Much discussion has occurred regarding the results of the ISCHEMIA trial, ever since its presentation at the American Heart Association (AHA) Scientific Sessions in Philadelphia this past November. While the results have not formally been published, there is unanimity amongst the presenters, cardiologists, and the lay press, including the Wall Street Journal on November 16, 20191, that this study was a resounding success. It falls on the heels of other recent contemporary studies such as the VANQUISH and COURAGE trials, where the industry edged ever closer to the notion that pharmacologic therapies are superior to coronary stenting, progressively becoming more like ‘oral stents’.
The ISCHEMIA trial tracked over 27,000 high-risk patients and as presented at the AHA, over the course of four years, found no significant absolute difference between an invasive approach (intracoronary stent) and a conservative approach (pharmacologic therapies such as statins). While it was recognized that there was a slight non-statistical inflexion point early on at approximately six months, in favor of pharmacologic therapy, the two approaches would ultimately cross at around 20 months such that by four years (although there was a non-statistical benefit in favor of the invasive arm), no significant difference between groups existed at the end of this half billion-dollar trial. The overall conclusions by the lead investigator, Judith Hochman, MD — that medical therapy is equivalent to stents — were unanimously endorsed by the very intrepid scientific panel and at once, were believed to herald a new era in our myopic focus on the ‘excesses’ of stenting for treatment of coronary artery disease.
Indeed, in one fell swoop, those patients who met the rather generous inclusion criteria, despite having angina and moderate-to-severe disease on provocative stress testing, were shown by the trial to be at no higher or lower risk overall at the end of four years, regardless of whether they received a stent. In a lightning-strike moment, the entire community of cardiologists, cardiothoracic surgeons, and all physicians that care daily for cardiac patients are bound to reconsider the need for aggressive interventional approaches in afflicted patients. The implications are many and varied.
ISCHEMIA has been proposed as a landmark change in medical care. As so much has been written about the socio-economic ramifications of the decades of coronary stent overuse and high false-positive rates, proponents of more conservative treatment strategies will naturally advocate guideline changes denigrating stent use. Societal guidelines have been utilized over the last two decades to decide, both at the physician and insurer levels, appropriate use criteria (AUC) for which physicians and patients are held accountable.
However, all that glitters is not gold, as Shakespeare once stated. Appearances can be deceiving. Again, while the official trial data has not yet been published, we attended its presentation at AHA, along with several thousand other cardiologist colleagues from all over the world. While our initial enthusiasm was just as euphoric as our associates, a prescient moment occurred as we took a quick photo of the primary outcomes slide. Upon review and interrogation of that slide over the following days, we experienced a startling revelation, arriving at a diametrically opposite conclusion from the presented trial conclusion.
It is known that in the study of statistics of biologic behavior, the concept of an early hazard curve is important to understand, namely, that for any intervention, there is a price to be paid. Simply stated, there is a certain cost, including death, that may occur for any intervention, particularly surgical. Against that price, a patient and physician must weigh the long-term benefit when deciding the ultimate value to both an individual patient and society as a whole. Or, even more simply constructed, “one has to crack an egg to make an omelet.” Such is the case upon more in-depth contemplation of the ISCHEMIA data. In the light of day, in a clear but focused interpretation of the data as depicted at the AHA presentation, there appears to be a precipitous increase in the early hazard rates during the first month of cardiac catheterization/intervention, such that the early slope of this hazard is approximately 3-fold higher and mathematically more than doubles the event rate of major adverse cardiovascular events (MACE), including death.
Though we are not told exactly the number of patients that suffered this early event, it is pristine in their graphics presentation. Nonetheless, it is a subtle but clearly important finding. More critical is how the oversight of this aspect of the data can cause even the most educated among us to misinterpret the overall finding. To wit, if one mathematically and statistically accounts for the early hazard curve and then readjusts the curve downwards for the intervention population, the outcome early at six months and late by four years is markedly different. Accounting for the early hazard curve now demonstrates a more favorable finding for the interventional arm. We suddenly come to the opposite conclusion that has been bantered so heavily in the cardiology and lay press.
This should cause us, as clinicians, surgeons, and the consuming public, to pause. What must be accounted for is what drove that early hazard curve. For this, we do not have the information. However, research into the specific demographics and nature of those patients that suffered the early hazard could illuminate the path towards their avoidance.
This should be the take-home message: necessarily, if we could somehow understand that specific patient population and the characteristics defining a patient that was otherwise demographically and ‘risk’ identical to the conventional group, it may be possible to favorably prevent such early hazard in the future. Thus assuredly demonstrating that an upfront interventional approach with coronary stenting may, in fact, despite much luster over the initial enthusiasm of the trial, point us in the opposite direction.
This observation has tremendous implications for the ultimate interpretation and clinical translation of the ISCHEMIA trial. Though we greatly anticipate the formal publication, it is likely that the general jubilation of a new ‘era of conservatism’ would have heretofore ushered in a sharp decrease in coronary stenting. It is our contradicting conviction that such a sentiment is simply mistaken. Coronary stenting, once the high-risk population is identified, is here to stay.
1. McKay B. Study finds limited benefits of stent use for millions with heart disease: drugs and healthier life-style can be as effective for patients with stable coronary artery disease, research shows. The Wall Street Journal. 16 November 2019. Available online at https://www.wsj.com/articles/study-finds-limited-benefits-of-stent-use-for-millions-with-heart-disease-11573931727. Accessed March 24, 2020.
Disclosure: Dr. Biederman and Dr. Doyle report no conflicts of interest regarding the content herein.
Robert W. W. Biederman, MD, FACC, FAHA, FSGC, FASA can be contacted at email@example.com.
Mark Doyle, PhD, can be contacted at firstname.lastname@example.org.