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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?
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.
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.
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?
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.
WordCloud by Zach Day; Article Title: Do Novel Anticoagulants Affect the PT/INR? The Cases of XARELTO (rivaroxaban) and PRADAXA (dabigatran)
UPDATED on 7/16/2019
More of Xarelto’s scripts came from Medicare Part D patients in Q2 of this year compared with last, according to J&J’s earnings presentation. And J&J was on the hook for a bigger share of patient costs in Medicare Part D’s donut hole. Congress implemented the donut hole change last year, forcing drugmakers to pay more to move patients out of the coverage gap.
Once J&J gets a few quarters ahead of those changes, Xarelto should start turning in more impressive growth percentages, Duato said. How? J&J plans to grow Xarelto’s market share and volume in existing uses, plus focus on launches in new indications, Duato said, though he didn’t specify exactly how it’ll pump up that volume.
Bristol-Myers Squibb and Pfizer’s rival drug Eliquis is surely facing some of the same issues—the donut hole provision, for instance—but its sales look much healthier. While BMS hasn’t yet released second-quarter results, it did report a 36% boost to U.S. Eliquis sales in the first quarter, to $1.2 billion. For comparison, J&J’s Xarelto posted a 6.3% decrease to $542 million for the same period in the U.S.
SOURCE
J&J execs have plenty to brag about in pharma. Why downplay Xarelto, Zytiga woes?
The blood-thinner Xarelto can cause uncontrolled bleeding — a dangerous and possibly fatal side effect for which there is no antidote. Plaintiffs who say they were harmed by the drug and family members who lost loved ones to severe bleeding filed lawsuits against Bayer, the drug’s maker. They claim Bayer failed to warn them and manufactured a faulty drug.
Rivaroxaban is the first oral factor Xa inhibitor approved in the US to reduce the risk of stroke and blood clots among people with non-valvular atrial fibrillation, treat deep vein thrombosis (DVT), treat pulmonary embolism (PE), reduce the risk of recurrence of DVT and PE, and prevent DVT and PE after knee or hip replacement surgery. The objective of this study was to evaluate the costs from a hospital perspective of treating patients with rivaroxaban vs other anticoagulant agents across these five populations.
Methods:
An economic model was developed using treatment regimens from the ROCKET-AF, EINSTEIN-DVT and PE, and RECORD1-3 randomized clinical trials. The distribution of hospital admissions used in the model across the different populations was derived from the 2010 Healthcare Cost and Utilization Project database. The model compared total costs of anticoagulant treatment, monitoring, inpatient stay, and administration for patients receiving rivaroxaban vs other anticoagulant agents. The length of inpatient stay (LOS) was determined from the literature.
Results:
Across all populations, rivaroxaban was associated with an overall mean cost savings of $1520 per patient. The largest cost savings associated with rivaroxaban was observed in patients with DVT or PE ($6205 and $2742 per patient, respectively). The main driver of the cost savings resulted from the reduction in LOS associated with rivaroxaban, contributing to ∼90% of the total savings. Furthermore, the overall mean anticoagulant treatment cost was lower for rivaroxaban vs the reference groups.
Limitations:
The distribution of patients across indications used in the model may not be generalizable to all hospitals, where practice patterns may vary, and average LOS cost may not reflect the actual reimbursements that hospitals received.
Conclusion:
From a hospital perspective, the use of rivaroxaban may be associated with cost savings when compared to other anticoagulant treatments due to lower drug cost and shorter LOS associated with rivaroxaban.
The classic medication for chronic anti-coagulation is coumadin, but it is problematic. Coumadin impedes the production of coagulation proteins that depend on vitamin K (factors 7, 9, 10, and 2, in order of half-lifes, which range 2-72 hours). Consequently, a change in dose today does not have full impact for 2-3 days. Physicians and pharmacists have difficulties adjusting the dose to its target effect on the biomarker test International Normalized Ratio (INR). The therapeutic range is very narrow. A change in intake of leafy green vegetables can have profound impact (by changing intake of vitamin K). A change in virtually any medication or vitamin that can bind to albumin can also profoundly change the INR to a life-threatening level, because 80% of coumadin is inactivated by binding to albumin, and displacement of coumadin by other agents can boost the effective circulating amount. Those limitations, and the need for testing each month and each medication change have stimulated the development of alternatives. For example, rivaroxaban is a new anticogulant that focuses on factor 10 (factor X), deemed as good as coumadin without the need for the blood tests. In fact, INR test for rivaroxaban is misleading, as values may range as high at 7 (“DANGER”) at normal therapeutic dosing. The following reviews some of the data on that unexpected issue. Physicians not aware of this “false positive” have demanded stoppage of therapy due to the inapplicable spuriously high INR values.
UPDATED on 9/25
Dabigatran versus Warfarin in Patients with Mechanical Heart Valves
Dabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves.
RESULTS
The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding.
CONCLUSIONS
The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. (Funded by Boehringer Ingelheim; ClinicalTrials.gov numbers, NCT01452347 and NCT01505881.)
AMSTERDAM — Edoxaban, a novel factor Xa inhibitor, met its primary endpoints in a trial that pitted it against warfarin for treatment of symptomatic venous thromboembolism (VTE).
Among more than 8,000 patients with deep-vein thrombosis (DVT) or pulmonary embolism (PE), 130 (3.2%) of the patients treated with edoxaban had a recurrent, symptomatic VTE versus 146 (3.5%) warfarin-treated patients, a hazard ratio of 0.89 (95% CI 0.70-1.13, P<0.004 for non-inferiority), Harry R. Büller, MD, of the Academic Medical Center, Amsterdam, reported in a Hot Line session at theEuropean Society of Cardiology meeting here.
The safety endpoint was bleeding (major or clinically relevant non-major bleeding), and in that analysis edoxaban was superior to warfarin, as 8.5% of the edoxaban patients had bleeding events versus 10.3% of the patients in the warfarin group (P=0.004 for superiority).
Moreover, edoxaban appeared to work best in the highest-risk patients — 938 patients with pulmonary embolism and right ventricular dysfunction assessed by N-terminal pro-brain natriuretic peptide levels. In those patients, the recurrent VTE rate was 3.3% in the edoxaban group versus 6.2% in the warfarin group, Büller said.
Based on the results in that very high risk population, Büller predicted that clinicians treating those patients will consider that efficacy profile when selecting an oral Factor Xa inhibitor.
In the highly competitive oral anticoagulant group, those numbers look good, but at first blush the two already approved Factor Xa inhibitors, rivaroxaban (Xarelto) and apixaban (Eliquis) looked better when they were studied in VTE.
In EINSTEIN-VTE, rivaroxaban had a recurrent symptomatic VTE rate of 2.1%, and 8.1% of patients met the safety endpoint.
Likewise, in another VTE trial — AMPLIFY-EXT — apixaban (2.5 mg or 5 mg twice a day) had a recurrent or VTE-related death rate of 1.7%, and 3.2% of the patients who received low-dose apixaban reached the safety endpoint, as did 4.3% of patients treated with 5 mg of apixaban.
Patrick T. O’Gara, MD, American College of Cardiology president-elect, praised the design of the trial, but he agreed that “for mortality benefit, apixaban does appear to have the edge.”
That apixaban benefit, O’Gara said, is militated by the fact that patients need to take the drug twice daily, while “edoxaban is once a day, as is rivaroxaban.”
Asked if there was a specific population that might benefit from edoxaban versus rivaroxaban or apixaban, O’Gara, who is director of clinical cardiology at Brigham and Women’s Hospital and a professor at Harvard Medical School, said the findings from the Hokusai researchers did not provide that answer.
The attempt at a cross-trial comparison drew harsh criticism from Elliott Antman, MD, principal investigator in a trial of edoxaban for prevention of stroke in patients with atrial fibrillation (ENGAGE-AF).
Antman, who like O’Gara is a Harvard professor, said that comparing the edoxaban VTE results to EINSTEIN-VTE or AMPLIFY-EXT would only lead to false conclusions. “You could repeat the rivaroxaban trial 100 times and still not achieve data that can be compared.”
Stavros V. Konstantinides MD, PhD, of the Medical University in Mainz, Germany, who was the ESC discussant for the paper, said that, despite the advantage of once-daily dosing of edoxaban, “apixaban has the best safety profile so far.”
Moreover, unlike the VTE studies of apixaban and rivaroxaban, all patients in the Hokusai trial received heparin for 5 days. After that heparin run-in, patients were randomized to edoxaban or to warfarin. The median duration of heparin after randomization was 7 days.
Antman said that design best replicated real-world clinical practice, in which heparin is usually started before warfarin.
Buller noted that he was an investigator for the EINSTEIN-VTE study, “and after that the thinking was maybe we don’t need low molecular weight heparin, but now I think we need to reconsider that assumption.”
The Hokusai-VTE trial recruited 4,921 patients with DVT and 3,319 patients with PE. Patients initially were treated with heparin, and then were randomized to edoxaban (60 mg or 30 mg) or warfarin. There was an overlap of the heparin therapy when warfarin was started.
During a press conference, Keith Fox, MBChB, chair of the ESC scientific program, asked Buller if that overlap could have increased bleeding risk in the warfarin arm, thus introducing bias, but Buller said the overlap merely allowed warfarin to reach therapeutic range.
The edoxaban regimen “may be less handy, especially for early-discharge patients… [though] some doctors may feel more comfortable starting with low molecular weight heparin and then switching to edoxaban for the one-third of patients with severe PE,” Konstantinides said.
He added, “The NOACs [new oral anticoagulants] have shown efficacy and safety. Now, the test under real life conditions begins. They have to prove efficacy and safety there. I expect that. And they now must justify the high cost by showing … an improvement in patient treatment satisfaction and quality of life and, hopefully, a reduction in healthcare costs … with lower hospitalizations.”
The average age of patients in the Hokusai study was 56-57, and just over half were men.
Patients were enrolled from January 2011 through October 2012 at 439 centers in 37 countries.
About 40% of patients were treated for a year, and 80% of the edoxaban group was adherent to study treatment. Among the warfarin patients, average time in therapeutic range was 63.5%.
The study was supported by Daiichi-Sankyo, which is developing edoxaban.
Buller reported personal fees from Daichi Sankyo during the study, as well as grant support and personal fees from Bayer Health Care and Pfizer. He also received personnal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Isis Pharmaceuticals, and ThromboGenics outside the submitted work.
Antman has a research grant from Daiichi-Sankyo through Brigham and Women’s Hospital. O’Gara said he had no financial disclosures.
Pathological thromboembolism, as seen in Myocardial Infarction or stroke, led to the use of low dose aspirin as an-antiplatelet drug, as a prophylaxis for subsequent intravascular thrombotic episodes. Aspirin, an irreversible Cyclo-oxygenase inhibitor, resulted in a reduction of the production of Thromboxane A2, which in itself is a powerful vaso-constrictor and a platelet aggregator. Certain limitation with the use of aspirin necessitated the search for newer anti-platelet drugs, with a quicker onset of action, quick termination of action on cessation of treatment, and minimal side effects like bleeding. ADP inhibitors like Clopidogrel, which inhibits the ADP dependent activation of Glycoprotein IIb/IIIa receptors, was the next in the armamentarium of these drugs. Later, oral anti-coagulants like coumadin (warfarin sodium) were added to anti-platelet approach, to tackle the overactive coagulation cascade in pathological intravascular thrombosis. Warfarin is a drug which counters the effects of Vit-K on the synthesis of coagulation factors in the liver. Thus, all green leafy vegetables, which contain high amounts of Vit-K, will interfere with the action of Warfarin. Moreover, warfarin is extremely prone to drug interations, owing to its biotransformation by hepatic microsomal enzymes, which are also metabolizing many other drugs. Thus, a therapeutic drug monitoring of warfarin action is mandatory, which, is a big limitation to its use. The quest for pharmacologically superior oral anticoagulants, as compared to Warfarin, reached an important milestone with the discovery of two major drugs, Dabigatran and Rivaroxaban. Both these drugs are Direct Thrombin Inhibitors, though the indications and adverse events are somewhat different. This post will discuss Rivaroxaban pharmacology in brief, and address certain clinical issues.
Question: Does rivaroxaban or dabigatran affect the PT or INR? Can either be monitored using the PT or INR?
Response from Jenny A. Van Amburgh, PharmD, CDE
Assistant Dean of Academic Affairs and Associate Clinical Professor, School of Pharmacy, Northeastern University; Director of the Clinical Pharmacy Team and Residency Program Director, Harbor Health Services, Inc., Boston, Massachusetts
Warfarin is the most commonly used anticoagulant for the prevention of thrombosis or stroke. Because of a narrow therapeutic window, it requires regular coagulation monitoring of the prothrombin time (PT)/international normalized ratio (INR).[1] As such, the inconvenience of frequent blood draws remains a major burden. For the first time in over 50 years, 2 new oral anticoagulants, dabigatran, a direct thrombin inhibitor, and rivaroxaban, a factor Xa inhibitor, were approved by the US Food and Drug Administration. While these anticoagulants carry similar side effects to warfarin, such as risk for gastrointestinal bleeding and intracranial hemorrhage, INR and PT monitoring are not required. How then are providers to gauge the safety and efficacy of the medication in a patient? Can clinicians monitor these medications with the conventional coagulation assays, or are they rendered useless?[1]
The effect of both dabigatran and rivaroxaban on commonly used coagulation assays has been evaluated in the literature, both in vitro and in vivo. The usefulness of these tests relates directly to the medications’ mechanisms of action. For both agents, the use of an INR to determine the effectiveness and safety is meaningless because INR is calibrated for use with vitamin K antagonists (such as warfarin) only.[1] Although use may be associated with an increase in INR, this increase does not relate to the effectiveness of therapy or provide a linear correlation of concentration and effect that is seen when measuring warfarin levels.[2,3] In some instances, point-of-care INR measurements have been drawn on patients using dabigatran; however, the results have failed to correlate to appropriateness in therapy and have varied greatly case by case.[4]
As dabigatran directly inhibits thrombin, PT measures lack the sensitivity to detect therapeutic levels.[1,5] Often, if this assay is measured in patients taking dabigatran, a subtherapeutic level is noted, regardless of concentration of dabigatran.[6] More appropriate assays for dabigatran may be activated partial thromboplastin time (aPTT), diluted thrombin time (TT), or ecarin clotting time (ECT). These tests are better able to capture changes throughout the clotting cascade. Using aPTT may underestimate high levels and could be used more as a qualitative assessment of activity instead of a quantitative assessment.[7] Where available and if desired, monitoring via the diluted TT or ECT has proved a more useful measure for dabigatran.[1]
Unlike dabigatran, studies have demonstrated a correlation between the levels of rivaroxaban and PT through inhibition of factor Xa, but not to the same extent as warfarin.[8] In some instances, the use of PT monitoring for this medication may be useful. A linear response between PT and rivaroxaban can be seen; however, the accuracy of the test improves when concentrations of rivaroxaban are higher. Additionally, the use of PT for monitoring rivaroxaban can be difficult because the measurement differs greatly depending on the reagent used to determine PT. Calibrating PT assays to assess rivaroxaban appropriately is an option currently being evaluated.[8]
In conclusion, the INR is not a viable option when assessing the use of dabigatran or rivaroxaban. Additionally, PT is not a viable option when monitoring a patient on dabigatran. However, PT may be an option for monitoring select patients on rivaroxaban until more reliable standardized tests are developed. Methods of measuring the effectiveness of these agents are currently being developed and tested; however, until they are made available, the existing tests may be adapted to be used in a more effective manner.
The author wishes to acknowledge the assistance of Jacqueline M. Kraft, PharmD, Ngoc Diem Nguyen, PharmD, and Phillipa Scheele, PharmD, PGY1 Residents, and Michael P. Conley, PharmD, and Nga T. Pham, PharmD, CDE, AE-C, Assistant Clinical Professors at Northeastern University — School of Pharmacy and Harbor Health Services, Inc., Boston, Massachusetts.
References
Favaloro EJ, Lippi G. The new oral anticoagulants and the future of haemostasis laboratory testing. Biochem Med (Zagreb). 2012;22:329-341.
Dager WE, Gosselin RC, Kitchen S, Dwyre D. Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother. 2012;46:1627-1636. Abstract
Samama MM, Martinoli JL, LeFlem L, et al. Assessment of laboratory assays to measure rivaroxaban — an oral, direct factor Xa inhibitor. Thromb Haemost. 2010;103:815-825. Abstract
O’Riordan M. Falsely elevated point-of-care INR values in dabigatran-treated patients. Heartwire. July 7, 2011.http://www.theheart.org/article/1251461.do. Accessed January 11, 2013.
Halbmayer WM, Weigel G, Quehenberger P, et al. Interference of the new oral anticoagulant dabigatran with frequently used coagulation tests. Clin Chem Lab Med. 2012;50:1601-1605. Abstract
Lindahl TL, Baghaei F, Blixter IF, et al. Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thromb Haemost. 2011;105:371-378. Abstract
Freyburger G, Macouillard G, Labrouche S, Sztark F. Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: two observational studies in patients undergoing total hip or total knee replacement. Thromb Res. 2011;127:457-465. Abstract
Hillarp A, Baghaei F, Fagerberg Blixter I, et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost. 2011;9:133-139. Abstract
COMPARE TO WARFARIN FOR AFIB NOT CAUSED BY A HEART VALVE PROBLEM
PRADAXA represents progress in helping to reduce the risk of stroke due to atrial fibrillation (AFib) not caused by a heart valve problem.
Review the chart below to compare PRADAXA and warfarin (also known as Coumadin® or Jantoven®). And find out why your doctor may choose PRADAXA. Remember, only your doctor can decide which treatment may be right for you.
Medication type:
Both PRADAXA and warfarin are anticoagulants. These blood-thinning medicines help to stop clots by targeting factors your blood needs to form clots.PRADAXA and warfarin work differently to help reduce the risk of stroke due to AFib not caused by a heart valve problem.
PRADAXA is a direct thrombin inhibitor that helps to stop clots from forming by working directly on thrombin.PRADAXA is not for use in people with artificial (prosthetic) heart valves
Warfarin is a vitamin K antagonist that helps to stop clots from forming by interfering with vitamin K—a vitamin your body needs to form clots.
Stroke risk reduction:
PRADAXA and warfarin help to stop clots by targeting factors your blood needs to form clots.
In a clinical trial of more than 18,000 people, PRADAXA 150 mg capsules was proven superior to warfarin at reducing the risk of stroke.
Warfarin has been extensively studied and prescribed by doctors to help reduce the risk of stroke in people with AFib since 1954.
How you take the medication:
PRADAXA is taken by mouth 2 times each day.
Warfarin is taken by mouth once every day.
Dosing options:
PRADAXA comes in 75 mg and 150 mg strengths.Your doctor will decide which dose is right for you based on a simple kidney function test.
Warfarin comes in 1 mg, 2 mg, 2-1/2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7-1/2 mg, and 10 mg strengths.Your doctor will decide which dose is right for you. He or she will adjust your dose based on the results ofregular blood tests.Based on these tests, your doctor will determine your dose and adjust it, if necessary.
Monitoring:
No need for regular blood tests.PRADAXA has been clinically proven to help reduce the risk of stroke in people with AFib not caused by a heart valve problem. And, unlike warfarin, there is no need for regular blood tests to see if your blood-thinning level is in the right range. Learn more
Requires regular blood test.Warfarin has also been proven to be an effective blood thinner. When you take warfarin, you need to have a regular blood test to measure International Normalized Ratio (INR) to determine the time it takes for your blood to clot.
Dietary restrictions:
No dietary restrictionsPRADAXA requires no changes to your diet.
Dietary restrictions requiredWhen you take warfarin, you need to limit foods high in vitamin K, such as large amounts of leafy green vegetables and some vegetable oils. This is because Vitamin K can affect the way warfarin works in your body.You may also need to limit alcohol, cranberry juice, and products containing cranberries.
XARELTO® is a prescription medicine used to reduce the risk of stroke and blood clots in people with atrial fibrillation, not caused by a heart valve problem. For patients currently well managed on warfarin, there is limited information on how XARELTO® and warfarin compare in reducing the risk of stroke.
XARELTO® is also a prescription medicine used to treat deep vein thrombosis and pulmonary embolism, and to help reduce the risk of these conditions occurring again.
XARELTO® is also a prescription medicine used to reduce the risk of forming a blood clot in the legs and lungs of people who have just had knee or hip replacement surgery.
IMPORTANT SAFETY INFORMATION
WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT XARELTO®?
For people taking XARELTO® for atrial fibrillation:
People with atrial fibrillation (an irregular heart beat) are at an increased risk of forming a blood clot in the heart, which can travel to the brain, causing a stroke, or to other parts of the body. XARELTO® lowers your chance of having a stroke by helping to prevent clots from forming. If you stop taking XARELTO®, you may have increased risk of forming a clot in your blood.
Do not stop taking XARELTO® without talking to the doctor who prescribes it for you. Stopping XARELTO® increases your risk of having a stroke.
If you have to stop taking XARELTO®, your doctor may prescribe another blood thinner medicine to prevent a blood clot from forming.
XARELTO® can cause bleeding, which can be serious, and rarely may lead to death. This is because XARELTO® is a blood thinner medicine that reduces blood clotting. While you take XARELTO® you are likely to bruise more easily and it may take longer for bleeding to stop.
You may have a higher risk of bleeding if you take XARELTO® and take other medicines that increase your risk of bleeding, including:
Aspirin or aspirin-containing products
Non-steroidal anti-inflammatory drugs (NSAIDs)
Warfarin sodium (Coumadin®, Jantoven®)
Any medicine that contains heparin
Clopidogrel (Plavix®)
Other medicines to prevent or treat blood clots
Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above.
Call your doctor or get medical help right away if you develop any of these signs or symptoms of bleeding:
Unexpected bleeding or bleeding that lasts a long time, such as:
Nosebleeds that happen often
Unusual bleeding from gums
Menstrual bleeding that is heavier than normal, or vaginal bleeding
Bleeding that is severe or that you cannot control
Red, pink, or brown urine
Bright red or black stools (looks like tar)
Cough up blood or blood clots
Vomit blood or your vomit looks like “coffee grounds”
Headaches, feeling dizzy or weak
Pain, swelling, or new drainage at wound sites
Spinal or epidural blood clots (hematoma): People who take a blood thinner medicine (anticoagulant) like XARELTO®, and have medicine injected into their spinal and epidural area, or have a spinal puncture, have a risk of forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is higher if:
A thin tube called an epidural catheter is placed in your back to give you certain medicine
You take NSAIDs or a medicine to prevent blood from clotting
You have a history of difficult or repeated epidural or spinal punctures
You have a history of problems with your spine or have had surgery on your spine
If you take XARELTO® and receive spinal anesthesia or have a spinal puncture, your doctor should watch you closely for symptoms of spinal or epidural blood clots. Tell your doctor right away if you have tingling, numbness, or muscle weakness, especially in your legs and feet.
XARELTO® is not for patients with artificial heart valves.
WHO SHOULD NOT TAKE XARELTO®?
Do not take XARELTO® if you:
Currently have certain types of abnormal bleeding. Talk to your doctor before taking XARELTO® if you currently have unusual bleeding.
Are allergic to rivaroxaban or any of the ingredients of XARELTO®.
WHAT SHOULD I TELL MY DOCTOR BEFORE OR WHILE TAKING XARELTO®?
Before taking XARELTO®, tell your doctor if you:
Have ever had bleeding problems
Have liver or kidney problems
Have any other medical condition
Are pregnant or plan to become pregnant. It is not known if XARELTO® will harm your unborn baby. Tell your doctor right away if you become pregnant while taking XARELTO®. If you take XARELTO® during pregnancy, tell your doctor right away if you have bleeding or symptoms of blood loss.
Are breastfeeding or plan to breastfeed. It is not known if XARELTO® passes into your breast milk. You and your doctor should decide if you will take XARELTO® or breastfeed.
Tell all of your doctors and dentists that you are taking XARELTO®. They should talk to the doctor who prescribed XARELTO® for you before you have any surgery, medical or dental procedure.
Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way XARELTO® works. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about XARELTO®?”
Ask your doctor if you are not sure if your medicine is one listed above. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
HOW SHOULD I TAKE XARELTO®?
Take XARELTO® exactly as prescribed by your doctor.
Do not change your dose or stop taking XARELTO® unless your doctor tells you to.
Your doctor will tell you how much XARELTO® to take and when to take it.
Your doctor may change your dose if needed.
If you take XARELTO® for:
Atrial Fibrillation: Take XARELTO® 1 time a day with your evening meal. If you miss a dose of XARELTO®, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
Blood clots in the veins of your legs or lungs:
Take XARELTO® once or twice a day as prescribed by your doctor.
Take XARELTO® with food at the same time each day.
If you miss a dose of XARELTO®:
and take XARELTO® 2 times a day: Take XARELTO® as soon as you remember on the same day. You may take 2 doses at the same time to make up for the missed dose. Take your next dose at your regularly scheduled time.
and take XARELTO® 1 time a day: Take XARELTO® as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
Hip or knee replacement surgery: Take XARELTO® 1 time a day with or without food. If you miss a dose of XARELTO®, take it as soon as you remember on the same day. Take your next dose at your regularly scheduled time.
If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take XARELTO®.
Your doctor will decide how long you should take XARELTO®. Do not stop taking XARELTO® without talking to your doctor first.
Your doctor may stop XARELTO® for a short time before any surgery, medical or dental procedure. Your doctor will tell you when to start taking XARELTO®again after your surgery or procedure.
Do not run out of XARELTO®. Refill your prescription for XARELTO® before you run out. When leaving the hospital following a hip or knee replacement, be sure that you have XARELTO® available to avoid missing any doses.
If you take too much XARELTO®, go to the nearest hospital emergency room or call your doctor right away.
WHAT ARE THE POSSIBLE SIDE EFFECTS OF XARELTO®?
Please see “What is the most important information I should know about XARELTO®?”
Tell your doctor if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You are also encouraged to report side effects to the FDA: visithttp://www.fda.gov/medwatchor call 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc., at 1-800-JANSSEN (1-800-526-7736).
Figure-1 : Targets for anti-coagulant drugs in the coagulation cascade
Pharmacology of Rivaroxaban
Rivaroxaban, chemically an oxazolidinone derivative, is a directly acting Coagulation factor Xa inhibitor, acting on both free Factor Xa as well as that bound to the Prothrombinase complex. It has a good oral bioavailability (~ 80-100%) and a rapid onset of action, with peak plasma concentrations being achieved in about 2-4 hours of oral intake. It is about 95% plasma protein bound, with an aVd of about 50L. It is partly metabolized in liver and excreted both unchanged as well as inactive metabolites in the urine, so also in the feces. Strong CYP3A4 inhibitors like Ketoconazole, Ritonavir, Clarithromycin, Conivaptan etc can increase the pharmacodynamic effects of Rivaroxaban by a gross reduction in its metabolism. Weaker CYP3A4 inhibitors like Amiodarone, Azithromycin, Diltiazem, Dronaderone, Erythromycin, Felodipine, Quinidine, Ranolazine, Verapamil maybe used with Rivaroxaban except in renal impairment. Similarly, enzyme inducers like Rifampicin can decrease the plasma concentrations of Rivaroxaban.
Indications : Prophylaxis of stroke and systemic embolism in patients of atrial fibrillation, treatment and prevention of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE).
Dosage : 10-20 mg with or without food, depending on the indication.
Adverse Effects : As with any other anticoagulant, an increased risk of bleeding. An increased risk of stroke after discontinuation of the drug in atrial fibrillation, and spinal and epidural hematomas.
Therapeutic monitoring : Both Dabigatran and Rivaroxaban do not mandate a therapeutic monitoring clinically, as in the case of Warfarin. Moreover, both Prothrombin Time (PT) as well as the International Normalized Ratio (INR) are not suitable to measure the pharmacodynamic profile of Rivaroxaban for various reasons1. Development of novel methods of assays, for instance Anti Factor Xa assay which utilizes rivaroxaban containing plasma calibrators, may provide optimal therapeutic monitoring modalities for Rivaroxaban in the future.
Figure – 2 : PT and aPTT dependent on plasma concentration of anticoagulant drugs.
(A) rivaroxaban (experimental data from internal studies);
(B) DX-9065a (experimental data from the literature, and
(C) ximelagatran (experimental data for PT and aPTT from the literature. aPTT, activated partial thromboplastin time; INR, international normalized ratio; PT, prothrombin time.
There is some concern regarding a spurious rise in the INR values if a patient stabilized on warfarin is switched over to Rivaroxaban. This concern is ill-founded since it is already mentioned above that INR is not a suitable investigation to give an indication of Rivaroxaban pharmacodynamics. Moreover, no suitable litrerature is available which can explain the rise in INR values on Rivaroxaban administration. It may require some additional clinical studies to throw some light on this clinical anomaly.
Figure-3 : Annualized Incidence of Complications of Rivaroxaban
REFERENCE
Lindhoff-Last et al. Assays for measuring Rivaroxaban : Their suitability and Limitations. Ther Drug Monitoring Dec 2010 (32, Issue 6): 673-79.
RESOURCES
Burghaus R, Coboeken K, Gaub T, Kuepfer L, et al. (2011) Evaluation of the Efficacy and Safety of Rivaroxaban Using a Computer Model for Blood Coagulation. PLoS ONE 6(4): e17626. doi:10.1371/journal.pone.0017626
Burghaus R, Coboeken K, Gaub T, Kuepfer L, et al. (2011) Evaluation of the Efficacy and Safety of Rivaroxaban Using a Computer Model for Blood Coagulation. PLoS ONE 6(4): e17626. doi:10.1371/journal.pone.0017626
Other articles published on this Open Access Online Scientific Journal include the following:
Xarelto (Rivaroxaban): Anticoagulant Therapy gains FDA New Indications and Risk Reduction for: (DVT) and (PE), while in use for Atrial fibrillation increase in Gastrointestinal (GI) Bleeding Reported
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