Will personalized drugs for cardiovascular disease become an option? – Defining ‘Evidence-based personalized medicine’ for its implementation and future use

Abstract

It is generally accepted that the implementation of pharmacogenomics and, more broadly, personalized medicine will have to be ‘evidence-based’. However, there is a lack of consensus on the level of evidence required to justify the use of pharmacogenomic testing in clinical practice. In the cardiovascular field, this lack of agreement has led to somewhat contradicting recommendations by different organizations regarding the clinical utility and use of pharmacogenomic tests or information. Here, we argue that randomized, controlled trials are paramount in order to enable and accelerate the widespread implementation of pharmacogenomics, not only to demonstrate the clinical efficacy and cost-effectiveness of such tests, but because such level of evidence is required to support the considerable changes associated with the implantation of pharmacogenomics in clinical practice.

Keywords:

• cardiovascular
• clinical trial
• dalcetrapib
• pharmacogenomics

1. Introduction

Personalized medicine proposes the customization of health-care practices to the individual patient. With the use of diagnostic testing, it can be possible to select the best therapies based on the context of a patient’s genetic profile, molecular diagnostics or imaging. As data in support of the use of genetic information toward personalized medicine in the prevention and treatment of cardiovascular diseases are accumulating, it is implicitly understood that their implementation will proceed according evidence-based practices. However, there is a lack of consensus on what is the appropriate level of evidence for personalized medicine interventions, or more precisely, what evidence is required to justify the use of pharmacogenomic testing in clinical practice [1-4]. This lack of agreement has led to somewhat contradicting recommendations by different organizations regarding the clinical utility and use of pharmacogenomic tests or information. In the cardiovascular field, examples include warfarin [3,5] and clopidogrel [1,4,6].

The Clinical Pharmacogenetic Implementation Consortium (CPIC) was and remains the forerunner in the development of pharmacogenomic clinical guidelines. CPIC guidelines do not specify when a genetic test should be ordered, but rather how to interpret and use the information to improve drug therapy [2]. These guidelines rate the evidence from the scientific literature as ‘high’ for consistent results from ‘well-designed, well-conducted studies’ [2], irrespective of the study design. In contrast, professional associations such as the American Heart Association (AHA), the American College of Cardiology (ACC) [1,4] and the American College of Chest Physicians (ACCP) [3] place randomized controlled trials (RCTs) at the center of their clinical guidelines development process and RCTs are a prerequisite for the quality of the evidence to be rated as ‘high’. In the case of clopidogrel, these differences in the evaluation of existing studies and meta-analyses have led CPIC to provide a strong recommendation to use alternative antiplatelet agents such as ticagrelor and prasugrel in poor metabolizers while, in absence of large RCTs, the current AHA/ACC guidelines recommend against the routine use of genetic testing [1,4], although a case-by-case approach might be considered. Similar incongruities exist in guidelines regarding the individualization of warfarin dosing [3,5], although both CPIC and ACCP guidelines preceded the publication of two medium-size RCT, suggesting little or no benefit of a genotype-guided warfarin dosing approach [7,8]. Furthermore, as the distribution and frequency of genetic variants can vary between populations of different ancestry, evidence obtained in one population may not necessarily apply to another.

Critics of those in favor of conducting large RCTs have highlighted that such high standards have generally not been required for the use of other biomarkers or characteristics to personalize drug selection or dosing, such as renal or hepatic function, or drug–drug interactions, a bias which has been termed ‘genetic exceptionalism’ [9]. One should nevertheless take into consideration a caveat that distinguishes genetic testing from these other types of variables, which is that the majority of such information is generally already available in a patient’s medical chart, thus at no cost, or can be easily obtained at a relatively low cost in the case of basic biochemistry tests. In contrast, genetic information is rarely available to clinicians, or can seldom be immediately and easily ordered in most clinical settings.

2. Dalcetrapib pharmacogenomics: moving toward a randomized, controlled trial

Perhaps one of the best examples of the potential of cardiovascular pharmacogenomics is provided by the recent report of a large reduction in clinical event rate among patients with coronary artery disease and a specific genetic profile when treated with the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib [10]. While the overall results of the Dal-OUTCOMES study in 15,871 patients with a recent acute coronary syndrome yielded similar results in the dalcetrapib and placebo groups, data consistent with other clinical trials of CETP inhibitors [11], the pharmacogenomic assessment of the 5749 patients who accepted to give DNA showed that those who were homozygous for the minor allele (AA) at polymorphism rs1967309 in the ADCY9 gene benefited from a reduction of 39% in the composite of cardiovascular endpoints when treated with dalcetrapib compared to placebo (p = 2.4 × 10^–8). Heterozygotes (AG) had a neutral result, while patients who were homozygous for the major allele (GG) suffered a 25% increase in cardiovascular event rate when treated with dalcetrapib. Supporting concordant evidence was provided by a second study called Dal-Plaque-2. Because this pharmacogenomic analysis was performed post-hoc, we are now preparing for a new RCT called Dal-GenE which will essentially be identical to Dal-OUTCOMES but will be limited to responsive patients (AA genotype at rs1967309). The results of the Dal-GenE study will allow regulatory review of results and hopefully lead to the introduction of dalcetrapib and its companion diagnostic test in the clinical setting.

For the approval of a new drug, the conduct of an RCT provides the high level of evidence necessary in order to guide evidence-based medicine. In this context, it is expected that a RCT will be necessary in order for dalcetrapib and its companion diagnostic to be approved by regulatory agencies toward its therapeutic use. There are, however, rapidly increasing numbers of genetic associations that are being reported for drugs that are already in general use. Such association reports are being made using small to large-sized observational studies, mainly using retrospective data collections and are typically based on patient populations of varying clinical profiles. There are established guidelines to inform on the appropriate levels of credibility to assign to cumulative evidence for genetic epidemiological studies that apply to pharmacogenomics [12]. Decisive elements of evidence for such studies should consider the extent of replication in different studies and the extent of protection from bias within studies. In most pharmacogenomics studies, additional input and guidance in support of credibility can be derived from biological data, as most associations reported to date involved genes of high biological relevance. Meta-analysis studies can also provide reliable summary estimates of genetic association. Such evidence from pharmacogenomics studies informs CPIC guidelines, which are developed in close accordance to the standards of the Institute of Medicine’s (IOM) for developing trustworthy clinical practice guidelines. The process accounts for evidence from systematic reviews, strength of recommendations, guideline development group composition, transparency, external review and have an established process for updating of the guidelines [2]. The majority of CPIC guidelines published to date, however, have not had the opportunity to rely on evidence generated from RCT studies.

3. Expert opinion

We believe that for the widespread implementation of pharmacogenomics to become a reality, RCT are indispensable, not only to demonstrate the clinical efficacy and cost-effectiveness of such tests, but because such level of evidence is required to support the considerable changes associated with the implantation of pharmacogenomics in clinical practice, whether these are organizational, practical or educational [13]. If the average health-care professional is not convinced that pharmacogenomics is necessary and useful to patient care, such colossal transformations will likely remain limited to a few specialized academic centers. Currently, the clinical utility of few pharmacogenomic tests has actually been unequivocally established in a RCT.

Once pharmacogenomics has been widely implemented and genetic information is available, the use of such information may not always require data from RCTs, a paradigm consistent with other markers currently used to guide therapies and CPIC recommendations. Specifically, when the genetic data are already available, thus at no additional cost, and the genetic information is used to choose between two agents considered as equivalent in clinical practice, then we believe it could be appropriate to use genetic information to guide therapy, if sufficient data exist for a potential improvement in patient outcome. Such decisions would have to be based on evidence considered of high quality as per CPIC guidelines [2]. In such instance, clinical decisions would be taken in a similar context as when selecting specific drugs within a therapeutic class based on the presence of drug interactions or renal dysfunction.

In the case where pharmacogenomic testing could lead to the use of an agent with different efficacy in a specific class, RCTs should remain mandatory to guide clinical decisions. The potential use of the beta-blocker bucindolol in the treatment of heart failure, which appears to be effective only in a subgroup of individuals carrying specific genetic variants in the adrenergic system represents such an example [14]. Indeed, contrary to carvedilol, bisoprolol and metoprolol succinate, bucindolol has not been shown to reduce all-cause mortality in heart failure patients, hence it is not currently used in clinical practice. Nevertheless, should the genotype-guided use of bucindolol be proven beneficial in patients in a RCT, it could become an interesting more personalized approach. Such a trial is currently ongoing, as are large event-driven trials of genotype-guided use of the antiplatelet clopidogrel. These trials follow smaller RCTs which have suggested that the individualized use of clopidogrel and alternative antiplatelet agents may help optimize the treatment of patients undergoing a percutaneous coronary intervention [15].

In conclusion, existing recommendations regarding the value and use of pharmacogenomics in the management of cardiovascular diseases are variable. We believe that RCTs are paramount to unequivocally demonstrate the clinical value of pharmacogenomics and to enable and accelerate the implementation of pharmacogenomics.

Declaration of interest

S de Denus has received research grants or been a coinvestigator on grants supported by AstraZeneca, Novartis, Roche and Pfizer. He has received speaker fees from Pfizer and consulting fees from Servier. MP Dubé has been a coinvestigator on grants supported by AstraZeneca and Pfizer, and has received honoraria and research contracts from Roche. JC Tardif and/or his academic institution have received research funds and/or fees from Pfizer, AstraZeneca, Roche, Merck, Eli-Lilly, Cerenis, Servier, Thrasos and Valeant. A patent was submitted on pharmacogenomic determinants of responses to cardiovascular drugs and JC Tardif and MP Dubé are listed as authors. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.