Mandrola Previews 2019 AHA and the ISCHEMIA Trial

John M. Mandrola, MD


November 12, 2019

I get butterflies when I think about Prof Judith Hochman's presentation of the ISCHEMIA trial on Saturday afternoon in Philadelphia.

Saying that ISCHEMIA is big doesn't cut it. Cardiology practice as we know it is on trial.

Clogged arteries cause ischemic myocardium. Ischemic heart disease is a leading killer. And so it goes… Cardiology practices the world over search for ischemia with noninvasive testing and then either open the blockage with a stent or bypass it with surgery. Blockages are bad; fixing them is good.

This process brings treasure to all involved, from the makers of the devices used, to the imagers and proceduralists, and, of course, the hospitals who oversee this grand assembly line.

In recent years, numerous trials have challenged the clogged-pipe frame. COURAGE, BARI 2D, and a meta-analysis of five RCTs found that relieving ischemia with stents did not reduce the rate of MI or death compared with optimal medical therapy (OMT) alone. The rates of percutaneous coronary intervention (PCI) for stable CAD declined but, really, few minds were changed.

Defenders of PCI for stable CAD cited external validity of the evidence. Namely, PCI trials have been null because doctors did not enroll their sick patients in the trials. Patients with severe ischemia (or scary blockages) got stents outside of the trial.

The ISCHEMIA trial used $100 million of American tax dollars to overcome this issue and truly test the clogged-pipe frame. The design is clever and bold.

ISCHEMIA is not just a test of PCI plus OMT vs OMT alone; rather, it pits the anointed and lucrative strategy of early angiography and intervention against the conservative approach of reserving angiography for those with recurrent symptoms. ISCHEMIA investigators accomplished this by randomly assigning patients before the coronary angiogram; neither the doctors nor the patients knew the anatomy.

To address the concern that a patient may have left main disease, ISCHEMIA trialists did blinded cardiac CT angiography (CCTA). This was an ingenious step because not only can the CCTA findings exclude patients with left main disease, but they also identify patients without coronary disease—eg, those with a false-positive stress test. The blinded CCTA screening, therefore, enriched the study with patients with real disease.

The most complicated issue for interpreting ISCHEMIA will be the primary endpoint, which is a composite of CV death, nonfatal MI, hospitalization for unstable angina, hospitalization for heart failure, or resuscitated cardiac arrest. The first result-slide that Prof Hochman shows probably will be the Kaplan-Meier curves for the primary endpoint.

Hold your applause; do not be fooled. This is not the key slide. The key finding will be the tally of the bias-proof hard endpoints: MI, CV death, resuscitated cardiac arrest, and all-cause death.

ISCHEMIA is open-label; participants and clinicians will know which patients are in the faith-healedthank goodness, I have been fixed—arm or in the medical arm, which could be thought of as the stent (or surgery)-subtracted arm. Thus, the ISCHEMIA trial could have a "positive" primary endpoint result, but if MI and death are not reduced in the active arm, it could totally fail to support the clogged-pipe theory of treating ischemic heart disease. The focus has to be on hard endpoints.

As for quality-of-life outcomes in an open-label trial, I would bet one of my bicycles that John Spertus, MD, MPH, from the Mid America Heart Institute in Kansas City, will tell us that quality-of-life outcomes will be better in the PCI/bypass arm. The caring signals of stents or bypass far exceed those of medications.

AHA program chair Donald Lloyd-Jones, MD, ScM, said it well in Patrice Wendling's preview article: We need to know if we are serving our patients best by committing them to a stent, dual antiplatelet therapy, and the potential side effects.

If ISCHEMIA confirms the mountains of data before it and shows no reduction of hard endpoints, it will be the queen of all medical reversals. 

Further Data From Two Recent Megatrials

Prof John McMurray from the BHF Cardiovascular Research Centre in Glasgow, United Kingdom, will expand on findings from two recent megatrials.

In the first late-breaking session, McMurray will provide detailed results from the patients without diabetes in the DAPA-HF trial. DAPA-HF found that in patients with heart failure with reduced ejection fraction (HFrEF), dapagliflozin, compared with placebo, reduced the rate of worsening heart failure or CV death by a statistically significant 4.9% in absolute terms. Crucially, more than half of the enrolled patients did not have diabetes, and in the subgroup analysis, the reduction of the primary endpoint was similar regardless of diabetes status. McMurray will tell us the details. This is important data because SGLT2 inhibitors are a novel and seemingly effective option in patients with HFrEF.

The more provocative, deeper look into a megatrial will come when McMurray and Scott Solomon, MD, from the Brigham and Women's Hospital in Boston, Massachusetts, present results of two substudies of the PARAGON-HF trial. Recall that PARAGON-HF found that sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and CV death among patients with heart failure with preserved ejection fraction (HFpEF).

These will be trickier substudies to interpret because, unlike DAPA-HF, the modest 13% reduction in the primary endpoint from PARAGON-HF did not reach statistical significance. HFpEF represents a potentially massive market for the pharmaceutical industry. These are not insignificant factors when interpreting the substudies.

Two Other Novel RCTs

The advent of transcatheter aortic valve replacement (TAVR) has brought with it the temptation to operate on patients with aortic stenosis before symptoms develop. Similar to a severe coronary blockage, a severely stenotic aortic valve is hard to walk away from. Until AHA, we had no RCT-level data that supported operating on patients with aortic stenosis  before symptoms developed.

The RECOVERY trial is an RCT from Korean investigators at Asan Medical Center that will randomly assign 145 patients with severe aortic stenosis to watchful waiting or early surgical therapy. Good on the investigators for choosing cardiac mortality and operative mortality as their primary endpoints. This trial is important because it could begin a new era of earlier interventions for patients with aortic stenosis.

Inflammation plays some role in promoting arterial disease. Last year, methotrexate failed to cut CV events in patients with established heart disease. Colchicine is one of the oldest anti-inflammatory drugs. I recently used it successfully to vanquish inflammation in a patient with Dressler syndrome. The COLCOT RCT is a placebo-controlled trial from the Montreal Heart Institute that included more than 4700 post-MI patients. At AHA, the investigators will tell us whether colchicine 0.5 mg daily reduced a composite endpoint of major adverse cardiac events. A positive finding could change practice.


I've written preview columns for major cardiology meetings for many years, and one truth remains constant: It's impossible to predict all of the big stories. The ISCHEMIA trial looms large over this year's AHA, but there will be other important developments.

That's why I recommend following the | Medscape Cardiology team online and on Twitter, Facebook, and Instagram.

John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.

Follow John Mandrola on Twitter @drjohnm . For more from | Medscape Cardiology, join us on Twitter , Facebook , and Instagram .


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