COURAGE

1. COURAGE William E. Boden et al. N Engl J Med 2007;356:1503-1516 Discussant: David Harpaz, M.D.

2. COURAGE Clinical Outcomes Utilizing Revascularization and Aggressive Guideline-Driven DrugEvaluation Optimal Medical Therapy with or without PCI for Stable Coronary Disease

3. Clinical Presentation • 65 y.o. male • Hypertension, Diabetes, Dyslipidemia • Effort AP for 6 months • Ischemic imaging defect

4. First coronary angioplasty lesion (circles) two days before (A), immediately after (B), and one month after (C) balloon dilation The First Coronary Angioplasty for Stable CAD; 1977

5. Conventional Wisdom • Treatment Assumptions in CAD Management: • Patients with symptomatic CAD and chronic angina who have significant coronary stenoses “need” revascularization • Revascularization is required to improve prognosis • PCI is less invasive than CABG surgery (i.e., is safer) and, therefore, should be selected

6. Background • More than 1 million PCI procedures are performed in the U.S. annually, the great majority of which are undertaken electively in patients with stable CAD • Although successful PCI of flow-limiting stenoses might be expected to reduce the rate of death, MI or hospitalization for ACS, prior studies have shown only that PCI decreases the frequency of angina and improves short-term exercise performance

7. A North American Trial 19 US Non-VA Hospitals 50 Hospitals 2,287 patients enrolled between 6/99-1/04 15 VA Hospitals 16 Canadian Hospitals

8. Hypothesis PCI + Optimal Medical Therapy will be Superior to Optimal Medical Therapy Alone

9. Primary Outcome Death or Nonfatal MI

10. Design • Randomization to PCI + Optimal Medical Therapy vs Optimal Medical Therapy alone • Intensive, guideline-driven medical therapy and lifestyle intervention in bothgroups • 2.5 to 7 year (mean 4.6 year) follow-up

11. Inclusion Criteria • Men and Women • 1, 2, or 3 vessel disease • (> 70% visual stenosis of proximal coronary segment) • Anatomy suitable for PCI • CCS Class I-III angina • Objective evidence of ischemia at baseline • ACC/AHA Class I or II indication for PCI

12. Exclusion Criteria • Uncontrolled unstable angina • Complicated post-MI course • Revascularization within 6 months • Ejection fraction <30% • Cardiogenic shock/severe heart failure • History of sustained or symptomatic VT/VF

13. Risk Factor Goals

14. Pharmacologic Anti-platelet: aspirin; clopidogrel in accordance with established practice standards Statin: simvastatin ± ezetimibe or ER niacin ACE Inhibitor or ARB: lisinopril or losartan Beta-blocker: long-acting metoprolol Calcium channel blocker: amlodipine Nitrate: isosorbide 5-mononitrate Optimal Medical Therapy Applied to Both Arms by Protocol and Case-Managed

16. 3,071 Patients met protocol eligibility criteria Enrollment and Outcomes 784 Did not provide consent - 450 Did not receive MD approval - 237 Declined to give permission - 97 Had an unknown reason 2,287 Consented to Participate (74% of protocol-eligible patients) 1,138 Were assigned to medical-therapy group 1,149 Were assigned to PCI group 46 Did not undergo PCI 27 Had a lesion that could not be dilated 1,006 Received at least one stent 97 Were lost to follow-up 107 Were lost to follow-up 1,138 Were included in the primary analysis 1,149 Were included in the primary analysis

17. Baseline Clinical andAngiographic Characteristics

18. Baseline Clinical andAngiographic Characteristics

19. Baseline Clinical andAngiographic Characteristics

20. Long-Term Improvement in Treatment Targets (Group Median ± SE Data)

21. At a median 4.6 year follow-up, 21.1% of the PCI patients required an additional revascularization, compared to 32.6% of the OMT group who required a 1st revascularization 77 patients in the PCI group and 81 patients in the OMT group required subsequent CABG surgery Median time to subsequent revascularization was 10.0 mo in the PCI group and 10.8 mo in the OMT group Need for Subsequent Revascularization

22. Survival Free of Death from Any Cause and Myocardial Infarction Optimal Medical Therapy (OMT) 1.0 0.9 0.8 PCI +OMT 0.7 Hazard ratio: 1.05 95% CI (0.87-1.27) P = 0.62 0.6 0.5 0.0 0 1 2 3 4 5 6 7 Years Number at Risk Medical Therapy 1138 1017 959 834 638 408 192 30 PCI 1149 1013 952 833 637 417 200 35

23. Overall Survival PCI +OMT 1.0 0.9 OMT 0.8 Hazard ratio: 0.87 95% CI (0.65-1.16) P = 0.38 0.7 0.6 0.5 0.0 0 1 2 3 4 5 6 7 Years Number at Risk Medical Therapy 1138 1073 1029 917 717 468 302 38 PCI 1149 1094 1051 929 733 488 312 44

24. Survival Free of Hospitalization for ACS OMT 1.0 0.9 PCI + OMT 0.8 0.7 Hazard ratio: 1.07 95% CI (0.84-1.37) P = 0.56 0.6 0.5 0.0 0 1 2 3 4 5 6 7 Years Number at Risk Medical Therapy 1138 1025 956 833 662 418 236 127 PCI 1149 1027 957 835 667 431 246 134

25. Survival Free ofMyocardial Infarction OMT 1.0 0.9 PCI + OMT 0.8 0.7 Hazard ratio: 1.13 95% CI (0.89-1.43) P = 0.33 0.6 0.5 0.0 0 1 2 3 4 5 6 7 Years Number at Risk Medical Therapy 1138 1019 962 834 638 409 192 120 PCI 1149 1015 954 833 637 418 200 134

26. Freedom from Angina During Long-Term Follow-up The comparison between the PCI group and the medical-therapy group was significant at 1 year ( P<0.001) and 3 years (P=0.02) but not at baseline or 5 years.

27. Subgroup Analyses Baseline Characteristics Hazard Ratio (95% Cl) Medical Therapy PCI Overall 1.05 (0.87-1.27) 0.19 0.19 Sex Male 1.15 (0.93-1.42) 0.19 0.18 Female 0.65 (0.40-1.06) 0.18 0.26 Age > 65 1.10 (0.83-1.46) 0.24 0.22 ≤ 65 1.00 (0.77-1.32) 0.16 0.16 Race White 1.08 (0.87-1.34) 0.19 0.18 Not White 0.87 (0.54-1.42) 0.19 0.24 Health Care System Canadian 1.27 (0.90-1.78) 0.17 0.14 U.S. Non-VA 0.71 (0.44-1.14) 0.15 0.21 U.S. VA 1.06 (0.80-1.38) 0.22 0.22 1.50 0.25 0.50 1.00 1.75 2.00 PCI Better Medical Therapy Better

28. Subgroup Analyses Baseline Characteristics Hazard Ratio (95% Cl) Medical Therapy PCI Myocardial Infarction Yes 1.15 (0.93-1.42) 0.19 0.18 No 0.65 (0.40-1.06) 0.18 0.26 Extent of CAD Multi-vessel disease 1.10 (0.83-1.46) 0.24 0.22 Single-vessel disease 1.00 (0.77-1.32) 0.16 0.16 Diabetes Yes 1.08 (0.87-1.34) 0.19 0.18 No 0.87 (0.54-1.42) 0.19 0.24 Angina CCS 0-I 1.27 (0.90-1.78) 0.17 0.14 CCS II-III 0.71 (0.44-1.14) 0.15 0.21 Ejection Fraction ≤ 50% 1.06 (0.80-1.38) 0.22 0.22 > 50% 1.06 (0.80-1.38) 0.22 0.22 Previous CABG No 1.06 (0.80-1.38) 0.22 0.22 Yes 1.06 (0.80-1.38) 0.22 0.22 1.50 0.25 0.50 1.00 1.75 2.00 PCI Better Medical Therapy Better

29. Time point PCI ($) Medical therapy ($) p Baseline 7,771 1,751 <0.0001 1 y 10,051 4,153 <0.0001 3 y 19,605 6,661 <0.0001 Quality-of-life-year-gained analyses: A difference of eight days. This translated into a cost of $217,000 per quality of life-year gained. Thus, less than 1% of patients treated with PCI would be deemed a cost-effective approach. Over 99% of estimates of cost effectiveness were in excess of the common benchmark of $50,000. Cost of therapy

30. As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, MI, or other major cardiovascular events when added to optimal medical therapy As expected, PCI resulted in better angina relief during most of the follow-up period, but medical therapy was also remarkably effective, with no between–group difference in angina-free status at 5 years Conclusions

31. Our findings reinforce existing ACC/AHA clinical practice guidelines, which state that PCI can be safely deferred in patients with stable CAD, even in those with extensive, multivessel involvement and inducible ischemia, provided that intensive, multifaceted medical therapy is instituted and maintained Optimal medical therapy and aggressive management of multiple treatment targets without initial PCI can be implemented safely in the majority of patients with stable CAD—two-thirds of whom may not require even a first revascularization during long-term follow-up Implications

32. Stable CAD is usually characterized by relatively stable, inward-remodeling lesions, which produce ischemia and anginal symptoms, and which are easily detected by coronary angiography. Unstable, outward-remodeling plaques do not always cause significant stenosis before rupture and subsequent onset of ACS. In other words, "unstable coronary lesions that lead to MI are not necessarily severely stenotic, and severely stenotic lesions are not necessarily unstable." Comments

33. Comments - 2 • Dr James Stein (University of Wisconsin, Madison): • "Patients don't understand that minor blockages, not seen on stress tests or opened by PCI, cause the vast majority of heart attacks. Most docs know that, but many don't practice that way.“

34. Comments - 3 • Dr Eric Topol (Scripps Translational Science Institute, La Jolla, CA): • "PCI has never been shown to reduce death or MI compared with medical therapy. COURAGE really does not present anything new but simply reinforces that the basis for revascularization is for control of ischemia. There is no surprise with this trial."

35. Stable CAD: PCI vs ConservativeMedical Management Meta-analysis of 11 randomized trials; N = 2,950 Favors PCI Favors Medical Management 0 1 2 Risk ratio (95% Cl) Katritsis DG et al. Circulation. 2005;111:2906-12.

36. Comments - 5 • Drs Judith S Hochman (New York University School of Medicine, NY) and P Gabriel Steg (Université Paris, France): • "The COURAGE trial should lead to changes in the treatment of patients with stable coronary artery disease, with expected substantial healthcare savings". PCI has an established place in treating angina but is not superior to intensive medical therapy to prevent myocardial and death in symptomatic or asymptomatic patients.”

37. Comments - 7 • Dr James Stein: • "Economic incentives favor procedures rather than medical therapy with lifestyle and medications. PCIs are very lucrative for hospitals and doctors; talking to patients and taking care of their risk factors, unfortunately, is not.”

38. Comments - 8 • Dr Salim Yusuf (McMaster University, Hamilton, ON): • “The financial incentives that keep stenting procedure rates higher than warranted. PCI is a $15 billion to $20 billion industry in North America. There are huge vested interests that are going to push back.”

39. Comments - 9 • Dr Salim Yusuf: • “Physicians and patients have been brainwashed and deluded into thinking that PCI will save them, whileinterventionalists fear that if they turn patients away, their referral base will dry up. The reason for PCI is not scientific, it's not medical, it's sociological, and—we all know it,although we don't want to say it—it's economic. It's really time to confront this becausemedicine here has gone wrong.” • "We're going to have a hell of a time putting the genie back in the bottle."

40. Comments - 10 • Dr Gabriel Steg : • European interventionalists say the sense that interventional cardiology is under attack is stronger in the US than on this side of the pond. "It's paranoia. Medicine is medicine; some procedures are useful and some are less useful. Just because a medical trial demonstrates that we don't need to do so many procedures in certain subsets of patients doesn't mean the profession is under attack.I can understand that this is not pleasant news to people who make a living off it, butI thinkthisreallyhas to do with the structure of the profession in the US, fee-for-servicesystems, and things like that."

41. Comments - 11 • Dr Patrick Serruys (Thoraxcenter, Rotterdam, the Netherlands): • “Ifyou are getting money for doing procedures, anddoing procedures became an incentive to do big numbers, thenyou'd take anybody on the street who has a narrowing on their multislice CT scan and put them on the table. . . . If[US interventionalists] feel persecuted it is because theyare doing something wrong. But if they did the kind of practice that the average European interventional cardiologist is doing, they wouldn't feel that way. We are overloaded with patients, we are paid by government, and it doesn't make a difference whether we do one patient or 10 patients. The mood here is good."

42. Comments - 12 • Dr Gabriel Steg : • "One of the consequences of COURAGE…has been that there is less ad hoc angioplasty.Now when interventionalists do an angiogram, they will stop and discuss the dossier and the angiogram with their colleagues and with the surgeons rather than deciding to embark on their own, not only making the diagnosis but choosing the treatment."

43. Comments - 14 • Dr James Stein: • "COURAGE results will provide hard data for physicians concerned about the medicolegal repercussions of not opting to revascularize on the basis of screening results.” • "The problem is fear of malpractice: docs are afraid of getting sued if they don't do a stress test and if they don't do a cath in response to an abnormality.”

44. Dr Robert M. Califf: Defining The Balance Of Risk And Benefit In The Era Of Genomics And Proteomics. Health Affairs 2004: 23;77-87 “One of the most dramatic effects of our national investmentin technology has been the proliferation of imaging technologyand diagnostic tests aimed at stratifying risk, which is a criticalelement of the strategy of personalized medicine. Intuitively,better and more accurate tests should be beneficial. At leastin the short run, however, the story is not so clear. More accuratediagnostic tests that lead to ill-advised intervention can beboth expensive and detrimental to health…. As we enter an era of risk stratificationusing … high-resolutionimaging …,appropriate methods for understanding the downstream effectsof such powerful technology remain elusive, and these methodshave not yet been developed to a refined state. Comments - 15

45. Dr. Bove: If patients continue to experience life-limitingangina on medical therapy or show other evidence of ischemia plus evidence of high risk, then consider angiography and revascularization.  We all may need a little courage to set aside conventional wisdom and recognize the strength of optimal medical therapy – with emphasis on “optimal.” Comments - 16

46. Comments - 17 • Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA): • "COURAGE is going to shake things up in the cath labs, pointing out that the trial addresses a very important segment of the population: the 30% to 40% of patients undergoing catheterization and PCI for stable disease.COURAGE … did not speak to the treatment of patients with refractory symptoms….it's perfectly valid for them to undergo revascularization to improve their symptoms. If patients have real angina, and if they're on one or two meds, or they're very bothered by their symptoms, and if the goal is to relieve those symptoms, not prevent future events, then that's okay."

47. Decline in stent implantation linked to COURAGE results. The Wall Street Journal (5.17.2007) reports: "The number of coronary stents implanted in the U.S. dropped sharply in April…, in what doctors saidwas an unusually quick responseto a study showing the devices provided little advantage over drug therapy in some patients.“The results of the COURAGE trial… have caused doctors and patients to think twice about stenting." "Doctors performed about 71,200 stentings in April... That was down more than 10% from March and down more than 15% from a year earlier." According toGregg W. Stone, a lead clinical researcher for Boston Scientific and Abbott Laboratories,"It's a little surprising, because usually it takes clinical-trial data years to have an impact." Comments - 19

48. Comments - 20 • Dr James Stein: • "The real question is whether cardiologists will have the 'courage' to change the way they practice, which in 2007 flies in the face of the evidence. We know PCI in the setting of an acute coronary syndrome saves lives, but 85% of PCIs in the US are done in stable patients, and of those I'd bet that at least 25% are asymptomatic patients. This study clearly shows something we all knew—but many did not want to believe—that angioplasties don't save lives, except in acutely ill patients, and don't prevent heart attacks. Cardiologists say yes, we know that, we are relieving symptoms, but why are so many done on people who are asymptomatic? And why all the 'screening' stress tests?"

49. THANK YOU FOR YOUR ATTENTION