Is your DAPT Approach Optimized to Reduce the Risk of Secondary Strokes?

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Is your DAPT Approach Optimized to Reduce the Risk of Secondary Strokes?

Recent evidence in minor stroke and TIA has led to a recommendation from the Clinical Pharmacogenetics Implementation Consortium (CPIC) that stroke patients who are being considered for clopidogrel antiplatelet therapy be genotyped for CYP2C19 prior to determining appropriate treatment.¹ The use of CYP2C19 genotyping in management of stroke patients requires rapid turnaround test availability. The recently FDA-cleared Genomadix Cube CYP2C19 test provides rapid 1-hour CYP2C19 genotyping results (PCR-based) using buccal swab samples.² Rapid CYP2C19 genotyping can enable a new optimized approach to clopidogrel treatment decision-making for minor stroke and TIA patients.

Current DAPT Standard for Minor Stroke & TIA

The 2021 Guideline for the Prevention of Stroke In Patients with Stroke and Transient Ischemic Attack: A Guideline from the American Heart Association/American Stroke Association³ provides updates on, among other things, recommended antiplatelet therapy for recent non-cardioembolic ischemic minor stroke (NIHSS <= 3) and high risk transient ischemic attack (TIA) patients (ABCD² >=4). In this patient group, dual antiplatelet therapy (DAPT) with clopidogrel plus aspirin for 21 to 90 days is recommended to significantly reduce the risk of recurrent stroke. DAPT is recommended to be started as early as possible, and preferably within 12 to 24 hours, due to the high risk of recurrence in the first 7 days. This recommendation is based on the CHANCE⁴ and POINT⁵ randomized controlled trials (RCTs), as well as 4 meta-analyses^6-9 and a systematic review by an AHA Evidence Review Committee.¹⁰ In addition, the Guideline states that short-term DAPT using ticagrelor plus aspirin in early minor to moderate stroke or high-risk TIA is appropriate to reduce the risk of recurrent stroke,³ but comes at the cost of increased risk of serious bleeding events, based on the THALES trial.¹¹ Based on this recommendation and those from other countries, DAPT using clopidogrel plus aspirin in minor stroke/TIA has become a widely adopted standard of care.

However, clopidogrel is a pro-drug that requires activation in the liver into its active metabolite to exert its P2Y12-mediated anti-thrombotic effect. The primary driver of this activation step is an enzyme called CYP2C19.¹² CYP2C19 is part of the P450 enzyme system, and as with several other P450 enzymes, there is significant genetic variability in the population with regards to CYP2C19 activity levels, genotypes and phenotypes.¹ Patients with one or two loss of function alleles of CYP2C19 are common in the population (approximately 30% of the U.S. population),¹³ and response to clopidogrel in these loss of function (LOF) allele carriers is often compromised.¹ Significant evidence exists in both cardiology and stroke that LOF carriers do not respond to clopidogrel as effectively as non-LOF carriers and suffer worse outcomes in terms of major adverse cardiac and/or cerebrovascular events.^{1, 14} The genetic variability in responsiveness to clopidogrel even resulted in FDA putting a black box warning on the drug.¹⁵ As a result, CPIC recently updated their guidance regarding CYP2C19 and clopidogrel use, based on a review of the most recent evidence.¹ In their update, CPIC recommends that stroke and TIA patients intended to receive clopidogrel be genotyped for CYP2C19 LOF alleles, and if the patient carries 1 or 2 LOF alleles, they should receive ticagrelor rather than clopidogrel.¹

The Problem of Delayed Results

With respect to DAPT to reduce the risk of recurrent stroke in minor stroke/TIA, CYP2C19 testing has not been available quick enough to implement the AHA/ASA guideline for rapid DAPT while also implementing the CPIC guideline for genotype-guided use of clopidogrel/ticagrelor. CYP2C19 genotyping has generally been performed using high-complexity laboratory assays (either laboratory-developed tests (LDTs) or FDA-cleared) that are time consuming and require highly skilled technicians.¹⁶ Often, CYP2C19 testing is performed as a send-out test by a reference lab. As a result, generally, CYP2C19 tests have been performed in batches and results returned to the clinician within 3-14 days.  With such a delayed turnaround, clinicians have often not performed CYP2C19 genotype testing on their patients and just prescribed clopidogrel, despite understanding that a significant percentage of patients do not respond ideally to clopidogrel due to their genetic profile.

The Rapid Genotyping Solution

Recently, FDA has cleared the Genomadix Cube CYP2C19 System for rapid genotyping of the CPIC tier 1 CYP2C19 alleles.² The Genomadix CYP2C19 test provides results in 1 hour, using buccal swab samples, and is a moderate complexity test that can be performed by healthcare providers in a variety of settings under the auspices of a CLIA lab. The test is indicated for use as an aid in therapeutic decisions for drugs such as clopidogrel, that are metabolized by the CYP2C19 enzyme. Because of the rapid turnaround time of the test, the system can provide CYP2C19 genotype results in a timeframe that is needed for urgent decision-making for minor stroke and TIA patients.

The Peer-Reviewed Evidence

There is a large body of evidence for improved outcomes in both cardiology (primarily percutaneous coronary interventions/acute coronary syndrome) and neurology (primarily recurrent stroke risk), as summarized in detail by CPIC in their recent updated guideline.¹ In terms of minor stroke and TIA, the most important evidence is from the recent CHANCE-2 randomized controlled trial.¹⁷ CHANCE-2 looked specifically at rapidly genotyped CYP2C19 LOF carriers with minor stroke or TIA, and randomized them (n=6412) to receive either clopidogrel plus aspirin (standard of care, SOC) or ticagrelor plus aspirin. The primary outcome was recurrent stroke events, and secondary outcomes included major bleeds. In this trial, CYP2C19 LOF carriers receiving ticagrelor plus aspirin had significantly fewer recurrent stroke events (21% relative reduction) compared to the SOC group receiving clopidogrel plus aspirin. This decrease in recurrent stroke was not accompanied by an increase in major bleeds. A post-hoc analysis demonstrated that the vast majority of decreased recurrent stroke events in the ticagrelor vs. clopidogrel cohort was observed in the first week after initiation of DAPT.¹⁸

Implementation of Rapid CYP2C19 Genotyping

Rapid CYP2C19 genotyping as an aid in therapeutic decision making for stroke and cerebrovascular stent patients has been implemented in a number of leading institutions since the recent FDA clearance of the first rapid CYP2C19 genotyping test from Genomadix. Peer support is available to plan for operational implementation of the test. Contact Genomadix at Genomadix.com/contact or [email protected] to ask for more information about the Genomadix Cube CYP2C19 System.

Useful Links Related to this article:

CPIC guideline on CYP2C19 and clopidogrel for stroke and cardiovascular disease, with additional supplementary data tables: https://cpicpgx.org/guidelines/guideline-for-clopidogrel-and-cyp2c19/

FDA Black box warning safety announcement regarding clopidogrel: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-drug-safety-communication-reduced-effectiveness-plavix-clopidogrel-patients-who-are-poor

CHANCE-2 Study: https://www.nejm.org/doi/full/10.1056/NEJMoa2111749

FDA 510(k) summary of Genomadix Cube CYP2C19 System: https://www.accessdata.fda.gov/cdrh_docs/pdf22/K220026.pdf

Genomadix contact page: https://genomadix.com/contact/

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