What is the Optimal Duration of Dual Antiplatelet Therapy After Stenting?

The optimal duration of dual antiplatelet therapy (DAPT) of aspirin and a P2Y12 receptor blocker after stenting is still being debated. The current recommendations for DAPT duration are significantly focused on reducing stent thrombosis; a less frequent event with later than earlier generation drug eluting stents (DES). A persistent occurrence of late and very late stent thrombosis with first generation DES supported extended use of DAPT beyond one year. However, recent studies have demonstrated that extended duration DAPT is associated with increased bleeding; an independent predictor for poor outcomes, including long-term mortality. Second-generation DES are associated with less late and very late stent thrombosis. Some recent studies have supported a shorter duration of DAPT for second generation DES. However, these studies were inadequately powered to assess significant differences in stent thrombosis. Furthermore, extended duration DAPT has been associated with a reduced risk of thrombotic events in non-culprit vessels in addition to stent thrombosis in patients with acute coronary syndromes (ACS). The higher risk of bleeding associated with extended DAPT therapy provides a strong rationale for personalized DAPT based on patient risk factors (e.g. ACS vs. non-ACS), type of stents, and cost-benefit analyses

Acetylsalicylic acid and clopidogrel hyporesponsiveness following acute coronary syndromes

This review discusses the response variability to acetylsalicylic acid (ASA) and particularly to clopidogrel, and their relation to adverse recurrent ischaemic events in patients with arterial diseases. The higher rate of ASA resistance reported in the literature may be mainly due to the cyclooxygenase-1 non-specific assays, non-compliance, and underdosing. Clopidogrel response variability and non-responsiveness are established concepts. Moreover, high platelet reactivity (HPR) to adenosine diphosphate during clopidogrel therapy is now a known risk factor for recurrent ischaemic events in high-risk percutaneous coronary intervention/acute coronary syndrome patients. Variable active metabolite generation is the primary explanation for clopidogrel response variability and non-responsivenes. Variable levels of active metabolite generation following clopidogrel administration could be mainly explained by functional variability in hepatic cytochrome (CYP)P450 isoenzyme activity that is influenced by drug–drug interactions and single nucleotide polymorphisms of specific genes encoding CYP450 isoenzymes. Treatment with more potent P2Y12 receptor blockers, such as prasugrel and ticagrelor are credible alternative strategies to overcome HPR during clopidogrel therapy

Increased Risk in Patients With High Platelet Aggregation Receiving Chronic Clopidogrel Therapy Undergoing Percutaneous Coronary Intervention Is the Current Antiplatelet Therapy Adequate?

ObjectivesWe sought to determine whether patients receiving chronic clopidogrel therapy undergoing nonemergent stenting who display high on-treatment preprocedural platelet aggregation measured by standard light transmittance aggregometry and thrombelastography (TEG) will be at increased risk for poststenting ischemic events.BackgroundPatients exhibiting heightened platelet reactivity to adenosine diphosphate (ADP) might be at increased risk for recurrent ischemic events after coronary stenting.MethodsA total of 100 consecutive patients receiving chronic antiplatelet therapy consisting of aspirin (325 mg qd) and clopidogrel (75 mg qd) were studied before undergoing nonemergent stenting. Patients were followed for 1 year after coronary stenting for the occurrence of death, myocardial infarction, stent thrombosis, stroke, or ischemia requiring a hospital stay.ResultsAll patients were aspirin responsive. Patients with ischemic events (23 of 100, 23%) within 1 year had greater on-treatment prestent ADP-induced platelet aggregation than patients without ischemic events by aggregometry and TEG (p < 0.001 for both measurements). Of patients with an ischemic event, 70% and 87% displayed high on-treatment platelet reactivity at baseline by aggregometry and TEG, respectively. High on-treatment platelet reactivity as measured by aggregometry and TEG were the only variables significantly related to ischemic events (p < 0.001 for both assays). The administration of eptifibatide reduced periprocedural elevation in platelet reactivity, with no significant differences in bleeding events.ConclusionsPatients receiving chronic clopidogrel therapy undergoing nonemergent percutaneous coronary intervention who exhibit high on-treatment ADP-induced platelet aggregation are at increased risk for postprocedural ischemic events. These findings might have implications for the alteration in clopidogrel maintenance dose and use of glycoprotein IIb/IIIa inhibitors in selected patients

Incidence of Dyspnea and Assessment of Cardiac and Pulmonary Function in Patients With Stable Coronary Artery Disease Receiving Ticagrelor, Clopidogrel, or Placebo in the ONSET/OFFSET Study

ObjectivesWe prospectively assessed cardiac and pulmonary function in patients with stable coronary artery disease (CAD) treated with ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET (A Multi-Centre Randomised, Double-Blind, Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease) study.BackgroundTicagrelor reduces cardiovascular events more effectively than clopidogrel in patients with acute coronary syndromes. Dyspnea develops in some patients treated with ticagrelor, and it is not known whether this is associated with changes in cardiac or pulmonary function.MethodsIn all, 123 stable aspirin-treated CAD patients randomly received either ticagrelor (180 mg load, then 90 mg twice daily; n = 57), clopidogrel (600 mg load, then 75 mg daily; n = 54), or placebo (n = 12) for 6 weeks in a double-blind, double-dummy design. Electrocardiography, echocardiography, serum N-terminal pro-brain natriuretic peptide, and pulmonary function tests were performed before (baseline) and 6 weeks after drug administration and/or after development of dyspnea.ResultsAfter drug administration, dyspnea was reported by 38.6%, 9.3%, and 8.3% of patients in the ticagrelor, clopidogrel, and placebo groups, respectively (p < 0.001). Most instances were mild and/or lasted <24 h, although 3 patients discontinued ticagrelor because of dyspnea. Eight of 22 and 17 of 22 ticagrelor-treated patients experiencing dyspnea did so within 24 h and 1 week, respectively, after drug administration. In all treatment groups, and in ticagrelor-treated patients with dyspnea, there were no significant changes between baseline and 6 weeks in any of the cardiac or pulmonary function parameters.ConclusionsDyspnea is commonly associated with ticagrelor therapy, but was not associated in this study with any adverse change in cardiac or pulmonary function. (A Multi-Centre Randomised, Double-Blind, Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease [ONSET/OFFSET]; NCT00528411

PAR1 (Protease-Activated Receptor 1) Pepducin Therapy Targeting Myocardial Necrosis in Coronary Artery Disease and Acute Coronary Syndrome Patients Undergoing Cardiac Catheterization: A Randomized, Placebo-Controlled, Phase 2 Study

OBJECTIVE: Arterial thrombosis leading to ischemic injury worsens the prognosis of many patients with cardiovascular disease. PZ-128 is a first-in-class pepducin that reversibly inhibits PAR1 (protease-activated receptor 1) on platelets and other vascular cells by targeting the intracellular surface of the receptor. The TRIP-PCI (Thrombin Receptor Inhibitory Pepducin in Percutaneous Coronary Intervention) trial was conducted to assess the safety and efficacy of PZ-128 in patients undergoing cardiac catheterization with intent to perform percutaneous coronary intervention. Approach and Results: In this randomized, double-blind, placebo-controlled, phase 2 trial, 100 patients were randomly assigned (2:1) to receive PZ-128 (0.3 or 0.5 mg/kg), or placebo in a 2-hour infusion initiated just before the start of cardiac catheterization, on top of standard oral antiplatelet therapy. Rates of the primary end point of bleeding were not different between the combined PZ-128 doses (1.6%, 1/62) and placebo group (0%, 0/35). The secondary end points of major adverse coronary events at 30 and 90 days did not significantly differ but were numerically lower in the PZ-128 groups (0% and 2% in the PZ-128 groups, 6% and 6% with placebo, p=0.13, p=0.29, respectively). In the subgroup of patients with elevated baseline cardiac troponin I, the exploratory end point of 30-day major adverse coronary events + myocardial injury showed 83% events in the placebo group versus 31% events in the combined PZ-128 drug groups, an adjusted relative risk of 0.14 (95% CI, 0.02-0.75); P=0.02. CONCLUSIONS: In this first-in-patient experience, PZ-128 added to standard antiplatelet therapy appeared to be safe, well tolerated, and potentially reduced periprocedural myonecrosis, thus providing the basis for further clinical trials. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02561000

Race-Related disparities in COVID-19 thrombotic outcomes: Beyond social and economic explanations

African Americans (AAs) have worse COVID-19-related outcomes than Caucasians and Asians, a disparity currently attributed to potential social and economic factors. In this commentary, we endeavor to examine important race-related differences in intrinsic thrombogenicity as another significant contributing factor and propose objective hemostasis assessments to address racial disparities in COVID-19 outcomes.Funding: Platelet and Thrombosis Research, LLC. Competing Interest: Dr. Kreutz has received consulting fees from Haemonetics. Dr. Jeong has received honoraria for lectures from AstraZeneca, Sanofi-Aventis, Daiichi Sankyo/Lilly, Haemonetics, Otsuka, Han-mi Pharmaceuticals and Yuhan Pharmaceuticals; and research grants or support from AstraZeneca, Korean Society of Interventional Cardiology, Han-mi Pharmaceuticals, Yuhan Pharmaceuticals, Otsuka and Haemonetics. Dr. Levy reports honoraria for advisory boards from Instrumentation Labs, Merck, Octapharma, and Janssen. Dr. Gurbel reports grants and personal fees from Bayer HealthCare LLC, Otitopic Inc, Amgen, Janssen, and US WorldMeds LLC; grants from Instrumentation Laboratory, Haemonetics, Medicure Inc, Idorsia Pharmaceuticals, and Hikari Dx; personal fees from UpToDate; Dr Gurbel is a relator and expert witness in litigation involving clopidogrel; in addition, Dr. Gurbel has two patents, Detection of restenosis risk in patients and Assessment of cardiac health and thrombotic risk in a patient. Other authors report no disclosure

Cardiac mortality in patients randomised to elective coronary revascularisation plus medical therapy or medical therapy alone: A systematic review and meta-analysis

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/)Aims:The value of elective coronary revascularisation plus medical therapy over medical therapy alone in managing stable patients with coronary artery disease is debated. We reviewed all trials comparing the two strategies in this population. Methods and results:From inception through November 2020, Medline, Embase, Google Scholar and other databases were searched for randomised trials comparing revascularisation to medical therapy alone in clinically stable coronary artery disease patients. Treatment effects were measured by rate ratios (RR) with 95% confidence intervals using random-effects models. Cardiac mortality was the prespecified primary endpoint. Spontaneous myocardial infarction (MI) and its association with cardiac mortality were secondary endpoints. Further endpoints included all-cause mortality, any MI and stroke. Longest follow-up data were abstracted. The study is registered with PROSPERO (CRD42021225598). Twenty-five trials involving 19,806 patients (10,023 randomised to revascularisation plus medical therapy and 9,783 to medical therapy alone) were included. Compared to medical therapy alone, revascularisation was associated with a lower risk of cardiac death (RR 0.79 [0.67-0.93], p<0.01) and spontaneous MI (RR 0.74 [0.64-0.86], p<0.01). By meta-regression, the cardiac death risk reduction after revascularisation, compared to medical therapy alone, was linearly associated with follow-up duration (RR per 4-year follow-up: 0.81 [0.69-0.96], p=0.008) and spontaneous MI absolute difference (p=0.01). Trial sequential and sensitivity analyses confirmed the reliability of the cardiac mortality findings. All cause mortality (0.94 [0.87-1.01], p=0.11), any MI (p=0.14) and stroke risk (p=0.30) did not differ significantly between strategies. Conclusion:In stable coronary artery disease patients, randomisation to elective coronary revascularisation plus medical therapy led to reduced cardiac mortality compared to medical management alone. The cardiac survival benefit after revascularisation improved with longer follow-uptimes and was associated with fewer spontaneous MIs.Peer reviewedFinal Published versio