Calcium channel blockers reduce the antiplatelet effect of clopidogrel

ObjectivesBecause of the known CYP3A4 inhibition by calcium-channel blockers (CCBs), we hypothesized that there might be a drug-drug interaction between clopidogrel and dihydropyridines in patients with coronary artery disease.BackgroundClopidogrel is activated by CYP3A4, which also metabolizes CCBs of the dihydropyridine class.MethodsResponsiveness to clopidogrel was assessed by the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and aggregometry in 200 patients with coronary artery disease undergoing percutaneous coronary intervention.ResultsThe platelet reactivity index (PRI) (in the VASP assay, normal range 69% to 100%) was higher in patients receiving both clopidogrel and CCBs (61%) as compared with patients receiving clopidogrel without CCBs (48%). The absolute difference was 13% (95% confidence interval: 6% to 20%; p = 0.001), and the relative difference approached 21%. A decreased platelet inhibition by clopidogrel (PRI >69%) was seen in 40% of patients with concomitant CCB treatment and in 20% of patients without concomitant treatment (chi-square test, p = 0.008). Intake of CCB remained an independent predictor of reduced platelet inhibition by clopidogrel after adjustment for cardiovascular risk factors. Adenosine diphosphate-induced platelet aggregation was 30% higher in patients on concomitant CCB treatment compared with patients without CCBs (p = 0.046). Moreover, intake of CCBs was associated with adverse clinical outcome. In vitro incubation with CCBs (nimodipine, verapamil, amlodipine, and diltiazem) did not alter the PRI or the adenosine diphosphate–induced platelet aggregation of patients taking clopidogrel. This finding indicates that the negative effect occurs in vivo, conceivably at the level of the CYP3A4 cytochrome.ConclusionsCoadministration of CCBs is associated with decreased platelet inhibition by clopidogrel

Optimal duration and combination of antiplatelet therapies following percutaneous coronary intervention: a meta-analysis.

Abstract Introduction The ideal duration of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) is still unknown. In this meta-analysis, we aimed to compare very short-term (1–3 months), short-term (6 months), standard-term (12 months) and long-term (>12 months) DAPT durations for efficacy and safety. Methods Overall DAPT comparisons were classified as "any shorter-term"/"any longer-term" DAPT. The primary outcome was a composite of major adverse cardiovascular events (MACE: non-fatal myocardial infarction, non-fatal stroke and cardiovascular death). The primary safety outcome was major bleeding. Results Twenty-six studies comprising 103.394 patients were included. Compared with standard-term DAPT duration, very short-term DAPT duration with subsequent drop of aspirin (RR 1.06, 95% CI, 0.95–1.18, p = 0.26) or drop of the P2Y12 inhibitor (RR 0.92, 95% CI, 0.72-1.16, p = 0.47) was not associated with a higher risk of MACE. Any longer-term compared with any shorter-term DAPT durations led to a significantly lower risk of MACE (RR 0.88, 95% CI, 0.81–0.96, p = 0.002), but a significantly higher risk of BARC 3-5 major bleeding events (RR 1.63, 95% CI, 1.22–2.17, p = 0.001). In the ACS subgroup receiving prasugrel or ticagrelor but not clopidogrel, any longer-term DAPT duration was associated with a significantly lower risk of MACE compared to any shorter-term DAPT duration (RR 0.84, 95% CI, 0.77–0.92, p = 0.0001). Conclusion DAPT may be shortened to 1-3 months in patients with low ischemic but high bleeding risk followed by aspirin or P2Y12 monotherapy. Prasugrel or ticagrelor based DAPT may be extended to >12 months in case of high ischemic and low bleeding risk. PROSPERO registration no CRD42020163719

Sex and gender in cardiovascular medicine: presentation and outcomes of acute coronary syndrome.

Although health disparities in women presenting with acute coronary syndrome (ACS) have received growing attention in recent years, clinical outcomes from ACS are still worse for women than for men. Women continue to experience higher patient and system delays and receive less aggressive invasive treatment and pharmacotherapies. Gender- and sex-specific variables that contribute to ACS vulnerability remain largely unknown. Notwithstanding the sex differences in baseline coronary anatomy and function, women and men are treated the same based on guidelines that were established from experimental and clinical trial data over-representing the male population. Importantly, younger women have a particularly unfavourable prognosis and a plethora of unanswered questions remains in this younger population. The present review summarizes contemporary evidence for gender and sex differences in vascular biology, clinical presentation, and outcomes of ACS. We further discuss potential mechanisms and non-traditional risk conditions modulating the course of disease in women and men, such as unrecognized psychosocial factors, sex-specific vascular and neural stress responses, and the potential impact of epigenetic modifications

Personalized antiplatelet therapy with P2Y12 receptor inhibitors: benefits and pitfalls.

Antiplatelet therapy with P2Y12 receptor inhibitors has become the cornerstone of medical treatment in patients with acute coronary syndrome, after percutaneous coronary intervention and in secondary prevention of atherothrombotic events. Clopidogrel used to be the most broadly prescribed P2Y12 receptor inhibitor with undisputable benefits especially in combination with aspirin, but a considerable number of clopidogrel-treated patients experience adverse thrombotic events in whom insufficient P2Y12-inhibition and a consequential high on-treatment platelet reactivity is a common finding. This clinically relevant limitation of clopidogrel has driven the increased use of new antiplatelet agents. Prasugrel (a third generation thienopyridine) and ticagrelor (a cyclopentyl-triazolo-pyrimidine) feature more potent and predictable P2Y12-inhibition compared to clopidogrel, which translates into improved ischemic outcomes. However, excessive platelet inhibition and consequential low on-treatment platelet reactivity comes at the price of increased risk of major bleeding. The majority of randomized clinical trials failed to demonstrate improved clinical outcomes with platelet function testing and tailored antiplatelet therapy, but results of all recent trials of potent antiplatelets and prolonged antiplatelet durations point towards a need for individualized antiplatelet approach in order to decrease thrombotic events without increasing bleeding. This review focuses on potential strategies for personalizing antiplatelet treatment

Ticagrelor, but not clopidogrel and prasugrel, prevents ADP-induced vascular smooth muscle cell contraction: A placebo-controlled study in rats

Introduction: Off-target effects of novel antiplatelet agents due to their potential clinical benefits are currently an area of intensive investigation. We aimed to compare the effects of different P2Y12 antagonists on the reactivity of vascular smooth muscle cells. Materials and methods: Wistar rats (n=30) were pretreated with an investigated drug or placebo. Clopidogrel (50 mg/kg, n=7), prasugrel (10 mg/kg, n=7), ticagrelor (10 mg/kg, n=7) or placebo (n=9) were administered orally 12 and 2 hours before experiments. Constrictions of rat tail arteries induced with a stable analogue of adenosine diphosphate (2-MeS-ADP), phenylephrine and arginine vasopressin weremeasured as an increase in perfusion pressure. Effects of ticagrelor were assessed in the presence of ticagrelor (1 μM/L) added to the perfusion solution as this drug reversibly inhibits the P2Y12 receptor. Results: Pretreatmentwith clopidogrel and prasugrel did not inhibit 2-MeS-ADP-induced contraction while ticagrelor did. Experiments employing endothelium-deprived arteries provided similar results. Clopidogrel and prasugrel did not influence concentration-response curves in the presence of neither phenylephrine nor arginine vasopressin. The curves obtained for both vasopressors in the presence of ticagrelor and 2-MeS-ADP were shifted to the right with a significant reduction in the maximal response. Conclusions: Oral administration of ticagrelor, in contrast to clopidogrel and prasugrel, prevents adenosine diphosphate-induced contraction of vascular smooth muscle cells in a rat model. Both the clinical significance and detailed mechanism of our findings warrant further investigation

Pantoprazole may enhance antiplatelet effect of enteric-coated aspirin in patients with acute coronary syndrome

Background: Antiplatelet therapy has proven beneficial in the treatment of cardiovascular disease. Proton pump inhibitors (PPIs) are commonly used for gastroprotection in patients receiving antiplatelet therapy. Several trials have been carried out to establish interactions between PPIs, clopidogrel and soluble formulations of aspirin, but no studies with PPIs and enteric-coated (EC) forms of aspirin have been conducted. The aim of this study was to assess if concomitant pantoprazole usage influences antiplatelet effect of EC aspirin in patients with acute coronary syndrome treated with percutaneous coronary intervention (PCI) and dual antiplatelet therapy. Methods: Thirty-one consecutive patients were prospectively enrolled in the randomized, crossover, open-labelled designed study. The first 16 patients were given orally 40 mg of pantoprazole for the first four days while the next 15 subjects were treated with pantoprazole from the fifth to the eighth day of hospitalisation. Blood samples were collected at 6.00 a.m., 10.00 a.m., 2.00 p.m., and 7.00 p.m. on the fourth and eighth day of hospitalization. Aggregation in response to arachidonic acid was assessed in the whole blood on a new generation impedance aggregometer. Results: Lower overall platelet aggregation in patients treated with pantoprazole (p < 0.03) was observed. When aggregation of platelets was analyzed separately at different times, the differences reached statistical significance six hours after the administration of pantoprazole and antiplatelet agents. The highest absolute difference in arachidonic acid-dependent aggregation was observed two hours after drug ingestion. Conclusions: Co-administration of pantoprazole may enhance the antiplatelet effect of enteric-coated aspirin in patients with acute coronary syndrome undergoing PCI

Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study

Background: Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies. Objectives: To compare different assays for prediction of events during long-term follow-up. Methods: In this prospective cohort study polymorphisms of CYP2C19*2 and CYP2C19*17 alleles, vasodilator- stimulated phosphoprotein phosphorylation (VASP) assay, multiple electrode aggregometry (MEA), cone and platelet analyser (CPA) and platelet function analyser (PFA- 100) were performed in 416 patients undergoing percutaneous coronary intervention. The rates of events were recorded during a 12-month follow-up. Results: Platelet aggregation by MEA predicted stent thrombosis (2.4%) better (c-index = 0.90; P < 0.001; sensitivity = 90%; specificity = 83%) than the VASP assay, CPA or PFA-100 (c-index 0.05; sensitivity < 70%; specificity < 70% for all) or even the CYP2C19*2 polymorphism (c-index 0.05; sensitivity = 30%; specificity = 71%). Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders (12.5% vs. 0.3%, P < 0.001, and 18.5% vs. 11.3%, P = 0.022, respectively), whereas poor metabolizers (CYP2C19*1/*2 or *2/*2 carriers) were not at increased risks (stent thrombosis, 2.7% vs. 2.5%, P > 0.05; MACE, 13.5% vs. 12.1%, P = 0.556). The incidence of major bleedings (2.6%) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA (4% vs. 0%) or in ultra-metabolizers vs. regular metabolizers (CYP2C19*17/*17 vs. CYP2C19*1/*1; 9.5% vs. 2%). The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status. Conclusions: Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping

Prasugrel overcomes high on-clopidogrel platelet reactivity in the acute phase of acute coronary syndrome and maintains its antiplatelet potency at 30-day follow-up

Background: The aim of this study was to assess antiplatelet effect of prasugrel in acute coronary syndrome (ACS) patients with high on-treatment platelet reactivity (HTPR) on clopidogrel, undergoing percutaneous coronary intervention (PCI).Methods: A prospective, platelet reactivity-guided, parallel-group, open-label study including 71 patients pretreated with clopidogrel 600 mg and assigned either to prasugrel (30 mg loading dose, 10 mg maintenance dose; n = 46) or clopidogrel (150 mg maintenance dose for 6 days and thereafter 75 mg maintenance dose; n = 25) regimen, based on vasodilator-stimulated phosphoprotein (VASP)-assessed platelet reactivity index (PRI; &gt; 50% vs. ≤ 50%) measured next morning post-PCI.Results: Median PRI value after switch to prasugrel sharply declined at 24 h (70.0 [61.3–75.6] vs. 11.9 [6.8–25.7]%; p &lt; 0.000001) and slightly but significantly rose between 24 h and 30 days (27.9 [15.5–46.8]%; p &lt; 0.0006). In contrast, median PRI values in the clopidogrel group were similar at baseline and at 24 h (25.1 [13.7–40.2] vs. 22.0 [18.4–36.8]%; p = NS) and then modestly rose at 30 days (30.3 [20.4–45.7]%; p &lt; 0.03). The prevalence of HTPR decreased in the prasugrel group between baseline and 24 h measurements (100.0 vs. 4.3%; p &lt; 0.0001). Rates of patients with HTPR at 24 h and 30 days were similar in both groups, so were the tendencies in patterns of platelet inhibition evaluated with multiple electrode aggregometry as compared with the VASP assay.Conclusions: Our study indicates that prasugrel overcomes HTPR on clopidogrel in the acute phase of interventionally treated ACS and maintains its antiplatelet potency in 30-day follow-up. Potential clinical benefits of personalized antiplatelet prasugrel-based therapy warrant further investigation in clinical ACS trials.