Genotype-based strategy reduces thrombotic events after heart-device implant

Reuters Health - 14/07/2021  - In patients receiving a Watchman heart device who are genetically predisposed to reduced clopidogrel metabolism, the use of aspirin plus a half-dose of a direct oral anticoagulant (DOAC) significantly reduces device-related thrombosis (DRT) and thromboembolic events compared with standard dual antiplatelet therapy (DAPT),according to new findings.

Clopidogrel is frequently prescribed with aspirin after an initial oral anticoagulation strategy to prevent DRT in patients who undergo Watchman implantation to close off the left atrial appendage. However, a high proportion of patients still experience DRT, with genetic factors implicated in this risk.

In particular, CYP2C19 loss-of-function (LOF) polymorphisms may contribute to variability in clopidogrel bioactivation, suggesting an individualized approach to DRT prevention may be necessary for some patients.

Dr. Domenico Della Rocca of St. David's Medical Center in Austin, Texas, and colleagues from several countries assessed the incidence of DRT and thromboembolic events in 758 patients who underwent implantation with the Watchman device.

Patients in this study were loss-of-function (LOF) allele carriers of the cytochrome CYP2C19 gene. Those with demonstrated clopidogrel resistance received either the P2Y12 inhibitor prasugrel or a half-dose of a DOAC, both of which were combined with aspirin.

The incidence of DRT/thromboembolic events was compared between patients who were genotyped (n=401) versus those not genotyped who received DAPT (n=357).

There was a trend toward more bleeding events in patients who received aspirin plus prasugrel (10.2% of 244 patients), leading to early discontinuation of the prasugrel-based regimen.

Out of 401 patients with clopidogrel resistance, 25.7% were considered reduced metabolizers of clopidogrel based on CYP2C19 genotyping. A total of 98 patients with clopidogrel resistance were given aspirin plus half dose DOAC, while fives were given aspirin and a full DOAC dose.

Patients received the genotype-guided antithrombotic therapy for 134 days on average, the researchers report in JACC: Clinical Electrophysiology.

Only one DRT event was documented in a single patient during this time period. In contrast, seven patients who did not undergo genetic testing experienced a DRT. The difference between these groups - 0.2% versus 1.96% - was statistically significant and in favor of the genotype-guided antithrombotic protocol (P=0.029).

All patients who had DRT during the study were on DAPT at the time thrombus was detected on the device.

In addition, a lower proportion of patients who underwent the genotype-guided antithrombotic strategy experienced the composite endpoint of DRT/thromboembolic events (0.75% vs. 3.1%; P=0.027).

The overall rates of bleeding events were not significantly different between the two groups. There were also no differences between the groups in regard to all-cause mortality (2.0% vs. 1.7%; P=0.79) or cardiovascular mortality (0.7% vs. 0.8%; P=0.99).

Dr. Walid Saliba, director of the electrophysiology lab at Cleveland Clinic, in Ohio, who wasn't involved in the study, told Reuters Health by email that the true mechanism of DRT is still unknown and its risk factors are not well defined. Additionally, there are no specific recommendations or guidelines to try to avoid DRT.

"There are some risk factors that tend to increase the risk of it happening, and in those high-risk patients, physicians tend to alter the current regimen to include a longer period of oral anticoagulation with an antithrombotic agent or even half-dose of such agent and bypassing the 6-month period of antiplatelet therapy," Dr. Saliba said.

Dr. Saliba noted that the genotype-based antithrombotic strategy in this study has also been used in patients receiving coronary stents. "However, its use after a left atrial appendage closure device is novel, specifically because of the problem of device-related thrombosis which tends to occur while patients are on antiplatelet therapy including clopidogrel," he added.

According to Dr. Saliba, the genotype-based strategy may take current antithrombotic strategies a step closer toward precision medicine.

"Its application will need a wider and larger clinical trial for validation," he explained, "if indeed other post-implant drug regimens prove not to be alternative options."

SOURCE: https://bit.ly/3hrc8Jp JACC: Clinical Electrophysiology, online June 30, 2021.

By Brandon May



Posted on 14 July 202126 July 2021