Faculty Peer Reviewed
According to the 2010 Heart Disease and Stroke Statistics update of the American Heart Association, there are 17.6 million Americans living with coronary heart disease (CHD) . Fortunately, mortality from heart disease is on the decline in the United States and in countries with advanced health care, likely due to better management of acute coronary syndrome (ACS) and a reduction in lifestyle risk factors such as smoking. However, for the millions of Americans with stable ischemic heart disease (SIHD), there is ambiguity over the best course of treatment. While there is little doubt that revascularization reduces mortality in the setting of ACS, there remains significant controversy over how to manage SIHD. For example, if a patient has angina and documented severe coronary artery disease, should he receive guideline-directed medical therapy (GDMT), followed by revascularization if his symptoms persist? GDMT would entail beta blockers, ACE inhibitors, statins, and a daily aspirin, in addition to lifestyle modifications which include smoking cessation, exercise, and a healthy diet. Or, should he instead receive immediate revascularization with GDMT?
The COURAGE* trial in 2007 demonstrated that initial management with revascularization plus optimal medical therapy (OMT) did not reduce the risk of death or non-fatal myocardial infarctions (MI) compared with OMT alone . In COURAGE, which followed 2287 patients with SIHD in multiple centers across the United States and Canada, the revascularization and conservative medical management groups had similar outcomes in the primary endpoint of death from any cause and non-fatal MI (19% and 18.5%, respectively, p=0.62). Additionally, hospitalization for ACS was approximately the same in both groups at 12% (p=0.56). The BARI 2D* trial showed similar results in patients with diabetes mellitus and stable angina. There was no significant difference in survival rates between the revascularization and medical therapy groups at 5 years of follow-up (88.3% and 88.2%, respectively, p=0.89) . Interestingly, both COURAGE and BARI 2D showed greater freedom from angina for patients undergoing prompt revascularization. These differences are no longer significant after several years of follow-up, which may partly be a result of the high rate (almost 40%) of revascularization in the OMT only group . More recently, Brown and colleagues (2012) performed a meta-analysis of 8 randomized controlled trials from 1970 to 2011, and arrived at similar conclusions as the aforementioned trials .
Taken together, these studies suggest that GDMT should be started before percutaneous coronary intervention (PCI), and have changed the way the medical profession thinks about stents. It created a paradigm shift from the “clogged pipe” model in which a coronary artery is thought to slowly accumulate plaque and cause decreasing blood flow to distal myocardium over time. Newer models now suggest a systemic atherosclerotic process, in which there are multiple plaques in the coronary arteries. These plaques can then rupture at any time, forming a clot and causing an MI . Therefore, those opposed to immediate revascularization argue that it is not feasible to balloon and stent each plaque, but instead advocate that the underlying disease be treated with medical therapy.
However, a study performed by Spertus and colleagues (2011) questions the impact of the COURAGE trial on general medical practice. The authors examined the National Cardiovascular Data Registry and found that patients undergoing PCI for SIHD only received a trial of GDMT less than half the time, and the rates did not change significantly after publication of the COURAGE trial . This may be due to important limitations in both COURAGE and BARI 2D. It can be argued that these trials did not enroll enough high risk-patients. For example, approximately 30% of patients in BARI 2D had a myocardial jeopardy index (MJI) < 25% and another 40% of patients had a MJI < 50%. Eighteen percent of the screened population in COURAGE were excluded due to “logistic reasons” and it is unclear how patients enrolled in the study differed from those not enrolled. Additionally, thousands of patients with SIHD were excluded from these trials, raising the question of selection bias and whether the results can be applied to the general patient population. Lastly, 97% of PCIs in the COURAGE trial were with bare metal stents, as drug-eluting stents were not available until the closing years of the trial. Although the authors do not consider this a limitation, more recent data, including a meta-analysis by Bangalore and colleagues (2012) and a study by Palmerini and colleagues (2012), demonstrate significant reductions in stent thrombosis and MI with newer generation drug-eluting (everolimus) stents [8-9].
The National Institutes of Health (NIH) recently awarded NYU Langone Medical Center an $84 million grant to determine the best course of management for patients with SIHD. The trial, called ISCHEMIA*, hypothesizes that patients with moderate-to-severe ischemia (as determined by stress test imaging) will benefit from early revascularization via PCI or coronary artery bypass grafting (CABG) . The trial, which expects to enroll 8000 patients across 400 research centers around the world, partly bases this hypothesis on an observational study from Cedars-Sinai. In this study, 10,627 patients underwent myocardial perfusion imaging, and those with at least moderate ischemia (>10%) had fewer cardiac deaths and experienced significant ischemic reduction with revascularization than patients treated with GDMT alone after a 3-year follow-up period . Furthermore, a COURAGE trial nuclear substudy looked at COURAGE patients with moderate-to-severe pre-treatment ischemia, and found that PCI and OMT combined resulted in greater reduction of ischemia than with OMT alone . However, as this was a substudy, there is still a need for a randomized clinical trial to compare coronary revascularization with OMT to OMT alone in a high-risk population, which is where ISCHEMIA will fill the void. The ISCHEMIA authors also argue that the COURAGE and the BARI 2D trials randomized patients after catheterization, not before, and may have excluded higher-risk patients who may have benefitted more, thus creating a significant selection bias. The ISCHEMIA study uses a unique protocol where eligible patients undergo CT angiography (CTA) first to rule out severe left main disease and normal coronary arteries. The results of the CTA are otherwise blinded, such that patients without the above findings are randomized to coronary revascularization with OMT or OMT alone prior to coronary angiography, thereby reducing the risk of selection bias related to knowledge of exact coronary anatomy. 
According to the American Heart Association, it is estimated that 600,000 stents are placed per year, costing upwards of $12 billion dollars per year . Although the risk of stroke, myocardial infarction, kidney damage, and life-threatening allergic reactions is low in the setting of contemporary technique, adjunctive medical therapy, and newer generation drug-eluting stents, when they do occur they are serious and sometimes fatal. After having a stent placed, there is also a possibility that the stent will occlude again over time and the patient will need to be revascularized. Additionally, patients need to be placed on anti-platelet medication for a period of time, which can significantly increase the chance of adverse bleeding events, and there is still uncertainty over the duration of therapy. Studies such as PRODIGY* show no difference between 6 months and 2 years of dual-antiplatelet therapy after PCI, while studies such DAPT* are currently ongoing .
In summary, the jury is still out over the best course of treatment for patients with stable angina, especially those categorized as high-risk based on imaging. Current guidelines suggest revascularization in patients with SIHD who have severe angina refractory to medical treatment, while acknowledging that PCIs do not improve survival in non-ACS settings. Trials such as ISCHEMIA will help guide the management of patients with stable angina and evidence of moderate to severe ischemia on physiologic studies, and ultimately, the decision to stent or not to stent in SIHD will have significant repercussions on the landscape of health care, and on the management of millions of Americans.
*Clinical Trial Acronyms:
COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation
BARI 2D: Bypass Angioplasty Revascularization Investigation 2 Diabetes
ISCHEMIA: International Study of Comparative Health Effectiveness with Medical and Invasive Approaches
PRODIGY: Prolonging Dual Antiplatelet Treatment after Grading Stent-Induced Intimal Hyperplasia
DAPT: Dual Antiplatelet Therapy Study
Anish Vani is a 4th year medical student at NYU School of Medicine
Peer reviewed by Binita Shah, MD, Medicine, NYU Langone Medical Center
Image courtesy of Wikimedia Commons
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