Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial

Mega, Jessica L.; Walker, Joseph R.; Ruff, Christian T.; Vandell, Alexander G.; Nordio, Francesco; Deenadayalu, Naveen; Murphy, Sabina A.; Lee, James; Mercuri, Michele; Giugliano, Robert P.; Antman, Elliott M.; Braunwald, Eugene; Sabatine, Marc S.

doi:10.1016/s0140-6736(14)61994-2

Cited by 156 publications

(133 citation statements)

References 37 publications

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“…Although previous studies on this topic 14,37 have relied on the same assumptions, we used more robust evidence to assess the impact of genetic testing on treatment outcomes. It is also however important to note that a recent analysis of the warfarin arm of the ENGAGE AF-TIMI 48 trial showed that patients who carry variants in CYP2C9 and/or VKORC1 were more likely to have unstable INRs and were at increased risk of bleeding events, 38 which provides support for our assumptions. Furthermore, it has been shown from the RELY trial that a 10% improvement in PTIR can lead to a 20% improvement clinical outcomes.…”

Section: Discussionsupporting

confidence: 69%

Cost-effectiveness of pharmacogenetic-guided dosing of warfarin in the United Kingdom and Sweden

et al. 2016

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We aimed to assess the cost-effectiveness of pharmacogenetic-guided dosing of warfarin in patients with atrial fibrillation (AF) in the United Kingdom and Sweden. Data from EU-PACT, a randomized controlled trial in newly diagnosed AF patients, were used to model the incremental costs per quality-adjusted life-year (QALY) gained by pharmacogenetic-guided warfarin dosing versus standard treatment over a lifetime horizon. Incremental lifetime costs were £26 and 382 Swedish kronor (SEK) and incremental QALYs were 0.0039 and 0.0015 in the United Kingdom and Sweden, respectively. The corresponding incremental cost-effectiveness ratios (ICERs) were £6 702 and 253 848 SEK per QALY gained. The ICER was below the willingness-to-pay threshold of £20 000 per QALY gained in 93% of the simulations in the United Kingdom and below 500 000 SEK in 67% of the simulations in Sweden. Our data suggest that pharmacogenetic-guided dosing of warfarin is a cost-effective strategy to improve outcomes of patients with AF treated with warfarin in the United Kingdom and in Sweden.

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Section: Discussionsupporting

confidence: 69%

Cost-effectiveness of pharmacogenetic-guided dosing of warfarin in the United Kingdom and Sweden

et al. 2016

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“…Additional studies with other biomarkers, including blood-based, genomic, and imaging markers that demonstrate improvements not only in stratification of predicted risk but also in the relative benefit from statins, are needed to better target statin eligibility to those with the most expected benefit. 35,36 An individualized benefit calculator (ie, Web based or mobile application) to allow clinicians to use and share this information at the point of care with their patients is needed and is currently in development.…”

Section: Downloaded Frommentioning

confidence: 99%

Individualized Statin Benefit for Determining Statin Eligibility in the Primary Prevention of Cardiovascular Disease

et al. 2016

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Association (ACC/AHA) cholesterol guidelines determined that except for those with diabetes mellitus or low-density lipoprotein (LDL) cholesterol (LDL-C) >190 mg/dL, individuals should be selected for statin therapy for primary prevention of cardiovascular disease on the basis of predicted 10-year cardiovascular risk.1 Such a risk-based approach leads to greater statin eligibility among older individuals with lower levels of LDL-C while limiting eligibility in younger individuals with higher LDL-C because predicted risk is driven primarily by age.2 Defining statin eligibility with the use of a predicted risk threshold also implicitly assumes that the benefit of statins is constant in all eligible individuals, regardless of the factors that contribute to their increased risk such as higher age as opposed to higher LDL-C.Alternative approaches in determining statin eligibility have also been proposed recently, including the use of novel markers for better risk classification 3,4 and the use of entry criteria for randomized, controlled trials (RCTs) to define statin benefit groups. 5,6 Moreover, Pandya et al 7 have shown that statin preventive therapy remains cost-effective even at lower risk thresholds than selected by the ACC/AHA guidelines. Although each of these approaches has advantages and disadvantages, none directly considers the clinical benefits from statin therapy for each individual on the basis of the available clinical trial data. We compared statin eligibilities using 2 separate approaches: a 10-year risk-based approach (≥7.5% 10-year risk) and an individualized benefit approach (ie, based on predicted absolute risk reduction over 10 years [ARR 10 ] ≥2.3% from randomized, controlled trial data). A risk-based approach led to the eligibility of 15.0 million (95% confidence interval, 12.7-17.3 million) Americans, whereas a benefit-based approach identified 24.6 million (95% confidence interval, 21.0-28.1 million). The corresponding numbers needed to treat over 10 years were 21 (range, 9-44) and 25 (range, 9-44). The benefit-based approach identified 9.5 million lower-risk (<7.5% 10-year risk) Americans not currently eligible for statin treatment who had the same or greater expected benefit from statins (≥2.3% ARR 10 ) compared with higher-risk individuals. This lower-risk/acceptable-benefit group includes younger individuals (mean age, 55.2 versus 62.5 years; P<0.001 for benefit based versus risk based) with higher low-density lipoprotein cholesterol (140 versus133 mg/dL; P=0.01). Statin treatment in this group would be expected to prevent an additional 266 508 cardiovascular events over 10 years. Conclusions-An individualized statin benefit approach can identify lower-risk individuals who have equal or greater expected benefit from statins in primary prevention compared with higher-risk individuals. This approach may help develop guideline recommendations that better identify individuals who meaningfully benefit from statin therapy.

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“…More recently, a fourth trial examined the issue of genetic guidance in the choice between warfarin and a recently approved alternative anticoagulant therapy, edoxaban that inhibits clotting factor Xa. 134 Edoxaban and other new non-vitamin K oral anticoagulants have been found to have at least noninferior efficacy to warfarin in clinical trials for management of atrial fibrillation and superior safety profile for some adverse events, but greater risk of gastrointestinal bleeding. 135,136 Participants with nonvalvular atrial fibrillation were randomly allocated to warfarin treatment or either higher (60 mg/d) or lower (30 mg/d) dose edoxaban.…”

Section: Anticoagulation Therapy With Warfarinmentioning

confidence: 99%

Are Genetic Tests for Atherosclerosis Ready for Routine Clinical Use?

Paynter

Ridker

Chasman

2016

Circulation Research

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T he Presidential Precision Medicine Initiative imagines a future in which medical decisions are increasingly tailored to the clinical profile of each patient.1 Incorporation of genetic information is a key component of the envisioned profile, continuing the goals of integration with patient care set out at the completion of the human genome sequence 15 years ago. As the cost of determining genetic information plummets and point-of-care genetic analysis is increasingly available, it Atherosclerosis Compendium© 2016 American Heart Association, Inc.

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Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial

Cited by 156 publications

References 37 publications

Cost-effectiveness of pharmacogenetic-guided dosing of warfarin in the United Kingdom and Sweden

Cost-effectiveness of pharmacogenetic-guided dosing of warfarin in the United Kingdom and Sweden

Individualized Statin Benefit for Determining Statin Eligibility in the Primary Prevention of Cardiovascular Disease

Are Genetic Tests for Atherosclerosis Ready for Routine Clinical Use?

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