It may be useful for trialists who present their results without a peer-reviewed publication to simultaneously archive their study on a preprint server

The results of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial were presented at the 2019 Scientific Sessions of the American Heart Association (AHA) held in Philadelphia. The study, sponsored by the United States National Institutes of Health, sparked interest and some controversy. As the dust has since settled and we begin the new year, it is a good time to reflect on what we know.

ISCHEMIA, launched in July 2012, sought to determine if a routine invasive strategy, compared with an optimal medical strategy, would improve outcomes for patients with stable ischemic heart disease. [1] The study enrolled 5179 people with a mean age of 64 years who had moderate to severe ischemia on noninvasive stress testing. Twenty-three percent were women, 41% had diabetes, and about half had severe inducible ischemia at baseline. They excluded people with left main stenosis, advanced kidney disease, recent myocardial infarction, low ejection fraction, severe angina, severe heart failure, or prior coronary revascularization. A third of the study population did not have any angina; about 1 in 50 had daily angina and 1 in 5 had weekly angina. That is, 78% of the participants had either no or monthly angina before enrollment. The primary outcome was cardiovascular death, myocardial infarction, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure. ISCHEMIA has more than 80% power to detect a 19% relative reduction in the primary endpoint, assuming a 4-year event rate of 14%. Significantly greater improvements in angina control and quality of life were found in the group that was randomized to the invasive strategy plus optimal medical therapy compared with the group that received optimal medical therapy alone. The additional ISCHEMIA-Chronic Kidney Disease (CKD) trial randomized 777 participants, including those with advanced kidney disease defined as being on dialysis or having an estimated glomerular filtration rate of <30mL/min/1.73m3. 

The AHA presentations reported several key findings. [2] In the invasive strategy group, 20% did not have revascularization, largely because they had insignificant disease. The first procedure in those undergoing revascularizations was percutaneous coronary intervention (PCI) in 74%; the others had bypass surgery. The cross-over rate to revascularization from the optimal medical therapy group was 23% at 4 years. There was no significant difference in the primary endpoint (adjusted HR 0.93; 95% CI 0.80–1.08). Also, there were no significant differences in other combinations of endpoints or the endpoints individually. There was no subgroup that benefitted. The ISCHEMIA-CKD study also showed no reduction in cardiac events with an invasive strategy and additionally, no improvement in symptoms or quality of life.

The context in which we view ISCHEMIA is important. Coronary revascularization for stable patients with ischemia was recommended by many cardiologists based on the belief that relieving the stenoses and reducing the ischemia would improve outcomes. As that traditional approach came under scrutiny, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, in 2007, showed that PCI in patients with stable coronary artery disease did not reduce the risk of death, myocardial infarction or other major cardiovascular events compared with optimal medical therapy. [3] A subsequent analysis, published in 2008, showed that both the PCI group and the optimal medical therapy group experienced improvement in symptoms, though the PCI group did slightly better for about 3 years. [4] Of note, COURAGE participants had a mean of six angina episodes per week before randomization. In 2017, Al-Lamee and colleagues published the Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina (ORBITA) trial, which used a sham control and reported that PCI did not increase exercise time or improve symptoms for people with stable coronary disease and at least 1 angiographically significant lesion. Interestingly, ORBITA did reveal that PCI improved the hemodynamic and imaging indices of the lesions. [5]

ISCHEMIA took an important step back in the diagnostic process and asked not whether PCI would be indicated, but whether, when faced with a positive non-invasive test indicating ischemia, a patient should be referred to the cardiac catheterization laboratory. The trial also focused particularly on those with a high burden of inducible ischemia. 

What we can discern from the ISCHEMIA trial—to this point—remains limited. The study was featured in a series of oral presentations at the AHA meeting but has not been reported in a publication or preprint. There have been interviews and discussions with the investigators, but as of yet no enduring, comprehensive presentation of the results beyond the slides and videos. If peer reviewed publication was not possible at the time of the meeting, then simultaneous posting of preprints might have helped in the documentation of the findings. Thus, we remain in a holding pattern and ought to be cautious about what we take away from presentations. Nevertheless, some lessons are apparent.

Studies such as ISCHEMIA are challenging. The talented team of investigators did a heroic job bringing the work to completion. But these studies are expensive and slow, begging the question about what could be done in a digital age to speed enrollment and ascertain outcomes. The cost to conduct ISCHEMIA was about $100 million, or about $20,000 per participant. The initial study sample target was 8000 but was pared back given challenges in enrollment. From the enrollment of the first patient, the study required seven years to complete. 

ISCHEMIA would seem to end any uncertainty about whether PCI improves survival or meaningfully reduces risk of subsequent ischemic events. The presented results are consistent with COURAGE and should further strengthen the evidence about what an invasive strategy can do. Unless the peer-reviewed publication differs from what was presented, this result would seem to end any lingering uncertainty about whether PCI could produce this benefit in people with moderate to severe ischemia. In particular, those with no or minimal angina symptoms have, on average, nothing to gain from the procedure. 

Finally, the results regarding quality of life benefits are likely to be where ISCHEMIA attracts the most controversy. On the heels of the presentations, attention was focused on the quality of life benefit. However, the quality of life measures were not the primary endpoint. The study was not blinded. The vast majority of the participants had very little angina. Yet, the data are intriguing. This aspect of the study will deserve the most scrutiny. The inclusion of health status in the study should be commended—and the patient perspective is important—but questions remain about what would be proper to infer from what the study produced. The publication that focuses on quality of life will deservedly attract the most attention. But for now, we find ourselves awaiting further information.

In the future, it may be useful for trialists who present their results without a peer-reviewed publication to simultaneously archive their study on a preprint server. Such an approach memorialises what was presented and invites public comment while the investigators prepare their publications. Meanwhile, the presentations have raised awareness of the trial and created anticipation for the availability of more information. Will ISCHEMIA eventually be seen as validation of an invasive approach for patients who are symptomatic, as some headlines suggested, or as the end to an invasive approach for so many of these patients? Will it lead to recommendations for far fewer non-invasive studies since in many cases today, studies are done to decide about whether to proceed with an invasive strategy? A fair, dispassionate evaluation of the data will need to guide us. Ultimately, I hope the investigators will share the data to augment more rapidly what we can learn together. What seems clear is that there should be little controversy about the lack of benefit for those with moderate or severe inducible ischemia and little to no symptoms.  

Harlan Krumholz is a cardiologist and Harold H. Hines, Jr. Professor of Medicine at Yale University and Yale New Haven Hospital.  Twitter: @hmkyale

Competing Interests: Harlan Krumholz works under contract with the Centers for Medicare & Medicaid Services to support quality measurement programs; was a recipient of a research grant, through Yale, from Medtronic and the U.S. Food and Drug Administration to develop methods for post-market surveillance of medical devices; was a recipient of a research grant with Medtronic and is the recipient of a research grant from Johnson & Johnson, through Yale University, to support clinical trial data sharing; was a recipient of a research agreement, through Yale University, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion; collaborates with the National Center for Cardiovascular Diseases in Beijing; receives payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation, from the Ben C. Martin Law Firm for work related to the Cook Celect IVC filter litigation, and from the Siegfried and Jensen Law Firm for work related to Vioxx litigation; chairs a Cardiac Scientific Advisory Board for UnitedHealth; was a participant/participant representative of the IBM Watson Health Life Sciences Board; is a member of the Advisory Board for Element Science, the Advisory Board for Facebook, and the Physician Advisory Board for Aetna; is a co-founder of HugoHealth, a personal health information platform, and is a co-founder of Refactor Health, an enterprise healthcare artificial intelligence-augmented data management company.

References:

1. ISCHEMIA Trial Research Group; Maron DJ, Hochman JS, O’Brien SM, Reynolds HR, Boden WE, Stone GW, Bangalore S, Spertus JA, Mark DB, Alexander KP, Shaw L, Berger JS, Ferguson TB, Jr., Williams DO, Harrington RA and Rosenberg Y. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: Rationale and design. Am Heart J. 2018;201:124-135.
2. ISCHEMIA. ISCHEMIA Study Results. https://wwwischemiatrialorg/ischemia-study-results.
3. Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS;  COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503-16.
4. Weintraub WS, Spertus JA, Kolm P, Maron DJ, Zhang Z, Jurkovitz C, Zhang W, Hartigan PM, Lewis C, Veledar E, Bowen J, Dunbar SB, Deaton C, Kaufman S, O’Rourke RA, Goeree R, Barnett PG, Teo KK, Boden WE, Mancini GB; COURAGE Trial Research Group. Effect of PCI on quality of life in patients with stable coronary disease. N Engl J Med. 2008;359:677-87.
5. Al-Lamee R, Thompson D, Dehbi HM, Sen S, Tang K, Davies J, Keeble T, Mielewczik M, Kaprielian R, Malik IS, Nijjer SS, Petraco R, Cook C, Ahmad Y, Howard J, Baker C, Sharp A, Gerber R, Talwar S, Assomull R, Mayet J, Wensel R, Collier D, Shun-Shin M, Thom SA, Davies JE, Francis DP on behalf of the ORBITA investigators. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet. 2018;391:31-40.