HIV infection, ACS, PCI and high platelet reactivity: ingredients for a perfect thrombotic storm

This editorial refers to ‘Platelet reactivity in human immunodeficiency virus infected patients on dual antiplatelet therapy for an acute coronary syndrome: the EVERE2ST-HIV study’†, by M. Hauguel-Moreau et al., on page 1676. Platelet activation and aggregation play critical roles in thrombus generation at sites of vascular injury that may result in cardiovascular catastrophes. Thrombus generation is the culmination of the complex interplay of platelets with atherosclerotic vasculature, inflammation, and coagulation. We have reported a ‘thrombo-inflammatory’ state—a distinct pathophysiological state of heightened platelet function, hypercoagulability, and inflammation marking the presence of unstable cardiovascular disease—and proposed a mechanistic link between inflammation and heightened thrombogenicity measured pre-procedurally in the patient at high risk for recurrent ischaemic events after stenting.1,2 The thrombo-inflammatory state becomes even more complex when patients with acute coronary syndromes (ACS) and human immunodeficiency virus (HIV) infection undergo percutaneous coronary intervention (PCI) to treat an occluded or partially occluded coronary artery. Since ACS, PCI, and HIV infection are all associated with inflammation, hypercoagulability, and heightened platelet reactivity, the co-existence of these prothrombotic influences creates a potential perfect storm for recurrent thrombotic event occurrence (Figure 1). The thrombo-inflammatory syndrome in ACS/PCI/HIV. HIV infection is associated with inflammation, hypercoagulability, and platelet activation. Activated platelets provide binding sites for coagulation factor activation and modulate leucocyte function. Activated leucocytes modulate platelet function. Generated thrombin activates platelets and other cells involved in atherogenesis. Highly reactive platelets identified by ex vivo assays have been independently associated with recurrent thrombosis. ACS, acute coronary syndrome; CD40L, CD 40 ligand; HIV, human immunodeficiency virus; ICAM, intercellular adhesion molecule; PCI, percutaneous coronary intervention; PMA, platelet-monocyte aggregates; RANTES, Regulated on Activation, Normal T Cell Expressed and Secreted. Human immunodeficiency virus infection has been associated with variable effects on platelets. For example, thrombocytopenia in patients with HIV may be due to reduced platelet production by infected megakaryocytes, damaged bone marrow following anti-infection therapy, or internalization of HIV by platelets and subsequent sequestration by specific monocyte subsets.3 Internalization of HIV by platelets has also been shown to activate platelets. Furthermore, chronic HIV infection is associated with elevated markers linked to heightened risk for cardiovascular events—markers of inflammation, coagulation, and platelet activation.4 For example, an elevated platelet response to agonists and increased levels of soluble p-selectin, CD-40L, and microparticles has been demonstrated in patients with HIV infection.5,6 An increased prevalence of cardiovascular death, including sudden cardiac death, and a 1.5- to 2-fold increased relative risk of acute myocardial infarction (MI) have been reported in HIV-infected patients as compared with HIV-negative individuals.7 Although antiretroviral therapy (ART) has been highly effective in reversing some of the deleterious effects of HIV infection, certain ARTs such as abacavir have been associated with increased platelet reactivity and increased risk of MI.8 However, in more recent studies, an independent relationship between ART and MI was not demonstrated, suggesting that higher rates of MI persist with HIV infection after controlling for traditional risk factors.7 At this time there are no established treatment strategies to mitigate the risk of cardiovascular disease in HIV-infected patients and the latter is also true for recurrent thrombotic event occurrences in HIV-infected patients with ACS undergoing PCI. In this issue, Hauguel-Moreau etal. report the finding of the EVERE2ST-HIV study where the platelet response to dual antiplatelet therapy (DAPT) was compared between ACS patients with and without HIV infection. Eighty ACS patients with HIV infection were matched with 160 patients without infection based on age, sex, smoking status, diabetes mellitus, and DAPT strategies.9 These patients experienced an ACS at least 1 month prior to being treated with PCI and were on DAPT [75–325 mg/day aspirin and 75 mg/day clopidogrel (68% of patients), 10 mg/day prasugrel (31%), or 90 mg b.i.d. ticagrelor (1%)] for at least 30 days prior to platelet function testing. Platelet response to DAPT was assessed by 20 μM ADP- and 1.25 mM arachidonic acid (AA)-induced platelet aggregation by conventional aggregometry, VerifyNow P2Y12 assay, and vasodilator-stimulated phosphoprotein (VASP)-phosphorylation (P) assay. In addition, genotyping for cytochrome (CYP)2C19 loss-of-function allele (LOF) carriage, plasma C-reactive protein, and CD+ T cell count (to indicate HIV infection) were also assessed. There was no difference in the prevalence of CYP2C19 LOF carriage between groups, and all patients with HIV were on ART, most commonly protease inhibitors. Why were the authors so interested in studying ex vivo platelet reactivity in these patients with high cardiovascular risk? Over a decade ago it was reported that patients with high platelet reactivity to ADP (HPR) post-stenting had greater 6-month recurrent ischaemic event rates.10 The latter observation laid the groundwork for the ‘personalization’ or ‘targeting’ of antiplatelet therapy based on the reactivity of the P2Y12 receptor and the rationale for developing more potent P2Y12 inhibitors than clopidogrel. Subsequent much larger observational studies have confirmed the independent association of HPR with thrombotic risk.11 Thus, as acknowledged by the authors of the current study, HPR serves as a surrogate for, and a potential mechanism to explain the higher rate of recurrent ischaemic outcomes observed in HIV patients with ACS. In the current study, patients with HIV infection exhibited significantly higher platelet reactivity to ADP as measured by all three established assays during clopidogrel therapy. Although platelet reactivity was lower in patients treated with more potent P2Y12 inhibitor therapy as compared with clopidogrel, it was still higher in HIV-infected patients as measured by residual platelet aggregation and VASP-P assay. Most importantly, the adjusted odds ratio (OR) for the rate of HPR was significantly higher (two- to eight-fold, P ≤ 0.004) in HIV-infected patients as measured by aggregometry and VASP-P assay. In addition, HPR in HIV-infected patients was independently associated with illicit drug (OR = 4.98, P = 0.04) and protease inhibitors (OR = 4.42, P = 0.04) use in a multivariate analysis. Abacavir use (35% of patients) was not associated with HPR. In Table 6, the authors provide a guide on ART–antiplatelet therapy interactions. All of the recommendations in Table 6 are based on hypothesized or demonstrated drug–drug interactions at the CYP level that are believed to influence the pharmacodynamic effect of the P2Y12 blockers. The latter pharmacodynamic effect measure ex vivo is felt to be important in the occurrence of clinical thrombotic events. The investigators address a clinically significant and complex problem. Their platelet function testing results present a compelling argument to study further prospectively: (i) the appropriate ART post-ACS; (ii) the role of HPR as a reliable surrogate for MACE (major adverse cardiovascular events) to indicate more potent P2Y12 inhibitors in the post-ACS setting for patients with HIV; and (iii) the efficacy of more aggressive attempts to modify reversible risk factors. While the role of protease inhibitors for risk of a first MI is controversial, for those with ACS, based on the results of a meta-analysis, outcomes were worse when protease inhibitors were part of ART.8,12,13 Now the authors have provided compelling preliminary surrogate findings in the form of an increased risk of HPR associated with the use of protease inhibitors. These findings, at a minimum, should be followed-up with an observational association with an increased risk of MACE in an HIV-infected population. Until then, it appears that careful consideration should be given to the use of the protease inhibitor class of ART post-ACS, particularly if associated with HPR. It would also be of interest to follow post-ACS HIV-infected subjects longitudinally with respect to platelet function testing. Certainly, if similar associations with HIV were present at 1 year post-ACS, a compelling case could be made to continue DAPT indefinitely in an HIV-infected ACS patient. There is also space to make a case to test if more potent DAPT post-ACS in HIV-infected patients, particularly in those with HPR, would result in a reduction in MACE. This is not a trivial recommendation given the cost of more potent DAPT and limited resources available to many HIV-infected patients. Lastly, risk factor modification can be challenging and particularly in patients infected with HIV. In this study, 59% of the HIV-infected patients were actively smoking >30 days post-ACS. This is not an unusually high proportion of active smokers in an HIV population.14 Smoking in HIV-infected subjects is associated with 5.3-fold higher non-AIDS mortality when compared with non-HIV-infected age-matched smokers.15 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.