2 – INVEST follow-up • Designed to compare two drug strategies with target BP of 130 • Follow-up compares patients who achieved SBP<130 to those who did not • Cohort study 6400 diabetic patients with hypertension and CAD, in many countries • Initially received ACEI plus either Ca- or B-blocker • Followed at least 2.5 years for MI, CVA or death

11. #3 – AASK • African-American study of kidney disease and hypertension • Compare intensive (MAP 92, 116/80) to standard (MAP 102-107, 135/85-140/90) BP control • RCT with cohort phase, 1094 African Americans with HBP, CKD, and mild or no diabetes • Received ACEI, B-blocker or Ca blocker as first agent • Added furosemide, doxazosin, clonidine, hydralizine • Followed up to 12 years, including cohort period, for death, ESRD, or doubling creatinine

12. Findings

13. Additional Findings • In ACCORD, intensive therapy reduced non-fatal strokes slightly • In INVEST, uncontrolled BP (over 140) was associated with much worse outcomes • In AASK, patients with some baseline proteinuria did benefit from intensive control

14. Limitations • In ACCORD, standard therapy yielded better than expected outcomes • INVEST, as a cohort study of achieved blood pressure, could be biased. For example, the best controlled patients were on the fewest drugs • AASK used a strange BP control strategy

15. Implications • Three studies suggest intensive BP control is not better in 3 different high-risk groups • Guidelines recommending intensive control need to be reviewed • Tight BP control might not be as important as using good drugs and managing multiple risk factors • I’m planning to ease up a little bit • EXCEPT in non-diabetic CKD patients with proteinuria

16. Atrial Fibrillation • Lenient versus strict rate control in patients with atrial fibrillation • I.C. van Gelder, et al, for “RACE-II” • NEJM, April 2010

17. Purpose • Determine whether strict rate control of atrial fibrillation is necessary • Background • For most patients with a. fib, rate control is equivalent or superior to rhythm control • Existing guidelines recommend strict rate control to improve symptoms, heart failure, and survival. • These guidelines lack an evidence base • Funded by Netherlands heart foundation and pharmaceutical and device makers

18. Method • Randomized clinical trial, unblinded • 614 Dutch patients • In permanent atrial fibrillation < 1 year, resting pulse > 80, on anticoagulation or aspirin • Used B-blockers, Ca-blockers, Dig to achieve • Strict control (P < 80 at rest, 110 with moderate exercise) OR • Lenient control (P<110 at rest) • Followed 3 years for CV for composite of CV death, stroke, CHF, bleeding, embolism, arrhythmias, pacers, defibrillators

19. Results

20. Limitations • 3 year follow-up • Rate-related complications could possibly take longer to develop • Relatively active, low-risk group • But subanalysis of higher risk subjects was the same • Unblinded – opportunity for different behaviors • I do not see it

21. Implications • Guidelines for rate control in atrial fibrillation need to be re-assessed • At least in lower risk patients over 3 years, strict rate control may offer no evident advantage • I will ease up my efforts to control rate in A Fib.

22. Hepatic Encephalopathy • Rifaximin treatment in hepatic encephalopathy • NM Bass et al. • NEJM, March 2010 • Funded by makers of rifaximin, authors received money and several are employed or on the board

23. Purpose • Establish whether rifaximin can improve maintenance of remission from hepatic encephalopathy • Background information • Rifaximin previously shown effective for treating acute cirrhosis-related hepatic encephalopathy • Very limited trial evidence of any chronic treatment (including lactulose) • Rifaximin recently released in US

24. Method • Randomized clinical trial, blinded • 299 patients in Russia, Canada, US • Cirrhosis and at least 2 episodes encephalopathy, in remission • No CRF or other major illness • Received Rifaximin 550 mg bid OR placebo • Lactulose permitted, not required • Followed 6 months for new episode of encephalopathy

25. Results NNT for one hospitalization for HE = 11 for 6 months

26. Limitations • Subjects not required to take lactulose • 10% of control group received no preventive treatment for hepatic encephalopathy • Price of Rifaximin is stunning • 1 month = $1,300 • $85,000 to prevent one hospitalization for HE

27. Implications • Rifaximin is effective for preventing hepatic encephalopathy in patients with cirrhosis and prior HE. • Whether it is superior to properly used lactulose is unproven • Rifaximin is extraordinarily expensive • Lactulose costs 94% less • I will use rifaximin, but only in patients who are clearly failing lactulose therapy

28. COPD Exacerbations • Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease • MB Rothberg et al. • JAMA, May 2010 • Funding not reported • No apparent commercial funding

29. Purpose • Determine whether giving antibiotics to patients hospitalized for COPD exacerbations improves outcomes • Background Information • ACP recommends antibiotics for patients with increased or purulent sputum • Only relatively small, older trials support this

30. Method • Cohort study using large multi-hospital database • 84,000 hospital discharges for COPD in US • Age at least 40, not admitted to ICU, not discharged within 2 days, not diagnosed with bacterial infection • Assessed whether at least 2 days of antibiotic given • Followed for mechanical ventilation, inpatient mortality, 30-day readmission

31. Results • Of 84,621 hospitalizations for COPD: • 79% received antibiotics within first 2 days • Antibiotics were MORE commonly used in patients who • Were white • Had no recent COPD admissions • Did not have heart failure • Lived in the South • Went to non-teaching hospitals • Got ABG’s and IV steroids

32. More Results NNT to prevent 1 death = 200

33. Limitations • Database study • Insufficient detail to determine why subjects did/didn’t get antibiotics • Cohort Study • Obvious confounding opportunities • Might expect more seriously ill patients to receive antibiotics • Did not identify subgroups who did/didn’t get the benefits

34. Implications • Antibiotics may be more helpful than I previously thought for hospitalized COPD patients • Academic centers have been less inclined to use antibiotics in this setting • I will be substantially more inclined to use them • Recall last year’s report of importance of antibiotics for “chest infections”

35. The Ratty Renal Artery • Revascularization versus medical therapy for renal-artery stenosis • NEJM, November 2009 • The ASTRAL investigators • Funded by UK government and Medtronic

36. Purpose • Determine whether revascularizing atherosclerotic renal arteries improves outcomes, compared to medical therapy alone • Background information • Renal artery stenosis is associated with refractory hypertension and CKD • Revascularization, whether open or endovascular, is commonly performed • Evidence of benefit is lacking • Significant rates of serious complications

37. Method • Randomized clinical trial, unblinded • 806 patients in the UK with “substantial” atherosclerotic RAS • Found because of problematic hypertension, unexplained kidney dysfunction • Not “requiring” revascularization within 6 months, approachable by endovascular route, MD uncertain of benefit • Received angioplasty +/- stent OR not • All received locally determined medical therapies • Followed 5 years for rate of decline in renal function, and multiple secondary outcomes

38. Results • Of 403 patients assigned to revascularization • 335 attempted • 317 successful, most with stent • Of 403 assigned to medical therapy: • 24 eventually revscularized • Baseline GFR 40, SBP 150

39. More Results • No difference in GFR decline • Both groups had very slow decline • No difference in renal, cardiac, survival outcomes • Frequent and severe complications of procedure • 5% of patients • Death, MI, renal failure, arterial perforation, systemic embolization, hemorrhage

40. Limitations • Unclear who was excluded • Perhaps physicians are good at selecting who might or might not benefit from RAS correction • The rate of disease progression was much lower than expected

41. Implications • At least for a substantial subset of patients with RAS, revascularization • Is dangerous • Doesn’t do any good • Current medical therapy may be better than we imagine • I won’t be referring many patients for revascularization • I won’t be looking for RAS much, either

42. So Many Shots… • Three-year efficacy of complex insulin regimens in type 2 diabetes • RR Holman et al. • NEJM. October 2009 • Funded by insulin maker, which had a major role in study design and execution

43. Purpose • Determine whether different strategies of insulin administration lead to different glycemic control • Background Information • Relatively few comparisons of type of insulin for diabetes • Recall that ACCORD, ADVANCE, AND the VA trial all suggest that tight glycemic control is not helpful and may be dangerous

44. Method • Randomized clinical trial, unblinded • 708 UK/Irish subjects with DM-2, A1C 7-10 • On metformin and sulfonylurea, never insulin or TZD • Started on one of: • Daily detimir • TID prandial aspart added if needed • BID 70/30 biphasic • Midday prandial aspart added if needed • TID prandial aspart • Daily detimir added if needed • Followed 3 years for A1C, Hypoglycemia, quality of life, many others

45. Results

46. Limitations • Most patients in all groups needed a second type of insulin • Target A1C of 6.5 likely increased • Insulin needs • Hypoglycemia • 15-25% dropout rate

47. Implications • Single daily long-acting insulin may be as good or better than other insulin strategies • Similar glycemic control • Less hypoglycemia • Less weight gain • Possibly lower mortality? • Glycemic control target remains unclear • I will use a basal insulin approach • This applies only to Type 2 diabetes

48. Another Look at the Colon? • Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial • WS Atkin et al • The Lancet, May 2010 • Funded by the UK government

49. Purpose • Establish whether a single flex sig can reduce colon cancer incidence and mortality • Background information • Colorectal cancer is common • Annual or biennial fecal occult blood testing has been demonstrated to reduce colon cancer mortality • Periodic colonoscopy, barium enema, flex sig and various combinations have been widely used for screening, but evidence of mortality benefit is lacking

50. Method • Randomized clinical trial, unblinded • 170,432 UK residents • Age 55-64 • No prior colon cancer, recent screening, other major illness, or strong family history • Single flex sig • Referred to colonoscopy if • Large or multiple polyps • Villous component • Severe dysplasia or malignancy • Followed 10-15 years for colorectal cancer incidence, and colorectal cancer death