Point-of-Care Test Opens Door to Tailored Antiplatelet Therapy

A new, rapid, point-of-care genetic test may help tailor antiplatelet therapy after percutaneous coronary intervention, so that patients receive an agent providing the best balance of benefits and risks for them, suggests the randomized, proof-of-concept RAPID-GENE trial.

The 200 trial patients who underwent PCI for acute coronary syndromes or stable angina were assigned evenly to a standard treatment arm or a tailored-treatment arm.

The former all received clopidogrel. The latter first had rapid genotyping for the CYP2C19*2 loss-of-function allele, which confers inadequate inhibition of the platelet P2Y12 receptor and increased rates of major adverse events among patients taking clopidogrel after PCI. Carriers of the allele were given prasugrel – a novel P2Y12 inhibitor that provides more potent platelet inhibition but with the trade-off of increased bleeding – whereas noncarriers were given clopidogrel. All trial patients received aspirin as well.

Trial results, reported online first in the Lancet, showed that after a week of dual antiplatelet therapy, nearly a third of CYP2C19*2 carriers who were given standard treatment had high on-treatment platelet reactivity, a marker of increased adverse cardiovascular events. This compared with none of their counterparts who received tailored treatment, reported Dr. Jason D. Roberts and his colleagues at the University of Ottawa Heart Institute (Lancet 2012 March 29 [doi:10.1016/S0140-6736(12)60161-5]).

"As far as we are aware, our study is the first to validate and to show clinical use of point-of-care genetic testing. It is the first randomised investigation of selective use of prasugrel in CYP2C19*2 carriers after PCI," wrote the investigators.

"Our findings suggest that personalisation of antiplatelet therapy might reduce adverse ischaemic outcomes; use of prasugrel only in high-risk individuals might also minimise adverse bleeding events. The development of practical point-of-care genetic testing in our study will help to integrate genetics into the clinical setting and will allow large-scale investigations to definitively assess the value of pharmacogenetic strategies," they wrote.

In an accompanying comment, Amber L. Beitelshees, Pharm.D., of the University of Maryland, Baltimore, noted that "widespread clinical implementation of clopidogrel pharmacogenetics has not progressed at the expected pace, and the RAPID GENE study provides much-needed impetus by showing that genotyping can be done in a timely manner and incorporated into the clinical workflow as we wait for the results of large outcome-driven randomised trials."

However, she also pointed out that the study "had a surrogate end point of ex-vivo platelet aggregation, so whether genotype-guided treatment will indeed improve major adverse cardiovascular outcomes is yet to be established."

In the trial, CYP2C19*2 allele status was assessed with Spartan Biosciences’ RX CYP2C19, a bedside test that uses a buccal swab, can be performed by clinicians having no previous training in genetic laboratory techniques, and yields results in about 1 hour.

All patients in the standard treatment group and noncarriers in the tailored-treatment group received 75 mg clopidogrel (Plavix) daily. Carriers in the tailored-treatment group received 10 mg prasugrel (Effient) daily.

Trial results showed that 25% of patients in the standard treatment group and 24% of patients in the tailored-treatment group carried at least one CYP2C19*2 allele.

The proportion of carriers who had high on-treatment platelet reactivity (defined as a P2Y12 reactivity unit [PRU] value greater than 234) after a week of dual antiplatelet therapy – the trial’s primary end point – was significantly lower for those in the tailored-treatment group (0% vs. 30%).

The findings were similar when a PRU value of 208 was used to define high on-treatment platelet reactivity (4% vs. 48%).

Additionally, compared with the reference standard of direct DNA sequencing, the point-of-care genetic test had excellent sensitivity (100%) and specificity (99%).

"For the first time in clinical medicine, we have proven that a simple bedside test can enable rapid genetic testing and subsequent personalised therapy. This is an important step towards integrating pharmacogenomic strategies into clinical care," senior author Dr. Derek Y. F. So commented in a prepared statement.

Dr. So disclosed receiving unrestricted research grants for physician-initiated studies from Sanofi-Aventis Canada, Abbott Vascular Canada, and Spartan Biosciences, and honoraria from Eli Lilly Canada. The trial was funded by Spartan Biosciences. Dr. Beitelshees disclosed having no relevant conflicts of interest.

A new, rapid, point-of-care genetic test may help tailor antiplatelet therapy after percutaneous coronary intervention, so that patients receive an agent providing the best balance of benefits and risks for them, suggests the randomized, proof-of-concept RAPID-GENE trial.

The 200 trial patients who underwent PCI for acute coronary syndromes or stable angina were assigned evenly to a standard treatment arm or a tailored-treatment arm.

The former all received clopidogrel. The latter first had rapid genotyping for the CYP2C19*2 loss-of-function allele, which confers inadequate inhibition of the platelet P2Y12 receptor and increased rates of major adverse events among patients taking clopidogrel after PCI. Carriers of the allele were given prasugrel – a novel P2Y12 inhibitor that provides more potent platelet inhibition but with the trade-off of increased bleeding – whereas noncarriers were given clopidogrel. All trial patients received aspirin as well.

Trial results, reported online first in the Lancet, showed that after a week of dual antiplatelet therapy, nearly a third of CYP2C19*2 carriers who were given standard treatment had high on-treatment platelet reactivity, a marker of increased adverse cardiovascular events. This compared with none of their counterparts who received tailored treatment, reported Dr. Jason D. Roberts and his colleagues at the University of Ottawa Heart Institute (Lancet 2012 March 29 [doi:10.1016/S0140-6736(12)60161-5]).

"As far as we are aware, our study is the first to validate and to show clinical use of point-of-care genetic testing. It is the first randomised investigation of selective use of prasugrel in CYP2C19*2 carriers after PCI," wrote the investigators.

"Our findings suggest that personalisation of antiplatelet therapy might reduce adverse ischaemic outcomes; use of prasugrel only in high-risk individuals might also minimise adverse bleeding events. The development of practical point-of-care genetic testing in our study will help to integrate genetics into the clinical setting and will allow large-scale investigations to definitively assess the value of pharmacogenetic strategies," they wrote.

In an accompanying comment, Amber L. Beitelshees, Pharm.D., of the University of Maryland, Baltimore, noted that "widespread clinical implementation of clopidogrel pharmacogenetics has not progressed at the expected pace, and the RAPID GENE study provides much-needed impetus by showing that genotyping can be done in a timely manner and incorporated into the clinical workflow as we wait for the results of large outcome-driven randomised trials."

However, she also pointed out that the study "had a surrogate end point of ex-vivo platelet aggregation, so whether genotype-guided treatment will indeed improve major adverse cardiovascular outcomes is yet to be established."

In the trial, CYP2C19*2 allele status was assessed with Spartan Biosciences’ RX CYP2C19, a bedside test that uses a buccal swab, can be performed by clinicians having no previous training in genetic laboratory techniques, and yields results in about 1 hour.

All patients in the standard treatment group and noncarriers in the tailored-treatment group received 75 mg clopidogrel (Plavix) daily. Carriers in the tailored-treatment group received 10 mg prasugrel (Effient) daily.

Trial results showed that 25% of patients in the standard treatment group and 24% of patients in the tailored-treatment group carried at least one CYP2C19*2 allele.

The proportion of carriers who had high on-treatment platelet reactivity (defined as a P2Y12 reactivity unit [PRU] value greater than 234) after a week of dual antiplatelet therapy – the trial’s primary end point – was significantly lower for those in the tailored-treatment group (0% vs. 30%).

The findings were similar when a PRU value of 208 was used to define high on-treatment platelet reactivity (4% vs. 48%).

Additionally, compared with the reference standard of direct DNA sequencing, the point-of-care genetic test had excellent sensitivity (100%) and specificity (99%).

"For the first time in clinical medicine, we have proven that a simple bedside test can enable rapid genetic testing and subsequent personalised therapy. This is an important step towards integrating pharmacogenomic strategies into clinical care," senior author Dr. Derek Y. F. So commented in a prepared statement.

Dr. So disclosed receiving unrestricted research grants for physician-initiated studies from Sanofi-Aventis Canada, Abbott Vascular Canada, and Spartan Biosciences, and honoraria from Eli Lilly Canada. The trial was funded by Spartan Biosciences. Dr. Beitelshees disclosed having no relevant conflicts of interest.

A new, rapid, point-of-care genetic test may help tailor antiplatelet therapy after percutaneous coronary intervention, so that patients receive an agent providing the best balance of benefits and risks for them, suggests the randomized, proof-of-concept RAPID-GENE trial.

The 200 trial patients who underwent PCI for acute coronary syndromes or stable angina were assigned evenly to a standard treatment arm or a tailored-treatment arm.

The former all received clopidogrel. The latter first had rapid genotyping for the CYP2C19*2 loss-of-function allele, which confers inadequate inhibition of the platelet P2Y12 receptor and increased rates of major adverse events among patients taking clopidogrel after PCI. Carriers of the allele were given prasugrel – a novel P2Y12 inhibitor that provides more potent platelet inhibition but with the trade-off of increased bleeding – whereas noncarriers were given clopidogrel. All trial patients received aspirin as well.

Trial results, reported online first in the Lancet, showed that after a week of dual antiplatelet therapy, nearly a third of CYP2C19*2 carriers who were given standard treatment had high on-treatment platelet reactivity, a marker of increased adverse cardiovascular events. This compared with none of their counterparts who received tailored treatment, reported Dr. Jason D. Roberts and his colleagues at the University of Ottawa Heart Institute (Lancet 2012 March 29 [doi:10.1016/S0140-6736(12)60161-5]).

"As far as we are aware, our study is the first to validate and to show clinical use of point-of-care genetic testing. It is the first randomised investigation of selective use of prasugrel in CYP2C19*2 carriers after PCI," wrote the investigators.

"Our findings suggest that personalisation of antiplatelet therapy might reduce adverse ischaemic outcomes; use of prasugrel only in high-risk individuals might also minimise adverse bleeding events. The development of practical point-of-care genetic testing in our study will help to integrate genetics into the clinical setting and will allow large-scale investigations to definitively assess the value of pharmacogenetic strategies," they wrote.

In an accompanying comment, Amber L. Beitelshees, Pharm.D., of the University of Maryland, Baltimore, noted that "widespread clinical implementation of clopidogrel pharmacogenetics has not progressed at the expected pace, and the RAPID GENE study provides much-needed impetus by showing that genotyping can be done in a timely manner and incorporated into the clinical workflow as we wait for the results of large outcome-driven randomised trials."

However, she also pointed out that the study "had a surrogate end point of ex-vivo platelet aggregation, so whether genotype-guided treatment will indeed improve major adverse cardiovascular outcomes is yet to be established."

In the trial, CYP2C19*2 allele status was assessed with Spartan Biosciences’ RX CYP2C19, a bedside test that uses a buccal swab, can be performed by clinicians having no previous training in genetic laboratory techniques, and yields results in about 1 hour.

All patients in the standard treatment group and noncarriers in the tailored-treatment group received 75 mg clopidogrel (Plavix) daily. Carriers in the tailored-treatment group received 10 mg prasugrel (Effient) daily.

Trial results showed that 25% of patients in the standard treatment group and 24% of patients in the tailored-treatment group carried at least one CYP2C19*2 allele.

The proportion of carriers who had high on-treatment platelet reactivity (defined as a P2Y12 reactivity unit [PRU] value greater than 234) after a week of dual antiplatelet therapy – the trial’s primary end point – was significantly lower for those in the tailored-treatment group (0% vs. 30%).

The findings were similar when a PRU value of 208 was used to define high on-treatment platelet reactivity (4% vs. 48%).

Additionally, compared with the reference standard of direct DNA sequencing, the point-of-care genetic test had excellent sensitivity (100%) and specificity (99%).

"For the first time in clinical medicine, we have proven that a simple bedside test can enable rapid genetic testing and subsequent personalised therapy. This is an important step towards integrating pharmacogenomic strategies into clinical care," senior author Dr. Derek Y. F. So commented in a prepared statement.

Dr. So disclosed receiving unrestricted research grants for physician-initiated studies from Sanofi-Aventis Canada, Abbott Vascular Canada, and Spartan Biosciences, and honoraria from Eli Lilly Canada. The trial was funded by Spartan Biosciences. Dr. Beitelshees disclosed having no relevant conflicts of interest.