Year in Review: ISCHEMIA Tops Coronary News in 2019 but Other Trials Shine, Too

Without a doubt, the $100-million, National Institutes of Health (NIH)-sponsored ISCHEMIA trial comparing revascularization to medical therapy in stable CAD patient with moderate-to-severe ischemia was the biggest cardiology clinical trial of 2019. But according to Ajay Kirtane, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), and Sukhjinder Nijjer, MBChB, PhD (Imperial College London, England), a number of other studies in the coronary space that deserve mention.  

Going back to the American College of Cardiology (ACC) 2019 Scientific Session, Nijjer pointed to AUGUSTUS, a trial that showed it was safe to use apixaban (Eliquis; Bristol-Myers Squibb) as part of dual antiplatelet therapy (DAPT) in patients with atrial fibrillation and ACS (or undergoing PCI). Also unveiled at ACC was DEFINE-PCI, indicating that angiography isn’t completely reliable when judging PCI success. In the trial, nearly one-quarter of patients with stable and unstable angina left the cath lab with some degree of residual ischemia identified on instantaneous wave-free ratio (iFR).  

“These were patients that [the investigators] thought they had done a good job on,” said Nijjer. “A lot of the time, interventionalists are not getting it right.”

For this reason, head-to-head comparisons of PCI versus CABG, or in trials such as ISCHEMIA, coronary revascularization with PCI isn’t going to fare as well as the comparator if 25% of lesions remain ischemic after the intervention, said Nijjer. He believes operators may be doing cases too quickly and using inadequate imaging to guide the procedure, which may result in the placement of an inappropriately sized stent.

If we’re going to do interventions, we should make sure we do them right. Sukhjinder Nijjer

When he spoke with TCTMD, Nijjer said his group had performed six angioplasties that day, conducting a physiological assessment in all patients with “pullback” mapping to assess coronary flow throughout the entire vessel. In addition, they used either optical coherence tomography or intravascular ultrasound to land the stents in the correct place. 

“That gives us much more confidence that we’re providing some benefit to the patient rather than just making the vessel look pretty,” said Nijjer. “If we’re going to do interventions, we should make sure we do them right.”   

Shortened DAPT, Symptomatic Improvement: ISCHEMIA

In addition to those studies, Nijjer flagged a couple of trials testing different durations of DAPT as clinically meaningful, citing STOP-DAPT and SMART-CHOICE as two in particular that gave physicians confidence in stopping aspirin early.

Kirtane, likewise, highlighted two trials testing a shortened duration of antithrombotic therapy following PCI. The TWILIGHT trial showed that dropping aspirin after 3 months of DAPT with ticagrelor (Brilinta; AstraZeneca) lowered the risk of bleeding without increasing ischemic risk while the EVOLVE Short DAPT study showed that elderly patients at high risk for bleeding could stop their P2Y12 inhibitor at 3 months and continue with aspirin alone. The Onyx ONE study, which compared a polymer-based DES against a polymer-free drug-coated stent in patients at high risk for bleeding, also demonstrated the feasibility of 1 month of DAPT.  

“I’m a little biased because I presented one of them, but still,” said Kirtane, the lead investigator of EVOLVE Short DAPT.

Kirtane also cited an analysis from ORBITA, published just last month by Rasha Al-Lamee, MBBS (Imperial College London), as a critically important addition to the literature in 2019. In that analysis, the ORBITA group showed that myocardial ischemia documented by dobutamine stress echocardiography was associated with a significant reduction in the frequency of angina among stable angina patients undergoing PCI.

“[For the patient] to have an abnormal stress echo, it shows us that they have a significant proportion of ischemia and it’s not typically a small vessel,” said Kirtane. What this analysis adds is that, in the setting of documented ischemia, PCI is associated with a significant improvement in symptoms, he said. “I think we’re seeing evidence from ORBITA, which was initially looked upon as a negative trial, that there are positive signals from within the trial.”

What They Took From ISCHEMIA

With respect to ISCHEMIA, Kirtane said the study reaffirms his day-to-day clinical practice for the most part. “I do think that the symptomatic improvement across the board was unexpected,” he said. “I thought, in some respects, that if you took a patient with minimal or no symptoms, there wouldn’t necessarily be an improvement in symptoms [with PCI].”

The one aspect of the trial that changes things a little is the observed reduction in spontaneous MI, he said. “I feel pretty comfortable saying to patients that if we’re able to do the procedure safely, there may be a benefit beyond just symptom relief,” said Kirtane. “That’s a little new. After COURAGE, I wasn’t really saying that to patients. The caveat is that you need to do the procedure safely and we also need further data, but that to me is an important finding and one that was underemphasized.”

To TCTMD, Nijjer said that soon after ISCHEMIA was presented, many cardiologists stated on social media that the results wouldn’t change their practice. In the United Kingdom, this may actually be the case. Patients are cared for under the National Health Service, he noted, and there is already a long period of time between symptom onset and landing on the cath lab table for stable ischemic heart disease. During that interval, there is ample opportunity to escalate medical therapy so that those who do end up undergoing PCI are patients who remain truly symptomatic despite an increase in medication dose, or the addition of another antianginal drug.

“What I take away [from ISCHEMIA] is to push our primary care physicians and clinic staff to get the antianginals up so that when patients do come to the cath lab, you’re satisfied we’ve done everything you can from the medical therapy point of view,” said Nijjer. ISCHEMIA, he added, teaches everybody to be better doctors and cardiologists.

Importance of Long-term Follow-up

Also on Kirtane’s list of top coronary news for 2019 are the 5-year data from EXCEL comparing PCI versus CABG for unprotected left main coronary artery disease. When the 3-year data were presented, there was a suggestion the endpoint curves had crossed and that there might be a protective effect of CABG in terms of MI prevention longer term.

That signal was borne out in the 5-year data, said Kirtane. At this time point, the rate of MI with PCI was 10.6% versus 9.1% with CABG (OR 1.14; 95% 0.84-1.55). In the landmark analysis, however, the rate of MI from 1 to 5 years was 5.1% with PCI versus 2.4% with CABG (HR 2.16; 95% CI 1.27-3.67).  

“The big message is that we really need longer-term follow-up from all these trials,” he said. “That’s why we need longer-term follow-up from ISCHEMIA, longer-term follow-up from PARTNER-2, and others. That message is becoming clear. If I have a 60-year-old patient come into my office, honestly what happens in the next 5 years is important, but we’re trying to change outcomes for most patients over the next 10 to 20 years. We shouldn’t only base our recommendations on short-term follow-up.”

Kirtane spoke with TCTMD earlier in December; before the year was out, the EXCEL trial would become one of the biggest talking points of 2019 following a BBC investigation that alleged important MI data were missing from the public reporting of EXCEL. This prompted a lengthy response from the EXCEL investigators, a rebuttal from a key trial critic, and a decision by the European Association for Cardio-Thoracic Surgery (EACTS) to withdraw their support from the left main CAD "chapter" in recent European practice guidelines for revascularization.