COMMENTARY

Jun 12, 2020 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

June 12, 2020

Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast.

In This Week’s Podcast

For the week ending Jun 12, 2020, John Mandrola, MD comments on the following news and features stories.

COVID-19 Stats

In the United States, the rate of growth of cases, 1.10x, is slightly increased. Deaths last week were at 109,000 and this week they are at 115,000; at 105x, the rate of rise is steady.

The one notable in the United States are areas of emerging increases in cases. Oregon, Arizona, and Texas have seen significant rises. Given the massive public protests, we are on the cusp of a major public health experiment. The next two to four weeks will teach us a lot about viral transmission.

Brief Note on Racism

The American Heart Association, American College of Cardiology, and the Association of Black Cardiologists have issued an urgent letter denouncing racial violence. Dr. Athena Pappas, president of the ACC, made clear that this isn’t just a letter but an ongoing effort to make change. The news story includes a short video from Dr. Travis Batts, a black cardiologist who speaks about the angst he has, especially with his sons.

Dr. Batts also had some fine words on the work in front of us to reduce health disparities for black men and women. Disparities is a super complex topic, one that transcends medical practice. The Medscape piece and the video are worth a listen.

I listened to an excellent conversation this week between the journalists Ezra Klein and Ta Nehisi Coates. Coates has gained a large following with his writings on systemic racism and white supremacy. He began the conversation by saying, “I can’t believe I’m gonna say this, but I see hope. I see progress right now.”

In our office this week, a colleague organized an 8:46-second moment of silence and kneeling in our large waiting room. I went to it, stood in the back, and kneeled in silence. Patients came in and joined in the moment. It reminded me of church. Head down; time to think and reflect. That seems like nothing; but it felt like much more than nothing.

The ISCHEMIA Trials

At the height of the pandemic in April, the long-awaited ISCHEMIA trial was published in the New England Journal of Medicine—not one but four papers and an editorial. There was the main paper; the ISCHEMIA-CKD paper; and two health outcomes papers, one for the general population and the other for patients with chronic kidney disease.

First, the Landscape. The ISCHEMIA trial was conducted to resolve equipoise regarding 1) the utility of up-front invasive coronary angiography and 2) the efficacy of early revascularization vs medical therapy alone in patients with suspected stable angina and high-risk findings on stress imaging.

No trial for stable ischemic heart disease (SIHD) has found that adding percutaneous coronary intervention (PCI) to guideline-directed medical therapy (GDMT) reduces outcomes The rationale for another outcomes trial was twofod. First, previous clinical trials in patients with SIHD randomized patients after invasive coronary angiography (ICA). This may have led to a selection bias where high-risk patients were excluded from enrollment. Second, contemporary medical management has improved with high-potency statins, ARBs, and antiplatelet drugs.

ISCHEMIA randomized patients before angiography. This allowed for a comparison of two strategies: an early invasive (angiography with or without revascularization plus medical therapy) vs an early conservative (medical therapy alone) approach. It also helped prevent selection of low risk patients. Another unique design feature was use of blinded coronary computed tomography angiography (CCTA) before randomization. This had two effects: 1) by excluding patients without obstructive disease, it enriched the trial population with patients who had significant CAD, and 2) by excluding patients with left main disease, it ensured safety for referral of patients before the anatomy was known.

ISCHEMIA Main Trial Results. The primary endpoint was a composite of cardiovascular death, nonfatal MI, hospitalization for unstable angina, hospitalization for heart failure, or resuscitated cardiac arrest. A key secondary endpoint was death or nonfatal MI.

After a median follow-up of 3.2 years, the adjusted hazard ratio for the primary endpoint was 0.93 (95% CI 0.80-1.08), which did not reach statistical significance. Cardiovascular death or MI did not differ significantly. Rates of all-cause death were nearly identical.

The crossover rate from the conservative arm to the invasive arm was 28%, with 21% undergoing revascularization, compared with 79% in the invasive arm. (This is super important because the same outcomes were achieved in the conservative arm despite the fact that nearly 80% never received revascularization!)

ISCHEMIA-CKD Results. The initial invasive strategy did not significantly reduce death or nonfatal MI compared with a conservative approach. Despite serious efforts to minimize harm from angiography, the invasive strategy was associated with a 50% increase in death or initiation of dialysis and nearly 4-fold higher incidence of stroke than the conservative strategy.

Key Subgroups of ISCHEMIA. There was no heterogeneity of treatment effect based on any baseline characteristic. For example, patients with triple vessel disease had more than double the rate of primary outcome events compared with patients with single vessel disease, but there was no statistically significant difference in the treatment outcome between the two arms.

Same in the ISCHEMIA-CKD. Compared with the main ISCHEMIA trial, patients in the conservative strategy arm in the CKD-trial were nearly 7-fold more likely to die (27.8% vs 4.3%) and nearly twice as likely to experience an MI (15.9% vs 8.5%) over 3 years of follow-up.

Patients in the ISCHEMIA-CKD trial had significantly higher rates of diabetes, peripheral vascular disease, and stroke than those in the main ISCHEMIA trial and yet the notion that sicker patients would do better with unclogged pipes was not proven.

ISCHEMIA Angina Paper. Angina was assessed with different questionnaire scales. Both groups improved immediately. The mean Seattle Angina Questionnaire (SAQ) summary scores for the invasive strategy vs. the conservative strategy at 3 years was 88.6 vs. 86.3.

The conclusions focus on the observation that significant improvement in angina control and quality of life with the invasive strategy in patients who had daily to weekly angina. BUT, this group comprised only 21% of the cohort.

In those with at least monthly angina (44%), the probability of a clinically important improvement in SAQ summary score was low; and in those with no angina (35.4%), the probability of a clinically important improvement in SAQ summary score was zero. The angina relief therefore is modest. And what’s more, the trial was unblinded.

The Great Curve Crossover Narrative. Many words and figures are spent on the crossing of MI curves over time. There are more MIs early in the invasive arm but then after few years there are more in the conservative arm. This is a distraction. In arms with about 2500 patients each, 210 had an MI in the invasive arm and 233 had an MI in the conservative arm. Do you really think a delta of 23 MIs is significant, given the nearly identical death rates seen in patients with seriously positive stress tests?

The CCTA Issue. Blinded CCTA before randomization was mandated by trial protocol to ensure patients with nonobstructive coronary artery disease were not enrolled and to enhance safety by excluding patients with left main coronary artery disease. This was brilliant for internal validity but, as it often does, better internal validity makes for tougher external validity, or generalizability.

CCTA is not currently considered standard of care prior to choice of treatment for patients with SIHD but some have argued that now it should be in all patients with angina and moderate to severe ischemia. However, because ISCHEMIA was not designed to address CCTA vs no CCTA, and nearly one in four enrolled patients did not have a CCTA, we need additional trials to confirm or refute the necessity of defining the coronary anatomy following stress testing, before implementation of either an initial invasive or conservative approach. Moreover, I’m not completely convinced that in 2020, a patient with stable symptoms who has left main disease necessarily would do better with revascularization.

Conclusions. ISCHEMIA reinforces the recommendations endorsed by the SIHD guidelines issued by the ACC/AHA in 2012: revascularization should only be considered for limiting angina with severe or extensive myocardial ischemia, hemodynamically significant stenosis, and insufficient response to GDMT.

Therefore, SIHD patients without high-risk features should be started on an initial strategy of therapeutic lifestyle intervention aimed at risk factor control plus GDMT.

Then we ought to tell our patients there is no penalty for waiting. In fact, the majority will not require revascularization over a 5-7-year follow-up. Revascularization can be reserved for a later time in the minority of patients whose symptoms or quality of life are either refractory or unacceptable on medical therapy with little risk that an unfavorable event. For patients with advanced CKD we should counsel strongly for a conservative approach.

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