The difference between assuming and knowing

November 23, 2020

Although our intellect always longs for clarity and certainty, our nature often finds uncertainty fascinating.

– Carl von Clausewitz

Clarity in patient-specific decision making may be the one thing clinicians wish for most. As a whole, we have deep insights into what determines health and drives health management of populations, yet we struggle to ascertain such factors for an individual patient. Individual patient- level variation and uncertainty elicit hard questions about a patient’s presentation, illness, and optimal management, which can be well outside the standard expectation for a population.

This search for clarity is what lies at the center of the clinical research to which we commit so much energy. We start with a question, define a primary outcome, and work to test a hypothesis in patient after patient. Nevertheless, sometimes uncertainty still remains.

For example, after seven years and $100+ million of investment, the ISCHEMIA trial has left us uncertain about how best to assess and treat our patients with coronary artery disease (CAD). ISCHEMIA showed us that the information provided by standard baseline stress tests has little to no correlation with the eventual clinical outcome of an individual patient. And furthermore, our best interventional procedures were found not to produce improved long-term outcomes when applied to patients with positive stress tests. Although addressing a patient’s anginal symptoms and quality of life are of course valuable, ideally one would like to be able to lessen the frequency of “hard” clinical events such as death, heart attack, or urgent medical need.

Since the ISCHEMIA trial was first presented at AHA 2019, there has been discussion of whether or not the negative findings were connected to the trial’s lack of physiology-driven treatment decision making, which has been shown to inform clinical decisions and improve long-term clinical outcomes in patients with stable CAD. This month’s Journal of the American Medical Association provides real-world evidence that lesion-specific information from invasive fractional flow reserve (FFR) offers insight that surely would have benefitted ISCHEMIA’s enrolled patients and can clearly benefit our patients today.1

Dr. Maneesh Sud and colleagues examined clinical outcomes of 9,106 patients in Ontario, Canada who underwent single-vessel FFR assessment during an invasive coronary angiogram (ICA) to help inform decision-making regarding PCI. The findings are clear and dramatic: In physiologically-significant lesions (FFR ≤0.80), performing PCI as opposed to not was associated with profoundly better outcomes including 53% lower risk of major adverse cardiac events (MACE) at 30 days follow-up and 20% lower risk after 1 year and 5 years. Diametrically different results were found in physiologically-insignificant lesions (FFR >0.80), where performing PCI as opposed to not more than doubled a patient’s risk of MACE at 30 days, and raised it more than 60% at 1 year and 35% at 5 years.

These data provide powerful clarity on the direct patient-specific impact and clarity that real-world use of FFR provides in the clinical decision whether to perform PCI on a patient with stable coronary disease. While PCI clearly improves outcomes in some patients, it worsens outcomes in others, and FFR provides the pathway to discriminate which patients and lesions are in which category.

These data also demonstrate that invasive intervention can provide durable clinical benefits, which is in stark contrast to the ISCHEMIA trial’s findings where these populations of FFR positive and FFR negative patients were mixed together. The driving difference is reliance on physiology to make the treatment decision rather than basing the decision on functional stress testing or coronary anatomy alone.

If “our nature often finds uncertainty fascinating,” then we can rely on today’s usual practice of trying to understand myocardial ischemia through the lens of functional stress testing or coronary stenosis severity to leave us deeply fascinated but also consigned to guessing which patient should move down which treatment pathway.

In stark contrast, since clarity, certainty, and improving long-term outcomes are of course our true clinical goal, the transition to lesion-specific physiology must be central to clinical decision-making in patients with stable CAD. With an increasing range of tools to assess physiology, whether non-invasively with FFRCT or through a host of modalities in the cath lab, access to actionable information is no longer the roadblock.

It appears that there is more certainty available than ever before in regard to stable symptomatic CAD, but the choice to allow our patients to benefit from it remains in our hands.

— A perspective from HeartFlow Chief Medical Officer, Campbell Rogers, MD
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1. See Sud, et al. JAMA 2020.
2. Driessen, et al. J Am Coll Cardiol 2019. Nørgaard, et al. Euro Radiology 2015.

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