SNOWMASS, COLO. – The concept that silent myocardial ischemia is clinically detrimental has fallen by the wayside, and routine screening for this phenomenon can no longer be recommended, Patrick T. O’Gara, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.
What a difference a decade or 2 can make.
“Think about where we were 25 years ago, when we worried about people who had transient ST-segment depression without angina on Holter monitoring. We would wig out, chase them down the street, try to tackle them and load them up with medications and think about balloon [percutaneous transluminal coronary angioplasty]. And now we’re at the point where it doesn’t seem to help with respect to quality of life, let alone death or myocardial infarction,” observed Dr. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.
The end of the line for the now-discredited notion that silent ischemia carries clinical significance approaching that of ischemia plus angina pectoris was the landmark ISCHEMIA trial, reported in November 2019 at the annual scientific sessions of the American Heart Association. This randomized trial asked the question: Is there any high-risk subgroup of patients with stable ischemic heart disease not involving the left main coronary artery for whom a strategy of routine revascularization improves hard outcomes in the current era of highly effective, guideline-directed medical therapy?
The answer turned out to be no. At 5 years of follow-up of 5,179 randomized patients with baseline stable coronary artery disease (CAD) and rigorously determined baseline moderate or severe ischemia affecting more than 10% of the myocardium, there was no difference between patients randomized to routine revascularization plus optimal medical therapy versus those on optimal medical therapy alone in the primary combined outcome of cardiovascular death, MI, heart failure, cardiac arrest, or hospitalization for unstable angina.
Of note, 35% of participants in the ISCHEMIA trial had moderate or severe silent ischemia. Like those who had angina, they achieved no additional benefit from a strategy of routine revascularization in terms of the primary outcome. ISCHEMIA participants with angina did show significant and durable improvements in quality of life and angina control with routine revascularization; however, those with silent ischemia showed little or no such improvement with an invasive strategy.
That being said, Dr. O’Gara added that he supports the ISCHEMIA investigators’ efforts to obtain funding from the National Institutes of Health for another 5 years or so of follow-up in order to determine whether revascularization actually does lead to improvement in the hard outcomes.
“Remember, in the STICH trial it took 10 years to show superiority of CABG [coronary artery bypass surgery] versus medical therapy to treat ischemic cardiomyopathy [N Engl J Med 2016; 374:1511-20]. My own view is that it’s too premature to throw the baby out with the bathwater. I think shared decision making is still very important, and I think, for many of our patients, relief of angina and improved quality of life are legitimate reasons in a low-risk situation with a good interventionalist to proceed,” he said.
Dr. O’Gara traced the history of medical thinking about silent ischemia. The notion that silent ischemia carried a clinical significance comparable with ischemia with angina gained wide credence more than 30 years ago, when investigators from the National Institutes of Health–sponsored Coronary Artery Surgery Study registry reported: “Patients with either silent or symptomatic ischemia during exercise testing have a similar risk of developing an acute myocardial infarction or sudden death – except in the three-vessel CAD subgroup, where the risk is greater in silent ischemia” (Am J Cardiol. 1988 Dec 1;62:1155-8).
“This was a very important observation and led to many, many recommendations about screening and making sure that you took the expression of ST-segment depression on exercise treadmill testing pretty seriously, even if your patient did not have angina,” Dr. O’Gara recalled.
The prevailing wisdom that silent ischemia was detrimental took a hit in the Detection of Ischemia in Asymptomatic Diabetics (DIAC) trial. DIAC was conducted at a time when it had become clear that type 2 diabetes was a condition associated with increased cardiovascular risk, and that various methods of imaging were more accurate than treadmill exercise testing for the detection of underlying CAD. But when 1,123 DIAC participants with type 2 diabetes were randomized to screening with adenosine-stress radionuclide myocardial perfusion imaging or not and prospectively followed for roughly 5 years, it turned out there was no between-group difference in cardiac death or MI (JAMA. 2009 Apr 15;301:1547-55).
“This pretty much put the lid on going out of one’s way to do routine screening of this nature in persons with diabetes who were considered to be at higher than average risk for the development of coronary disease,” the cardiologist commented.
Another fissure in the idea that silent ischemia was worth searching for and treating came from CLARIFY, an observational international registry of more than 20,000 individuals with stable CAD, roughly 12% of whom had silent ischemia, a figure in line with the prevalence reported in other studies. The 2-year rate of cardiovascular death or MI in the group with silent ischemia didn’t differ from the rate in patients with neither angina nor provocable ischemia. In contrast, rates of cardiovascular death or MI were significantly higher in the groups with angina but no ischemia or angina with ischemia (JAMA Intern Med. 2014 Oct;174:1651-9).
“There’s something about the expression of angina that’s a very key clinical marker,” Dr. O’Gara observed.
He noted that just a few months before the ISCHEMIA trial results were released, a report from the far-smaller, randomized second Medicine, Angioplasty, or Surgery Study “threw cold water” on the notion that stress-induced ischemia in patients with multivessel CAD is a bad thing. Over 10 years of follow-up, the risk of major adverse cardiovascular events or deterioration in left ventricular function was identical in patients with or without baseline ischemia on stress testing performed after percutaneous coronary intervention, CABG surgery, or initiation of medical therapy (JAMA Intern Med. 2019 Jul 22. doi: 10.1001/jamainternmed.2019.2227).