DOne would think that re-establishing normal blood flow by implanting a stent at the site of coronary stenosis to relieve the obstruction would result in a positive clinical outcome. While this hypothesis remains the founding principle behind percutaneous coronary intervention (PCI), the premise has been questioned multiple times in the past, including in the ISCHEMIA trial presented at the American Heart Association scientific sessions at Philadelphia in Nov. 2019. There are a few things to unpack here:
Identifying the culprit stenosis leading to ‘compromised’ blood flow is the Achilles heel of Interventional Cardiology. Patients with acute coronary syndrome (ACS) typically have a total or subtotal occlusion of a major epicardial artery, or an unambiguous critical area of arterial narrowing. PCI, by implanting a stent, has been unequivocally shown to be beneficial in such patients.
On the contrary, patients with chronic stable angina (CSA) may have one or more areas of stenoses with varying degrees of severity. Algorithms have been put in place to identify which, if any, of the stenoses is causing compromised blood flow. The visual impression remains the most commonly used assessment tool and is far from being accurate.
‘Positive clinical outcome’ is a vague term, to say the least. Clinical outcomes can be broadly divided into 2 groups; the first pertaining to clinical hardpoints like mortality, heart failure, recurrent ACS etc.; the second relating to a quality-of-life (QOL) matrix like angina-free survival, angina-free exercise capacity etc.. While patients with ACS who undergo timely PCI have mortality benefit and enjoy a better quality of life, the same can’t be said with similar scientific vigour for CSA. Nonetheless, trials do show improved QOL in patients with CSA who undergo PCI.
Post-COURAGE era: Drop in PCI
Drug-eluting stents (DES), introduced in the year 2003, led to a significant reduction in restenosis rates. A surge in DES implantation in patients with CSA was axiomatic in the following years. The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial published in the year 2007 compared the clinical performance of optimal medical therapy with or without PCI in patients with stable coronary artery disease (CAD). The trial demonstrated that, while PCI led to improved QOL matrices compared to medical therapy alone, it did not
The trial was vehemently criticised for its design flaws, a few of which I list here. First, the patients were randomized after a diagnostic angiogram. This introduced major bias, as patients with more significant stenoses were excluded from the trial. Second, the degree of ischemic myocardium was not taken into consideration. Third, a lesion assessment using fractional flow reserve (FFR) was not done, leading to indiscriminate lesion selection for angioplasty. Fourth, the trial used outdated stents. And finally, there were crossovers, with patients randomized to the medical arm getting PCI. Nevertheless, the trial results garnered a lot of media attention and did divide coronary interventions in the United States into pre and post-COURAGE era, with post-COURAGE era seeing a significant reduction in PCI for CSA.
The ISCHEMIA trial was designed to answer the questions that were left over by the COURAGE trial. The ISCHEMIA trial, conducted in 37 countries, randomized 5,179 patients with moderate to severe ischemia on a stress test to either a conservative approach with optimal medical therapy (OMT) alone or OMT plus angiography followed by revascularization as needed (the invasive arm). The protocol dictated a blinded coronary CT (CCTA) scan to detect severe left main or equivalent stenosis so that such patients can be treated out of the trial (a total of 434 patients were excluded based on CCTA findings). At 3.3 years follow up, invasive approach (PCI or CABG), when added to OMT, resulted in a similar combined endpoint of cardiovascular death, MI, hospitalisation for heart failure or angina, and resuscitation due to cardiac arrest (13.3% in the invasive group vs 15.5% in the OMT group). PCI or CABG was associated with improved angina and QOL though.
Gaps in ISCHEMIA
Just like COURAGE, ISCHEMIA trial results also got significant media attention with titles like “Study finds limited benefits of stent use for millions with heart disease”.
Allow me to unpack the story of ISCHEMIA trial:
The trial talks about patients with stable coronary artery disease. Patients with ACS, accelerated angina, or new-onset chest pain should undergo the current standard of care. The post-courage era in the US not only saw a drop in PCI for the stable disease but also less PCI in ACS patients, probably due to perceived stent-phobia. Similarly, patients with depressed left ventricular systolic function with concomitant CAD should follow standard treatment algorithms.
While the primary outcome was statistically insignificant at 3.3 years follow up, curves tend to separate at the end of 5 years, favouring invasive strategy. An extended follow up may provide additional insights on long-term comparisons of the two strategies.
The original primary end-point criteria were expanded to include hospitalisation and resuscitated cardiac arrest. The definition of significant ischemia was modified to what can be considered a watered-down version. Indeed, such modifications, done probably to compensate for slow enrollment, invited criticism from the scientific community.
While the trial indeed randomized patients ‘prior’ to angiography (in contrast to COURAGE), it did exclude patients based on blinded CCTA scans. If this trial is translated to clinical practice, left main or equivalent stenosis must be excluded in patients with CSA before opting for OMT alone. Such a feat can be reliably achieved only by CCTA or invasive angiogram.
The complete trial is not yet published in a peer-reviewed journal. Additional patient-related data and any quirks of the study design can only be analyzed once the complete dataset is out.
The take-home message from the ISCHEMIA trial is as follows: In patients with stable CAD, optimal medical treatment along with other lifestyle measures can be safely considered as the default strategy once left main or an equivalent disease is ruled out, irrespective of the degree of ischemia on the stress test. Deferring invasive treatment in such patients is not associated with increased clinical hardpoints, including mortality/MI. Invasive management, on the other hand, is demonstrated to be safe and effective in improving angina over OMT alone and should be considered in patients who have significant symptoms at baseline, whose symptoms are not well controlled on OMT, or who develop accelerating angina.
The author is a Consultant, Interventional Cardiology, CARE Hospitals, Banjara Hills, Hyderabad.