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Anticoagulation Genotype guided Dosing

Posted in Cardiovascular Pharmacogenomics, Coagulation Therapy and Internal Bleeding, Genome Biology, Genomic Testing: Methodology for Diagnosis, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacotherapy of Cardiovascular Disease, tagged Anticoagulation Therapy, bivalrudin, clinical dosing, Clopidogrel, COAG trial, Coagulation, CYP2C9, genotyping, INR, pharmacogenomic-guided dosing, platelets, VKORC1, Warfarin on December 8, 2013| Leave a Comment »

Anticoagulation Genotype guided Dosing

Author and Curator: Larry H. Bernstein, MD, FCAP 

 

A common complication of patients on Warfarin (coumadin) is massive hematoma associated with a fall.  Warfarin is an inhibitor of the liver production of prothrombin.  Inadequate Warfarin dosing results in a risk of thromboembolism to the lungs or the brain, depending on where the clot is initiated.  However, there is a pharmacogenomic problem in that there are individuals who have a genetic polymorphism (CYP2C9 and VKORC1) that affects the coagulation effect of the coumadin.  This introduces the question of whether such individuals should be identified and dosed according to pharmacogenomic testing.  The usual measurement of the effect of the drug is the International Normalized Ratio (INR) from the Prothrombin Time (PT).  The existence of chronic liver disease and the use of coumadin are perhaps almost the exclusive value for the PT.
A similar question arises for the genotyping of clopidogrel for antiplatelet guidance. Does it reduce risk in stenting?

A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing

Stephen E. Kimmel, M.D., Benjamin French, Ph.D., Scott E. Kasner, M.D., Julie A. Johnson, Pharm.D., and others

Center for Therapeutic Effectiveness Research,  Philadelphia, PA 19104-6021, or at stevek@mail.med.upenn.edu.

A complete list of investigators and committees in the Clarification of Optimal Anticoagulation through Genetics (COAG) trial is provided in the Supplementary Appendix, available at NEJM.org.

November 19, 2013 | NEJM
http://dx.doi.org/10.1056/NEJMoa1310669

Comparison of  genotype-guided dosing algorithm with the clinically guided dosing algorithm for Warfarin dosing

Abstract

nejmoa1310669.pdf  

Background

The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results.

Methods

We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy.

Results

At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], −0.2; 95% confidence interval, −3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy.

Conclusions

Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.)

Figure 1 Distribution of Time in the Therapeutic Range.

Figure 2 Range of INRs during the 4-Week Study.

nejmoa1310669.pdf  nejm1310669_appendix.pdf 

Introduction

The need for clinical trials before widespread adoption of genotype-guided drug dosing and selection remains widely debated.1-4 Warfarin therapy has served as a model for the potential for pharmacogenetics to improve patient care.1 Observational studies have identified two genes, CYP2C9 and VKORC1, that are associated with variation in warfarin maintenance doses. However, the clinical utility of starting warfarin at the maintenance dose predicted by genotype-guided algorithms has been tested only in small trials, none of which were definitive.5-8 In contrast, observational studies have suggested potential benefits from genotype-guided dosing.9,10 In addition, previous clinical trials could not determine the usefulness of current dosing algorithms among black patients, for whom genotype-guided algorithms perform less well than for other populations.11-13

On the basis of available data, the Food and Drug Administration (FDA) has updated the label for warfarin twice, suggesting that variants in CYP2C9 and VKORC1 may be taken into consideration when choosing the initial warfarin dose. However, the Centers for Medicare and Medicaid Services did not find sufficient evidence to cover the cost of genotyping for warfarin dosing.14 Our study, called the Clarification of Optimal Anticoagulation through Genetics (COAG) trial, was designed to test the effect of genotype-guided dosing on anticoagulation control.

Methods

Study Design and Oversight

The COAG trial was a multicenter, double-blind, randomized, controlled trial that compared a genotype-guided warfarin-dosing strategy with a clinically based dosing strategy during the first 5 days of therapy among patients initiating warfarin treatment.15-17 The study was designed by the authors and approved by the institutional review board at the University of Pennsylvania and at each participating clinical center. The data were collected, analyzed, and interpreted by the authors. A steering committee provided oversight of the trial (for details, see the Supplementary Appendix, available with the full text of this article at NEJM.org). An independent data and safety monitoring board monitored the trial and made recommendations to the National Heart, Lung, and Blood Institute. The first two authors wrote the first draft of the manuscript, which was edited and approved by all the authors. The National Heart, Lung, and Blood Institute supported this study. Bristol-Myers Squibb donated Coumadin (warfarin). GenMark Diagnostics and AutoGenomics loaned genotyping platforms to the clinical centers. None of the companies supporting the trial had any role in the design of the protocol or in the collection, analysis, or interpretation of the data. The authors vouch for the data and the analyses, and for the fidelity of this report to the trial protocol, which is available at NEJM.org.

Study Patients and Randomization

From September 2009 through April 2013, we enrolled both inpatients and outpatients at 18 clinical centers in the United States. All the patients were adults initiating warfarin therapy with a target international normalized ratio (INR) of 2 to 3. Detailed inclusion and exclusion criteria are provided in the Supplementary Appendix. All patients provided written informed consent.

Patients were randomly assigned, in a 1:1 ratio, to the use of a dosing algorithm that included both clinical variables and genotype data or to a clinically guided dosing strategy. Randomization was stratified according to clinical center and self-reported race (black vs. nonblack).

Genotyping for CYP2C9 and VKORC1 at each clinical center was performed with the use of one of two FDA-approved platforms, the GenMark Dx eSensor XT-8 or the AutoGenomics INFINITI Analyzer. Per protocol, genotyping was performed in all patients immediately after blood-sample collection to maintain blinding to the treatment assignment. Genotyping was repeated at the central laboratory with the use of either pyrosequencing or real-time polymerase-chain-reaction assay to measure the accuracy at clinical centers.

Study Intervention and Follow-up

The study intervention period was the first 5 days of warfarin therapy. During this period, the prespecified algorithms were used to determine the warfarin dose. For each dosing strategy, a dose-initiation algorithm was used during the first 3 days of therapy, and a dose-revision algorithm was used on day 4, 5, or both. The algorithms for the genotype-guided dosing strategy12,18 included clinical variables and genotype data for CYP2C9*2, CYP2C9*3, and VKORC1. The algorithms for the clinically based dosing strategy included clinical variables only. The dosing algorithms are provided in the Supplementary Appendix. If genotype information was not available for a patient in the genotype-guided dosing group before the administration of warfarin on any given day in the first 5 days, the clinical algorithm was used on that day.

During the first 4 weeks of therapy, patients and clinicians were unaware of the actual dose of warfarin that was administered, because the pills were encapsulated to prevent identification of the dose (see the Supplementary Appendix). After the 5-day initiation period, we adjusted the dose during the first 4 weeks using standardized dose-adjustment techniques,5,10 starting with the doses predicted by the algorithms and making the same relative adjustments on the basis of the INR in the two study groups. Clinicians were informed of the relative dose change (e.g., a 10% dose increase) at each INR measurement but not the actual dose of warfarin. Clinicians could contact the medical monitor (who was aware of the study-group assignments) to request an override of these relative dose changes without being informed of the actual dose. All patients were to be followed for a total of 6 months.

Study Outcomes

The primary outcome was the percentage of time in the therapeutic range (INR, 2 to 3) from the completion of the intervention period (day 4 or 5) through day 28 of therapy. We calculated the percentage of time in the therapeutic range using a standard linear interpolation method between successive INR values,19 as detailed in the Supplementary Appendix. Each clinical center measured INRs with the use of instruments certified by the Clinical Laboratory Improvement Amendments and following strict quality assurance.

Secondary outcomes included a composite outcome of any INR of 4 or more, major bleeding, or thromboembolism in the first 4 weeks (principal secondary outcome); the time to the first therapeutic INR; the time to the determination of a maintenance dose (which was defined as the time to the first of two consecutive INR measurements, measured at least 1 week apart, that were in the therapeutic range without a dose change); and the time to an adverse event (death from any cause, major bleeding, thromboembolism, or any clinically relevant nonmajor bleeding event20,21) in the first 4 weeks. Two physicians who were unaware of the study-group assignments adjudicated major bleeding and thromboembolic serious adverse events. The definitions of major bleeding,22 clinically relevant nonmajor bleeding, and thromboembolism are provided in the Supplementary Appendix.

Statistical Analysis

We analyzed the primary outcome in the modified intention-to-treat population, which included all patients who underwent randomization with the exception of patients for whom INR data were not available (Fig. S1 in the Supplementary Appendix). Safety outcomes were analyzed in the entire cohort, regardless of whether patients received the study drug. We used regression models to analyze the primary and secondary outcomes, using linear regression for the percentage of time in the therapeutic range and Cox regression for time-to-event outcomes. The protocol specified that we conduct coprimary analyses in which we evaluated the primary outcome in all patients and in a primary subgroup, which comprised patients who had an absolute difference of 1.0 mg or more in the predicted initial daily dose between the genotype-guided dosing algorithm and the clinical dosing algorithm. We used an alpha allocation approach, which formally allows for the evaluation of the treatment benefit in an enriched subgroup as a coprimary end point. In this approach, the overall type I error rate of 0.05 for the primary outcome was split between the analyses performed among all patients and among those in the primary subgroup.17 All models were adjusted for the stratification variables (center and race). Additional subgroups, which were prespecified, were race (black vs. nonblack), sex, and the total number of allelic variants (1 variant vs. 0 or >1 variant in either CYP2C9 or VKORC1 5). All statistical tests were two-sided. All analyses were performed with the use of the R statistical package, version 3.0.1 (R Development Core Team).

We specified a minimum detectable difference of 5.5% in the mean percentage of time in the therapeutic range between the genotype-guided group and the clinically guided group in the entire study population.16 We assumed a standard deviation for the percentage of time in therapeutic range of 25% and a potential dropout rate of 10%. On the basis of recruitment rates,15 the initial sample size of 1238 patients was revised to 1022 patients on September 16, 2012 (with the approval of the data and safety monitoring board). The revised sample size provided a power of at least 80% to detect a between-group difference of 5.5% at a type I error rate of 0.04 among all patients and a 9.0% difference at a type I error rate of 0.01 among patients in the coprimary analysis.

Results

Patients, Genotyping, and Follow-up

A total of 1015 patients were enrolled and randomly assigned to either the genotype-guided dosing algorithm or the clinically guided dosing algorithm (Fig.S1 in the Supplementary Appendix). There were no significant between-group differences at baseline (Table 1Table 1Characteristics of the Patients at Baseline.). The characteristics of the patients according to self-reported race are provided in Table S1 in the Supplementary Appendix. A total of 60 participants (30 in each group) withdrew before completing the intervention period and did not have an available percentage of time in the therapeutic range, resulting in an analytic sample size of 955. A median of six INRs were measured during the first 4 weeks in each of the two study groups. Dispensed doses during the intervention period are summarized in Table S2 in the Supplementary Appendix.

Genotype data were available in the genotype-guided group for 45% of the patients before the first warfarin dose, for 94% before the second warfarin dose, and for 99% before the application of the dose-revision algorithm on day 4 or 5. The mean (±SD) difference between the dose calculated for patients without genotype data on day 1, as compared with the dose they would have received if genotype data had been available, was −0.1±0.4 mg per day during the first 3 days. The central laboratory confirmed 99.8% of all genotyping results from the clinical centers. All genotype distributions were in Hardy–Weinberg equilibrium (P>0.20 for all comparisons).

Primary Outcome

At 4 weeks, there was no significant between-group difference in the mean percentage of time in the therapeutic range: 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference [genotype-guided group minus clinically guided group], −0.2%; 95% confidence interval, −3.4 to 3.1; P=0.91) (Table 2Table 2Percentage of Time in the Therapeutic INR Range through Week 4 of Therapy, According to Subgroup. and Figure 1Figure 1Distribution of Time in the Therapeutic Range.). There was also no significant between-group difference in the percentage of time in the therapeutic range among patients in the coprimary analysis (Table 2). When the 4-week trial was divided into two 2-week intervals, there was also no significant difference between the groups in either interval (Table 2).

However, there was a significant interaction between race and dosing strategy (P=0.003) (Table 2). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group (35.2% vs. 43.5%; adjusted mean difference, −8.3%; P=0.01). Among nonblack patients, the mean percentage of time in the therapeutic range was slightly higher in the genotype-guided group than in the clinically guided group (48.8% vs. 46.1%; adjusted mean difference, 2.8%; P=0.15). There were no significant differences in the percentage of time in the therapeutic range according to sex or the total number of genetic variants (Table 2).

Anticoagulation Control and Dose Prediction

There were no significant between-group differences in the mean percentage of time above the therapeutic range (INR, >3) or below the therapeutic range (INR, <2) (Figure 2Figure 2Range of INRs during the 4-Week Study., and Table S3 in the Supplementary Appendix). However, black patients in the genotype-guided group were more likely to have INRs above the therapeutic range than were those in the clinically guided group (Fig. S2 and Table S3 in the Supplementary Appendix).

There was no overall between-group difference in the time to the first INR in the therapeutic range (Table S4 in the Supplementary Appendix). However, black patients in the genotype-guided group took longer on average to reach the first therapeutic INR than did those in the clinically guided group (Table S4 and Fig. S3 in the Supplementary Appendix). The time to the determination of the maintenance dose did not differ significantly between the two groups overall or according to the primary subgroup, race, or total number of genetic variants (Table S5 in the Supplementary Appendix).

The performance characteristics of the dosing algorithms with respect to the maintenance dose that was determined are shown in Table S6 (which includes the accuracy of a hypothetical, empirical dosing strategy of 5 mg per day) and in Fig. S4, both in the Supplementary Appendix. The genotype-guided algorithms performed better at predicting the maintenance dose among nonblack patients than among black patients. Dose overrides during the first 4 weeks were rare, occurring in only 3.9% of doses in the genotype-guided group and 3.6% of those in the clinically guided group; rates of overrides did not differ according to race.

Adverse Events

At 4 weeks, there were no significant between-group differences in the principal secondary outcome (the time to any INR of ≥4, major bleeding, or thromboembolism) or any other adverse events (Table 3Table 3Adverse Events through Day 28 of Warfarin Therapy., and Table S7 in the Supplementary Appendix). Safety data for the entire duration of follow-up (i.e., past the primary outcome duration) are provided in Table S8 in the Supplementary Appendix.

Discussion

In our study, we found no benefit of genotype-guided dosing of warfarin with respect to the primary outcome of the percentage of time in the therapeutic INR range, either overall or among patients with a predicted dose difference between the genotype-guided algorithm and the clinically guided algorithm of at least 1 mg per day. Our findings exclude a meaningful effect of genotype-guided dosing on the percentage of time in the therapeutic range during the first month of warfarin treatment. However, there was a significant difference in the effects of the algorithms in the prespecified subgroup of black patients, as compared with nonblack patients. Although the interaction between race and dosing strategy with respect to the primary outcome could be due to chance, the analysis was prespecified and was consistent with our a priori hypothesis that there would be race-based differences.

The dosing algorithms that we used in the trial have been validated and account for race (specifically black vs. nonblack).11-13,18 The genotype-guided algorithm performed as well as anticipated on the basis of previous studies,5,8,10-12,18,23 with an R2 of 0.48 and a mean absolute error of 1.3 mg per day for the dose-initiation algorithm and an R2 of 0.69 and a mean absolute error of 1.0 mg per day for the dose-revision algorithm. Despite this accuracy in predicting maintenance doses, there was no benefit of genotype-guided dosing with respect to anticoagulation control.

Observational studies have shown an association between the use of genetic algorithms and improved outcomes, but because of limitations in the study design, they were unable to assess whether the observed associations were causal.1,9,10 Previous clinical trials have produced equivocal results,5-8 but these trials were limited by a small size and lack of blinding to the warfarin dose. The two trials that suggested possible benefit also were limited by large numbers of dropouts6 and a comparison with nonalgorithm-based dosing.8 Previous studies also enrolled either no black patients6-8 or a minimal number of black patients5 (a total of 3) (Anderson J: personal communication).

The average percentage of time in the therapeutic range of 45% in our study is similar to that in other trials, taking into account the range of INRs used for the calculation and the timing and duration of therapy (Tables S9A and S9B in the Supplementary Appendix).5,10,24,25 Unlike previous trials that used only a baseline genotype-guided algorithm, our study used both a dose-initiation and a dose-revision algorithm. A recent study comparing a similar initiation algorithm with a combined initiation and revision algorithm showed no effect on the percentage of time in the therapeutic range with the addition of the revision algorithm.10

There are several questions that our study was not designed to answer. First, the trial did not compare genotype-based dosing with usual care or a fixed initial dose (e.g., 5 mg per day). However, such a comparison could not have discerned whether differences in outcomes were due to the marginal benefit of genetic information or to the use of the clinical information that is included in all genotype-guided dosing algorithms. Second, our study does not address the question of whether a longer duration of genotype-guided dosing would have improved INR control,26 an issue that is being addressed in another trial.27 Third, the dosing algorithms that we used included the three single-nucleotide polymorphisms among the two genes that are most likely to influence warfarin dosing. Although other genes may contribute to warfarin dosing, it is unlikely that they have a substantial effect, particularly in white populations.28 Fourth, although there were no significant between-group differences in the rates of bleeding or thromboembolic events during the primary follow-up period of 4 weeks, the trial was not powered for these outcomes. Fifth, the first dose of warfarin was not informed by genotyping in 55% of the patients; whether this influenced the results is unknown. However, the effect of missing genetics data on day 1 on the dose administered during the first 3 days of therapy was trivial.

In conclusion, our findings do not support the hypothesis that initiating warfarin therapy at a genotype-guided maintenance dose for the first 5 days, as compared with initiating warfarin at a clinically predicted maintenance dose, improves anticoagulation control during the first 4 weeks of therapy. Our results emphasize the importance of performing randomized trials for pharmacogenetics, particularly for complex regimens such as warfarin.

References

1 Ginsburg GS, Voora D. The long and winding road to warfarin pharmacogenetic testing. J Am Coll Cardiol 2010;55:2813-2815
2 Burke W, Laberge AM, Press N. Debating clinical utility. Public Health Genomics 2010;13:215-223
3 Ashley EA, Hershberger RE, Caleshu C, et al. Genetics and cardiovascular disease: a policy statement from the American Heart Association. Circulation 2012;126:142-157
4 Woodcock J, Lesko LJ. Pharmacogenetics — tailoring treatment for the outliers. N Engl J Med 2009;360:811-813
5 Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007;116:2563-2570
6 Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther 2008;83:460-470
A complete list of investigators and committees in the Clarification of Optimal Anticoagulation through Genetics (COAG) trial is provided in the Supplementary Appendix, available at NEJM.org.

Editorial

Do Pharmacogenetics Have a Role in the Dosing of Vitamin K Antagonists?

Bruce Furie, M.D.
Nov 19, 2013    http://dx.doi.org/10.1056/NEJMe1313682

 

Article

Vitamin K plays a single role in human biology — as a cofactor for the synthesis of γ-carboxyglutamic acid. This amino acid is a component of at least 14 proteins, including 4 blood-coagulation proteins (factor IX, factor VII, factor X, and prothrombin) and 2 regulatory proteins (protein C and protein S), and it is critical for the physiologic function of these proteins. Humans do not synthesize vitamin K. Rather, we ingest it in our diet. The vitamin K quinone is reduced to the semiquinone, and this reduced vitamin K is a cofactor that is required for the conversion of specific glutamic-acid residues on the vitamin K–dependent proteins to γ-carboxyglutamic acid by the vitamin K–dependent carboxylase. Vitamin K epoxide, a product of this reaction, is converted back to the vitamin K quinone by the vitamin K epoxide reductase, otherwise known as VKOR. This vitamin K cycle can be broken, and a state of vitamin K deficiency at the carboxylase level effected, by the inhibition of VKOR by vitamin K antagonists, including warfarin.
Warfarin and its analogues have been used as oral anticoagulant agents for more than 50 years. By targeting VKOR, the post-translational modification of the vitamin K–dependent blood-coagulation proteins is impaired. A reduced functional level of factor IX, factor VII, factor X, and prothrombin leads to delayed blood coagulation. This inhibition is monitored in the clinical laboratory with the use of the prothrombin time and is corrected for the varied potencies of tissue factor used in the assay by means of a calibration factor, yielding the international normalized ratio (INR). The intensity of therapy with vitamin K antagonists varies according to the indication for anticoagulation, and the INR is adjusted by varying the dose of the vitamin K antagonist.
The goal of therapy is to keep the INR in the therapeutic range, since patients with an INR that is subtherapeutic are at increased risk for thrombosis and patients with an INR that is supratherapeutic are at increased risk for bleeding. Keeping the INR within the therapeutic range can be challenging. Warfarin binds to albumin, and only about 3% is free and pharmacologically active. A number of medications can displace warfarin, leading to its increased activity and subsequent increased rate of degradation. Diet, specifically the intake of foods containing vitamin K, can offset the effect of the daily dose of the vitamin K antagonist. Age, weight, and sex are other factors that influence the dose.
In addition, the catabolic rate of the vitamin K antagonists appears to have a genetic basis. Genetic polymorphisms in the cytochrome P-450 enzyme CYP2C9 include two variants, C144R in CYP2C9*2 and I359L in CYP2C9*3. These variants have substantially reduced activity, as compared with CYP2C9*1, and are associated with reduced clearance and thus a decrease in the warfarin-dose requirement.1 Similarly, mutations in VKOR, the target of the vitamin K antagonists, lead to various degrees of warfarin resistance. Polymorphisms in VKORC1, the gene encoding this protein, lead to variability in the sensitivity to vitamin K antagonists.2
Might genotyping of CYP2C9 and VKORC1 in patients initiating anticoagulant therapy with vitamin K antagonists lead to more precise dosing and, by extrapolation, reduce the risk of thrombotic and bleeding complications? Numerous anecdotal, observational, and small clinical trials have been published on the use of this information, with many authorities promoting this approach.
The results of three large, randomized clinical trials that test this hypothesis have now been published in the Journal.3-5 Although they vary in organization and structure (duration of study, vitamin K antagonist used, double-blind vs. single-blind design, racial characteristics of the study group, and method for dosing in the control group), they are also similar (large, multicenter, randomized studies; primary end point of the time in the therapeutic range; genotyping of CYP2C9 and VKORC1; and the use of the INR target as a biomarker for the risk of bleeding and thrombosis). Importantly, these trials all examine the initiation of therapy with vitamin K antagonists and use as a primary end point the percentage of time that a patient is within the therapeutic range during the initial phase of treatment. The more important end point, the rate of bleeding and thrombotic complications, was beyond the power design of these trials.
Despite design differences, the conclusions of the three studies are similar. In an initial period of 4 weeks of anticoagulation with warfarin, the randomized, double-blind study by Kimmel et al.3 showed results in the study group that included pharmacogenetic information to supplement clinically guided dosing that were nearly identical to the results in the group that used clinically guided dosing alone (percentage of time in the therapeutic INR range, 45.2% vs. 45.4%). In the 12 weeks after the initiation of anticoagulation with acenocoumarol and phenprocoumon, Verhoef et al.4 used a new point-of-care device and found that a genotype-guided algorithm that included clinical variables yielded results that were similar to those achieved with an algorithm based on clinical variables (61.6% vs. 60.2% at 12 weeks). Pirmohamed et al.5 compared genotype-guided dosing of warfarin, also using a point-of-care device, with standard dosing methods used in clinical practice. The results at 12 weeks were 67.4% and 60.3%, which are significantly different albeit similar, indicating a modest improvement.
What can we conclude from these trials? First, we must recall that these trials address the process of the initiation of anticoagulant therapy — during the very first week — and not an approach to intermediate or long-term anticoagulation. Second, it would appear that, despite the variation in trial design, these trials indicate that this pharmacogenetic testing has either no usefulness in the initial dosing of vitamin K antagonists or, at best, marginal usefulness, given the cost and effort required to perform this testing.
Improved safety with the use of vitamin K antagonists is nonetheless an important goal, and it remains so, despite the introduction of new oral anticoagulants. Perhaps we should concentrate on improvements in the infrastructure for INR testing, including better communication among the laboratory, the physician, and the patient (e.g., through social media); in the use of formal algorithms for dosing, without concern for genotype; in patient adherence to therapy and possibly more responsibility for dosing being assumed by the patient; and in increased diligence by medical and paramedical personnel in testing, monitoring, and dosing on the basis of the INR, given the high percentage of medical mismanagement associated with these anticoagulant agents.  http://dx.doi.org/nejm1313682.pdf

References

1 Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999;353:717-719
2 D’Andrea G, D’Ambrosio RL, Di Perna P, et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 2005;105:645-649
3 Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med 2013. DOI: 10.1056/NEJMoa1310669.
4 Verhoef TI, Ragia G, de Boer A, et al. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N Engl J Med 2013. DOI: 10.1056/NEJMoa1311388.
5 Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 2013. DOI: 10.1056/NEJMoa1311386.

Rapid Warfarin Reversal With 4-Factor Prothrombin Complex Concentrate

Samuel Z. Goldhaber, MD    Nov 07, 2013     Clotblog at theheart.org

Hello. This is Dr. Sam Goldhaber from the Clotblog at theheart.org, speaking to you from Brigham and Women’s Hospital and Harvard Medical School on the important topic of 4-factor prothrombin complex concentrate (4F-PCC), which is the optimal approach to urgent warfarin reversal.

The US Food and Drug Administration only recently approved 4F-PCC to reverse excessive bleeding from warfarin. We have had 3-factor PCC around for a long time but it doesn’t have much factor XII in it. Our European colleagues have had 4F-PCC for the past few years.

I was very pleased recently to have had the opportunity to use 4F-PCC to reverse an intracranial hemorrhage in a patient who had an international normalized ratio (INR) of 2.8 and a spontaneous head bleed. She was receiving warfarin for anticoagulation, and within about 15 minutes the 4F-PCC, along with 10 mg of intravenous vitamin K, returned her INR to normal. Of greater importance, the head bleeding stopped and she regained virtually all of her neurologic function. It seemed miraculous to me and it happened so quickly that it was very gratifying.

Almost simultaneously with my clinical experience, we published an observational study in Circulation [1] with about 300 patients who bled on warfarin. Approximately 80% of these patients were on warfarin because of permanent atrial fibrillation, and they had an average age in the 70s. Initially patients received fresh frozen plasma (before 4F-PCC became available in Canada) and their outcomes with fresh frozen plasma were tracked very carefully. When 4F-PCC came along and practice switched to that therapy, those outcomes were tracked as well.

Clopidogrel Genotyping for Antiplatelet Guidance in MI Stenting: Maybe Reduced Ischemic Risk

Steve Stiles    Nov 06, 2013

SAN FRANCISCO, CA — A novel study of genotype-guided antiplatelet therapy in patients who received a stent for acute MI saw a sharp drop in ischemic events over one year among those who tested positive for a clopidogrel loss-of-function (LOF) gene pattern and had their originally prescribed antiplatelet therapy altered based on the assay results.

In the prospective GIANT trial with 1445 patients, reported here at TCT 2013 , it was discretionary whether clinicians raised the clopidogrel dosage or switched thienopyridine agents based on the assay results, which they had in hand within 48 hours after stenting. Such changes were made in 86% of the 316 who tested positive for the LOF genotype, a group known to be at increased ischemic risk on standard clopidogrel-containing antiplatelet therapy after stenting.

Among those 272 patients with assay-guided antiplatelet changes, the one-year composite risk of death, MI, or stent thrombosis closely matched that of patients lacking the high-risk genotype, according to co–principal investigator Dr Bernard R Chevalier (L’Institut CardioVasculaire Paris-Sud, Massy, France), who presented the study.

Dr Bernard R Chevalier

Of note, the composite end point was about five times higher for the remaining 14% of LOF-genotype patients whose antiplatelet therapy wasn’t changed based the assay.

“These are really the first clinical-trial data in the genotype space compared with the phenotype space, and I think it’s long overdue,” according to Dr Daniel I Simon (University Hospitals Case Medical Center, Cleveland, OH), speaking from the panel charged with critiquing GIANT after its formal presentation. As did many throughout TCT 2013, Simon was weighing two different approaches to sharpening thienopyridine selection for dual-agent antiplatelet therapy after coronary interventions, specifically those focusing on genotyping for the CYP2C19 clopidogrel loss-of-function variant vs platelet-function assays like VerifyNow (Accumetrics).

Such platelet-function testing with coronary stenting has its supporters and detractors but hasn’t found a consistent role in managing patients undergoing PCI, even for acute coronary syndromes, as heartwire has long reported.

One-Year Rates (%) of Primary End Point (Death, MI, or Stent Thrombosis) by Clopidogrel LOF Genotype Status

End point Normal

LOF, treatment is adjusted LOF, treatment is not adjusted

                              n=1118           n=272                     n=55

Primary              3.04                 3.3*                        15.6

 *p=0.83 vs normal; p<0.0001 for noninferiority; p=0.04 vs LOF-treatment-is-not-adjusted

“I think these are amazing results,” Dr Cindy L Grines (Detroit Medical Center Cardiovascular Institute, MI) said at a press briefing on GIANT, referring to both the high event rate in LOF-genotype patients whose treatment wasn’t changed and similarly lower event rates in the other two groups. “Both of those [findings] are a little bit unexpected, I’d guess?” She asked Chevalier why clinicians did not modify antiplatelet therapy in 14% of patients positive for the LOF genotype.

In GIANT, said Chevalier in his presentation, investigators were “strongly recommended” to give such patients prasugrel (Effient, Lilly/Daiichi-Sanyo) or, if they had contraindications to prasugrel, to double their clopidogrel dosage.

But prasugrel, a more potent antiplatelet than clopidogrel, had already been chosen for initial antiplatelet therapy in more than half of patients in the study. Perhaps clinicians believed such patients would benefit from it regardless of their ultimate genotype status. Indeed, some patients later found not to have the clopidogrel LOF genotype were switched from prasugrel to clopidogrel, perhaps satisfied by the assay that the latter drug would be adequate after all.

Chevalier speculated that clinicians also may not have boosted antiplatelet therapy in some LOF-genotype patients if it was considered too risky, such as for those with bleeding risk factors. The high event rate in patients with the LOF genotype whose antiplatelet therapy wasn’t adjusted, therefore, may be more related to how sick the patient was, rather than any cues from genotyping. He said his group is currently looking for the answer in further analyses.

Prevalence of Thienopyridine Use and Dosages, Before and After Genotyping, by Assay Outcome

Thienopyridine and dosage by timing

n=1118                                     treatment is  adjusted,   (%)                 n=272 (%)

                                                                           Normal,     LOF          p

Clopidogrel 75 mg/d (preassay)           35.6           34.7      NS

Clopidogrel 75 mg/d (postassay)        44.5             0       <0.001

Clopidogrel 150 mg/d (preassay)        10               9.1         NS

Clopidogrel 150 mg/d (postassay)    8.9             16.8   <0.05

Prasugrel 10 mg/d (preassay)            53.3           55.5       NS

Prasugrel 10 mg/d (postassay)         46.1            83.1    <0.001

NS=nonsignificant

GIANT was funded by Biotronik. Chevalier discloses consulting for or receiving research grants or speaker fees from Abbott Vascular, Asahi, Astra Zeneca, AVI, Boston Scientific, Biotronik, Colibri, Cook, Cordis, Daiichi Sankyo, Eli-Lilly, Iroko, Medtronic, and Terumo and being general director of and owning equity interest in the European Cardiovascular Research Center.

 Bivalirudin Started during Emergency Transport for Primary PCI

Philippe Gabriel Steg, M.D., Arnoud van ‘t Hof, M.D., Ph.D., Christian W. Hamm, M.D., Peter Clemmensen, M.D., Ph.D., Frédéric Lapostolle, M.D., Ph.D., Pierre Coste, M.D., Jurrien Ten Berg, M.D., Ph.D., Pierre Van Grunsven, M.D., Gerrit Jan Eggink, M.D., Lutz Nibbe, M.D., Uwe Zeymer, M.D., Marco Campo dell’ Orto, M.D., Holger Nef, M.D., Jacob Steinmetz, M.D., Ph.D., Louis Soulat, M.D., Kurt Huber, M.D., Efthymios N. Deliargyris, M.D., Debra Bernstein, Ph.D., Diana Schuette, Ph.D., Jayne Prats, Ph.D., Tim Clayton, M.Sc., Stuart Pocock, Ph.D., Martial Hamon, M.D., and Patrick Goldstein, M.D. for the EUROMAX Investigators

N Engl J Med 2013; 369:2207-2217December 5, 2013DOI: 10.1056/NEJMoa1311096

 

 Background

Bivalirudin, as compared with heparin and glycoprotein IIb/IIIa inhibitors, has been shown to reduce rates of bleeding and death in patients undergoing primary percutaneous coronary intervention (PCI). Whether these benefits persist in contemporary practice characterized by prehospital initiation of treatment, optional use of glycoprotein IIb/IIIa inhibitors and novel P2Y₁₂ inhibitors, and radial-artery PCI access use is unknown.

 

 Methods

We randomly assigned 2218 patients with ST-segment elevation myocardial infarction (STEMI) who were being transported for primary PCI to receive either bivalirudin or unfractionated or low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors (control group). The primary outcome at 30 days was a composite of death or major bleeding not associated with coronary-artery bypass grafting (CABG), and the principal secondary outcome was a composite of death, reinfarction, or non-CABG major bleeding.

 Results

Bivalirudin, as compared with the control intervention, reduced the risk of the primary outcome (5.1% vs. 8.5%; relative risk, 0.60; 95% confidence interval [CI], 0.43 to 0.82; P=0.001) and the principal secondary outcome (6.6% vs. 9.2%; relative risk, 0.72; 95% CI, 0.54 to 0.96; P=0.02). Bivalirudin also reduced the risk of major bleeding (2.6% vs. 6.0%; relative risk, 0.43; 95% CI, 0.28 to 0.66; P<0.001). The risk of acute stent thrombosis was higher with bivalirudin (1.1% vs. 0.2%; relative risk, 6.11; 95% CI, 1.37 to 27.24; P=0.007). There was no significant difference in rates of death (2.9% vs. 3.1%) or reinfarction (1.7% vs. 0.9%). Results were consistent across subgroups of patients.

 Conclusions

Bivalirudin, started during transport for primary PCI, improved 30-day clinical outcomes with a reduction in major bleeding but with an increase in acute stent thrombosis. (Funded by the Medicines Company; EUROMAX ClinicalTrials.gov number, NCT01087723.)

  Source Information

The authors’ affiliations are listed in the Appendix.
Dr. Steg at Cardiologie, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris,  Paris, France, or at gabriel.steg@bch.aphp.fr.
A complete list of the European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

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