Conceptual Framework for Addressing Residual Atherosclerotic Cardiovascular Disease Risk in the Era of Precision Medicine
2018; Lippincott Williams & Wilkins; Volume: 137; Issue: 24 Linguagem: Inglês
10.1161/circulationaha.118.035289
ISSN1524-4539
AutoresKershaw V. Patel, Ambarish Pandey, James A. de Lemos,
Tópico(s)Cardiac Health and Mental Health
ResumoHomeCirculationVol. 137, No. 24Conceptual Framework for Addressing Residual Atherosclerotic Cardiovascular Disease Risk in the Era of Precision Medicine Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBConceptual Framework for Addressing Residual Atherosclerotic Cardiovascular Disease Risk in the Era of Precision Medicine Kershaw V. Patel, MD, Ambarish Pandey, MD, MSCS and James A. de Lemos, MD Kershaw V. PatelKershaw V. Patel Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas. , Ambarish PandeyAmbarish Pandey Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas. and James A. de LemosJames A. de Lemos Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas. Originally published11 Apr 2018https://doi.org/10.1161/CIRCULATIONAHA.118.035289Circulation. 2018;137:2551–2553Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2018: Previous Version 1 Until recently, therapies to mitigate atherosclerotic cardiovascular disease (ASCVD) risk have been limited to lifestyle interventions, blood pressure-lowering medications, high-intensity statin therapy, antiplatelet agents, and, in select patients, coronary artery revascularization. Despite administration of these evidence-based therapies, substantial residual risk for cardiovascular events persists, particularly among individuals with known ASCVD. Moreover, the current guideline-based approach does not adequately account for patient-specific, causal pathways that lead to ASCVD progression and complications. In the past few years, multiple new pharmacological agents, targeting conceptually distinct pathophysiological targets, have been shown in large and well-conducted clinical trials to lower cardiovascular risk among patients with established ASCVD receiving guideline-directed medical care. These evidenced-based therapies reduce event rates and, in some cases, all-cause and cardiovascular mortality; these benefits confirm important new disease targets and challenge the adequacy of the current standard of care for secondary prevention.After years of treating our patients after an acute coronary syndrome event with the same core group of medications that have been proven to be safe, beneficial, and cost-effective, a diverse array of potentially beneficial options to address residual risk is now available. The near simultaneous development of these new approaches to secondary prevention disrupts existing paradigms regarding assessment and treatment of residual risk. For example, consider a hypothetical patient with obesity, hypertension, type 2 diabetes mellitus, and hyperlipidemia who had a non-ST elevation myocardial infarction and received an intracoronary drug-eluting stent. This patient would likely be given instructions on healthy lifestyle practices and prescribed current guideline-directed medical therapy, including low-dose aspirin, P2Y12 inhibitor, high-intensity statin, β-blocker, ACE inhibitor, and metformin. In addition, we must now consider a new evidence base of available treatment options to lower residual ASCVD risk even further by targeting causal pathways. Based on recent trial data, an evidence-based case could be made for the addition of ezetimibe, a PCSK9 inhibitor, canakinumab, an SGLT2 inhibitor, a GLP-1 agonist, and after 12 months from the ASCVD event, extended duration dual antiplatelet therapy or low-dose rivaroxaban and aspirin. How are clinicians supposed to choose from this portfolio of options?Clearly, there is now an abundance—perhaps even an excess—of therapies to target residual risk in patients with ASCVD, and clinicians will need new strategies to navigate through the various treatment options and guide selection of the one or several choices best suited for the individual patient. Although the move toward precision cardiovascular medicine is still in its infancy, we will need to accelerate translational efforts so that as clinicians we can make sensible choices among the many options for reducing residual risk.Here we propose an approach for considering residual risk in light of these important new data (Figure). We propose 5 broad residual risk targets: lipoproteins, inflammation, metabolism, platelets, and coagulation. This conceptual framework builds on prior constructs that have considered soluble biomarkers such as LDL (low-density lipoprotein) and hs-CRP (high-sensitivity C-reactive protein) as residual risk targets.1,2 The approach recognizes distinct ASCVD pathophysiological pathways and identifies therapies to combat these targets and mitigate residual risk. We propose potential precision medicine tools (which in many cases are highly speculative) that may provide insights into pathophysiological mechanisms underlying an individual's residual risk and may potentially help guide selection among the newer agents. We suggest that the precision cardiovascular care toolbox should include clinical history and physical examination findings, lifestyle information (eventually including wearable device physiological data), genetics, biomarkers, data-derived risk scores, and, in some cases, on-treatment responses to an initial trial of a targeted therapy.3,4 Of course, long-term safety and economic implications will remain paramount as we focus on residual risk. Indeed, until the precision medicine toolkit is operationalized, we believe that safety and cost should be the primary considerations for selection among the potential treatment options, particularly those with similar treatment effects.Download figureDownload PowerPointFigure. Proposed conceptual framework for addressing residual atherosclerotic cardiovascular disease risk in the era of precision medicine. We propose 5 broad residual risk targets for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) and identify therapies either shown to be effective in large randomized trials (blue) or available for clinical use but not yet demonstrated to lower ASCVD risk (green). Precision medicine tools are proposed for each category (in many cases, highly speculative) that could be used to guide selection among the potential therapies. BMI indicates body mass index; DAPT, dual antiplatelet therapy; DM, diabetes mellitus; GLP-1, glucagon-like peptide 1; Hb A1c, glycated hemoglobin; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; hs-CRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; Lp(a), lipoprotein (a); PARIS, Patterns of Non-Adherence to Anti-Platelet Regimen in Stented Patients; PCSK9, proprotein convertase subtilisin/kexin type 9; PRECISE-DAPT, Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Anti Platelet Therapy; PVD, peripheral vascular disease; SGLT2, sodium-glucose cotransporter 2; TG, triglycerides; and VTE, venous thromboembolism.Targeting residual risk with new strategies will be met with enormous challenges. There is a lack of data as to who will benefit most from specific residual risk reduction strategies. Although existing data support some precision medicine tools, such as LDL cholesterol, hs-CRP, and the Dual Antiplatelet Therapy risk score, most treatments do not have validated surrogate markers to evaluate treatment response. Even for those therapies with a putative marker, we have little or no evidence to support that initiating or titrating therapy to the biomarker target improves outcomes. As the most sobering example, in 2018, we still do not know whether LDL cholesterol levels should be used as a treatment target for LDL-lowering therapies.Comparative effectiveness trials among these new therapies will be extremely difficult. The number of potential permutations and drug combinations is staggering, and given the progressive decline in ASCVD event rates, sample size requirements will be large and perhaps even prohibitive. Moreover, identifying comparator and control groups will present a dilemma given the number of potential options. Thus, the design of robust clinical trials will be arduous, and the pharmaceutical industry will likely not be incentivized to support such an endeavor. Observational comparative effectiveness studies have been proposed as an alternative or complement to randomized trials, but we have strong concerns that the inherent limitations of observational studies, even when performed with the most robust methodologies, will preclude identifying optimal drug combinations. Novel, adaptive trial designs testing precision medicine-targeted therapies, which have been pioneered in oncology, may provide a path forward for the necessary studies in precision cardiovascular medicine.5These are remarkable times for researchers, clinicians, and, most important, our patients. The surprising and unprecedented recent successes from randomized clinical trials testing novel therapies to lower residual risk have forced a reexamination of the underlying pathophysiological basis of ASCVD and opened new doors for precision medicine in targeting specific causal pathways.DisclosuresDr de Lemos has received grant support from Abbott Diagnostics; consulting income from Abbott Diagnostics, Ortho Clinical Diagnostics, Quidel Cardiovascular, and Roche Diagnostics; fees for participation on data safety and monitoring boards from Novo Nordisc and Regeneron; and fees for participating on a steering committee from Amgen. The other authors report no conflicts of interest.Footnoteshttp://circ.ahajournals.orgThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.James A. de Lemos, MD, Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390. E-mail [email protected]References1. Bohula EA, Giugliano RP, Cannon CP, Zhou J, Murphy SA, White JA, Tershakovec AM, Blazing MA, Braunwald E. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT.Circulation. 2015; 132:1224–1233. doi: 10.1161/CIRCULATIONAHA.115.018381.LinkGoogle Scholar2. Morrow DA, de Lemos JA, Sabatine MS, Wiviott SD, Blazing MA, Shui A, Rifai N, Califf RM, Braunwald E. 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June 12, 2018Vol 137, Issue 24 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.035289PMID: 29643058 Originally publishedApril 11, 2018 Keywordssecondary preventionbiomarkersresidual riskatherosclerosisprecision medicinePDF download Advertisement SubjectsPrecision Medicine
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