Alirocumab and evolocumab: an indirect comparison of cardiovascular benefits

This editorial refers to ‘Indirect comparison of the efficacy and safety of alirocumab and evolocumab: a systematic review and network meta-analysis’, by P. Guedeney et al., pp. 225--235.

Over the last decades, epidemiological, observational, and case–control studies have increased our perception of disease mechanisms and treatment strategies. Significant progress has also been achieved concerning bio-ethical issues, patient’s rights, safety, data collection, and analysis. A randomized controlled trial has been established as the way in which to obtain the most robust results on the safety and outcome of new treatment strategies.¹ Nevertheless, the cost of undertaking a randomized controlled trial as well as ethical issues may leave questions, especially concerning the comparison of treatments addressing the same target. Given this problem, systematic reviews and meta-analyses have been proposed to stand at a high level of the evidence hierarchy.²

From the first description of evidence-based practice,³ cardiology has adopted the new trend; guidelines, based on robust clinical data, are published and updated annually, contributing significantly to effective management of cardiovascular morbidity and mortality. At the centre of cardiovascular diseases, subintimal cholesterol accumulation and atherosclerosis continue to be the substrate of most cardiovascular disorders, with LDL-cholesterol identified as a major risk factor.⁴ Since the first commercially available inhibitor of 3-hydroxy-3-methyglutaryl-coenzyme A reductase (lovastatin) was introduced in clinical practice, in September 1987,⁵ statins had proved their efficacy in reducing cardiovascular mortality and morbidity in subjects with cardiovascular risk and high cholesterol levels.⁶ Despite the outstanding results of statins, in subjects with familial hypercholesterolaemia and in cases of intolerance, the protection is suboptimal with a considerable residual risk.

Monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) have proved their efficacy in lowering LDL-cholesterol levels efficiently on top of the maximum tolerated dose of statins, filling the gap in the current management of high cholesterol levels. However, with an estimated cost of US$14 000 per year⁷ and with uncertainties concerning the long-term safety of this new class of drugs, their efficiency in lowering cardiovascular and all-cause mortality should be established.

Fortunately, large randomized controlled trials have confirmed that the lipid-lowering effects of PCSK9 inhibitors are associated with beneficial outcomes concerning all-cause mortality and composites endpoints, consisting of cardiovascular events and cardiovascular mortality.^8,9

However, the main outcome studies which established the use of alirocumab (ODYSSEY OUTCOMES trial) and evolocumab (FOURIER trial) enrolled subjects with different clinical profiles. The ODYSSEY OUTCOMES trial included subjects with heterozygous familial hypercholesterolaemia and recent acute coronary syndrome (the latter consisting of a population at increased risk for further events). The FOURIER trial involved subjects with homozygous familial hypercholesterolaemia (a population not represented in the ODYSSEY OUTCOMES) but did not focus on the post-acute coronary syndrome period. Although both trials adequately documented cardiovascular benefits, discrepancies in the characteristics of the enrolled patient as well as differences in statistical analysis methodology and endpoint selection have led to different conclusions. Solid evidence favours alirocumab in patients at high risk for atherosclerotic cardiovascular diseases, while the balance of evidence is in favour of evolocumab in subjects with heterozygous familial hypercholesterolaemia. Therefore, the lack of a direct comparison of these two drugs generates controversies and clinical uncertainties as to which one should be optimally selected for the benefit of patients.

Guedeney et al., in a study published in this issue of the European Heart Journal – Cardiovascular Pharmacotherapy, now shed light on this topic by combining data from 30 studies and >59 000 patients who received either evolocumab, alirocumab, or placebo to compare their clinical efficacy.¹⁰ First of all they confirm the safety profile of both evolocumab and alirocumab, with the latter associated only with increased risk of injection site reaction. Several efficacy outcomes were also tested. Both drugs were found to be effective concerning cardiovascular mortality, incidence of myocardial infarction and stroke, and need for revascularization. Indeed, alirocumab has also been associated with a significant reduction in all-cause mortality, a finding attributed to the different study population and design of the ODYSSEY OUTCOMES trial.

Therefore, this network meta-analysis aiming to bridge the gap in the evidences due to lack of direct comparison provides some useful key points: (i) PCSK9 inhibitors based on human antibodies have a class effect concerning cardiovascular disease; (ii) both drugs can be used in the majority of subjects with increased atherosclerotic risk not achieving the LDL target, with similar efficacy; and (iii) there are no significant safety concerns with either of the drugs. Furthermore, this project once again emphasizes the difficulty in and the unwillingness to take on the cost of comparative studies and the value of meta-analytic approaches to solve clinical dilemmas where evidence-based medicine cannot reach a conclusion. Last, but not least, it should be endorsed that comparative studies should be organized whenever the safety/benefit ratio of agents targeting similar pathways is in question.

Conflict of interest: none declared.

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal – Cardiovascular Pharmacotherapy or of the European Society of Cardiology.

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