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Study Reports Fewer Dose Adjustments With PGx-Guided Warfarin Versus Standard Care in Asian Patients

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NEW YORK (GenomeWeb) – A study evaluating the use of pharmacogenetic testing to administer the blood thinner warfarin in an Asian population showed that genotyped patients required fewer dose titrations in the first two weeks of starting therapy compared to those receiving the anticoagulant based on their clinical factors.

The authors of the 322-patient study, published in BMC Medicine earlier this month and led by Nicholas Syn and Boon-Cher Goh from the National University Cancer Institute in Singapore, claim this is the largest randomized assessment of genotype-guided warfarin dosing in an Asian population and the first assessment of a multi-ethnic Asian population. The investigators hypothesized that administering warfarin based on patients’ genotypes would be just as good as using clinical features in terms of the number of dose adjustments they would need in the first two weeks on therapy, when they are at the highest risk for experiencing adverse events from warfarin.

The study, which involved Chinese, Indian, and Malaysian patients, met this non-inferiority endpoint based on an analysis of 269 evlauable patients, and showed that those in the genotyping arm required fewer average dose adjustments compared to controls — 1.77 versus 2.93.

The researchers also considered whether patients in the genotyping arm or the standard of care group would fare better across a number of secondary endpoints, such as the percentage of time patients were in therapeutic range, the time they took to achieve stable international normalized ratio, and bleeding episodes. However, the authors reported that the percentage of time that patients were in therapeutic range over the three-month study period and the median time it took for patients to achieve stable international normalized ratio didn't differ between the groups. Rates of minor and significant bleeding events, recurrent venous thromboembolism, and out-of-range INRs were also similar between the two arms.

To date, most randomized warfarin PGx studies have been done in Caucasian populations, which makes it difficult to extrapolate the utility of genotyping in other ethnic groups. Some experts have opined that warfarin PGx dosing algorithms should be used in the populations in which they were developed.

One of the strengths of the present study is that the racial composition of the cohort is similar to the population in which the PGx algorithm used in the study was developed and validated by Lai-San Tham from the Oncology Research Institute in Singapore. The majority of the study cohort, which included patients of Chinese, Malay, and Indian ethnicities, was enrolled at the National University Hospital in Singapore, and the rest were enrolled at the University of Malaya Medical Center in Malaysia, and Tan Tock Seng Hospital in Singapore.

Patients were randomized to the genotyping or standard warfarin administration arms and initiated on low molecular weight heparin as they waited for PGx test results. Out of 159 patients randomized to the PGx arm, 147 received their test results in the first four days of starting the trial and got a genotype-tailored warfarin dose. A dozen patients who didn't have their PGx results by day five were crossed over to the control arm and received standard dosing.

In the PGx arm, patients received their warfarin dose based on an algorithm that incorporated their age, weight, their CYP2C9*3 allele status, and VKORC1-381 genotype. Genotyping was performed within a lab at the Cancer Science Institute of Singapore, led by Richie Soong, one of the study authors.

It is estimated that 74 percent of Chinese, 42 percent of Malay, and 7 percent of Indian patients have the VKORC1 H1/H1 haplotype, making them highly sensitive to warfarin, while 7 percent, 9 percent, and 18 percent of patients, respectively, carry a CYP2C9*3 allele, making them poor metabolizers. According to past studies, Asian patients who are homozygous for less sensitive, H7, H8, or H9 VKORC1 haplotypes, and wild-type CYP2C9, require more than 3.5 times the maintenance dose for warfarin compared to patients with the VKORC1 H1/H1 haplotype and a copy of the CYP2C9*3 allele.

The study authors wrote in BMC Medicine that the fact that their study showed that the PGx tested group required fewer warfarin dose titrations compared to the control group may be useful information for patients in Asian countries with limited access to healthcare. "Reduction of frequency of dose titrations (the primary endpoint) using genotype-based algorithms is highly desirable in the context of Asia, where long distances from rural or suburban areas to healthcare facilities poses a barrier to optimal anticoagulation therapy," wrote the authors.

In Asian countries, although there is growing awareness among doctors that genetics impacts warfarin dosing, according to Syn, the first study author, warfarin PGx testing is not readily performed due to the lack of validated commercial tests that physicians can order. While the study conducted by his group may not by itself spur clinical adoption of warfarin PGx testing, Syn said that it serves as a proof-of-concept that genotyping could improve warfarin dosing over traditional methods and motivate other researchers to develop PGx dosing algorithms for Asian patients.

Warfarin is commonly prescribed in patients with deep vein thrombosis, pulmonary embolisms, or to prevent strokes. Despite the fact that trial-and-error drug dosing based on patients' clinical factors leads to highly variable outcomes, and getting the dose wrong can cause life-threatening bleeding events, doctors in the West, including in the US, remain largely unconvinced that PGx testing will get patients to the correct warfarin dose faster or improve patient outcomes based on the studies that have been published to date.

For example, a few years ago, the simultaneously published COAG and EU-PACT studies came to different conclusions about the utility of administering warfarin based on genotyping. COAG — a 1,000-patient randomized trial comparing warfarin dosing using an algorithm based on clinical features and genotypes or by an algorithm that factored in only clinical features — found that in the first four weeks of treatment, genotype-guided warfarin administration was no better than the clinical algorithm in terms of the mean time patients remained in therapeutic range.

In contrast, EU-PACT — a study comparing patients who received warfarin with the help of a point-of-care genetic test and a PGx-based dosing algorithm against those receiving standard, fixed dosing — found that the PGx-guided group stayed longer within therapeutic range in the first 12 weeks of treatment. Although neither COAG nor EU-PACT looked at how genotyping or a standard strategy impacted patient outcomes, and there were important differences in the study designs that could have impacted the findings, experts in the field tend to cite the study that fits their personal views about the utility of warfarin PGx testing.

More recently, in the randomized GIFT trial involving 1,650 older patients undergoing elective hip or knee arthroplasty, those receiving genotype-guided warfarin had a lower incidence adverse events compared to patients who got clinically-guided dosing (as determined by a combined endpoint including major bleeding, international normalized ratio of four or greater, venous thromboembolism, or death). But because GIFT involved patients electing for hip or knee surgery, experts have wondered how generalizable the results are to patients who need to get on warfarin quickly for acute conditions (particularly since turnaround of test results has been a big barrier to test adoption and a limitation in research).

Similarly, Syn and colleagues also made a number of design decisions in their trial, that may make it challenging to apply the learnings from the study to real-world care. For example, the study was designed to gauge the non-inferiority between the two arms in average number of dose titrations over two weeks, but not the superiority of PGx testing in this regard. Syn explained that this was because the study was designed between 2005 and 2007, when there was no comparative data on genotype-guided versus traditional warfarin dosing.

"It was arguably a reasonable concern that pharmacogenetically-guided dosing could be worse than traditional dosing in terms of the number of dose adjustments required in the first two weeks," and therefore, a trial was designed to demonstrate that PGx-guided dosing was no less efficacious than conventional dosing, he said.

Additionally, the authors wrote in the paper that the study wasn't designed to assess differences in the percentage of time patients were in therapeutic range, and it wasn’t powered to detect differences in bleeding or re-thrombosis outcomes. Syn also pointed out that this trial looked at PGx-guided fixed dose initiation on warfarin, and didn't evaluate the ability of PGx to inform the loading doses for each patient or make dose adjustments, primarily because the algorithm used in the study didn't give guidance in these areas.

Syn highlighted a Monte Carlo simulation study published in 2015, which suggested that the combination of PGx-guided loading doses and PGx-guided dose revisions might yield better outcomes than starting patients on fixed doses based on genotyping information. "Alas, it was too late to amend the [present study] protocol at the time our simulation study was published," he said.

Syn and his colleagues will conduct a number of follow-up studies to further evaluate the utility of PGx testing to administer warfarin in Asian patients. For example, they will use a statistical technique, called CUSUM analysis, to analyze the turnaround time for obtaining genetic test results. The researchers are also planning a cost-effectiveness analysis of PGx warfarin testing and exploring subgroups (differentiated by age, warfarin indications, and race) that might particularly benefit from a PGx strategy. They also plan to reach out to other investigators in Asia to conduct a pooled analysis of genotype-guided warfarin dosing trials that involve patients from the region.