American Heart Association

American Heart Association

November 25, 2019
10 min read

At Issue: ISCHEMIA trials provoke debate on treatment of stable ischemic heart disease

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PHILADELPHIA — Results from the ISCHEMIA and ISCHEMIA-CKD trials of invasive vs. conservative strategies in patients with stable ischemic heart disease were the biggest news to come out of the American Heart Association Scientific Sessions, with some observers saying they were the most important trials in stable ischemic heart disease in more than a decade.

In both trials, patients assigned the invasive strategy, who received optimal medical therapy plus diagnostic catheterization and underwent PCI or CABG based on results of the catheterization, and patients assigned the conservative strategy, who received optimal medical therapy alone and diagnostic catheterization if they failed optimal medical therapy, had similar clinical outcomes. In ISCHEMIA, the invasive group had better outcomes related to quality of life and angina relief, especially in patients with angina, but that was not true in ISCHEMIA-CKD, which exclusively enrolled patients who also had chronic kidney disease (CKD), who were excluded from the main ISCHEMIA trial.

To put the results in context, Healio spoke to a variety of experts, including Darshan Doshi, MD, interventional cardiologist at Massachusetts General Hospital; Kirk N. Garratt, MD, MSc, MSCAI, John H. Ammon Chair of Cardiology, director of the Center for Heart & Vascular Health, Christiana Care, Wilmington, Delaware and past president of the Society for Cardiovascular Angiography and Interventions; Cardiology Today Next Gen Innovator Dharam J. Kumbhani, MD, SM, associate professor in the department of internal medicine and section chief of interventional cardiology at University of Texas Southwestern Medical Center; Nicole L. Lohr, MD, PhD, FACC, assistant professor of medicine (cardiovascular medicine), Froedtert & Medical College Cardiovascular Center, Medical College of Wisconsin; Cardiology Today Chief Medical Editor Carl J. Pepine, MD, MACC, professor of medicine at the University of Florida College of Medicine; Athena Poppas, MD, FACC, FASE, chief of cardiology, director of the Lifespan Cardiovascular Institute and director of echocardiography at Rhode Island, The Miriam and Newport Hospitals and vice president of the American College of Cardiology; and C. Michael Valentine, MD, MACC, cardiologist at Stroobants Cardiovascular Center, Centra Health, Lynchburg, Virginia, and immediate past president of the ACC. – by Erik Swain, Katie Kalvaitis and Scott Buzby

Kirk N. Garratt

Kirk N. Garratt, MD, MSc, MSCAI

The main ISCHEMIA trial showed that, consistent with earlier studies, use of PCI early for management of patients with moderate to severe ischemia is not required to provide benefit as measured by the endpoints of the trial. Good medical therapy is what ought to be used first as a means of managing patients with this heart problem.


We did see, though, that use of PCI early was safe, with no indication of hazard associated with a strategy of early PCI use. Interestingly, there was a signal of lower rates of spontaneous MI within 4 years after treatment for patients who got PCI rather than medical therapy alone. That’s consistent with what we saw in the FAME 2 trial and wasn’t too much of a surprise, but was a gratifying finding from the perspective of interventional cardiology. Having that information now will let us have more meaningful conversations with our patients about how PCI might be able to benefit them.

The big news for interventionalists was the quality of life findings. Those findings were key because in American practice today we don’t typically offer PCI to patients with the promise of lower rates of death or even lower rates of MI. We are offering this therapy to patients primarily as a way of improving their quality of life. The data shown by Spertus show that PCI is superior to medical therapy alone for anginal relief across anginal symptom classes. That’s also going to let us have better conversations with patients about just how PCI might be able to help them.

The types of patients enrolled had moderate to severe ischemia, but they generally did not have severe symptoms. By intention, patients with very severe symptoms were not enrolled, on the belief that angioplasty would likely be needed to help them manage their symptoms. We have to keep that in mind. These were not the most symptomatic nor highest-risk patients. Still, the type of patients who were enrolled are the type of people we see every day. This information is going to help doctors and patients.

For ISCHEMIA-CKD, the similar message is that there is not an indication that PCI is needed in the early management of patients with CKD and moderate to severe ischemia. Rather, medical therapy alone is sufficient to keep them safe. It is much smaller than the main study, so the reliability of the findings will be less. The take-home message is we need to be prudent in the use of PCI in these very high-risk patients. These patients were at high risk for subsequent CVD events, so there was some hope of benefit from aggressive treatment. That was not forthcoming. These patients are also at high risk for procedural complications. While most patients from the invasive group did not have worsening kidney function, that is always a point of anxiety for interventional cardiologists. Most interventional cardiologists, if they’re not already conservative about offering angioplasty in this population, will be going forward.


We don’t have information about the highly ischemic patient, but I don’t think we’ll ever get a chance to study that. Remember, these patients were not enrolled due to the belief that PCI was already indicated for them.

We have to celebrate that we have new, important information to use.

Athena Poppas

Athena Poppas, MD, FACC, FASE

This was a crucial study to do, and the investigators should be commended for seeing it through. The trial design, by not having diagnostic catheterization as an entry point and by having blinded coronary CT, was important to reduce biased sample. The data that Judith Hochman, MD, MA, presented were clear. The question has been answered: Mortality is not reduced by an invasive strategy for patients with chronic stable angina irrespective of degree of ischemia. Time and again, we have seen that optimal medical therapy works very well. 

Yet, even within this study, where patients were followed closely, we saw a large proportion of patients not on a high-intensity statin and with their BP and LDL not at goal. This should encourage us to do more about making sure our patients are adherent to a regimen of optimal medical therapy.

The substudy of patients with CKD adds to the literature, because those can be the most challenging patients. But this is another population that benefits from early optimal medical therapy. Another finding is for the patient concerned with possible dialysis, the study showed that there are tools and clinical pathways that can minimize that risk.

Carl J. Pepine

Carl J. Pepine, MD, MACC

The ISCHEMIA trial results support the position that there is likely to be no advantage for an invasive management strategy over optimal medial therapy among patients with stable ischemic heart disease. For those in the invasive strategy, eight patients out of 10 received coronary revascularization (74% PCI, 26% CABG). From the perspective of someone who was doing angioplasty since 1979, I didn’t believe that PCI changed death or MI outcomes among patients with stable ischemic heart disease and most trials indicated that PCI and CABG are both tied to small increased risks for periprocedural-related MI and, in the case of CABG, also for stroke. Yet, many believed that the initial choice of revascularization strategy would reduce risks for MI and death. ISCHEMIA, with upfront CT angiography to identify patients with left main obstruction and get them to revascularization, proved that among remaining patients, there is not likely to be much difference in outcomes between an optimal medical or an invasive management strategy. Interestingly, the presence of diabetes, new or more frequent angina, more severe CAD (one-, two- or three-vessel obstruction), or more severe ischemia on noninvasive testing did not identify a subgroup with benefit from the invasive strategy. Also interesting, more than one-third of the patients had no angina at baseline, but among those with angina, there was evidence for relief. However, there was no sham treatment group, so in light of the ORBITA results, how much or this angina benefit was simply because patients knew that they had a procedure is unknown.

What concerns me most is the mainstream press take: “Patients do not need to go to the cath lab,” presumably because there appeared to be no benefit from the invasive strategy. However, multiple large registry studies confirm that about 60% of women and 25% to 30% of men with symptoms and/or signs of ischemic heart disease will not have a flow-limiting obstruction. These patients consume tremendous heath care resources and do not have a benign outcome, as previously believed. The CorMicA trial (J Am Coll Cardiol. 2018; doi:10.1016/j.jacc.2018.09.006) showed that if such patients go to the cath lab and, excluding those with obstructive disease, based upon coronary function information gained from testing in the lab, it’s possible to significantly impact angina and quality of life. CorMicA findings were viewed by the ESC guideline on chronic coronary syndromes as strong enough to change their 2019 recommendations, to a Class IIa indication for catheterization with functional testing. Unfortunately, the update to our U.S. guideline is not published.


All of this suggests that symptoms and signs of ischemia do not necessarily help determine who is going to benefit from an invasive strategy even with revascularization. That's why we should better emphasize invasive functional testing. Those CorMicA patients had dramatic reduction in angina (about 12 points on the Seattle Angina Questionnaire). In ISCHEMIA, the patients assigned to the invasive strategy had only an approximately 5-point improvement in angina score.

Darshan Doshi

Darshan Doshi, MD

The biggest take-home is that, right now, there appears to be clinical equipoise between the invasive and the conservative strategy for management of patients with moderate ischemia by stress testing. That is what many cardiologists anticipated.

But there are other aspects of the trial that are thought-provoking. The first is that for the primary and key secondary endpoints, the invasive strategy appears worse initially, driven predominantly by periprocedural MIs. At 2 years, the curves cross, and after that are in favor of an invasive approach. This appears to be driven by lower rates of spontaneous MIs and hospitalizations for unstable angina. This makes me think that if the patients were followed longer, a statistically significant benefit in favor of the invasive approach could be reached. This is what happened with the STICH trial, which compared revascularization plus optimal medical therapy with optimal medical therapy alone in patients with ischemic cardiomyopathy. It was perceived as a negative trial at its initial 5-year endpoint. However, in an extension study out to 10 years, it was markedly positive in favor of revascularization for every primary and secondary issues. That makes us ponder what might happen in ISCHEMIA at 10 years, after more events accrue over time. I hope the investigators are able to obtain funding for an extension study.

The second unique finding is that the protocol mandated cardiac CT angiography as part of the randomized process. More than 400 patients actually had left main disease and were screened out. We know patients with left main disease benefit from revascularization. If you treat all comers with medical therapy, even if they have a moderate- to high-risk ischemic stress test, approximately 5% of patients may have left main disease that may not be treated. Perhaps the correct strategy is a CTA or cardiac cath to make sure there is no left main disease. If there is none, then determine which is appropriate between optimal medical therapy alone and revascularization with optimal medical therapy.

As an interventional cardiologist, the way I see it is that the invasive strategy is no worse than the conservative strategy and could perhaps lead to more significant anginal relief for symptomatic patients.

ISCHEMIA-CKD was surprising because patients with renal dysfunction or who are on dialysis or awaiting a kidney transplant tend to have more adverse CV events. I was somewhat surprised that an invasive strategy was not superior to a conservative strategy. Part of it may be that the procedure itself necessitates the use of contrast dye, which may perhaps lead to worse outcomes. I was expecting this to be wildly positive in favor of an invasive strategy.

Going forward, we need to understand the patient and their risk factors, and make a determination of additional stratification through stress tests. If the stress test shows no or mild ischemia, you can fairly confidently treat the patient with medical therapy. If there is moderate to severe ischemia, based on the paradigm demonstrated in the ISCHEMIA trial, consider getting additional imaging, whether it be a cardiac CTA or a cath. If it demonstrates left main disease, consider revascularization. If it doesn’t, optimal medical therapy or revascularization would be appropriate, depending on the conversation with the patient. If the patient is overtly symptomatic, proceeding with revascularization is likely warranted because there is a meaningful and durable improvement in anginal symptoms and quality of life after revascularization. Among those with angina, half the patients in the invasive group were angina-free at 1 year compared with 20% in the optimal medical therapy group. The durability of those findings makes me think this is not a placebo effect, but a true effect of invasive therapy.

C. Michael Valentine

C. Michael Valentine, MD, MACC

ISCHEMIA gives us great reason to continue managing  patients who have stable ischemic heart disease in a conservative fashion, unless they have significant lifestyle-limiting or progressive angina. We saw that in all groups, there were similar long-term results in patients with optimal medical therapy, even in the patients with advanced CKD. We did not see any tremendous advantages for the early invasive approach, except in patients with significant angina. In those patients, there was improvement in angina scores and quality of life measurement.

The studies also highlight advances in medical therapy that have helped us over the last several years, and the synopsis is that shared decision making becomes critical. Patients with angina will benefit from an improvement in symptoms and potentially lifestyle with an early invasive approach.

Shared decision making is also critical in patients with advanced CKD. Those patients with silent ischemia are not going to benefit from an early invasive strategy, but those with significant angina certainly can show improvements in angina scores and lifestyle overall. These issues have to be discussed with our patients.

The low CV death rates in the patients in this trial also give us great comfort that if we treat patients optimally, then their long-term outlook still appears favorable. Keep in mind that the trials excluded patients with recent ACS or intervention, left main disease and ischemic cardiomyopathy.

This is the largest trial we’ve seen  in stable ischemic heart disease, and it gives us optimism as we move forward. These are the patients we are seeing in the office, so the findings will have an immediate impact on practice.

Nicole L. Lohr

Nicole L. Lohr, MD, PhD, FACC
I am a noninvasive cardiologist, but I was not surprised at the results because when I talk to patients, we discuss how “stents don’t make you live longer, they make you feel better.” ISCHEMIA essentially proved that. This was a more rigorous study than what we had in the past with COURAGE, but the conclusions were similar to what we knew a decade ago. Other than acute MI, when immediate stenting saves lives, we can be confident in starting medical management and engage our patients in shared decision-making to pursue future stenting.  

Dharam J. Kumbhani

Dharam J. Kumbhani, MD, SM

We are very conscientious about telling patients that PCI for stable ischemic heart disease is not going to modify their risk for MI or death. However, we do not want to throw the baby out with the bathwater. There are, clearly, patients that do benefit, including patients with angina. This trial did not include patients with ACS, for whom invasive therapies are clearly very beneficial.

Bangalore S, et al.
Hochman JS, et al.
Spertus JA, et al. Late Breaking Science II: Results for the ISCHEMIA Trials: To Intervene or Not to Intervene. All presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.

Disclosures: Doshi reports he receives honoraria from Boston Scientific and Medtronic. Lohr reports she serves on an advisory board for Janssen. Garratt, Kumbhani, Pepine, Poppas and Valentine report no relevant financial disclosures.