Increased Bleeding Risks in Patients Sensitive to Warfarin: ENGAGE AF-TIMI 48 Analysis

March 13, 2015

BOSTON, MA — Individuals with a genetic-based sensitivity to warfarin have a significantly increased risk of bleeding within the first 90 days of treatment compared with individuals who respond normally to the anticoagulant, a new analysis of the ENGAGE AF-TIMI 48 study has shown[1].

In addition, the individuals classified as sensitive or highly sensitive to warfarin—on the basis of genetic variants of CYP2C9 and VKORC1—derived a greater early safety benefit from edoxaban (Savaysa, Daiichi-Sankyo), the novel factor Xa inhibitor tested in ENGAGE AF-TIMI 48.

"If you look among patients who were treated with warfarin, what we observed was that those who were sensitive or highly sensitive responders to warfarin based on their genotype spend more time overanticoagulated, defined as an INR greater than 3.0, and they also have higher rates of bleeding in the first 90 days," lead investigator Dr Jessica Mega (Brigham and Women's Hospital, Boston, MA) told heartwire from Medscape. "So there was a pharmacologic effect as well as a clinical-outcomes effect."

In their report, published online March 10, 2015 in the Lancet, the researchers said the goal was to determine whether they could identify patients who were at an increased risk of bleeding with warfarin treatment. The US Food and Drug Administration (FDA) label for warfarin states that variants in CYP2C9 and VKORC1 can help physicians select the optimal dose of the drug. While the genetic information can be used to guide treatment and achieve an INR in the therapeutic range, studies to date have failed to show that treatment based on genotype could reduce adverse events, such as stroke or bleeding.

As the analysis was embedded within the ENGAGE AF trial, the researchers sought to determine whether the variants could help predict clinical outcomes.

"Obviously, those outcomes will be in the early period because we check INRs on patients and we eventually figure out the right dose," senior investigator Dr Marc Sabatine (Brigham and Women's Hospital) told heartwire . "The challenge for warfarin is that you're guessing. This study finally had enough individuals and enough events to make the link between genetics and bleeding events, not just pharmacologic measures."

At present, the Centers for Medicare & Medicaid (CMS) does not reimburse pharmacogenomic testing because clinical trials to date have failed to show a clinical benefit with warfarin-dosing algorithms based on a patient's genotype.

From Genetics to Bleeding Outcomes

As reported by heartwire , the ENGAGE AF-TIMI 48 study was a randomized, double-blind, placebo-controlled trial investigating two doses of edoxaban and warfarin for stroke prevention in patients with AF. After a median follow-up of 2.8 years, both doses of edoxaban were noninferior to warfarin for stroke and systemic embolism prevention and were also associated with significantly lower rates of bleeding and cardiovascular mortality. On the basis of this study, edoxaban was approved for stroke prevention in patients with AF.

In the genetic analysis, 62% of the 4833 individuals taking warfarin were considered normal responders (wild-type CYP2C9 and VKORC1), 35.4% were considered sensitive to warfarin (typically one to two variant alleles), and 2.9% were highly sensitive responders to warfarin (typically three to four variant alleles). As noted, sensitive and highly sensitive responders to warfarin had greater INR values. At 90 days, the mean INR values among normal, sensitive, and highly sensitive warfarin responders was 1.7%, 2.5%, and 6.6%, respectively.

Overall, individuals sensitive to warfarin had a 31% increased risk of bleeding within the first 90 days of treatment when compared with normal responders. For the highly sensitive responders, they were more than two-and-a-half times more likely to bleed with warfarin than normal responders (hazard ratio 2.66, P<0.0001).

The patient's genotype provided independent information about subsequent bleeding risks beyond clinical risk-scoring measures, such as the HAS-BLED score, said Mega. Among the individuals who were sensitive or highly sensitive to warfarin, the data also showed that when compared with treatment with warfarin, those randomized to edoxaban had a significantly greater benefit in terms of reduced bleeding than normal responders.

Mega told heartwire the novel anticoagulants, among them edoxaban, apixaban (Eliquis, Bristol-Myers Squibb), and rivaroxaban (Xarelto, Bayer), as well as dabigatran (Pradaxa, Boehringer Ingelheim), are important new drugs, but clinicians are still trying to figure out how and when to use them. Within their analysis, they were able to determine differential benefits with edoxaban based on a patient's genetic sensitivity to warfarin. "It was telling us again clinically who might benefit most in this early time period," she said.

Genetic Testing to Establish Optimal Drug Treatment Early

In an editorial accompanying the analysis[2], Dr Alan Wu (University of California, San Francisco) said the gradation of benefit with edoxaban over warfarin based on genotype within the first 90 days suggests that instead of establishing an optimal dose of warfarin, "pharmacogenomic testing could be used in patients with atrial fibrillation to optimize choice of treatment."

"In terms of overt bleeding, the ENGAGE AF-TIMI 48 trial showed that the higher dose of edoxaban and warfarin were equally safe in normal responders to warfarin in the first 90 days of treatment," he writes. "Edoxaban and other novel anticoagulants, therefore, could be reserved for individuals who are classified as sensitive or highly sensitive responders."

Such a concept would need to be tested in a randomized, controlled clinical trial, however, one where sensitive or highly sensitive responders to warfarin are randomized to treatment with warfarin or a novel anticoagulant. If the bleeding event rates do not differ, warfarin could continue to be used as the optimal treatment choice until the newer drugs go generic.

"Unfortunately, further warfarin pharmacogenomics trials are unlikely to be funded because the drug is off patent and the results would not benefit pharmaceutical manufacturers," writes Hu. In the meantime, he suggests the CMS pay for reimbursement of genetic testing so that individuals with variants in CYP2C9 and VKORC1 can be offered alternatives to warfarin.

The study was funded by Daiichi-Sankyo. Mega has received research grant support through Brigham and Women's Hospital from Bristol-Myers Squibb, Bayer, Janssen, Daiichi-Sankyo, and AstraZeneca and personal fees from Janssen, American Genomics, and Boehringer Ingelheim outside the submitted work. Sabatine has received research grant support through Brigham and Women's Hospital from Abbott Laboratories, Accumetrics, Amgen, AstraZeneca, AstraZeneca–Bristol-Myers Squibb Alliance, BRAHMS, Bristol-Myers Squibb–Sanofi Joint Venture, Critical Diagnostics, Daiichi-Sankyo, diaDexus, Eisai, Genzyme, GlaxoSmithKline, Intarcia, Merck, Nanosphere, Ortho-Clinical Diagnostics, Roche Diagnostics, Sanofi, Singulex, and Takeda; he has consulted for Aegerion, Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo/Eli Lilly, GlaxoSmithKline, Intarcia, Merck, MyoKardia, Pfizer, Sanofi, Vertex, Zeus, Cubist, and Quest Diagnostics. Wu reports no relevant financial relationships.


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