Clopidogrel, prasugrel, ticagrelor or vorapaxar in patients with renal impairment: do we have a winner?

The optimal utilization of antiplatelet therapy in patients with renal impairment (RI) following acute coronary syndromes (ACS) represents an urgent, unmet and yet unsolved need with regards to the choice of agents, duration of treatment and potential dose/regimen adjustment. The lack of any large randomized trials designed and powered specifically in such high-risk patients, absence of the uniformed efficacy and safety data reporting policy to the FDA and endless overoptimistic publications based on post hoc analyses of primary trials sometimes exaggerating benefits and hiding risks, clouds reality. In addition, triaging RI patients is problematic due to ongoing kidney deterioration and the fact that such patients are prone to both vascular occlusions and bleeding.

Disbalance between mortality and non-fatal vascular events in the CHAMPION-PHOENIX trial: the cangrelor efficacy challenge.

The recently published, largest trial with cangrelor, the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION)-PHOENIX, suggested that the experimental agent significantly reduced the rate of stent thrombosis (ST) and myocardial infarction (MI) during PCI at 48 hours (h) and 30 days. However, the declared impressive cangrelor vascular non-fatal benefit was contradicted by identical deaths at 48 h, and a trend toward excess mortality at 30 days. We analysed the mismatch between outcomes in the CHAMPION-PHOENIX trial.

Effect of aliskiren and valsartan combination versus aliskiren monotherapy on hemostatic biomarkers in hypertensive diabetics: Aliskiren and Valsartan Impact in Diabetics pilot trial.

Valsartan is known to inhibit platelet activity in both in vitro and ex vivo clinical setting, whereas aliskiren in vitro modulates antithrombin-III in plasma. The authors tested how aliskiren and valsartan combination versus aliskiren monotherapy will affect hemostatic biomarkers in mild-to-moderate hypertensive diabetics in the frame of the Aliskiren and Valsartan Impact in Diabetics (AVID) trial. A total of 52 patients with type 2 diabetes and mild-to-moderate hypertension were equally randomized to aliskiren (150-300 mg/d) and valsartan (160 mg/d) versus aliskiren (150-300 mg/d) alone for 4 weeks.

Early impact of prescription Omega-3 fatty acids on platelet biomarkers in patients with coronary artery disease and hypertriglyceridemia.

Background: Prescription omega-3-acid ethyl esters (PO-3A) have been tested for outcome benefits in patients with coronary artery disease (CAD), arrhythmias and heart failure. Some evidence suggests that PO-3A may exert their benefit via inhibiting platelets. We tested the hypothesis that PO-3A may inhibit platelet activity in patients with documented stable CAD, beyond the antiplatelet properties of aspirin and statins.

A randomized trial of aspirin at clinically relevant doses and nitric oxide formation in humans.

Background: we performed the first test in humans of whether aspirin at clinically relevant doses increases nitric oxide (NO) formation.

Methods: seventy primary prevention patients with metabolic syndrome were randomly assigned to 81 mg, 162.5 mg, 325 mg, 650 mg, or 1300 mg aspirin daily for 12 weeks to test changes in heme oxygenase (HO-1), a downstream target of NO formation and asymmetrical dimethylarginine (ADMA), a competitive inhibitor of NO synthase.

Antiplatelet profiles of the fixed-dose combination of extended-release dipyridamole and low-dose aspirin compared with clopidogrel with or without aspirin in patients with type 2 diabetes and a history of transient ischemic attack: a randomized, single-blind, 30-day trial.

Background: Clopidogrel, aspirin (ASA), and the fixed-dose combination of extended-release dipyridamole and ASA (ER-DP+ASA) are widely used in post-stroke regimens.

Objective: This study compared serial changes in multiple biomarkers of platelet activation with ER-DP+ASA and clopidogrel with or without ASA in patients with type 2 diabetes mellitus and a history of transient ischemic attack (TIA).

Methods: This was a randomized, single-blind pilot study conducted at an outpatient center in the United States.

Antiplatelet properties of escitalopram in patients with the metabolic syndrome: a dose-ranging in vitro study.

There is an increasing body of evidence suggesting that selective serotonin reuptake inhibitors exhibit clinical benefit beyond treating depression, by simultaneously inhibiting platelet activity. We recently demonstrated that escitalopram (ESC), but not its major metabolites, inhibits multiple platelet biomarkers in healthy volunteers. Considering that the metabolic syndrome represents one of the major risk factors for vascular disease, we here determined how ESC affects platelet activity in such patients.

Effect of statins on platelet PAR-1 thrombin receptor in patients with the metabolic syndrome (from the PAR-1 inhibition by statins [PARIS] study).

We investigated whether, in primary prevention patients with metabolic syndrome, statins affect the platelet protease-activated receptor-1 (PAR-1) thrombin receptor by performing serial measurements of its activity and the antigen expression level by flow cytometry before and during treatment. Recent data from randomized trials of statins are compatible with the possibility of clinically relevant pleiotropic effects. The use of statins is associated with a reduced thrombosis burden and diminished platelet activity, as shown in animal models and in vitro studies.

Escitalopram, but not its major metabolites, exhibits antiplatelet activity in humans.

Background: Clinical depression has been identified as an independent risk factor for increased mortality during follow-up in patients suffered from acute coronary events, whereas increased platelet activity has been proposed as one of the mechanisms for this association. Some evidence suggests that selective serotonin reuptake inhibitors and/or their metabolites exhibit potent antiplatelet properties.

Methods: We assessed the in vitro effects of preincubation with escalating (50-200 nmol/L) concentrations of escitalopram (ESC) S-desmethyl-citalopram (S-DCT), and S-di-desmethyl-citalopram, (S-DCT) on platelet aggregation through the expression of major surface receptors using flow cytometry and quantitatively using platelet function analyzers in 20 healthy volunteers.

Monitoring platelet inhibition after clopidogrel with the VerifyNow-P2Y12(R) rapid analyzer: the VERIfy Thrombosis risk ASsessment (VERITAS) study.

Introduction: Clopidogrel inhibits platelet P2Y12 ADP receptors, while ADP, as an inductor of aggregation, stimulates both P2Y12 and P2Y1 platelet receptors. Despite a clinical loading dose routine with clopidogrel, some patients still experience coronary stent thrombosis suggesting persistent platelet activation. The VerifyNow-P2Y12 is a rapid assay that test platelet activity over 3 min and uses of the combination of ADP and prostaglandin E1 (PGE1) to directly measure the effects of clopidogrel on the P2Y12 receptor.

Valsartan inhibits platelet activity at different doses in mild to moderate hypertensives: Valsartan Inhibits Platelets (VIP) trial.

Background: Previous in vitro studies have suggested that valsartan produces significant inhibition of human platelets, probably targeting angiotensin I platelet receptors. To test whether valsartan inhibits platelet activity in mild to moderate hypertensives we conducted the randomized Valsartan Inhibits Platelets (VIP) trial.

Methods And Results: Seventy-five patients with mild to moderate hypertension were randomized to valsartan 80 (n = 25), valsartan 160 (n = 29), or valsartan 320 mg/d (n = 21) for 9 weeks.

Dipyridamole decreases protease-activated receptor and annexin-v binding on platelets of post stroke patients with aspirin nonresponsiveness.

Background: Although controversial, the phenomenon of aspirin resistance (AR) has been correlated in some small studies with poor clinical outcomes in patients with coronary artery disease. Even less is known regarding the role of AR in the post stroke population. The reason for and the underlying mechanism of AR is unknown.

Effects of clopidogrel and aspirin in combination versus aspirin alone on platelet activation and major receptor expression in patients after recent ischemic stroke: for the Plavix Use for Treatment of Stroke (PLUTO-Stroke) trial.

Background And Purpose: Clopidogrel is widely used in patients after recent ischemic stroke; however, its ability to yield additional antiplatelet protection on top of aspirin has never been explored in a controlled study. To determine whether clopidogrel with aspirin (C+ASA) will produce more potent platelet inhibition than aspirin alone (ASA) in patients after ischemic stroke, we conducted the Plavix Use for Treatment of Stroke trial.

Methods: Seventy patients after ischemic stroke were randomly assigned to C+ASA or ASA groups.