Top 10 Practice-Changing Articles of 2008

1. Top 10 Practice-Changing Articles of 2008 ACP Colorado Chapter Annual Meeting February 6, 2009 Jamaluddin Moloo, MD, MPH Associate Editor, Journal Watch Cardiac and Vascular Center Departments of Medicine and Radiology University of Colorado jamaluddin.moloo@ucdenver.edu

2. Top 10 Practice-Changing Articles of 2008 • Articles selected from Journal Watch • Sometimes single study, sometimes cluster of studies on one topic • Selection criteria is informal: • Interest to primary care physicians • Important “landmark” studies • Media publicity and patient awareness

4. Medical Therapy vs. PCI in Patients with Stable AnginaNEJM 2008;359:677-87 • Current study is based on the COURAGE trial published in 2007 • The 2007 study assessed clinical outcomes • The 2008 study focused on quality of life

5. Medical Therapy vs. PCI in Patients with Stable AnginaNEJM 2008;359:677-87 • Close to 2300 pts with evidence of myocardial ischemia and at least 70% stenosis in a proximal coronary vessel • Randomized to optimal medical therapy alone vs. optimal medical therapy plus PCI • At a median of 4.6 yrs: • no difference in mortality or MI among medical therapy vs. medical therapy plus PCI group (18.5 vs. 19%)

6. Medical Therapy vs. PCI in Patients with Stable AnginaNEJM 2008;359:677-87 • At 3 months significant difference between groups • No significant difference at 36 mos

7. Kaplan-Meier Curve NEJM 2008;359:677-87

8. Medical Therapy in COURAGE • Level of control achieved by medical management (baseline vs. 5 yrs): • SBP: 131 vs. 122 • DBP: 74 vs. 70 • LDL cholesterol: 100 vs. 72 • BMI: 28.7 vs. 29.5 • Current smoker: 23% vs. 20%

9. Conclusions from COURAGE • In pts with stable CAD, PCI (compared with optimal medical treatment) does not save lives or prevent MI, but improves symptoms in those with frequent angina for 1-2 yrs • Pursue optimal medical therapy initially, add PCI if medical therapy ineffective • Caveat: very-high-risk pts excluded (EF < 30%, left main disease, markedly abnormal ETT)

10. Another study on PCI…

11. Frequency of Stress Testing Prior to PCIJAMA 2008;300:1765 • Guidelines favor stress testing to document the presence and extent of ischemia prior to elective PCI • Using Medicare data researchers assessed how often patients underwent stress testing prior to elective PCI • Approximately 24,000 pts included • Only 45% had stress testing before PCI • Considerable geographic variation – 22% to 71% • Authors’ conclusions: too much PCI

13. Prevention of Osteoporotic Fractures Osteoporosis Int 2008;19:437-447 & 449-458 • Treatment with bisphosphonates is recommended for: • postmenopausal women with BMD T-scores of 2.5 SD or more below young controls • Individuals who have experienced fractures • Need for therapy is less clear for lower-risk individuals

14. Prevention of Osteoporotic Fractures Osteoporosis Int 2008;19:437-447 & 449-458 For lower risk individuals: • The WHO developed a new model to predict 10-year risk of osteoporotic fractures • Based on large observational trials • Fracture Risk Assessment Tool / “FRAX” • Calculator available online through: www.nof.org / www.shef.ac.uk/FRAX

16. Prevention of Osteoporotic Fractures Osteoporosis Int 2008;19:437-447 & 449-458 • FRAX Tool provides an estimate of an individuals 10-year risk of osteoporotic fracture • When does it become cost-effective to treat with bisphosphonates? • In a cost-effective analysis • Incorporated cost and health consequences of fractures • Cost of medication estimated $600/yr

17. Prevention of Osteoporotic Fractures Osteoporosis Int 2008;19:437-447 & 449-458 Conclusion: • Given a threshold of $60,000 per QALY • Bisphosphonate therapy becomes cost-effective if the 10-year risk of hip fracture is 3% or greater • Example: • 50 yo, WM, 125lbs, 5ft 10 inches, drinks 3 glasses of ETOH/night and has a parent with a hip fracture = risk of hip fracture over 10 yrs is 3.3%

19. Statins for Primary Prevention of CV Disease: The Jupiter Study NEJM 2008;359:2195-207. • Half of all MIs and strokes occur in individuals whose cholesterol levels are below the threshold for treatment • Some studies have shown an independent association between CRP (marker of inflammation) and risk of vascular events • Studies have also shown that statin therapy lowers CRP levels

20. Primary Prevention CVD – Jupiter • In an industry sponsored study • Researchers assessed whether apparently healthy individuals • With LDL cholesterol < 130 mg/dl and CRP > 2 mg/L • Would benefit from treatment with rosuvastatin, 20 mg daily, compared with placebo

21. Primary Prevention CVD – Jupiter • 18,000 individuals enrolled • Included: • women > 60 yo, men > 50 yo (median age 66) • Excluded: • Patients with a history of CVD • Patients with DM • Patients with uncontrolled HTN (SBP>190, DBP>100)

22. Primary Prevention CVD – Jupiter • Baseline characteristics • 57% hypertensive • 12% FH of early CHD • 41% metabolic syndrome (3 of 5: abdominal obesity, high TG, low HDL, high BP, high FBS) • Median LDL 108 mg/dL • Median Hs-CRP 4.3

23. Primary Prevention CVD – Jupiter • Trial stopped after median follow-up of 2 years • At 24 months (rosuvastatin vs. placebo): • Median LDL: 54 vs. 108 • Median CRP: 2.2 vs. 3.5 • Primary endpoint (MI, stroke, UA, revascularization, or CV death): • 1.6% vs. 2.8% (rosuvastatin vs. placebo) • All-cause mortality: • 2.2% vs. 2.8%

24. Primary Prevention CVD – Jupiter • Treat 170 people like those in this trial for 2 years prevent 1 death • Treat 80 people for 2 years prevents 1 CV event • Adverse effect (rosuvastatin vs. placebo): • Median HgbA1C at 24 mos: 5.9% vs. 5.8% • Newly Diagnosed DM: 3% vs. 2.4%

25. JUPITER Trial: What is the Take Home Message? • This was a trial of statin therapy, not CRP • Do the absolute benefits justify the costs? • Long-term safety of rosuvastatin? • Expect cholesterol treatment guidelines to change with this study • CRP testing? Limit testing to those with borderline indications for statins

27. Perioperative β-Blockers – POISE Trial Lancet 2008;371:1839-47. • 2 small trials in 1990s suggested that β-blockers lowered risk of perioperative CV events in high-risk pts undergoing noncardiac surgery • In 2006, 2 medium-sized trials found no benefit

28. Perioperative β-Blockers – POISE Trial Lancet 2008;371:1839-47. • POISE Trial: • Enrolled 8300 patients, age > 45 • who were undergoing non-cardiac surgery and • who had CVD or who were at risk for atherosclerosis • Randomized to: • metoprolol extended release 100 mg 2-4 hrs prior to surgery and 100-200 mg/day post-operatively or • placebo

29. Perioperative β-Blockers – POISE Trial Lancet 2008;371:1839-47. * CV death, non-fatal MI, or non-fatal cardiac arrest. All outcomes at 30 days.

30. POISE: Conclusions • No subgroup benefited • Increase in stroke and mortality mediated in part by hypotension / bradycardia • Conclusion: in my view… • Don’t start β-blockers during the hours before noncardiac surgery in β-blocker-naïve patients • May consider starting β-blocker weeks before surgery in high-risk patients • Ensure that neither BP nor HR is lowered too aggressively

32. New USPSTF Cancer Screening Guidelines Ann Intern Med 2008;149:627,638,659,680 Colon Cancer • New recommendations based on a systematic review and a decision analysis which compared differing testing strategies • Age of Screening: • Initiate screening at age 50 but when to stop? • Individuals 76-85 yrs old: generally recommended against screening • Individuals > 85 yrs old: recommended against screening

33. New USPSTF Cancer Screening Guidelines Ann Intern Med 2008;149:659,627,638,680 Colon Cancer • Screening modality: • Insufficient evidence to recommend stool DNA testing or CT colonography • Also found older less-invasive tests were as effective as colonoscopy at 10-year intervals: • Annual high sensitivity FOBT (Hemoccult SENSA or fecal immunochemical testing) or • Flexible sigmoidoscopy every 5 years with mid-interval Hemocult SENSA testing

34. New USPSTF Cancer Screening Guidelines Ann Intern Med 2008;149:185,192 Prostate Cancer: new guidelines based on a systematic review Age of Screening: • For younger individuals USPSTF maintained the “insufficient evidence” recommendation • Recommended against prostate cancer screening for individuals > 75 yrs old (2002 guideline “insufficient evidence”) • Because screening among individuals > 75 provided small or no benefit and known harms

36. Benefit of Treating HTN in Patients 80 Years and Older - HYVET NEJM 2008;358:1887-98. • Previous HTN trials in the “elderly” focused on individuals 60 to 80 yrs of age • Less is known about patients 80 and older • Some observational studies found a higher mortality with lower BP levels • A meta-analysis of previous RCT looked at the subgroup of patients > 80 yo and found a decrease in stroke but increased mortality

37. Benefit of Treating HTN in Patients 80 Years and Older - HYVET HYVET: • 13 countries, enrolled 3800 pts age > 80 • SBP: 160-200 mm Hg • DBP: <110 mm Hg • Exclusion criteria included: patients with K < 3.5 • At baseline: only 12% had history of CVD, 7% DM, 6% current smokers

38. Benefit of Treating HTN in Patients 80 Years and Older - HYVET • Randomized to: • Indapamide vs placebo • perindopril or placebo was added as needed to achieve target BP of 150/80 mm Hg • Mean follow-up was 2 years • Primary endpoint: any stroke

39. Benefit of Treating HTN in Patients 80 Years and Older - HYVET Results: • At 2 yrs mean SBP/DBP was 15/6.1 mmHg lower in the treatment arm

40. Benefit of Treating HTN in Patients 80 Years and Older - HYVET • Fatal/non-fatal stroke: 2.6% (indapamide) vs. 3.6% placebo (p=0.06) • Death from any cause: 10.1% vs. 12.3% (p=0.02)

41. Benefit of Treating HTN in Patients 80 Years and Older - HYVET • Number Needed to Treat: • Treat 100 patients for 2 years to prevent 1 fatal/non-fatal CVA (not statistically significant) • Treat approximately 50 individuals for 2 years to prevent 1 death

42. Benefit of Treating HTN in Patients 80 Years and Older - HYVET Issues / Questions: • These were generally healthy individuals • What about pts with multiple medical problems who take many meds? • Almost-zero incidence of adverse events – is it too good to be true? • Can we extrapolate from indapamide to HCTZ or to other agents?

44. ARBs: No Significant Advantages • ACE-I reduce mortality, MI, CVA and CHF among patients with CVD or advanced DM • However, up to 20% of patients are unable to tolerate ACE-I • ARB have been shown to reduce adverse events in specific populations such as those intolerant to an ACE-I and with a low EF and CHF • Yet, its potential benefit upon a broader population of patients was not well known

45. ARBs: No Significant Advantages - TRANSCENDLancet 2008;372:1174-83 TRANSCEND: • Industry sponsored • Randomized close to 6000 individuals • With known CV disease or advanced DM • Who were intolerant of an ACE-I • To telmisartan 80 mg or placebo

46. ARBs: No Significant Advantages - TRANSCENDLancet 2008;372:1174-83 TRANSCEND: • Excluded: • Patients with heart failure • SBP > 160 mm Hg • Creatinine > 3.0 mg/dl • Primary outcome: CV death, MI, CVA, or heart failure hosp.

47. ARBs: No Significant Advantages - TRANSCENDLancet 2008;372:1174-83 At baseline: • Mean age 67 • 43% female • 74% CAD, 22% CVA/TIA, 36% DM

48. ARBs: No Significant Advantages - TRANSCENDLancet 2008;372:1174-83 17% • At 5 yrs, no significant difference in primary outcome: CV death, MI, CVA, or heart failure hosp • no significant difference in secondary outcome (data not shown) 15.7%

49. ARBs: No Significant Advantages - TRANSCENDLancet 2008;372:1174-83 TRANSCEND Conclusion: • At best, there was only a modest benefit of telmisartan over placebo among individuals with known CVD or advanced DM who were intolerant to ACE-I • When compared to similar studies of ACE-I, telmisartan appears to have a less robust impact upon outcomes

50. ARBs: No Significant Advantages - PRoFESSNEJM 2008;359;:1225-37 PRoFESS: • Industry sponsored • Over 20,000 individuals with recent ischemic stroke • Randomized to ASA plus dipyridamole or clopidogrel and in a 2 x 2 factorial design, received telmisartan 80 mg or placebo • This study focused on the comparison between telmisartan and placebo