Increased platelet reactivity in HIV patients with ACS on dual antiplatelet therapy
Platelet reactivity in human immunodeficiency virus infected patients on dual antiplatelet therapy for an acute coronary syndrome: the EVERE2ST-HIV study
HIV-infected patients are at higher coronary heart disease (CHD) risk compared with the general population, due to a higher prevalence of cardiovascular (CV) risk factors and the cardiometabolic effects of antiretroviral drugs [1-3]. However, the underlying mechanisms leading to increased CHD risk in HIV patients have not been fully explored. One explanation might be the higher on-treatment platelet reactivity in HIV patients, which was shown to be an independent risk factor of major adverse CV events after acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI) [4,5].
In the EVERE2ST-HIV study (EValuation of REsidual Platelet Reactivity after acute coronary syndrome, STþ/ST-, in HIV study), platelet reactivity was evaluated in HIV- (n=80) and non-HIV (n=160) patients with a first episode of ACS on dual antiplatelet therapy (DAPT). Platelet reactivity was evaluated by measuring residual platelet aggregation (RPA) with light transmission aggregometry (LTA), VerifyNow aspirin assay (ARU), and P2Y12 assay (PRU) and with the Vasodilator-stimulated phosphoprotein (VASP) platelet reactivity index (VASP-PRI). Most patients were on clopidogrel (68%), others were on prasugrel (31%) or ticagrelor (1%) and all took aspirin.
- The relative increase of P2Y12-mediated platelet aggregation in HIV patients compared to non-HIV patients was 55.5% for RPA, 23.4% for PRU and 40.6% for VASP-PRI.
- The increase of platelet reactivity among HIV patients was largest in those treated with clopidogrel, but RPA and the VASP-PRI remained significantly higher in HIV- compared to non-HIV patients in analyses with only prasugrel- and ticagrelor-treated patients.
- After adjustment for known risk factors of high residual platelet reactivity (HPR), the increased platelet reactivity remained significantly higher in HIV patients with all platelet function tests.
- The prevalence of HPR in response to P2Y12 inhibitors was significantly higher in HIV than non-HIV patients: 25% vs. 8% (P<0.001) with RPA, 23% vs. 14% (P=0.08) with PRU, and 39% vs. 21% (P=0.01) with VASP-PRI.
- After adjustment, HIV status was still significantly associated with higher prevalence of HPR with RPA and VASP, and borderline with PRU: adjusted OR for RPA 7.6, 95% CI: 3.3-17.3, P <0.001, OR for VASP 2.9, 95% CI: 1.4–6.0, P=0.004, OR for PRU 2.1, 95% CI: 0.97–4.4, P=0.06.
- Under aspirin, ACS patients with HIV had significantly higher RPA (P=0.004) and higher ARU (P=0.002) compared with patients without HIV. Accordingly, the HPR in response to aspirin therapy was significantly more frequent in HIV compared with non-HIV patients (ARU 14.0% vs. 1.9%, P=0.004 and RPA 5.2% vs. 0.6%, P=0.04).
- After adjustment, HIV status was significantly associated with higher HPR prevalence under aspirin according to ARU (OR 11.5, 95% CI: 1.9–68.7, P=0.007), but tended to be associated with higher HPR according to RPA (OR 6.9, 95% CI: 0.7–65.3, P=0.09).
- Patients receiving antiretroviral therapy with protease inhibitors vs. other combinations had increased platelet reactivity to P2Y12 inhibitors and higher prevalence of HPR, which was consistent across all three tests (OR with RPA 4.4, 95% CI: 1.1–18.1, P=0.04; OR with VASP-PRI 3.1, 95% CI: 0.84–11.5, P=0.09; OR with PRU 4.3, 95% CI: 1.02–18.1, P=0.047).
- Patients treated with non-nucleoside reverse transcriptase inhibitors had consistently decreased platelet reactivity and lower prevalence of HPR (OR with RPA 0.44, 95% CI: 0.12–1.6, P=0.2; OR with VASP-PRI 0.23, 95% CI: 0.06–0.89, P=0.03; OR with PRU 0.46, 95% CI: 0.12–1.7, P=0.2).
In 80 ACS patients with HIV, the levels of platelet reactivity and the prevalence of HPR were increased when treated with P2Y12 receptors inhibitors and aspirin, compared with 160 ACS patients without HIV. Moreover, patients treated with protease inhibitors had an increase in platelet reactivity. These findings provide an explanation for the poor prognosis of ACS patients with HIV, and raise the question of the most effective combination of antiplatelet and antiretroviral agents.
In their editorial article, Gurbel et al describe the pathophysiological ‘thrombotic storm’ that results from the combination of ACS, PCI, and HIV-infection, which are all associated with inflammation, hypercoagulability, and increased platelet reactivity. They also discuss the finding of increased platelet reactivity in patients who were treated with protease inhibitors, and suggest careful consideration regarding the use of these agents after an ACS, until further follow-up data are available. Finally, they conclude: ‘In summary, the authors present part of the forecast for the perfect ‘thrombotic storm’—high ex vivo platelet reactivity in an atmosphere of hypercoagulability and heightened inflammation. The ultimate goal of all studies employing a surrogate marker (high ex vivo platelet reactivity) is to identify the risk of an in vivo event (coronary thrombosis) in order to determine the optimal antiplatelet regimen in the individual patient. We agree with the authors that their finding of high ex vivo platelet reactivity in HIV-infected ACS patients potentially provides part of the mechanism to explain the higher risk of these patients. Avoiding the perfect storm in these high-risk patients requires complex navigational skills. Based on the preliminary findings of this provocative study, it appears that platelet function testing may be one of those skills.’