Invasive strategy no better than meds for stable ischaemic heart disease

An invasive strategy, on top of optimal medical therapy (OMT), is no better than OMT alone in preventing cardiovascular (CV) events in patients with stable, moderate-to-severe coronary artery disease (CAD), the largest randomized trial to date of an invasive vs conservative strategy, ISCHAEMIA*, has shown. This, the cardiologist world sees as a monumental achievement that is set to change practice.

Out to 4 years, the “expanded” primary endpoint of CV death, myocardial infarction (MI), resuscitated cardiac arrest, hospitalization for unstable angina or heart failure did not differ significantly between the invasive and conservative strategies (13.3 percent and 15.5 percent, respectively). Nor was there a significant between-group difference in the original primary endpoint of  CV death or MI at 4 years at 11.7 percent vs 13.9 percent, respectively (adjusted hazard ratio [adjHR], 0.90; 95 percent confidence interval [CI], 0.77—1.06; p=0.21). [AHA 2019, abstract LBS2]

Rates of all-cause death were also low and comparable between the invasive and conservative strategies (6.5 percent vs 6.4 percent; adjHR, 1.05; 95 percent CI, 0.83—1.1). The probability of at least a 10 percent benefit of revascularization on all-cause mortality was less than 10 percent based on a prespecified Bayesian analysis, said study author Dr Judith Hochman from the New York University School of Medicine, New York City, US.

Of note, the invasive strategy was associated with an increase in upfront, type 4a or 5 procedural MIs vs optimal medical therapy (adjHR, 2.98; p<0.01) but spontaneous type 1, 2, 4b or 4c MIs were lower (adjHR, 0.67; p<0.01).

“We know that spontaneous MI has a higher risk of death subsequently. It’s just surprising that the all-cause mortality curves were superimposable over the years studied. But we want to look at ISCHEMIA Extend for divergence of the curves,” said Hochman. “We’re going to dig deep into the spontaneous MI issue.”

A rethink of the current strategy

The ISCHEMIA trial sort of picked up where COURAGE trial had left off, demonstrating no benefit for revascularization over OMT in stable CAD. [N Engl J Med 2007; 356:1503-1516]  Interventional cardiologists and noninterventionalists alike said the results of ISCHEMIA would prompt a rethink of the current strategy for ischaemic heart disease and likely put a pause to asymptomatic revascularization, excluding left main disease. On top of that, the study addressed an important issue that has long been surrounded by equipoise because of a paucity of high-quality data on revascularization in this population.

“As a clinician, now I would feel comfortable advising my patients not to undergo an invasive strategy if their angina was absent, controlled, or tolerated,” said discussant for ISCHEMIA trial Dr Alice Jacobs from the Boston University Medical Center in Boston, Massachusetts, US,  at  AHA Congress 2019. “ In these patients, I don’t think we feel obligated to take them right to the cath lab.”

The study included 5,179 adult patients from 37 countries, with moderate or severe ischaemia on stress imaging or exercise tolerance testing, randomized to early invasive cardiac catheterization followed by percutaneous coronary intervention (PCI) or coronary bypass surgery if feasible, plus OMT, or OMT alone. Patients with left main disease were excluded from the trial.

At baseline, 87 percent of the patients had moderate or severe ischaemic disease on core lab findings, 90 percent had angina, and 75 percent had stress imaging as the qualifying test.

“The ISCHEMIA study is a lot to digest. The results have not been published yet in a peer-reviewed journal. Yet, what seems clear is that patients with stable ischaemic disease are safe with medical therapy, which is consistent with many other studies. A side question is whether stress myocardial perfusion studies are providing much value for these patients,” commented Professor Harlan Krumholz from Yale University School of Medicine, New Haven, Connecticut, US, who is unaffiliated with the study.

ISCHEMIA had drawn flak because of its prolonged duration, cost, and shifting endpoints. The primary endpoint was expanded beyond CV death and MI, to include other outcomes. Even the definition of ischaemia was extended to include patients with 5 percent ischaemic burden at low levels of exertion (≤7 METS) and those with ECG changes during exercise tolerance testing without imaging. And recently, the QoL endpoint was changed to the shortened, seven-item version of the Seattle Angina Questionnaire.

But with the results in hand,  investigators were confident the new evidence would have an impact on the AHA/American College of Cardiology (ACC) guidelines on chest pain and revascularization which is  currently being updated. Jacobs said the study was sufficiently powered, and the results were not altered by the change in the primary endpoint.

Takeaways from experts

“We’re doing too many stress tests on these patients who have mild or moderate symptoms, may be one episode of angina a month? May be, it is more important to rule out left main disease with a CTA [computed tomography angiography] and really understand this,” commented panelist Dr Roxana Mehran from the Icahn School of Medicine at Mount Sinai, Manhattan, New York City, US. “This is practice changing. At the moment, most of these patients are landing in the cath lab and we’re expected to fix them.”

Jacobs, in response, said: “We will still need stress [tests] to make the diagnosis ... But in a patient [in whom] you are certain that they have angina, or you know they have coronary disease, the only conundrum in my mind is the left main disease. If you do the stress test and it’s markedly positive, you are going to want to exclude that; so then, are you going to do a CTA on everybody?”

“Why not do a CT upfront to make the diagnosis?”, asked Mehran.  To which, Jacobs replied: “That might be a reasonable outcome if [CT] is available."

Virtual dead heat in ISCHEMIA-CKD

Similar to the findings of the main trial, the ancillary ISCHEMIA-CKD* trial also found no benefit for the invasive approach over OMT in patients with CKD and stable CAD, reported investigator Dr Sripal Bangalore, professor of medicine and director of complex coronary intervention at New York University in New York, US.

“Overall, invasive strategy did not demonstrate a reduced risk of clinical outcomes vs conservative strategy,” said Bangalore. “After 3 years, the primary endpoint of death or MI occurred in 36.7 percent of patients on OMT alone vs 36.4 percent in those receiving early invasive strategy.”

Similarly, the major secondary endpoint of death, MI, and hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest, was also a virtual dead heat, occurring in about 39 percent of subjects. Over 27 percent of study participants had died by the 3-year mark, regardless of how their disease was managed. The adjusted risk of stroke was 3.76-fold higher with the invasive strategy.

Discussant Dr Glenn Levine, a cardiologist  from Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas, US, said  ISCHEMIA-CKD is both practice and guideline changing and will fill the void in the AHA/ACC guidelines which currently offers no recommendations on revascularization in CKD in the absence of a robust evidence to date.

Angina control, QoL effect in angina patients

In the quality of life (QoL) outcomes analysis of  ISCHEMIA-CKD** and ISCHEMIA trials, presented separately at AHA 2019, patients had significant and durable improvements in angina control and QoL with the invasive strategy if they  had angina at baseline. In those without, the invasive strategy led to minimal symptom or QoL benefits vs the conservative strategy, said investigator Dr John Spertus from the Saint Luke’s Mid America Heart Institute in Kansas City, Missouri, US. “In patients with angina, shared decision-making should occur to align treatment with patients’ goals and preferences.”