Understanding the ORBITA and COURAGE Trials in Stable Angina: Key Insights

Case Study 14 PCI in Stable Angina (Bechhofer) Materials ORBITA: Results Al-Lamee, et al., Lancet , 391, 31-40 (2018); Comments by Brown & Redberg in the same issue; The 2/12/2018 NYT editorial by Aaron Carroll https://www.nytimes.com/2018/02/12/upshot/heart-stents-are-useless-for-most-stable-patients-theyre-still-widely-used.html and also the podcast https://www.medpagetoday.com/cardiology/pci/71340 1

14. PCI 14. PCI in Stable Angina in Stable Angina Key Words: Interpretation, Endpoints, Device Trials, Blinding, Ethics of Sham Procedures, Drop-ins (Control Group Noncompliance) Rick Chappell, Ph.D. Professor, Department of Biostatistics and Medical Informatics University of Wisconsin Medical School Stat 542 2

PCI in Stable Angina Results and Controversy Surrounding Two Key Trials, COURAGE (NEJM 2007) and ORBITA (Lancet 2017) Robin Bechhofer March 15, 2018 For BMI 542

Motivation for Discussion Since its debut a week ago, the ORBITA trial has provoked the most furious debate in cardiology since the COURAGE trial a decade earlier.

Background Coronary artery disease (CAD) Most common heart disease: > 3 million US cases per year Leading cause of death for both men and women Atherosclerosis: fat deposits (plaque) restrict blood flow Can lead to symptoms of chest pain (angina) or heart attack (MI) Acute coronary syndrome (ACS) Sudden blockage of blood supply to the heart muscle Unstable angina Myocardial infarction

Coronary Artery Disease and PCI Treatments for CAD blockages Medical treatment Coronary artery bypass graft (CABG) Percutaneous coronary intervention (PCI) Balloon angioplasty Stent (bare metal or drug-eluting) Previous trials had shown that PCI reduces incidence of death and MI in patients who present with ACS PCI decreases frequency of angina and improves short-term exercise performance

COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation Overview of trial Sponsored by Department of VA Cooperative Study Program Randomized, multicenter Subjects entered from 1999-2004 Follow-up period of 2.5 to 7.0 years (median 4.6) Population Patients with objective evidence of myocardial ischemia and significant coronary disease 2287 subjects from 50 sites in US and Canada, randomized 1:1 1149 to undergo PCI with optimal medical therapy 1138 to receive optimal medical therapy alone

COURAGE Medical Therapy Antiplatelet therapy with aspirin or clopidogrel Metroprolol (beta blocker) Amlodipine (calcium channel blocker) Isosorbide mononitrate (dilates blood vessels) Lisinopril or losartan (ACE inhibitor) Simvastatin alone or in combination with ezetimibe (statin) Exercise and/or niacin or fibrates to increase HDL

COURAGE Clinical Outcomes Primary outcome: composite of death from any cause and non-fatal MI PCI group: 211 events, 19.0% cumulative event rate MT group: 202 events, 18.5% cumulative event rate Hazard ratio 1.05; 95% CI, 0.87 1.27; p=0.62 Secondary outcomes: Death, MI, stroke: HR 1.05; CI 0.87 1.27; P=0.62 Hosp for ACS: HR 1.06; CI 0.84 1.37; P=0.56 Non-fatal MI: HR 1.13; CI 0.89 1.43; P=0.33

COURAGE Outcomes Favoring PCI Group Percent of subjects angina-free (%PCI vs MT groups; p-value) At baseline: 12 vs. 13% At Year 1: 66 vs 58%; P<0.001 At Year 3: 72 vs 67%; P=0.02 At Year 5: 74 vs 72% Revascularization (PCI or CABG) PCI group: 228, MT group: 348 HR 0.60; CI 0.51 to 0.71 ; P<0.001

Conclusion of Authors Our findings reinforce existing clinical practice guidelines, which state that PCI can be safely deferred in patients with stable CAD provided that intensive, multifaceted medical therapy is instituted and maintained. Although the addition of PCI to optimal medical therapy reduced the prevalence of angina, it did not reduce long-term rates of death, nonfatal MI and hospitalization for ACS.

Points Raised in Accompanying Editorial Treatments are designed to make people feel better or live longer. Asymptomatic patients are often referred for PCI. Substantial increase in proportion of angina-free patients in MT group derives mostly from intensive control of risk factors. Despite widespread belief that PCI may reduce incidence of cardiac events, findings of study are understandable. The COURAGE trial should lead to changes in the treatment of patients with stable CAD, with expected substantial health care savings. PCI should not play a major role as part of a secondary prevention strategy.

Concerns Raised in Letters to the NEJM Editor Authors overestimated number of elective procedures results reflect findings in only small minority of patients with CAD Patient-selection bias (35,539 screened, 2287 randomized) PCI methodology (not all vessels stented, not drug-eluting stents) Failed to stratify by ischemic burden Analyzed ITT, but lots of cross-over (33% subsequent revascularization in MT group) Possible under-treatment of clopidogrel in those who received stents

Truth and Consequences of COURAGE Expedited publication in JACC by 14 authors Examine the construct, execution, and observations of the COURAGE trial (the truth ) Findings are nothing new Subject selection, low levels of angina Underpowered (low event rate) Surprisingly high rate of crossover Non-optimal performance of PCI; underuse of DES Use of all cause mortality might have obscured important differences Disparity in outcomes based on where procedure was performed

COURAGE Under Fire Series of point, counterpoint to claims in previous article Enrollment criteria in COURAGE were conventional Most patients undergoing elective PCI often do so under belief that it prolongs their life or prevents heart attack If the principal benefit of PCI in stable disease lies in relief of symptoms and improvement in QOL, why are PCIs being performed in asymptomatic patients? Standard of performance in COURAGE was high Although CABG clearly provides more complete revascularization than PCI, it does not prevent more death or MI Crossover was similar to other revascularization trials; subsequent revascs are manifestation of progressive nature of disease Many patients with stable angina or asymptomatic disease are undergoing PCI without having received sufficient medical therapy

Why Many Will Resist COURAGE Conclusions Eliot Freidson identified 5 traits that characterize typical clinicians We believe in what we are doing. When things go right, we take the credit. We prefer action to inaction. Even action with little chance of success is preferred over no action at all. We are pragmatic. We see apparent cause-effect relationships even in the absence of any theoretic foundation. We are highly subjective. We depend more on gut feelings than on book knowledge. We emphasize uncertainty in our defense. When things go wrong, it is not our fault.

ORBITA: Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina Background >500,000 PCI procedures done annually worldwide for stable angina Angina relief primary reason for PCI in stable CAD Data from unblinded randomized trials show significant improvement in exercise time, angina relief, QOL improvement from PCI Placebo effects known to be larger for invasive treatments Decisiveness and certainty of interventionists Cardiologists resistant to idea of placebo-controlled trial Widespread perception that PCI unquestionably improves angina Might be unethical to expose patients to invasive placebo procedure Essential to identify true efficacy of intervention

ORBITA Overview Overview of Trial Sponsored by NIHR Research Centre (investigator-initiated) Multicenter (UK), randomized, double-blind, sham placebo procedure controlled trial 2014 through 2017 Goal: to assess the efficacy of PCI compared with a sham placebo procedure for angina relief among patients with stable angina Population Patients with stable angina and evidence of severe single-vessel stenosis After 6 weeks of medication optimization, 200 subjects randomized 1:1 to

ORBITA Primary Outcome Primary endpoint Difference in exercise time increment from pre-randomization to 6 week visit Power calculation Evidence from previous studies showed that single antianginal therapies provide improvements in exercise time of 48-55 seconds ORBITA conservatively designed to be able to detect effect size of 30 seconds Results PCI group: +28.4 seconds; 95% CI 11.6 to 45.1 Placebo: +11.8 seconds; 95% CI 7.8 to 31.3

ORBITA Additional Outcomes Efficacy endpoints Time to 1 mm ST depression Peak oxygen uptake Seattle Angina Questionnaire: Physical Limitation; Angina Frequency; Angina Stability EQ-5D-5L Peak stress wall motion index score (significant treatment effect, though not clinically important) Duke treadmill score Safety results No deaths SAEs

ORBITA Conclusions ORBITA made a blinded comparison of PCI and a placebo procedure in patients with stable angina and severe coronary stenosis. The primary endpoint of exercise time increment showed no difference between groups. The trial suggests that the common clinical observation of symptomatic improvement from PCI might well contain a large placebo component. Placebo-controlled efficacy data could be just as important for assessing invasive procedures, where the stakes are higher, as for assessing pharmacotherapy, where it is already standard practice.

Points Raised in Accompanying Editorial ACC and ESC recommend PCI to improve symptoms only in patients with unacceptable angina despite guideline-directed medical therapy Only half of all PCI procedures for stable CAD are appropriate by criteria Fewer than half of patients undergoing PCI receive optimal medical therapy Results of ORBITA show (once again) why regulatory agencies, the medical profession, and the public must demand high-quality studies before approval and adoption of new therapies. ORBITA investigators are to be applauded for rigor of their trial. ORBITA highlights the importance of including sham controls and double blinding in a trial. Health-care providers should focus attention on treating patients with stable CAD with optimal medical therapy and on improving the lifestyle choices that represent a large proportion of modifiable CV risk.

Criticisms/Caveats in Cardiosource Articles Clinical consequences largely already supported by guidelines Trial was too small to answer such a big question Lack of precision in estimating effect sizes Changes in exercise time and Duke treadmill numerically higher in PCI group Subjects selection Low frequency of multi-vessel CAD Low angina burden prior to randomization Questionable choice of endpoint Exercise time as primary endpoint Short duration of F/U Less about lack of effect of PCI, and more about power of optimal medical therapy Medical optimization phase more intensive than routine clinical practice Patients prefer few medications

Milton Packer: What Are the Real Lessons from the ORBITA Trial? Just think about it: If PCI is not warranted in ORBITA-type patients, then millions of dollars are being spent for a procedure that does not add anything to current medical therapy. If payers stopped paying for PCI in ORBITA-type patients, then cardiologists, hospitals and medical schools would lose a major funding source. The legacy of ORBITA is: if an investigator presents the results of unpopular research at a scientific meeting, he/she should be prepared to fight an all-out war on social media. Some are saying that PCI did not work in the trial, because patients were receiving medical therapy that was too good. I do angioplasty and I have grateful patients. It s not rocket science

References COURAGE Optimal Medical Therapy with or without PCI for Stable Coronary Disease. Boden et al, NEJM, April 12, 2007 Editorial: Does Preventive PCI Work? Hochman and Steg, NEJM, April 12, 2007 PCI for Stable Coronary Disease, correspondance. NEJM, July 26, 2007 The Truth and Consequences of the COURAGE Trial. Kereiakes et al, JACC, October 16, 2007. COURAGE Under Fire. Diamond and Kaul, JACC, October 16, 2007 ORBITA Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomized controlled trial. Al-Lamee et al; Lancet,