Comment on Association of guideline-directed medical therapy adherence with outcomes after fractional flow reserve-based deferral of revascularization

The aims of pharmacological management of patients with chronic coronary syndrome (CCS) are to reduce angina symptoms and exercise-induced ischaemia, and to prevent cardiovascular events.¹ Optimal treatment can be defined as the treatment that satisfactorily controls symptoms and prevents cardiac events associated with CCS, with maximal patient adherence and minimal adverse events.

As stated in the 2019 European Society of Cardiology (ESC) guideline on CCS,¹ there is no universal definition of an optimal pharmacological treatment in patients with CCS, and drug therapies must be adapted to each patient's characteristics and preferences. Initial drug therapy usually consists of one or two antianginal drugs, as necessary, plus drugs for secondary prevention of cardiovascular disease. Whether combination therapy with two antianginal drugs is superior to monotherapy with any class of antianginal drug in reducing clinical events remains still unclear.

The post hoc analysis of the J-CONFIRM registry [Long-Term Outcomes of Japanese Patients with Deferral of Coronary Intervention Based on Fractional Flow Reserve (FFR) in Multicenter Registry], published in this issue of the European Heart Journal—Cardiovascular Pharmacotherapy, studied whether guideline-directed medical therapy (GDMT) is able to prevent long-term cardiovascular events.² To that purpose, the authors used a prospective, multicentre, observational study investigating clinical outcomes of patients with deferral of revascularization based on FFR measurement at 28 hospitals in Japan. The J-CONFIRM registry prospectively enrolled 1263 patients and 1113 patients were included in the present study.

The authors found that the patients with optimal GDMT had a lower 5-year incidence of major cardiovascular events (MACE) as compared with the suboptimal GDMT group. MACE was defined as a composite of all-cause death, target vessel-related myocardial infarction, and clinically driven target vessel revascularization.

As GDMT has no general definition, it is important to note what was the definition of it in this study. Optimal GDMT was defined as combining four types of medications [antiplatelet drug, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEi/ARB), beta blocker, and statin]. Correspondingly, the patients who had continued ≤ 3 types of medications were classified into suboptimal GDMT group.

One of the main findings of this analysis was that the optimal GDMT was achieved only in a small fraction (12.5%) of the patients 2 years after FFR-based deferral of revascularization. The optimal GDMT was more likely achieved as a consequence of unfavourable circumstances and diagnoses (e.g. dyslipidaemia, prior myocardial infarction, revascularization, left main disease, left ventricular dysfunction). Despite these patients typically having a high risk of cardiovascular events, GDMT was associated with better long-term outcomes.

The study confirms that GDMT, in addition of being a moving target, is a myth more than a reality. The results also imply that the generalizability of trials of an intervention vs. GDMT should be revisited, because in real life GDMT may be suboptimal compared with clinical trials, where the effect of the intervention may be more nuanced. The study also emphasizes that more focus should be targeted to primary prevention and outpatient clinics as in these situations GDMT is even less commonly achieved.

Interesting findings came also from various sensitivity analyses. The results remained unchanged even when the optimal GDMT did not require ACEi/ARB in patients with preserved left ventricular function. In addition, using an FFR cut-off of 0.75 or 0.80 did not change the results. Finally, accepting also the use of calcium channel blockers instead of beta blockers in the cases of intolerance to beta blockers did not change the results.

The authors also studied the effects of individual drugs on their findings, although the study is likely underpowered for such analyses. There were no significant differences in MACE in patients with and without antiplatelet drugs or ACEi/ARB. However, patients who continued beta blockers and statins had better event-free survival. These finding suggest that beta blockers and statins might play an important role in preventing cardiovascular events in patients with intermediate coronary stenosis after FFR-based deferral of revascularization.

An interesting additional finding that warrants further studies was that the MACE rate decreased as the FFR value increased in the optimal GDMT group but this was not observed in the suboptimal GDMT group. This difference in clinical outcomes between optimal and suboptimal GDMT in patients with higher FFR values and less significant stenosis is a novel finding and warrants further studies. Additional studies are also needed on the optimal dosage of drugs and to understand the heterogeneity—if any—in the treatment effect of GDMT by sex and age. Also, further studies are needed to understand the relationship between GDMT and improvement of symptoms and quality of life.

The authors are to be congratulated for their sophisticated statistics, multiple sensitivity analyses that corroborate the primary findings and adjudicated events. The results have obvious practical implications for patients with CCS and are a call for more stringent adherence to guidelines recommendations.

Conflict of interest

Dr. Knuuti received consultancy fees from GE Healthcare and AstraZeneca and speaker fees from GE Healthcare, Bayer, Lundbeck, Boehringer-Ingelheim, Merck and Pfizer. Dr. Capodanno received honoraria from Amgen, Arena, Biotronik, Daiichi Sankyo, Sanofi andTerumo. Dr Saraste received consultancy or speaker fees from Amgen, Astra Zeneca, Boehringer Ingelheim, Abbott and Bayer. All declarations are outside of the present study.

Notes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal—Quality of Care and Clinical Outcomes or of the European Society of Cardiology.

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