You never fail until you stop trying
It is common wisdom that all patients with coronary artery disease (CAD) should be treated with guideline-directed medical therapy (GDMT).1 Purposing this indication, physicians evidently want to reduce patients' risk of death and ischemic events and to improve their quality of life. Two approaches are generally used to achieve this goal. The conservative approach is based solely (or mainly) on medical therapy, including beta-blockers, calcium channel antagonists, long-acting nitrates, statins, antithrombotic, and renin–angiotensin system (RAS) blocking therapies (angiotensin-converting enzyme inhibitor [ACEI] and angiotensin receptor blocker [ARB]). Most recent antianginal drugs, such ivabradine and ranolazine, demonstrated a clear advantage improving the exercise tolerance and the angina symptoms and are thus now often considered, despite their substantial cost, within the conservative management armamentarium.2–4 Otherwise, the second strategy, labeled invasive management, is founded on early coronary angiography, with eventual percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), as clinically indicated. Notably, often practitioners opting for PCI or CABG tend to overlook the subtleties of GDMT, for instance, by prescribing fewer agents or lower than appropriate doses.
Considering that important advances have occurred in both strategies, the 2 approaches reached a perfect equipoise on which one has more efficacy for patients with stable ischemic heart disease.5 Indeed, initially the invasive strategy seemed to be the “turning point” of the treatment of the patients with CAD. Nevertheless, previous trials that tested the incremental effect of revascularization on top of best medical therapy did not show a clear-cut reduction in the incidence of death or myocardial infarction. More recently, a direct comparison between the 2 strategies in patients with CAD and moderate-to-severe ischemia (at stress electrocardiographic test and/or noninvasive imaging stress test) did not find evidence that the initial invasive strategy reduced the risk of ischemic cardiovascular events or death from any cause.6 One of the reasons for this remarkable result was probably the maximization of GDMT in both study arms, the noninvasive arm and the invasive group. Can this also apply to real-world patient care, or are patients routinely managed in a less appropriately intense fashion?
In this issue of the Journal, Park et al offer a poignant perspective on the importance of maximizing medical management irrespective of the chosen strategy for CAD. Specifically, they designed a propensity-matched population-based retrospective cohort study to resolve the dilemma regarding differences in clinical benefits between ACEIs and ARBs used as part of optimal medical therapy (OMT) to prevent adverse cardiovascular outcomes in patients with CAD after PCI,7 a goal that is even more timely in the current coronavirus disease 2019 (COVID-19) era.8,9 The results hereby reported detail the comparative effect of RAS blockade on all-cause mortality (primary end point) in patients receiving OMT after PCI in South Korea. The authors divided the nation-wide study sample on the basis of OMT at hospital discharge (ACEI-based OMT or ARB-based OMT) and if they had been admitted for acute myocardial infarction (AMI) or angina. They created a large retrospective registry including 6693 patients in the angina cohort and 8219 in the AMI cohort, after refined propensity-score matching. The main findings of this study were that, in patients with AMI, ACEI-based OMT was associated with a lower risk of all-cause mortality compared with ARB-based OMT, whereas in those with angina, there was no significant difference between ACEI- and ARB-based OMTs. Similar trends favoring ACEI-based OMT in patients with AMI were noted across all appraised subgroups.
The authors suggest that the superior benefit of ACEI over ARB in AMI patients may depend on their different mode of action. Although both ACEI and ARB reduce blood pressure and improve remodeling by reducing the formation of angiotensin II, only ACEI increase bradykinin, a potent vasodilatory agent. Given this difference, ACEI provide additional risk reduction in a blood pressure–independent manner. It is also suggested that ACEI may exert beneficial effect by suppressing angiotensin II level and neurohumoral activation more effectively, at least in absolute terms, in patients with AMI, where these pathologic mechanisms are substantial, at odds with those with angina. This could indeed explain why ACEI was proved beneficial in AMI patients and less than so in anginal patients in the analysis reported by Park et al.
The choice of RAS inhibitors in the primary or secondary prevention of patients with CAD is a matter of particular importance because there is controversial recent data on whether ACEI or ARB should be used as a first-line drug within OMT, depending on cardiovascular risk and patient safety assessment. And the issue gets further complicated by the emerging evidence on the usefulness of the combination of ARB/neprilysin inhibitor, such as sacubitril/valsartan, in patients with reduced left ventricular ejection fraction.10 Nevertheless, as with most observational inference based on administrative data, there are several limitations that should be recognized. Indeed, this registry may lead to mistaken conclusions if not perused attentively. First, the effects of these drugs added to OMT on all-cause death may be misleading. Indeed, cardiac death would have been more appropriate as end point but could not be precisely captured. It is evident that in this large population, the choice of all-causes death could include also neoplastic disease, respiratory disease, and accidental death not linked to any disease (eg, trauma). Moreover, the analysis based on national South Korean Health Insurance Review & Assessment Service (HIRA) could underestimate another significant aspect addressing the chosen end point, that is, adherence and compliance. Adherence is very important to actually achieve the theoretical benefits of any medical therapy, and ARB may promote better adherence and thus ultimately benefit patients more than ACEI. Accordingly, because adherence to multiagent regimens of long-term evidence-based therapies among cardiovascular patients is generally poor, development of novel approaches that may increase adherence should be a priority, for instance, telehealth or distance medical care. In previous large trials, when investigating the persistence with secondary prevention medication, many patients unfortunately discontinued the prescribed medication within few months after ACS. In addition, it is important to focus on dose modification and titration during follow-up. Discharge therapy could be changed afterward, and the dosage could be increased or decreased related to life habits, work situation, age, and the compliance of the patient's doctor. These aspects emphasize the importance of a well-structured follow-up system, which may investigate with a practical model the cardiovascular treatment adherence and the occurrence of adverse cardiovascular events.
In conclusion, real-world evidence suggests that ACEI-based GDMT/OMT may prove superior to one including ARB in patients with AMI. Whether this holds true in a future encompassing additional modern therapies for cardiovascular disease, ranging from ARB/neprilysin inhibitor to glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium/glucose cotransporter-2 inhibitors (SGLT2i) remains to be confirmed by additional trials, observational studies, and their compilation in systematic reviews, meta-analyses, and umbrella reviews.
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