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PGx Variants Linked to Poor Plavix Response in UK South Asians Renews Calls for Expanding Testing

Doctor listening to a male patient's heartbeat with stethoscope

NEW YORK – A real-world study showing that South Asian patients who have had a heart attack and harbor certain pharmacogenetic variants are unlikely to respond well to a widely prescribed anti-platelet drug has put the spotlight once again on the need to diversify research and broaden access to genetic tests. 

Bristol Myers Squibb/Sanofi-Aventis' Plavix (clopidogrel), a P2Y12 inhibitor commonly used to treat heart problems like acute coronary syndrome and stroke, works by stopping platelets from clotting. Studies have shown that cardiovascular disease patients who carry certain CYP2C19 variants poorly metabolize Plavix and are unlikely to derive the full benefit of the drug, which puts them at risk for another cardiac event. The US Food and Drug Administration since 2010 has warned about this in Plavix's label and has informed doctors that CYP2C19 PGx testing can identify poor metabolizers who may fare better from another anti-platelet drug. 

In a study published last month focusing on British patients of Bangladeshi and Pakistani ancestry, researchers made the case that while PGx testing for CYP2C19 variants may be broadly useful for identifying best responders to Plavix, such testing may be particularly useful in the South Asian population, which has high rates of cardiometabolic disease in the UK. 

"This 'real-world' data show that clopidogrel is frequently prescribed and this appears to be particularly detrimental in individuals of South Asian ancestry due to the high proportion of [poor metabolizers]," study authors wrote in the Journal of the American College of Cardiology: Advances.

CYP2C19 genotyping is not part of routine care in the UK, although the National Institute for Health and Care Excellence has recommended instituting it for guiding stroke treatment, said Emma Magavern, a clinical pharmacologist at the William Harvey Research Institute at Queen Mary University of London and first author of the published paper. 

However, most research on the anti-platelet drug to date has focused on patients of European ancestry, in which nearly 30 percent have been found to carry a genetic mutation that makes it difficult to metabolize the drug, Magavern said. The prevalence of these loss-of-function mutations in other populations, such as South Asians, has been understudied.

South Asians are a growing demographic in the UK, especially in central and east London, Magavern said. As of 2021, the most recent UK census, about 7 percent of the population in England and Wales was Bangladeshi, Indian, or Pakistani, compared to 5 percent the decade prior. "But, unfortunately, South Asian ancestry peoples are really woefully underrepresented within both genetic studies and therapeutic clinical trials," Magavern said.

Magavern and colleagues analyzed data from Genes & Health, a UK study collecting genetic and medical data from volunteers of Bangladeshi and Pakistani ancestry, to explore the prevalence of CYP2C19 PGx variants and their association with recurrent myocardial infarction.

They found that 57 percent of the more than 44,000 participants were likely intermediate or poor CYP2C19 metabolizers with at least one loss-of-function allele. Thirteen percent of participants were deemed poor metabolizers with two loss-of-function CYP2C19 alleles. By contrast, according to previous studies, around 2.4 percent of Europeans are poor metabolizers.

From there, investigators homed in on the subset of patients who had experienced an acute heart attack and been prescribed Plavix. They observed a threefold increased risk of recurrent myocardial infarction for poor metabolizers prescribed the drug compared to normal metabolizers, adding to growing evidence suggesting that PGx testing may help lower patients' risk of future cardiovascular events. Investigators did not observe an increased risk for heart attacks among patients with intermediate metabolizer status.

"If, after a heart attack, you prescribe these medicines, they're unlikely to work for those [poor metabolizer] patients," said Mark Caulfield, a professor of clinical pharmacology at Queen Mary University of London and a senior author on the paper. "If we know, we can avoid giving people medicines that are unlikely to help them at all."

Caulfield, who previously served as chief scientist for Genomics England and led the 100,000 Genomes Project, noted that almost all patients have at least one genetic mutation that could affect their ability to metabolize medications.

In an editorial accompanying the paper in JACC: Advances, Rolf Kreutz, an associate professor in the cardiovascular medicine division at Indiana University School of Medicine, noted how clinical trials that led to Plavix's approval were largely conducted in European ancestry patients. And despite the FDA label warning, healthcare providers in the US also aren't routinely conducting PGx testing before prescribing the drug, Kreutz said. 

The lack of professional society backing for PGx testing may be one reason for the lack of uptake in this setting, he suggested. The European Society of Cardiology, for example, in guidelines for managing acute coronary syndromes said there is insufficient evidence showing that genetic testing to guide de-escalation of P2Y12 inhibitors improves outcomes.

The Clinical Pharmacogenetics Implementation Consortium (CPIC), an internationally recognized guidelines body, however, recommends other P2Y12 inhibitors like AstraZeneca's Brilinta (ticagrelor) or Eli Lilly's Effient (prasugrel) for CYP2C19 intermediate or poor metabolizers. 

Still, Plavix remains widely used, in part because other drugs in the same class have a higher risk of bleeding, making it a preferred treatment for normal metabolizers. There are also generic versions of Plavix on the market now, making clopidogrel a less expensive option than newer P2Y12 inhibitors.

"There are still many patients who end up taking clopidogrel and are potentially at risk," Kreutz said. Addressing that is a task for clinicians and healthcare systems, he added, noting that solutions could involve PGx testing for all patients before they're prescribed the drug, or specifically testing patient populations at higher risk, such as South Asian patients, for example.

"Clinicians have to be aware that certain subpopulations of patients may be at particular risk based on genetic ancestry [and] that may not be reflected in what they may have seen in the outcomes of clinical trials," Kreutz said. "Personalized medicine starts at the bedside."

South Asian populations have a high rate of cardiometabolic disease, with one recent study indicating they are at greater risk of developing type 2 diabetes, hypertension, ischemic heart disease, and heart failure compared to white patients in the UK. Another literature review found that South Asians are more likely to die from cardiovascular disease compared to white patients, despite having a decreased risk of all-cause mortality.

All this makes it critical that when clinicians are considering prescribing Plavix to their South Asian patients after a cardiovascular event, they need to be aware of the data that shows they may harbor PGx variants that make them poor metabolizers. "We very much hope that this [study] will drive implementation in the clinic," Magavern said.