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

Evaluation of Clinical Risk Factors to Predict High On-Treatment Platelet Reactivity and Outcome in Patients with Stable Coronary Artery Disease (PREDICT-STABLE)

Objectives This study was designed to identify the multivariate effect of clinical risk factors on high on-treatment platelet reactivity (HPR) and 12 months major adverse events (MACE) under treatment with aspirin and clopidogrel in patients undergoing non-urgent percutaneous coronary intervention (PCI). Methods 739 consecutive patients with stable coronary artery disease (CAD) undergoing PCI were recruited. On-treatment platelet aggregation was tested by light transmittance aggregometry. Clinical risk factors and MACE during one-year follow-up were recorded. An independent population of 591 patients served as validation cohort. Results Degree of on-treatment platelet aggregation was influenced by different clinical risk factors. In multivariate regression analysis older age, diabetes mellitus, elevated BMI, renal function and left ventricular ejection fraction were independent predictors of HPR. After weighing these variables according to their estimates in multivariate regression model, we developed a score to predict HPR in stable CAD patients undergoing elective PCI (PREDICT-STABLE Score, ranging 0-9). Patients with a high score were significantly more likely to develop MACE within one year of follow-up, 3.4% (score 0-3), 6.3% (score 4-6) and 10.3% (score 7-9); odds ratio 3.23, P=0.02 for score 7-9 vs. 0-3. This association was confirmed in the validation cohort. Conclusions Variability of on-treatment platelet function and associated outcome is mainly influenced by clinical risk variables. Identification of high risk patients (e.g. with high PREDICT-STABLE score) might help to identify risk groups that benefit from more intensified antiplatelet regimen. Additional clinical risk factor assessment rather than isolated platelet function-guided approaches should be investigated in future to evaluate personalized antiplatelet therapy in stable CAD-patients

Low-molecular-weight heparins vs. unfractionated heparin in the setting of percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis

Summary. Background: The aim of the current study was to perform two separate meta-analyses of available studies comparing low-molecular-weight heparins (LMWHs) vs. unfractionated heparin (UFH) in ST-elevation myocardial infarction (STEMI) patients treated (i) with primary percutaneous coronary intervention (pPCI) or (ii) with PCI after thrombolysis. Methods: All-cause mortality was the prespecified primary endpoint and major bleeding complications were recorded as the secondary endpoints. Relative risk (RR) with a 95%confidence interval (CI) and absolute risk reduction (ARR) were chosen as the effect measure. Results: Ten studies comprising 16 286 patients were included. The median followup was 2 months for the primary endpoint. Among LMWHs, enoxaparin was the compound most frequently used. In the pPCI group, LMWHs were associated with a reduction in mortality [RR (95% CI) = 0.51 (0.41–0.64), P < 0.001, ARR = 3%] and major bleeding [RR (95% CI) = 0.68 (0.49–0.94), P = 0.02, ARR = 2.0%] as compared with UFH. Conversely, no clear evidence of benefits with LWMHs was observed in the PCI group after thrombolysis. Metaregression showed that patients with a higher baseline risk had greater benefits from LMWHs (r = 0.72, P = 0.02). Conclusions: LMWHs were associated with greater efficacy and safety than UFH in STEMI patients treated with pPCI, with a significant relationship between risk profile and clinical benefits. Based on this meta-analysis, LMWHs may be considered as a preferred anticoagulant among STEMI patients undergoing pPCI

Antithrombotic therapy in patients with acute coronary syndrome complicated by cardiogenic shock or out-of-hospital cardiac arrest: a Joint Position Paper from the European Society of Cardiology (ESC) Working Group on Thrombosis, in association with the Acute Cardiovascular Care Association (ACCA) and European Association of Percutaneous Cardiovascular Interventions (EAPCI)

© The Author 2020. This is a pre-copyedited, author-produced version of an article accepted for publication in European Heart Journal - Cardiovascular Pharmacotherapy following peer review. The version of record [Gorog et al., Antithrombotic therapy in patients with acute coronary syndrome complicated by cardiogenic shock or out-of-hospital cardiac arrest: a Joint Position Paper from the European Society of Cardiology (ESC) Working Group on Thrombosis, in association with the Acute Cardiovascular Care Association (ACCA) and European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Journal - Cardiovascular Pharmacotherapy, pvaa009] is available online at: https://doi.org/10.1093/ehjcvp/pvaa009.Peer reviewedFinal Accepted Versio

COVID-19 vaccine-associated myocarditis: Analysis of the suspected cases reported to the EudraVigilance and a systematic review of the published literature

BACKGROUND: Myocarditis secondary to Coronavirus Disease 2019 (COVID-19) vaccination has been reported in the literature. OBJECTIVE: This study aimed to characterize the reported cases of myocarditis after COVID-19 vaccination based on age, gender, doses, and vaccine type from published literature and the EudraVigilance database. METHODS: We performed an analysis in the EudraVigilance database (until December 18, 2021) and a systematic review of published literature for reported cases of suspected myocarditis and pericarditis (until 30th June 2022) after the COVID-19 vaccination. RESULTS: EudraVigilance database analysis revealed 16,514 reported cases of myocarditis or pericarditis due to the vaccination with COVID-19 vaccines. The cases of myo- or pericarditis were reported predominantly in the age group of 18-64 (n = 12,214), and in males with a male-to-female (M: F) ratio of 1.7:1. The mortality among myocarditis patients was low, with 128 deaths (2 cases per 10.000.000 administered doses) being reported. For the systematic review, 72 studies with 1026 cases of myocarditis due to the vaccination with COVID-19 vaccines were included. The analysis of published cases has revealed that the male gender was primarily affected with myocarditis post-COVID-vaccination. The median (IQR) age of the myocarditis cases was 24.6 [19.5-34.6] years, according to the systematic review of the literature. Myocarditis cases were most frequently published after the vaccination with m-RNA vaccines and after the second vaccination dose. The overall mortality of published cases was low (n = 5). CONCLUSION: Myocarditis is a rare serious adverse event associated with a COVID-19 vaccination. With early recognition and management, the prognosis of COVID-19 vaccine-induced myocarditis is favorable

Ticagrelor attenuates the increase of extracellular vesicle concentrations in plasma after acute myocardial infarction compared to clopidogrel

Background Platelet P2Y12 antagonist ticagrelor reduces mortality after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown. Because activated platelets, leukocytes, and endothelial cells release proinflammatory and prothrombotic extracellular vesicles (EVs), we hypothesized that the release of EVs is more efficiently inhibited by ticagrelor compared to clopidogrel. Objectives We compared EV concentrations and EV procoagulant activity in plasma of patients after AMI treated with ticagrelor or clopidogrel. Methods After percutaneous coronary intervention, 60 patients with first AMI were randomized to ticagrelor or clopidogrel. Flow cytometry was used to determine concentrations of EVs from activated platelets (CD61(+), CD62p(+)), fibrinogen(+), phosphatidylserine (PS+), leukocytes (CD45(+)), endothelial cells (CD31(+), 146(+)), and erythrocytes (CD235a(+)) in plasma at randomization, after 72 hours and 6 months of treatment. A fibrin generation test was used to determine EV procoagulant activity. Results Concentrations of platelet, fibrinogen(+), PS+, leukocyte, and erythrocyte EVs increased 6 months after AMI compared to the acute phase of AMI (P = .17). Conclusions Ticagrelor attenuates the increase of EV concentrations in plasma after acute myocardial infarction compared to clopidogrel. The ongoing release of EVs despite antiplatelet therapy might explain recurrent thrombotic events after AMI and worse clinical outcomes on clopidogrel compared to ticagrelor.Peer reviewe

Expression of miR-223 to predict outcomes after transcatheter aortic valve implantation

Background: Transcatheter aortic valve implantation (TAVI) is an established treatment for aortic stenosis (AS) in patients at increased surgical risk. Up to 29% of patients annually experience major adverse cardiac and cerebrovascular events (MACCE) after TAVI. MicroRNAs (miRNA) are currently widely investigated as novel cardiovascular biomarkers. The aim of this study was to determine the influence of TAVI on the expressions of selected miRNAs associated with platelet function (miR-125a-5p, miR-125b and miR-223), and evaluate the predictive value of these miRNAs for MACCE in 65 patients undergoing TAVI. Methods: Venous blood samples for miRNA expression analysis were collected 1 day before TAVI and at hospital discharge. The expression of miR-223, miR-125a-5p, miR-125b was evaluated in platelet-depleted plasma. Results: The expression of miR-223 and miR-125b increased after TAVI, compared to the measurement before (p = 0.020, p = 0.003, respectively). Among 63 patients discharged from the hospital, 18 patients experienced MACCE (29%) during the median 15 months of observation. Baseline low miR-223 expression was a predictor of MACCE in univariate Cox regression analysis (hazard ratio [HR]: 2.71, 95% confidence interval [CI]: 1.04–7.01; p = 0.041). After inclusion of covariates, age, gender (male), New York Heart Association class and diabetes into the multivariate Cox regression model, miR-223 did not reach statistical significance (HR: 2.56, 95% CI: 0.79–8.33; p = 0.118). Conclusions: To conclude, miR-223 might improve risk stratification after TAVI. Further studies are required to confirm the clinical applicability of this promising biomarker