Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing - CoumaGen-II

Description:

Warfarin is a commonly prescribed medication that has a narrow therapeutic range, with marked interpatient variability in PK and PD. Pharmacogenetic (PG) studies have identified two genes, CYP2C9 (cytochrome p450 isoform) and VKORC1 (vitamin K epoxide reductase complex subunit 1), to consistently determine warfarin dose requirements. However, studies incorporating genotype analysis and tailored therapy have been inconsistent. The current trial sought to study the safety and efficacy of two PG algorithms on the ability to achieve therapeutic anticoagulation with warfarin.

Hypothesis:

A new PG-guided algorithm (PG-2) would be noninferior to a previously studied algorithm (PG-1).

Study Design

  • Blinded
  • Parallel
  • Randomized

Patient Populations:

  • Age ≥18 years
  • Indication for warfarin anticoagulation

    Number of enrollees: 504
    Duration of follow-up: 3 months (1 month for orthopedic surgery patients)
    Mean patient age: 60.6 years
    Percentage female: 53%

Exclusions:

  • Women who were pregnant, breastfeeding, or of child-bearing potential
  • Rifampin within 3 weeks
  • Severe comorbidities (e.g., creatinine >2.5, hepatic insufficiency, active malignancy, advanced physiological age, expected survival <6 months)
  • Noncompliance risk
  • Those deemed inappropriate for PG-guided dosing for any other reason

Primary Endpoints:

  • OOR INRs at 1 and 3 months
  • TTR% at 1 and 3 months

Secondary Endpoints:

  • Serious adverse events

Drug/Procedures Used:

Patients with an indication for warfarin were randomized to one of two PG-guided algorithms: PG-1, a one-step algorithm based on a modified International Warfarin Pharmacogenetics Consortium (IWPC) model; or PG-2, a three-step algorithm with further modifications of the IWPC model. Dose adjustment after 7 days used the validated INR-based Intermountain Healthcare Chronic Anticoagulation Clinic Protocol Algorithm for both PG-guided arms. As part of the study design, patients undergoing PG-guided management in this trial were also compared with contemporary parallel controls undergoing standard management for anticoagulation at the three participating hospitals.

Principal Findings:

A total of 504 patients were randomized, 257 to PG-1 on and 247 to PG-2. In addition, 1,911 parallel controls were studied. Baseline characteristics were fairly similar between the two arms, while a number of differences existed as compared with the controls. The main reasons for anticoagulation were postoperative for orthopedic procedures (55.8%), deep vein thrombosis (DVT)/pulmonary embolism (PE) (29.6%), and atrial fibrillation (AF) (10.6%) in the PG arms, whereas the main indications for the controls were DVT/PE (33.7%), AF (19.3%), and other/unclear (36.6%). Genotype profile was similar between the two PG arms: 19.1% were heterozygous for CYP2C9*2, 13.2% for CYP2C9*3, and 48.6% for VKORC1-1639, whereas 2.0% were homozygous for CYP2C9*2, 0.6% for CYP2C9*3, and 16.4% for VKORC1-1639. Stable maintenance dose in the combined PG group could be determined in 444 patients and varied inversely (by 2.5-fold) and highly significantly (p < 0.001) with the number of reduced-function variant alleles.

PG-1 versus PG-2 randomized comparison: The primary endpoint of out of range (OOR) INRs was noninferior for PG-2 compared with PG-1 at 1 month (30.6% vs. 31.8%, pinf = 0.0025, psup = 0.59) and 3 months (30.3% vs. 30.3%, pinf = 0.0068, psup = 0.99). Values for time in therapeutic range (TTR) were also similar at 1 month (70.2% vs. 67.5%, pinf = 0.12, psup = 0.22) and 3 months (71.7% vs. 70.8%, pinf = 0.0019, psup = 0.68). Adjudicated adverse effects (death, myocardial infarction [MI], stroke, thromboembolic event, moderate to severe hemorrhage) were similar between the two arms (4% vs. 2.5%, p = 0.45). The mean number of days to therapeutic INR (4.43 vs. 4.61 days, p = 0.56) and to stable maintenance dose (15.9 vs. 17.9 days, p = 0.11) were similar.

PG-guided strategy versus controls nonrandomized comparison: The primary endpoint of OOR INRs was superior in the PG arms as compared with standard controls at 1 month (31.2% vs. 41.5%, p < 0.001) and 3 months (30.3% vs. 42.3%, p < 0.001). Values for TTR were also similar at 1 month (68.9% vs. 58.4%, p < 0.001) and 3 months (71.2% vs. 58.6%, p < 0.001). The mean number of days to therapeutic INR were similar (4.52 vs. 4.88, p = 0.08). PG guidance much more accurately (p < 0.001) predicted maintenance dose in wild-type (no variant) and multiple (>1) variant groups than a virtual standard regimen (i.e., 5 mg/d).

Interpretation:

The results of this trial indicate that a modified three-step PG-guided algorithm (PG-2) incorporating information from rapid CYP2C9 and VKORC1 genotyping is noninferior, but not superior to a one-step PG-guided algorithm (PG-1) for maintaining TTR and reducing OOR INRs at 1 and 3 months in patients with an indication for warfarin. In a nonrandomized comparison, both PG strategies were superior to conventional management. Bleeding and efficacy endpoints were similar between the two PG strategies, but were not directly comparable to the control group.

These results are interesting, and suggest that PG-guidance based on CYP2C9 and VKORC1 information in patients requiring warfarin, especially the one-step algorithm, may be useful. Cost-effectiveness analyses and direct head-to-head comparison with standard management powered for hard outcomes are necessary.

References:

Anderson JL, Horne BD, Stevens SM, et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation 2012;125:1997-2005.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Vascular Medicine, EP Basic Science

Keywords: Cytochrome P-450 Enzyme System, Stroke, Myocardial Infarction, Pulmonary Embolism, Warfarin, Vitamin K Epoxide Reductases, Orthopedics, Thromboembolism, Venous Thrombosis, Genotype, Pharmacogenetics


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