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Rationale and design of the Clarification of Optimal Anticoagulation through Genetics trial.

ABSTRACT: BACKGROUND:Current dosing practices for warfarin are empiric and result in the need for frequent dose changes as the international normalized ratio gets too high or too low. As a result, patients are put at increased risk for thromboembolism, bleeding, and premature discontinuation of anticoagulation therapy. Prior research has identified clinical and genetic factors that can alter warfarin dose requirements, but few randomized clinical trials have examined the utility of using clinical and genetic information to improve anticoagulation control or clinical outcomes among a large, diverse group of patients initiating warfarin. METHODS:The COAG trial is a multicenter, double-blind, randomized trial comparing 2 approaches to guiding warfarin therapy initiation: initiation of warfarin therapy based on algorithms using clinical information plus an individual's genotype using genes known to influence warfarin response ("genotype-guided dosing") versus only clinical information ("clinical-guided dosing") (www.clinicaltrials.gov Identifier: NCT00839657). RESULTS:The COAG trial design is described. The study hypothesis is that, among 1,022 enrolled patients, genotype-guided dosing relative to clinical-guided dosing during the initial dosing period will increase the percentage of time that patients spend in the therapeutic international normalized ratio range in the first 4 weeks of therapy. CONCLUSION:The COAG will determine if genetic information provides added benefit above and beyond clinical information alone.

SUBMITTER: Kimmel SE

PROVIDER: S-EPMC4415273 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Rationale and design of the Clarification of Optimal Anticoagulation through Genetics trial.

Kimmel Stephen E SE French Benjamin B Anderson Jeffrey L JL Gage Brian F BF Johnson Julie A JA Rosenberg Yves D YD Geller Nancy L NL Kasner Scott E SE Eby Charles S CS Joo Jungnam J Caldwell Michael D MD Goldhaber Samuel Z SZ Hart Robert G RG Cifelli Denise D Madigan Rosemary R Brensinger Colleen M CM Goldberg Suzanne S Califf Robert M RM Ellenberg Jonas H JH

American heart journal 20130712 3

<h4>Background</h4>Current dosing practices for warfarin are empiric and result in the need for frequent dose changes as the international normalized ratio gets too high or too low. As a result, patients are put at increased risk for thromboembolism, bleeding, and premature discontinuation of anticoagulation therapy. Prior research has identified clinical and genetic factors that can alter warfarin dose requirements, but few randomized clinical trials have examined the utility of using clinical ...[more]

PMID: 24016491

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Project description:BackgroundThere is currently much interest in pharmacogenetics: determining variation in genes that regulate drug effects, with a particular emphasis on improving drug safety and efficacy. The ability to determine such variation motivates the application of personalized drug therapies that utilize a patient's genetic makeup to determine a safe and effective drug at the correct dose. To ascertain whether a genotype-guided drug therapy improves patient care, a personalized medicine intervention may be evaluated within the framework of a randomized controlled trial. The statistical design of this type of personalized medicine intervention requires special considerations: the distribution of relevant allelic variants in the study population; and whether the pharmacogenetic intervention is equally effective across subpopulations defined by allelic variants.MethodsThe statistical design of the Clarification of Optimal Anticoagulation through Genetics (COAG) trial serves as an illustrative example of a personalized medicine intervention that uses each subject's genotype information. The COAG trial is a multicenter, double blind, randomized clinical trial that will compare two approaches to initiation of warfarin therapy: genotype-guided dosing, the initiation of warfarin therapy based on algorithms using clinical information and genotypes for polymorphisms in CYP2C9 and VKORC1; and clinical-guided dosing, the initiation of warfarin therapy based on algorithms using only clinical information.ResultsWe determine an absolute minimum detectable difference of 5.49% based on an assumed 60% population prevalence of zero or multiple genetic variants in either CYP2C9 or VKORC1 and an assumed 15% relative effectiveness of genotype-guided warfarin initiation for those with zero or multiple genetic variants. Thus we calculate a sample size of 1238 to achieve a power level of 80% for the primary outcome. We show that reasonable departures from these assumptions may decrease statistical power to 65%.ConclusionsIn a personalized medicine intervention, the minimum detectable difference used in sample size calculations is not a known quantity, but rather an unknown quantity that depends on the genetic makeup of the subjects enrolled. Given the possible sensitivity of sample size and power calculations to these key assumptions, we recommend that they be monitored during the conduct of a personalized medicine intervention.Trial registrationclinicaltrials.gov: NCT00839657.

Project description:BackgroundThe Clarification of Optimal Anticoagulation through Genetics (COAG) trial is a large, multicenter, double-blinded, randomized trial to determine whether use of a genotype-guided dosing algorithm (using clinical and genetic information) to initiate warfarin treatment will improve anticoagulation status when compared to a dosing algorithm using only clinical information.PurposeThis article describes prospective alpha allocation and balanced alpha allocation for the design of the COAG trial.MethodsThe trial involves two possibly heterogeneous populations, which can be distinguished by the difference in warfarin dose as predicted by the two algorithms. A statistical approach is detailed, which allows an overall comparison as well as a comparison of the primary endpoint in the subgroup for which sufficiently different doses are predicted by the two algorithms. Methods of allocating alpha for these analyses are given - a prospective alpha allocation and allocating alpha so that the two analyses have equal power, which we call a 'balanced alpha allocation.'ResultsWe show how to include an analysis of the primary endpoint in a subgroup as a co-primary analysis. Power can be improved by incorporating the correlation between the overall and subgroup analyses in a prospective alpha allocation approach. Balanced alpha allocation for the full cohort and subgroup tests to achieve the same desired power for both of the primary analyses is discussed in detail.LimitationsIn the COAG trial, it is impractical to stratify the randomization on subgroup membership because genetic information may not be available at the time of randomization. If imbalances in the treatment arms in the subgroup are found, they will need to be addressed.ConclusionsThe design of the COAG trial assures that the subgroup in which the largest treatment difference is expected is elevated to a co-primary analysis. Incorporating the correlation between the full cohort and the subgroup analyses provides an improvement in power for the subgroup comparison, and further improvement may be achieved via a balanced alpha allocation approach when the parameters involved in the sample size calculation are reasonably well estimated.

Project description:INTRODUCTION:Warfarin is an effective anticoagulant and the only oral anticoagulant available for patients with mechanical heart valves. The prothrombin time and the associated international normalised ratio (INR) are routinely tested to monitor the response to anticoagulation therapy in patients. Patients who undergo mechanical heart valve replacement need lifelong anticoagulation therapy, and their INR is regularly measured to adjust the anticoagulation strength and the dose of anticoagulation drugs. Appropriate warfarin anticoagulation management can reduce patient complications, such as bleeding and thrombosis, and improve the long-term survival rate. We propose modern internet technology as a platform to build a warfarin anticoagulation follow-up system after valve replacement surgery. This system will provide doctors and patients with more standardised and safer follow-up methods as well as a method to further reduce the risk of warfarin anticoagulation-related complications and improve its therapeutic effects. METHODS AND ANALYSIS:A prospective, multicentre, randomised, controlled trial will be conducted. A total of 700 patients who require long-term warfarin anticoagulation monitoring after heart valve replacement will be enrolled and randomly divided at a 1:1 ratio into a traditional outpatient anticoagulation management group and a group undergoing a new method of management based on the internet technology with follow-up for 1?year. Differences in the percentage of time in the therapeutic range (TTR), drug dose adjustments, bleeding/thrombosis and other related complications will be observed. The primary endpoint is the difference in the TTR between the two groups. The purpose of this study is to explore a safer and more effective mode of doctor-patient interaction and communication in the internet era. As of 13 July 2019, 534 patients had been enrolled. ETHICS AND DISSEMINATION:This study protocol was approved by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University. The results will be published in a peer-reviewed medical journal. TRIAL REGISTRATION NUMBER:ChiCTR1800016204.

Project description:Muscle loss and fat gain contribute to the disability, pain, and morbidity associated with knee osteoarthritis (OA), and thigh muscle weakness is an independent and modifiable risk factor for it. However, while all published treatment guidelines recommend muscle strengthening exercise to combat loss of muscle mass and strength in knee OA patients, previous strength training studies either used intensities or loads below recommended levels for healthy adults or were generally short, lasting only 6 to 24 weeks. The efficacy of high-intensity strength training in improving OA symptoms, slowing progression, and affecting the underlying mechanisms has not been examined due to the unsubstantiated belief that it might exacerbate symptoms. We hypothesize that in addition to short-term clinical benefits, combining greater duration with high-intensity strength training will alter thigh composition sufficiently to attain long-term reductions in knee-joint forces, lower pain levels, decrease inflammatory cytokines, and slow OA progression.This is an assessor-blind, randomized controlled trial. The study population consists of 372 older (age ? 55 yrs) ambulatory, community-dwelling persons with: (1) mild-to-moderate medial tibiofemoral OA (Kellgren-Lawrence (KL) = 2 or 3); (2) knee neutral or varus aligned knee ( -2° valgus ? angle ? 10° varus); (3) 20 kg.m-2 ? BMI ? 45 kg.m-2; and (3) no participation in a formal strength-training program for more than 30 minutes per week within the past 6 months. Participants are randomized to one of 3 groups: high-intensity strength training (75-90% 1Repetition Maximum (1RM)); low-intensity strength training (30-40%1RM); or healthy living education. The primary clinical aim is to compare the interventions' effects on knee pain, and the primary mechanistic aim is to compare their effects on knee-joint compressive forces during walking, a mechanism that affects the OA disease pathway. Secondary aims will compare the interventions' effects on additional clinical measures of disease severity (e.g., function, mobility); disease progression measured by x-ray; thigh muscle and fat volume, measured by computed tomography (CT); components of thigh muscle function, including hip abductor strength and quadriceps strength, and power; additional measures of knee-joint loading; inflammatory and OA biomarkers; and health-related quality of life.Test-retest reliability for the thigh CT scan was: total thigh volume, intra-class correlation coefficients (ICC)?=?0.99; total fat volume, ICC?=?0.99, and total muscle volume, ICC?=?0.99. ICC for both isokinetic concentric knee flexion and extension strength was 0.93, and for hip-abductor concentric strength was 0.99. The reliability of our 1RM testing was: leg press, ICC?=?0.95; leg curl, ICC?=?0.99; and leg extension, ICC?=?0.98. Results of this trial will provide critically needed guidance for clinicians in a variety of health professions who prescribe and oversee treatment and prevention of OA-related complications. Given the prevalence and impact of OA and the widespread availability of this intervention, assessing the efficacy of optimal strength training has the potential for immediate and vital clinical impact.ClinicalTrials.gov, NCT01489462.

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Rationale and design of the Clarification of Optimal Anticoagulation through Genetics trial.

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Rationale and design of the Clarification of Optimal Anticoagulation through Genetics trial.

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