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Effect of CYP2C9 and VKORC1 Gene Variants on Warfarin Response in Patients with Continuous-Flow Left Ventricular Assist Devices

Topkara, Veli K.; Knotts, Robert J.; Jennings, Douglas L.; Garan, A. Reshad; Levin, Allison P.; Breskin, Alexander; Castagna, Francesco; Cagliostro, Barbara; Yuzefpolskaya, Melana; Takeda, Koji; Takayama, Hiroo; Uriel, Nir; Mancini, Donna M.; Eisenberger, Andrew; Naka, Yoshifumi; Colombo, Paolo C.; Jorde, Ulrich P.

doi: 10.1097/MAT.0000000000000390
Adult Circulatory Support

Bleeding and thrombotic complications continue to plague continuous-flow left ventricular assist device (CF-LVAD) therapy in patients with end-stage heart failure. Warfarin genotyping information can be incorporated into decision making for initial dosing as recommended by the Food and Drug Administration; however, clinical utility of this data in the CF-LVAD population has not been well studied. Genotypes testing for CYP2C9 and VCORC1 polymorphisms were determined in 90 CF-LVAD patients. Outcomes studied were the association of CYP2C9 (*1, *2, or *3) and VKORC1 (-1639 G>A) gene variants with time-to-target international normalized ratio (INR), total warfarin dose, maintenance warfarin dose. Continuous-flow left ventricular assist device patients carrying a rare variant in the VKORC1 gene had a significantly lower cumulative warfarin dose until target INR achieved (18.9 vs. 35.0 mg, p = 0.002), days spent until INR target achieved (4.9 vs. 7.0 days, p = 0.021), and discharge warfarin dose (3.2 vs. 5.6 mg, p = 0.001) compared with patients with wild-type genotype. Genotype-guided warfarin dosing may lead to safer anticoagulation and potentially improve outcomes in CF-LVAD patients.

From the *Division of Cardiology, Department of Medicine, Department of Pharmacy, Division of Cardiothoracic Surgery, Department of Surgery, Columbia University Medical Center, New York Presbyterian, New York, New York; §Division of Cardiology, Department of Medicine, University of Chicago, Chicago, Illinois; Division of Hematology, Department of Medicine, Columbia University Medical Center, New York Presbyterian, New York, New York; and Division of Cardiology, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.

Submitted for consideration February 2016; accepted for publication in revised form May 2016.

Disclosures: Dr. Naka and Dr. Jorde received consulting fees from Thoratec. Dr. Jorde and Dr. Uriel received consulting fees from Heartware. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

This research has been supported by funds from Lisa and Mark Schwartz Program to Reverse Heart Failure at New York-Presbyterian Hospital/Columbia University.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML and PDF versions of this article on the journal’s Web site (www.asaiojournal.com).

Correspondence: Veli K. Topkara, Mechanical Circulatory Support Program, Center for Advanced Cardiac Care, Columbia University Medical Center – New York Presbyterian, 622 West 168th St, PH9-977, New York, NY. Email: vt2113@cumc.columbia.edu.

Continuous-flow left ventricular assist device (CF-LVAD) therapy has become standard of care in patients with end-stage heart failure for bridge-to-transplantation and destination therapy purposes.1,2 Although dramatically lower adverse event rates have been achieved with the CF-LVADs as compared with older pulsatile-flow technology, thrombotic and bleeding complications remain unacceptably high in this population.3 Significant rates of gastrointestinal (GI) bleeding events were initially reported in CF-LVAD populations, which was mechanistically linked at least in part to the enzymatic breakdown of circulating high-molecular weight von Willebrand factor multimers and prompted lowering international normalized ratio (INR) targets or discontinuation of antiplatelet or anticoagulant agents in affected patients.4 However, more recently an abrupt increase in pump thrombosis rates has been reported with the HeartMate II device (Thoratec, Inc, Pleasanton, CA) in major implanting centers despite widespread use of antithrombotic agents as specified by the device manufacturers.5

Continuous-flow left ventricular assist devices require the use of warfarin-based anticoagulation, which is proven to be effective in prevention of thromboembolic complications. However, warfarin has a narrow therapeutic index and a wide variation in inter-individual dose requirements, which may contribute to bleeding and thrombotic complications because of over- and/or under-coagulation. Growing lines of evidence suggest that genetic variants in two genes involved in warfarin metabolism and action (CYP2C9 and vitamin K epoxide reductase complex submit 1 [VKORC1]) account for roughly 40% to 50% of the variability observed in warfarin dosing. Although the American College of Chest Physicians do not recommend routine use of pharmacogenetic testing, the Food and Drug Administration (FDA) has changed the drug label for warfarin to include the statement that CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose.6,7

These recommendations are supported by evidence in non-LVAD patient populations demonstrating that genotype-directed dosing is associated with higher percentage of time in the therapeutic INR than standard dosing.8 Although the available data in CF-LVAD patients is extremely sparse, a recently published small cohort revealed a high prevalence of CYP2C9/VKORC1 mutations in this population.9 Although these authors report a lower daily and total warfarin dose in those with any mutation compared with wild-type patients, their findings were hampered by the limited size of their cohort. The purpose of our analysis is to further characterize the prevalence of CYP2CP/VKORC1 mutations in CF-LVAD patients and to analyze the impact of these mutations on warfarin dose response in the early postimplant period.

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Methods

All CF-LVAD patients who were genotyped for warfarin metabolism genes at Columbia University Medical Center between December 2007 and February 2015 were eligible for inclusion. The DNA was isolated from peripheral blood and genotyped using multiplex polymerase chain reaction followed by electrochemical detection with allele-specific probes using the “e-Sensor” test kit (FDA-cleared assay). Alleles tested were CYP2C9 (*1, *2, and *3 [rs1799853 and rs1057910]) and VKORC1 (–1639 G>A [rs9923231]) variants. Patients were categorized into wild-type and variant groups based on their genotype information. For the CYP2C9 gene, patients carrying both copies of wild-type allele (*1/*1) were considered as the wild-type group, whereas patient carrying at least one copy of *2 or *3 variants were considered as the variant group. Similarly, for the VKORC1 gene, patients carrying two copies of wild-type allele (GG) were considered as the wild-type group, whereas patient carrying at least one copy of the A allele (GA and AA) were considered as the variant group.

Baseline characteristics including age, gender, etiology of heart failure, and CF-LVAD type were reported for the overall cohort. Distribution of CYP2C9 and VKORC1 genotypes according to race were differentially examined. Response to warfarin in the postimplantation period was assessed by investigating initial warfarin dose (first dose administered after CF-LVAD implant, typically in the Cardiac Surgery Intensive Care Unit), last warfarin dose before target INR reached, cumulative warfarin dose administered until target INR reached, days spent until target INR reached (number of days between first and last warfarin doses), and average warfarin dose (cumulative dose divided by days spent until INR reached) in each genotype group. Daily warfarin doses and daily INR levels for each genotype group were plotted to assess INR/warfarin trends within the first week after warfarin initiation. Discharge warfarin doses were also compared among genotype groups. Target INR was defined as INR 2–3.

Percentage of time in therapeutic range (TTR) and INR variability were determined in the early postimplantation (initial 30 days) as well as outpatient follow-up and comparatively analyzed for each genotype group. Success of intravenous heparin coverage during the initiation of warfarin therapy was assessed among various genotype groups by calculating percentage time spent at target- activated partial thromboplastin time (aPTT), which is defined as a range of 60–90 seconds.

Continuous variables were reported as mean ± standard deviation. Categorical variables were reported as percentages. Differences in wild-type versus variant genotypes were determined using independent two-sample t-tests for continuous variables and Pearson χ2 or Fisher’s exact tests for categorical variables. Hardy-Weinberg equilibrium (HWE) testing for genetic variants were conducted using χ2 and exact tests where appropriate. Linear regressions with random intercepts to account for repeated measurements were used to compare warfarin dose and INR trajectories between genotypes. Logistic regressions with generalized estimating equations to account for repeated measurements were used to compare time spent at sub-therapeutic range between genotypes. All analyses were conducted in SAS version 9.4 (SAS Institute, Cary, NC). The study was approved by the institutional review board.

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Results

Study Population

Of 351 patients who were implanted during the study period, 90 CF-LVAD patients (20 females/70 males) with warfarin genotype data were identified (Table 1). Ten patients were excluded from the warfarin dosing and INR trend analysis: eight patients were implanted before 2012 when a lower INR target (1.5–2.0) was used, and two patients expired during the index hospitalization before receiving warfarin. Genotype data were available before CF-LVAD implant (i.e., at the time of warfarin initiation) only in 25 patients. Mean follow-up time on CF-LVAD support was 1.5 ± 1.3 years. All three single nucleotide polymorphisms (SNPs) were in HWE for European–American patients, however a significant deviation was noted for rs9923231 (SNP) in African–American patients, likely because of the limited sample size as well as possible subpopulation heterogeneity (see Table, Supplemental Digital Content 1, http://links.lww.com/ASAIO/A97). Twenty two patients (24.4%) carried at least one copy of CYP2C9 variant allele (*2, *3, or both) and 28 patients (31.1%) carried at least one copy of VKORC1 variant allele (A). The percentage of patients carrying rare variants were significantly higher for European–Americans than for African–Americans for CYP2C9 (38.0% vs. 9.7%, p = 0.049) and VKORC1 (50.0% vs. 3.2%, p < 0.001) genes (Table 2).

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Warfarin Dosing and INR Kinetics in the Early Postimplantation Period

Presence of CYP2C9 variants did not have an effect on initial warfarin dose, last warfarin dose (before INR target achieved), cumulative warfarin dose (until target achieved), average daily warfarin dose (until target achieved), days spent until INR target achieved, and discharge warfarin dose in CF-LVAD patients (Table 3). However, CF-LVAD patients carrying a rare variant in VKORC1 gene had a significantly lower last warfarin dose, cumulative warfarin dose, average daily warfarin dose, days spent until INR target achieved, and discharge warfarin dose compared with patients with wild-type genotype, despite a comparable initial warfarin dose in both groups (Table 3). A significant gene-dose effect on warfarin dosing and INR response was observed based on VKORC1 genotype leading to lower warfarin dosing requirements and days spent until INR target achieved in the homozygous variant group (AA) compared with heterozygous variant group (AG; Figure 1). Patients who were on already warfarin anticoagulation before LVAD implantation (n = 39) required paradoxically more time to reach to target range than patients who were not using warfarin (7.3 ± 3.7 vs. 5.5 ± 3.8 days, p = 0.033). However, patients who were on warfarin before LVAD implantation also required a higher mean cumulative (37 ± 25 vs. 23 ± 25 mg, p = 0.013) dose that those who were not.

International normalized ratio and warfarin dose trends within the first week after initiation of warfarin therapy in the postimplantation period were represented in Figure 2. As shown, CYP2C9 genotype groups did not have an effect on daily warfarin dosing and INR levels early after initiation of therapy. However, VKORC1 genotype was significantly associated with daily warfarin dosing and INR levels. Patients carrying two copies of variant allele (AA) had significantly higher INR values and lower warfarin doses required within the first week of initiation of therapy compared with AG and GG patients. Days to target INR did not have any correlation with serum creatinine, serum protein, serum albumin, or total bilirubim (p = not significant [NS] for all comparisons).

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Effect of CYP2C9 and VKORC1 Variants on Time in Therapeutic Range and INR Variability

Time in therapeutic window was 30.4% in the early postimplantation (initial 30 days) and 57.2% in the outpatient setting in the overall patient cohort. Risk of over-anticoagulation (INR >3.0) was 6.7% in the early and 12.4% in the outpatient setting. Consistent with the noted differences in early INR trajectories, time in sub-therapeutic INR range was significantly lower in patients with rare VKORC1 variants in the early postimplant period (Figure 3A). However, TTR was not different among genotype groups during the outpatient follow-up (Figure 3B). Outpatient INR variance was also comparable between patients carrying CYP2C9 (0.44 for wild-type vs. 0.52 for rare variants) or VKORC1 (0.46 for GG, 0.41 for GA, and 0.32 for AA) variants (p = NS).

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Heparin Coverage in Genotype Groups

CYP2C9 variants did not have an effect on number of aPTT testing or percentage of therapeutic aPTT during initiation of warfarin therapy. However, patients with rare VKORC1 variants had a trend toward less number of aPTT levels checked (13.9 ± 8.0 vs. 18.5 ± 10.6, p = 0.057), and significantly lower percentage time spent at therapeutic aPTT (28.2% vs. 42.7%, p = 0.019) compared with patients with wild-type genotype.

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Discussion

We investigated the role of warfarin metabolism genotype in 80 patients with CF-LVADs. The principal findings of this study are as follows: 1) Genotyping for CYP2C9 (*1, *2, and *3) and VKORC1 (–1639 G>A) variants are high-yield in European–American CF-LVAD recipients, because these variants occur at higher frequencies in this population; 2) VKORC1 (–1639 G>A) genotype successfully predicts INR response and warfarin dose requirements in the early postimplantation period. Taken together, these results suggest a potential utility of warfarin genotype testing in CF-LVAD patients.

Previous data exploring the relationship between warfarin genotype variants and INR dose response in CF-LVAD recipients is limited to one retrospective cohort of 65 patients.9 Although these authors demonstrated that the presence of any mutant allele was associated with an enhanced warfarin response, the limited sample size of this analysis precluded exploration of the impact of individual variants (e.g., CYP2C9 vs. VKORC1). Our analysis indicates that genetic variants in VKORC1, but not in CYP2C9 gene (*2 or *3), confer an effect on early response to warfarin therapy in CF-LVADs patients. This finding corroborates with prior studies suggesting a larger contribution of VKORC1 to warfarin dosing and early INR response compared with CYP2C9 genotype.10–12 Although precise mechanisms for this finding are unknown, it is likely that other variants in CYP2C9 that are routinely not tested may contribute to warfarin metabolism by regulating the function of this highly polymorphic gene.13 Moreover, only a limited number of patients (n = 5) in our study were compound heterozygous or homozygous for variant alleles (*2 or *3), which limits our ability to demonstrate differences in dosing patterns. Nevertheless, irrespective of presence or absence of clinical risk factors, VKORC1 genotype alone successfully predicted early INR response in CF-LVAD patients in a dose-dependent manner.

Genotype frequencies differed significantly for CYP2C9 and VKORC1 genes across racial groups of CF-LVAD patients, which is consistent with previous reports.14 Compared with European–American population, African–Americans had significantly lower frequencies of rare alleles in CYPC9 and VKORC1 genes. Moreover, these variants explain less variability for individuals of African–American descent, suggesting that testing of additional genetic variants may improve predictive power of genotyping in this population. A recent genome-wide association study identified a novel CYP2C9 gene variant (rs12777823), which significantly predicts warfarin dosing variability in the African–American population independent of CYP2C9 *2, *3, or *11 variants.15 Despite its low prevalence, VKORC1 1639 G>A genotype predicts similar dose requirements across all racial groups.16

Higher risk of overall hemorrhagic complications on warfarin therapy in has been previously reported in non-LVAD patients carrying rare variants (in particular CYP2C9 *3); however, such a relationship was not demonstrated for GI bleeding events.17–20 In CF-LVAD patients, GI bleeding and epistaxis typically occur months after initial implantation, at which point the warfarin dosing and INR levels stabilize for the majority of patients. However, these patients are potentially at higher risk for surgical bleeding complications and need for reoperation in the early postimplantation period. Conversely, warfarin sensitive patients may also be predisposed to increased risk of thrombosis during initiation of therapy, because elevation of INR in this period is primarily due to the rapid reductions in factor VII and may not truly reflect the full antithrombotic effect of warfarin, which does not occur until the prothrombin levels are reduced.21–23 The half-lives of factor VII and prothrombin are 4 and 60 hours, respectively, so warfarin depletes the former much more rapidly than the latter. Although temporal levels and activity of coagulation factors during initiation of therapy have not been investigated in detail for specific genotype groups, previous warfarin dosing experiments indicate that higher warfarin loading doses do not accelerate the reduction in prothrombin levels despite inducing a more rapid decline in Factor VII and elevation in INR levels.24,25 This in combination with unopposed rapid reductions in anticoagulant protein C and S levels may contribute to a higher procoagulant state observed during initiation of warfarin therapy in patients who are loaded with higher warfarin doses, and similarly in patients who are genetically sensitive to warfarin (i.e., patients with the rare VKORC1 variant).

The early procoagulant effect of warfarin was recently highlighted in large population-based study that demonstrated an increased risk of ischemic stroke associated with initiation of warfarin therapy.26 Similarly, CF-LVAD patients may particularly be vulnerable to nidus formation and/or clot propagation during the early pro-coagulant state, especially when heparin dosing and adjustments tend to be variable. In fact, our analysis showed that patients with VKORC1 rare variants are less likely to reach stable therapeutic aPTT levels. This is likely due to the relatively shorter time spent on intravenous heparin and the limited opportunity to optimize dosing, which may place these patients at an increased risk for thrombosis. Although clinical outcomes were not investigated in this report because of limited sample size, it is plausible that warfarin genotype and resultant warfarin response may have an effect on both bleeding and clotting complications in LVAD patients.

International normalized ratio variability may predict warfarin adverse events independent of TTR,27 however we were unable to demonstrate differences in outpatient INR variability among genotype groups. Another consideration is that whether INR is a reliable measure of coagulation status in CF-LVAD patients, similar to patients with cirrhosis who exhibit increased thrombotic complications despite elevated INR levels.28 Using advanced coagulation measures such as specific factor antigen and/or activity levels may be more informative in this population. This is particularly relevant for CF-LVAD patients because of high incidence of right-heart failure, liver dysfunction, and chronic malnutrition, all of which may impact INR levels by modulating the vitamin K metabolism.

Novel oral anticoagulants (NOACs) such as direct thrombin inhibitors or Factor Xa inhibitors are not yet recommended for use in CF-LVAD patients. Although NOACs are shown to be effective and safe in patients with atrial fibrillation, data regarding use of NOACs in CF-LVAD patients are scarce. In addition, given the absence of specific NOAC antidotes, strategies for the reversal of the anticoagulant effects are limited, which may be problematic in CF-LVAD patients with high incidence of bleeding events. Nevertheless, a recent crossover study performed in seven Heartmate II patients suggested that dabigatran use was safe and effective in this population.29 Larger follow-up studies are required to demonstrate safety and efficacy of NOACs in CF-LVAD patients compared with warfarin anticoagulation.

There are several limitations of our analysis that warrant further discussion. First, warfarin genotyping during the study period was collected at the discretion of the treating physician. As such, this lack of a systematic approach to testing may have introduced bias into the study population. Despite this limitation, we feel that our robust sample size of 80 patients is still adequate to describe the effect of warfarin genotype variants on dose response in CF-LVAD patients. Second, as the genotype data were often not available in time to assist with initial warfarin dose selection, we could not evaluate whether a prospective genotype-guided strategy would enhance anticoagulation management. However, the results of our clinical-based dosing strategy yielded similar findings (e.g., time to therapeutic INR and total warfarin dose) when compared with a previously published genotype-guided report.9 Finally, although our analysis demonstrated that obtaining warfarin genotype information may assist with predicting dose requirements, the cost–effectiveness of such an approach has not been established in CF-LVAD patients.

In conclusion, genotype data in warfarin metabolism/action genes accurately differentiate warfarin dosing and INR kinetics after CF-LVAD implantation. Use of routine genotyping may potentially lead to safer and more effective anticoagulation in these patients. Specifically, knowledge of genotype data before device implantation may allow for avoidance of excessive doses in warfarin sensitive patients with an exaggerated response (prevention strategy 1), and shortening of bridging time in patients who are warfarin resistant with typically prolonged time to therapeutic INR (prevention strategy 2; Figure 4). Given the high prevalence of bleeding and thrombotic events in CF-LVAD patients, warfarin genotype data have the potential to predict these adverse events in genetically susceptible individuals. Our findings emphasize the need for a prospective multicenter study to test the hypothesis that the genotype-directed anticoagulation in CF-LVAD patients is cost-effective and leads to improved clinical outcomes such as reduction in bleeding/thrombotic events, hospital length-of-stay, and readmission rates.

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left ventricular assist device; pharmacogenomics; warfarin; thrombosis

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