Impact of Society Guidelines on Trends in Use of Newer P2Y12 Inhibitors for Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Over the past decade, major society guidelines have recommended the use of newer P2Y12 inhibitors over clopidogrel for those undergoing percutaneous coronary intervention for acute coronary syndrome. It is unclear what impact these recommendations had on clinical practice. METHODS AND RESULTS: All percutaneous coronary intervention procedures (n=534 210) for acute coronary syndrome in England and Wales (April 1, 2010, to March 31, 2022) were retrospectively analyzed, stratified by choice of preprocedural P2Y12 inhibitor (clopidogrel, ticagrelor, and prasugrel). Multivariable logistic regression models were used to examine odds ratios of receipt of ticagrelor and prasugrel (versus clopidogrel) over time, and predictors of their receipt. Overall, there was a significant increase in receipt of newer P2Y12 inhibitors from 2010 to 2020 (2022 versus 2010: ticagrelor odds ratio, 8.12 [95% CI, 7.67-8.60]; prasugrel odds ratio, 6.14 [95% CI, 5.53-6.81]), more so in ST-segment-elevation myocardial infarction than non-ST-segment-elevation acute coronary syndrome indication. The most significant increase in odds of receipt of prasugrel was observed between 2020 and 2022 (P<0.001), following a decline/plateau in its use in earlier years (2011-2019). In contrast, the odds of receipt of ticagrelor significantly increased in earlier years (2012-2017, Ptrend<0.001), after which the trend was stable (Ptrend=0.093). CONCLUSIONS: Over a 13-year-period, there has been a significant increase in use of newer P2Y12 inhibitors, although uptake of prasugrel use remained significantly lower than ticagrelor. Earlier society guidelines (pre-2017) were associated with the highest rates of ticagrelor use for non-ST-segment-elevation acute coronary syndrome and ST-segment-elevation myocardial infarction cases while the ISAR-REACT 5 (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome) trial and later society guidelines were associated with higher prasugrel use, mainly for ST-segment-elevation myocardial infarction indication.

Ticagrelor alone versus ticagrelor plus aspirin from month 1 to month 12 after percutaneous coronary intervention in patients with acute coronary syndromes (ULTIMATE-DAPT): a randomised, placebo-controlled, double-blind clinical trial.

BACKGROUND: Following percutaneous coronary intervention with stent placement to treat acute coronary syndromes, international clinical guidelines generally recommend dual antiplatelet therapy with aspirin plus a P2Y12 receptor inhibitor for 12 months to prevent myocardial infarction and stent thrombosis. However, data on single antiplatelet therapy with a potent P2Y12 inhibitor earlier than 12 months after percutaneous coronary intervention for patients with an acute coronary syndrome are scarce. The aim of this trial was to assess whether the use of ticagrelor alone, compared with ticagrelor plus aspirin, could reduce the incidence of clinically relevant bleeding events without an accompanying increase in major adverse cardiovascular or cerebrovascular events (MACCE). METHODS: In this randomised, placebo-controlled, double-blind clinical trial, patients aged 18 years or older with an acute coronary syndrome who completed the IVUS-ACS study and who had no major ischaemic or bleeding events after 1-month treatment with dual antiplatelet therapy were randomly assigned to receive oral ticagrelor (90 mg twice daily) plus oral aspirin (100 mg once daily) or oral ticagrelor (90 mg twice daily) plus a matching oral placebo, beginning 1 month and ending at 12 months after percutaneous coronary intervention (11 months in total). Recruitment took place at 58 centres in China, Italy, Pakistan, and the UK. Patients were required to remain event-free for 1 month on dual antiplatelet therapy following percutaneous coronary intervention with contemporary drug-eluting stents. Randomisation was done using a web-based system, stratified by acute coronary syndrome type, diabetes, IVUS-ACS randomisation, and site, using dynamic minimisation. The primary superiority endpoint was clinically relevant bleeding (Bleeding Academic Research Consortium [known as BARC] types 2, 3, or 5). The primary non-inferiority endpoint was MACCE (defined as the composite of cardiac death, myocardial infarction, ischaemic stroke, definite stent thrombosis, or clinically driven target vessel revascularisation), with an expected event rate of 6·2% in the ticagrelor plus aspirin group and an absolute non-inferiority margin of 2·5 percentage points between 1 month and 12 months after percutaneous coronary intervention. The two co-primary endpoints were tested sequentially; the primary superiority endpoint had to be met for hypothesis testing of the MACCE outcome to proceed. All principal analyses were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03971500, and is completed. FINDINGS: Between Sept 21, 2019, and Oct 27, 2022, 3400 (97·0%) of the 3505 participants in the IVUS-ACS study were randomly assigned (1700 patients to ticagrelor plus aspirin and 1700 patients to ticagrelor plus placebo). 12-month follow-up was completed by 3399 (>99·9%) patients. Between month 1 and month 12 after percutaneous coronary intervention, clinically relevant bleeding occurred in 35 patients (2·1%) in the ticagrelor plus placebo group and in 78 patients (4·6%) in the ticagrelor plus aspirin group (hazard ratio [HR] 0·45 [95% CI 0·30 to 0·66]; p<0·0001). MACCE occurred in 61 patients (3·6%) in the ticagrelor plus placebo group and in 63 patients (3·7%) in the ticagrelor plus aspirin group (absolute difference -0·1% [95% CI -1·4% to 1·2%]; HR 0·98 [95% CI 0·69 to 1·39]; pnon-inferiority<0·0001, psuperiority=0·89). INTERPRETATION: In patients with an acute coronary syndrome who had percutaneous coronary intervention with contemporary drug-eluting stents and remained event-free for 1 month on dual antiplatelet therapy, treatment with ticagrelor alone between month 1 and month 12 after the intervention resulted in a lower rate of clinically relevant bleeding and a similar rate of MACCE compared with ticagrelor plus aspirin. Along with the results from previous studies, these findings show that most patients in this population can benefit from superior clinical outcomes with aspirin discontinuation and maintenance on ticagrelor monotherapy after 1 month of dual antiplatelet therapy. FUNDING: The Chinese Society of Cardiology, the National Natural Scientific Foundation of China, and the Jiangsu Provincial & Nanjing Municipal Clinical Trial Project. TRANSLATION: For the Mandarin translation of the abstract see Supplementary Materials section.

Ticagrelor downregulates the expression of proatherogenic and proinflammatory miR125-b compared to clopidogrel: A randomized, controlled trial.

BACKGROUND: Platelet P2Y12 antagonist ticagrelor reduces cardiovascular mortality after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown. Because activated platelets release proatherogenic and proinflammatory microRNAs, including miR-125a, miR-125b and miR-223, we hypothesized that the expression of these miRNAs is lower on ticagrelor, compared to clopidogrel. OBJECTIVES: We compared miR-125a, miR-125b and miR-223 expression in plasma of patients after AMI treated with ticagrelor or clopidogrel. METHODS: After percutaneous coronary intervention on acetylsalicylic acid and clopidogrel, 60 patients with first AMI were randomized to switch to ticagrelor or to continue with clopidogrel. Plasma expression of miR-223, miR-125a-5p, miR-125b was measured using quantitative polymerase chain reaction at baseline and after 72 h and 6 months of treatment with ticagrelor or clopidogrel in patients and one in 30 healthy volunteers. Multiple electrode aggregometry using ADP test was used to determine platelet reactivity in response to P2Y12 inhibitors. RESULTS: Expression of miR-125b was higher in patients with AMI 72 h and 6 months, compared to healthy volunteers (p = 0.001), whereas expression of miR-125a-5p and miR-223 were comparable. In patients randomized to ticagrelor, expression of miR-125b decreased at 72 h (p = 0.007) and increased back to baseline at 6 months (p = 0.005). Expression of miR-125a-5p and miR-223 was not affected by the switch from clopidogrel to ticagrelor. CONCLUSIONS: Ticagrelor treatment leads to lower plasma expression of miR-125b after AMI, compared to clopidogrel. Higher expression of miR-125b might explain recurrent thrombotic events and worse clinical outcomes in patients treated with clopidogrel, compared to ticagrelor.

Low-dose prasugrel versus standard-dose ticagrelor in east Asian patients with acute coronary syndrome.

Low-dose prasugrel demonstrated a similar effectiveness profile to clopidogrel in East Asian ACS patients, but its comparison with another new-generation potent P2Y12 inhibitor, ticagrelor, remains unclear. To compare the effectiveness and safety of low-dose prasugrel against those of standard-dose ticagrelor in East Asian patients with ACS. This retrospective cohort study used Taiwan's National Health and Welfare Database. This study included ACS patients who underwent percutaneous coronary intervention and, at discharge between January 1, 2018 and December 31, 2020, were prescribed with low-dose prasugrel plus aspirin or standard-dose ticagrelor plus aspirin. Stabilized inverse probability of treatment weighting was used to balance the covariates across these two groups. The primary effectiveness outcome was a composite of acute myocardial infarction, ischemic stroke, and cardiovascular death; the secondary effectiveness outcome was each of the individual components of the primary outcome, transient ischemic attack, and repeat revascularization. The primary safety outcome was a composite of intracranial hemorrhage and gastrointestinal bleeding, and the two secondary safety outcomes were intracranial hemorrhage and gastrointestinal bleeding. A total of 24,807 patients were included in this study. Among them, 1,493 were low-dose prasugrel users and 23,314 were standard-dose ticagrelor users. No significant differences were found in primary effectiveness [HR: 0.97 (0.74-1.28)] or primary safety outcomes [HR: 1.22 (0.73-2.01)] between the two study groups. For East Asian patients with ACS, low-dose prasugrel provides comparable effectiveness without increasing bleeding risk compared to standard-dose ticagrelor. Low-dose prasugrel may be an appropriate alternative for East Asian populations.

Antiplatelet Treatment Preferences of a Group of Cardiologists from Türkiye: A Survey Research Study.

OBJECTIVE: Deciding on the optimal duration of dual antiplatelet treatment (DAPT) remains a complex decision. This survey aims to explore the preferences for antiplatelet therapy and the daily routine regarding DAPT duration in coronary artery disease among a group of cardiologists in Türkiye. METHOD: Using an online questionnaire with 38 questions, the preferences of 314 cardiologists were collected. Qualitative descriptive characteristics of the answers received from the participants were examined. RESULTS: Participating cardiologists mostly worked in training and research hospitals (51.59%) and university hospitals (21.66%). Participants primarily favored ticagrelor in patients undergoing PCI with a diagnosis of STEMI and NSTE-ACS (69.75% and 55.73% respectively). Clopidogrel was the most preferred P2Y12 treatment in patients with chronic coronary syndrome (CCS) after PCI (94.90%). Pre-treatment with a loading dose of a P2Y12 receptor inhibitor was administered to 57.01% of patients with NSTE-ACS, irrespective of the planned treatment strategy. In NSTE-ACS patients with low bleeding risk treated with PCI, 83.12% of participants recommended DAPT for 12 months and 14.65% for >12 months. In high-bleeding-risk NSTE-ACS patients treated with PCI, DAPT durations of six months (74.52%), three months (19.75%), and one month (5.73%) were chosen. Among CCS patients treated with PCI without an increased risk of bleeding, 12 months of DAPT was preferred by 68.15% of participants. Most participants (70.70%) were switching to a more potent P2Y12 receptor inhibitor therapy in emergency department clopidogrel-loaded patients with ACS. CONCLUSION: The aim of this survey to capture a snapshot of the preferences of a group of cardiologists in Türkiye regarding DAPT treatment and duration. The responses were both in accordance and in conflict with the current guidelines.

Ticagrelor or Clopidogrel Monotherapy vs Dual Antiplatelet Therapy After Percutaneous Coronary Intervention: A Systematic Review and Patient-Level Meta-Analysis.

Importance: Among patients undergoing percutaneous coronary intervention (PCI), it remains unclear whether the treatment efficacy of P2Y12 inhibitor monotherapy after a short course of dual antiplatelet therapy (DAPT) depends on the type of P2Y12 inhibitor. Objective: To assess the risks and benefits of ticagrelor monotherapy or clopidogrel monotherapy compared with standard DAPT after PCI. Data Sources: MEDLINE, Embase, TCTMD, and the European Society of Cardiology website were searched from inception to September 10, 2023, without language restriction. Study Selection: Included studies were randomized clinical trials comparing P2Y12 inhibitor monotherapy with DAPT on adjudicated end points in patients without indication to oral anticoagulation undergoing PCI. Data Extraction and Synthesis: Patient-level data provided by each trial were synthesized into a pooled dataset and analyzed using a 1-step mixed-effects model. The study is reported following the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data. Main Outcomes and Measures: The primary objective was to determine noninferiority of ticagrelor or clopidogrel monotherapy vs DAPT on the composite of death, myocardial infarction (MI), or stroke in the per-protocol analysis with a 1.15 margin for the hazard ratio (HR). Key secondary end points were major bleeding and net adverse clinical events (NACE), including the primary end point and major bleeding. Results: Analyses included 6 randomized trials including 25 960 patients undergoing PCI, of whom 24 394 patients (12 403 patients receiving DAPT; 8292 patients receiving ticagrelor monotherapy; 3654 patients receiving clopidogrel monotherapy; 45 patients receiving prasugrel monotherapy) were retained in the per-protocol analysis. Trials of ticagrelor monotherapy were conducted in Asia, Europe, and North America; trials of clopidogrel monotherapy were all conducted in Asia. Ticagrelor was noninferior to DAPT for the primary end point (HR, 0.89; 95% CI, 0.74-1.06; P for noninferiority = .004), but clopidogrel was not noninferior (HR, 1.37; 95% CI, 1.01-1.87; P for noninferiority > .99), with this finding driven by noncardiovascular death. The risk of major bleeding was lower with both ticagrelor (HR, 0.47; 95% CI, 0.36-0.62; P < .001) and clopidogrel monotherapy (HR, 0.49; 95% CI, 0.30-0.81; P = .006; P for interaction = 0.88). NACE were lower with ticagrelor (HR, 0.74; 95% CI, 0.64-0.86, P < .001) but not with clopidogrel monotherapy (HR, 1.00; 95% CI, 0.78-1.28; P = .99; P for interaction = .04). Conclusions and Relevance: This systematic review and meta-analysis found that ticagrelor monotherapy was noninferior to DAPT for all-cause death, MI, or stroke and superior for major bleeding and NACE. Clopidogrel monotherapy was similarly associated with reduced bleeding but was not noninferior to DAPT for all-cause death, MI, or stroke, largely because of risk observed in 1 trial that exclusively included East Asian patients and a hazard that was driven by an excess of noncardiovascular death.

Treatment and outcomes of patients with chronic lung disease and acute myocardial infarction: Insights from the nationwide AMIS plus registry.

BACKGROUND: Limited data are available on patients with chronic lung disease (CLD) presenting with acute myocardial infarction (AMI). We aimed to analyse baseline characteristics, treatment and outcome of those patients enrolled in the Swiss nationwide prospective AMIS Plus registry. METHODS: All AMI patients enrolled between January 2002 and December 2021 with data on CLD, as defined in the Charlson Comorbidity Index, were included. The primary endpoints were in-hospital mortality and major adverse cardiac and cerebrovascular events (MACCE), defined as all-cause death, reinfarction and cerebrovascular events. Baseline characteristics, in-hospital treatments and outcomes were analysed using descriptive statistics and logistic regression. RESULTS: Among 53,680 AMI patients enrolled during this time, 5.8% had CLD. Compared with patients without CLD, CLD patients presented more frequently with non-ST-elevation myocardial infarction (MI) and type 2 MI (12.8% vs. 6.5%, p < 0.001). With respect to treatment, CLD patients were less likely to receive P2Y12 inhibitors (p < 0.001) and less likely to undergo percutaneous coronary interventions (68.7% vs. 82.5%; p < 0.001). In-hospital mortality declined in AMI patients with CLD over time (from 12% in 2002 to 7.3% in 2021). Multivariable regression analysis showed that CLD was an independent predictor for MACCE (adjusted OR was 1.28 [95% CI 1.07-1.52], p = 0.006). CONCLUSION: Patients with CLD and AMI were less likely to receive evidence-based pharmacologic treatments, coronary revascularization and had a higher incidence of MACCE during their hospital stay compared to those without CLD. Over 20 years, in-hospital mortality was significantly reduced in AMI patients, especially in those with CLD.

The impact of frailty on initiation, continuation and discontinuation of secondary prevention medications following myocardial infarction.

AIM: To evaluate the association between frailty and initiating, continuing, or discontinuing secondary prevention medications following myocardial infarction (MI). METHODS: We conducted a cohort study using linked health data, including all adults aged ≥65 years who discharged from hospital following MI from January 2013 to April 2018 in Victoria, Australia (N = 29,771). The Hospital Frailty Risk Score (HFRS) was used to assess frailty. Logistic regression was used to investigate associations of frailty with initiation, continuation, and discontinuation of secondary prevention medications (P2Y12 inhibitor antiplatelets, beta-blockers, renin-angiotensin-aldosterone system (RAAS) inhibitors, and lipid-lowering therapies) in the 90 days from discharge post-MI, by HFRS, adjusted for age, sex, and Charlson Comorbidity Index. RESULTS: Increasing frailty was associated with lower probability of initiating and continuing P2Y12 inhibitors, RAAS inhibitors, and lipid-lowering therapies, but not beta-blockers. At at an HFRS of 0, the predicted probabiliy of having all four medications initiated or continued was 0.59 (95 %CI 0.57-0.62) for STEMI and 0.35 (0.34-0.36) for non-STEMI, compared to 0.38 (0.33-0.42) and 0.16 (0.14-0.18) at an HFRS of 15. Increasing frailty was associated with higher probability of discontinuing these medications post-MI. The predicted probability of discontinuing at least one secondary prevention medication post-MI at an HFRS of 0 was 0.10 (0.08-0.11) for STEMI and 0.14 (0.13-0.15) for non-STEMI, compared to 0.27 (0.22-0.32) and 0.34 (0.32-0.36) at an HFRS of 15. CONCLUSION: People with higher levels of frailty were managed more conservatively following MI than people with lower levels of frailty. Whether this conservative treatment is justified warrants further study.

Racial differences in P2Y12 inhibitor responsiveness in patients undergoing neuro-endovascular procedures: A cohort from the Middle East.

BACKGROUND: Data on P2Y12 inhibitors responsiveness from the middle east is scarce. We sought to investigate patient responsiveness to P2Y12 inhibitors within a cohort of major races that characterize the UAE population. The secondary objective was to assess risk factors for hyper and hypo-responsiveness in this population. METHODS: We conducted a cross-sectional study on adults who received either clopidogrel or ticagrelor treatments and had platelet responsiveness testing before undergoing neuro-endovascular interventions at our quaternary care hospital between March 2015 and April 2019. RESULTS: During the study period, 249 subjects met the inclusion criteria. Overall, 17.3 % were hyper-responsive and 25.7 % were hypo-responsive to P2Y12 inhibitors. When comparing between the P2Y12 inhibitors, rates of hyper-responsiveness were significantly higher to ticagrelor when compared to clopidogrel (11 versus 6 %, p = 0.02 respectively). Contrarily, hypo-responsiveness rates were significantly higher in clopidogrel treated patients compared to their ticagrelor treated counterparts (23 versus 2 %, p < .001 respectively). Patients of Middle-Eastern origin showed a significantly higher rate of hypo-responsiveness to both clopidogrel and ticagrelor when compared to other races (41.1 % and 26.7 %, P < 0.001 respectively). Asians showed the highest rates of hyper-responsiveness for both agents. Multivariate logistic regression analysis showed that proton pump inhibitors and statin combination, (OR: 6.39, 95 %CI [1.60, 25.392]), and Middle East vs. Indian subcontinent patients (OR: 4.67, 95 %CI [1.79-12.14]) were independent predictors of hypo-responsiveness to both P2Y12 inhibitors. CONCLUSION: This study demonstrated a high rate of hypo-responsiveness to P2Y12 inhibitors in a UAE cohort of patients undergoing neuro-endovascular procedures. In addition, therapeutic responsiveness to P2Y12 inhibitors varied markedly based on the racial background. Future larger studies are needed to evaluate genetic variations that may contribute to this rate of hypo-responsiveness in our population.

Aspirin loading and coronary no-reflow after percutaneous coronary intervention in patients with acute myocardial infarction.

BACKGROUND: The association of aspirin loading with the risk of coronary no-reflow (CNR) after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) has not been investigated. We assessed the association of aspirin loading before PCI with CNR in patients with AMI. MATERIALS AND METHODS: This study included 3100 patients with AMI undergoing PCI. Of them, 2812 patients received aspirin loading (a single oral [or chewed] or intravenous dose of 150-300 mg) and 288 patients did not receive aspirin loading before PCI. The primary endpoint was CNR, defined as Thrombolysis in Myocardial Infarction blood flow grade of <3 after the PCI. RESULTS: CNR occurred in 130 patients: 127 patients in the group with aspirin loading and 3 patients in the group without aspirin loading before PCI (4.5% vs. 1.0%; odds ratio [OR] = 4.50, 95% confidence interval, [1.42-14.21], p = 0.005). After adjustment, the association between aspirin loading and CNR was significant (adjusted OR = 4.49 [1.56-12.92]; p < 0.001). There was no aspirin loading-by-P2Y12 inhibitor (ticagrelor or prasugrel) interaction (pint = 0.465) or aspirin loading-by-chronic aspirin therapy on admission (pint = 0.977) interaction with respect to the occurrence of CNR after PCI. Chronic low-dose aspirin therapy on admission was not independently associated with higher risk of CNR after PCI (adjusted OR = 1.06 [0.65-1.72]; p = 0.824). CONCLUSION: In patients with AMI undergoing PCI, aspirin loading before the PCI procedure at the guideline-recommended doses was associated with higher odds of developing CNR. However, due to the limited number of events, the findings should be considered as hypothesis generating.

Aspirin-free antiplatelet strategies after percutaneous coronary interventions.

Dual antiplatelet therapy (DAPT) with aspirin and a platelet P2Y12 receptor inhibitor is the standard antithrombotic treatment after percutaneous coronary interventions (PCI). Several trials have challenged guideline-recommended DAPT after PCI by testing the relative clinical effect of an aspirin-free antiplatelet approach-consisting of P2Y12 inhibitor monotherapy after a short course (mostly 1-3 months) of DAPT-among patients undergoing PCI without a concomitant indication for oral anticoagulation (OAC). Overall, these studies have shown P2Y12 inhibitor monotherapy after short DAPT to be associated with a significant reduction in the risk of bleeding without an increase in thrombotic or ischaemic events compared with continued DAPT. Moreover, the effects of the P2Y12 inhibitor monotherapy without prior DAPT or following a very short course of DAPT after PCI are being investigated in emerging studies, of which one has recently reported unfavourable efficacy results associated with the aspirin-free approach compared with conventional DAPT. Finally, P2Y12 inhibitor alone has been compared with aspirin alone as chronic therapy after DAPT discontinuation, thus challenging the historical role of aspirin as a standard of care for secondary prevention following PCI. A thorough understanding of study designs, populations, treatments, results, and limitations of trials testing P2Y12 inhibitor monotherapy vs. DAPT or vs. aspirin is required to consider adopting this treatment in clinical practice. This review addresses the use of aspirin-free antiplatelet strategies among patients undergoing PCI without a concomitant indication for OAC, providing an overview of clinical evidence, guideline indications, practical implications, ongoing issues, and future perspectives.

Platelet P2Y12 signalling pathway in the dysregulated immune response during sepsis.

Sepsis is a complicated pathological condition in response to severe infection. It is characterized by a strong systemic inflammatory response, where multiple components of the immune system are involved. Currently, there is no treatment for sepsis. Blood platelets are known for their role in haemostasis, but they also participate in inflammation through cell-cell interaction and the secretion of inflammatory mediators. Interestingly, an increase in platelet activation, secretion, and aggregation with other immune cells (such as monocytes, T-lymphocytes and neutrophils) has been detected in septic patients. Therefore, antiplatelet therapy in terms of P2Y12 antagonists has been evaluated as a possible treatment for sepis. It was found that blocking P2Y12 receptors decreased platelet marker expression and limited attachment to immune cells in some studies, but not in others. This review addresses the role of platelets in sepsis and discusses whether antagonizing P2Y12 signalling pathways can alter the disease outcome. Challenges in studying P2Y12 antagonists in sepsis also are discussed. LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.