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Whether guided selection of antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) is effective in improving outcomes compared with standard antiplatelet therapy remains controversial. We assessed the safety and efficacy of guided versus standard selection of antiplatelet therapy in patients undergoing PCI. For this systematic review and meta-analysis, from Aug 20 to Oct 25, 2020, we searched MEDLINE (via PubMed), Cochrane, Embase, and Web of Science databases for randomised controlled trials and observational studies published in any language that compared guided antiplatelet therapy, by means of platelet function testing or genetic testing, versus standard antiplatelet therapy in patients undergoing PCI. Two reviewers independently assessed study eligibility, extracted the data, and assessed risk of bias. Risk ratios (RRs) and 95% CIs were used with random-effects or fixed-effect models according to the estimated heterogeneity among studies assessed by the I2 index. Coprimary endpoints were trial-defined primary major adverse cardiovascular events and any bleeding. Key secondary endpoints were all-cause death, cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis, and major and minor bleeding. This study is registered with PROSPERO (CRD42021215901). 3656 potentially relevant articles were screened. Our analysis included 11 randomised controlled trials and three observational studies with data for 20 743 patients. Compared with standard therapy, guided selection of antiplatelet therapy was associated with a reduction in major adverse cardiovascular events (RR 0·78, 95% CI 0·63–0·95, p=0·015) and reduced bleeding, although not statistically significant (RR 0·88, 0·77–1·01, p=0·069). Cardiovascular death (RR 0·77, 95% CI 0·59–1·00, p=0·049), myocardial infarction (RR 0·76, 0·60–0·96, p=0·021), stent thrombosis (RR 0·64, 0·46–0·89, p=0·011), stroke (RR 0·66, 0·48–0·91, p=0·010), and minor bleeding (RR 0·78, 0·67–0·92, p=0·0030) were reduced with guided therapy compared with standard therapy. Risks of all-cause death and major bleeding did not differ between guided and standard approaches. Outcomes varied according to the strategy used, with an escalation approach associated with a significant reduction in ischaemic events without any trade-off in safety, and a de-escalation approach associated with a significant reduction in bleeding, without any trade-off in efficacy. Guided selection of antiplatelet therapy improved both composite and individual efficacy outcomes with a favourable safety profile, driven by a reduction in minor bleeding, supporting the use of platelet function or genetic testing to optimise the choice of agent in patients undergoing PCI. None.

In patients with manifestations of cardiovascular disease, acetylsalicylic acid (popularly known as aspirin) has been the mainstay of treatment for decades owing to its capacity to reduce the risk of ischaemic events. Accordingly, novel antithrombotic therapies have been traditionally tested on a background of acetylsalicylic acid therapy. Although the adjunctive use of such antithrombotic therapies can potentially further reduce the risk of ischaemic events, these agents are also inevitably associated with an increased risk of bleeding. However, acetylsalicylic acid also increases the risk of bleeding, challenging the paradigm that this agent should remain the cornerstone of antiplatelet treatment when alternative antithrombotic agents are also used. Many antithrombotic compounds are characterized by increased potency and consistent efficacy, which might lessen the need for concomitant acetylsalicylic acid. Accordingly, numerous investigations are testing the hypothesis that acetylsalicylic acid-sparing regimens based on newer antithrombotic agents might have an increased net benefit for individual patients owing to the reduction in bleeding risk, without a trade-off in efficacy. This Review summarizes the state of the art relating to antithrombotic approaches with and without acetylsalicylic acid for the prevention of cardiovascular disease and cardioembolic stroke. Discussion of the scientific rationale, from bench to bedside, for ongoing studies of acetylsalicylic acid-free pharmacological strategies is included.

Prasugrel and ticagrelor are potent oral platelet P2Y12 inhibitors and are recommended over clopidogrel in patients with acute coronary syndrome (ACS). Oral platelet P2Y12 inhibitors are characterized by varying degrees of pharmacodynamic response profiles as assessed by a variety of commercially available assays. Because of its ease of use, rapid turnaround times and ability to provide results specific to P2Y12 inhibitory effects, VerifyNow has emerged as one of the most commonly utilized platelet function assays. However, reference ranges with VerifyNow have been reported mainly for clopidogrel and there has not yet been any study specifically conducted to provide the expected on treatment reference ranges following administration of prasugrel and ticagrelor. This was a prospective single center investigation conducted in 120 patients with ACS who were treated with prasugrel or ticagrelor as per standard of care. Patients who underwent percutaneous coronary interventions (PCI) were treated with a loading dose of prasugrel (60 mg) or ticagrelor (180 mg), and patients who were on maintenance therapy were taking prasugrel (10 mg qd or 5 mg qd) or ticagrelor (90 mg bid). Platelet function testing was performed using the VerifyNow™ PRUTest™. The overall range of PRUTest values was lower than that observed in studies of patients treated with clopidogrel. The use of a maintenance dose regimen had a wider range of PRUTest values compared to the use of a loading dose for both prasugrel (1–179 vs. 2–128) and ticagrelor (1–196 vs. 1–177). The average PRUTest values in patients on prasugrel and ticagrelor maintenance dosing were 20% and 9% higher those observed in patients treated with a loading dose. PRUTest results following loading dose administration were very similar between drugs, but were 20% higher with prasugrel compared with ticagrelor during maintenance dosing. This study establishes expected PRUTest ranges for patients taking loading and maintenance doses of prasugrel and ticagrelor.Clinical Trial Registrationhttp://www.clinicaltrials.gov Unique Identifier: NCT04492423, registered July 2020 retrospectively registered.

Background The CYP2C19 nonfunctional genotype reduces clopidogrel effectiveness after percutaneous coronary intervention (PCI). Following clinical implementation of CYP2C19 genotyping at University Florida (UF) Health Shands Hospital in 2012, where genotype results are available approximately 3 days after PCI, testing was expanded to UF Health Jacksonville in 2016 utilizing a rapid genotyping approach. We describe metrics with this latter implementation. Methods Patients at UF Health Jacksonville undergoing left heart catheterization with intent to undergo PCI were targeted for genotyping using the Spartan RX™ system. Testing metrics and provider acceptance of testing and response to genotype results were examined, as was antiplatelet therapy over the 6 months following genotyping. Results In the first year, 931 patients, including 392/505 (78%) total patients undergoing PCI, were genotyped. The median genotype test turnaround time was 96 min. Genotype results were available for 388 (99%) PCI patients prior to discharge. Of 336 genotyped PCI patients alive at discharge and not enrolled in an antiplatelet therapy trial, 1/6 (17%) poor metabolizers (PMs, with two nonfunctional alleles), 38/93 (41%) intermediate metabolizers (IMs, with one nonfunctional allele), and 119/237 (50%) patients without a nonfunctional allele were prescribed clopidogrel (p = 0.110). Clopidogrel use was higher among non-ACS versus ACS patients (78.6% vs. 42.2%, p < 0.001). Six months later, among patients with follow-up data, clopidogrel was prescribed in 0/4 (0%) PMs, 33/65 (51%) IMs, and 115/182 (63%) patients without a nonfunctional allele (p = 0.008 across groups; p = 0.020 for PMs versus those without a nonfunctional allele). Conclusion These data demonstrate that rapid genotyping is clinically feasible at a high volume cardiac catheterization facility and allows informed chronic antiplatelet prescribing, with lower clopidogrel use in PMs at 6 months. Trial registration ClinicalTrials.gov Identifier: NCT02724319; registered March 31, 2016; https://www.clinicaltrials.gov/ct2/show/NCT02724319?term=angiolillo&rank=7

The University of Florida (UF) Health Personalized Medicine Program launched in 2012 with genotyping for clopidogrel response at UF Health Shands Hospital. We have since expanded genotyping to UF Health Jacksonville and established the infrastructure at UF Health to support clinical implementation for five additional gene-drug pairs: -thiopurines, ( )-PEG IFN-α-based regimens, -opioids, -antidepressants and -proton pump inhibitors. We are contributing to the evidence based on outcomes with genotype-guided therapy through pragmatic studies of our clinical implementations. In addition, we have developed a broad array of educational programs for providers, trainees and students that incorporate personal genotype evaluation to enhance participant learning.

IntroductionCurrent dietary guidelines recommend limiting sugar intake for the prevention of diabetes mellitus (DM). Reduction in sugar intake may require sugar substitutes. Among these, D-allulose is a non-calorie rare monosaccharide with 70% sweetness of sucrose, which has shown anti-DM effects in Asian populations. However, there is limited data on the effects of D-allulose in other populations, including Westerners.Research design and methodsThis was a prospective, randomized, double-blind, placebo-controlled, crossover study conducted in 30 subjects without DM. Study participants were given a standard oral (50 g) sucrose load and randomized to placebo or escalating doses of D-allulose (2.5, 5.0, 7.5, 10.0 g). Subjects crossed-over to the alternate study treatment after 7–14 days of wash out. Plasma glucose and insulin levels were measured at five time points: before and at 30, 60, 90 and 120 min after ingestion.ResultsD-allulose was associated with a dose-dependent reduction of plasma glucose at 30 min compared with placebo. In particular, glucose was significantly lower with the 7.5 g (mean difference: 11; 95% CI 3 to 19; p=0.005) and 10 g (mean difference: 12; 95% CI 4 to 20; p=0.002) doses. Although glucose was not reduced at the other time points, there was a dose-dependent reduction in glucose excursion compared with placebo, which was significant with the 10 g dose (p=0.023). Accordingly, at 30 min D-allulose was associated with a trend towards lower insulin levels compared with placebo, which was significant with the 10 g dose (mean difference: 14; 95% CI 4 to 25; p=0.006). D-allulose did not reduce insulin at any other time point, but there was a significant dose-dependent reduction in insulin excursion compared with placebo (p=0.028), which was significant with the 10 g dose (p=0.002).ConclusionsThis is the largest study assessing the effects of D-allulose in Westerners demonstrating an early dose-dependent reduction in plasma glucose and insulin levels as well as decreased postprandial glucose and insulin excursion in subjects without DM. These pilot observations set the basis for large-scale investigations to support the anti-DM effects of D-allulose.Trial registration numberNCT02714413.

[...]some pharmacologic and procedural choices still remain not fully investigated, leading to inhomogeneous treatments. [...]new studies designed to provide clinical practice and patient-centered recommendations addressing unmet needs in terms of duration of DAPT and drugs and devices of choice according to clinical setting are needed.

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor antagonist represents the current standard of care to prevent atherothrombotic recurrences in patients with acute coronary syndrome (ACS). However, despite the use of DAPT, the recurrence rate of cardiovascular ischemic events still remains high. This persistent risk may be in part attributed to the sustained activation of the coagulation cascade leading to generation of thrombin, which may continue to play a key role in thrombus formation. The use of vitamin K antagonists (VKAs) as a strategy to reduce atherothrombotic recurrences after an ACS has been previously tested, leading to overall unfavorable outcomes due to the high risk of bleeding complications. The recent introduction of non-VKA oral anticoagulants (NOACs), characterized by a better safety profile and ease of use compared with VKA, has led to a reappraisal of the use of oral anticoagulant therapy for secondary prevention in ACS patients. The present article provides an overview of the rationale and prognostic role of oral anticoagulant therapy in ACS patients as well as recent updated clinical data, in particular with NOACs, in the field and future perspectives on this topic.

Key Points Dual antiplatelet therapy with aspirin and a P2Y 12 -receptor inhibitor is the cornerstone of treatment of patients with acute coronary syndromes and of those undergoing percutaneous coronary intervention Although the novel P2Y 12 -receptor inhibitors prasugrel and ticagrelor have been associated with better net clinical outcomes than clopidogrel in patients with acute coronary syndromes, clopidogrel is still frequently used Switching between P2Y 12 inhibitors is common in clinical practice, which has been attributed to multiple factors, including individual risk of bleeding and ischaemic events, socioeconomic factors, and pharmacodynamics and/or genetics Drug interactions have been described when switching between P2Y 12 -receptor inhibitors (oral and intravenous) with different receptor-binding properties, which raises concerns about the optimal switching strategies Guideline recommendations on how to switch from clopidogrel to prasugrel or ticagrelor and vice versa , as well as between prasugrel and ticagrelor, and between intravenous and oral therapies, are lacking Understanding the pharmacological properties of P2Y 12 -inhibiting therapies (competitive or noncompetitive) and the timing of disease presentation (acute or chronic) are important factors to define switching strategies Antiplatelet therapy with oral P2Y 12 -receptor inhibitors (clopidogrel, prasugrel, and ticagrelor) is widely used in patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. However, patients often need to switch between these drugs for a variety of clinical reasons. In this Review, Rollini et al . summarize the practical considerations when switching therapies, including discussion of the new intravenous P2Y 12 -receptor inhibitor cangrelor. Dual antiplatelet therapy—the combination of aspirin and a P2Y 12 -receptor inhibitor—is the cornerstone of treatment of patients with acute coronary syndromes (ACS) and of those undergoing percutaneous coronary intervention. Prasugrel and ticagrelor have more prompt, potent, and predictable antiplatelet effects than those of clopidogrel, and result in reduced ischaemic outcomes in patients with ACS, albeit at the expense of an increased risk of bleeding. However, clopidogrel is still very commonly used. Switching between oral P2Y 12 -inhibiting therapies occurs very frequently in clinical practice for a variety of reasons, which raises the question of which switching approaches are preferable. In 2015, cangrelor (an intravenous P2Y 12 -receptor inhibitor) was approved for clinical use, which adds to the conundrum of how to switch between intravenous and oral therapies. Differences in the pharmacology of P2Y 12 -receptor inhibitors, such as their binding sites (competitive or noncompetitive), half-life, and speed of onset and offset of action, are important factors that might lead to drug interactions when switching between agents. In this Review, we provide an overview of the literature on switching antiplatelet treatment strategies with P2Y 12 -receptor inhibitors, and discuss practical considerations for switching therapies in the acute and chronic phases of disease presentation.

Key Points Antithrombotic therapy is the cornerstone of pharmacological treatment to optimize clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) Anticoagulant therapy is mandatory in PPCI and includes heparins and bivalirudin, which have different pharmacological and clinical profiles; the choice between these agents is mainly on the basis of bleeding risk profile Intravenous antiplatelet drugs mainly include glycoprotein IIb/IIIa inhibitors and the P2Y 12 -receptor inhibitor cangrelor, which can provide immediate platelet inhibition until the full antiplatelet effect of oral agents is achieved Dual antiplatelet therapy with a combination of aspirin and one of the new-generation P2Y 12 -receptor inhibitors prasugrel or ticagrelor is the recommended first-line treatment in patients undergoing PPCI In the absence of data supporting superiority of one agent over the other, the choice between prasugrel and ticagrelor should take into consideration contraindications and patient characteristics; clopidogrel should be used when both prasugrel and ticagrelor are contraindicated or not available Agents targeting thrombin-mediated effects on platelet activation, namely vorapaxar and rivaroxaban, have been developed and can be used in selected patients with STEMI to reduce long-term atherothrombotic events Antithrombotic therapy, including antiplatelet and anticoagulant agents, is the cornerstone of pharmacological treatment to optimize clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). In this Review, Franchi et al . provide an overview of currently available antithrombotic therapies used in these patients, results from pivotal clinical trials and their implications for guidelines, as well as recommendations for clinical practice. Antithrombotic therapy, including antiplatelet and anticoagulant agents, is the cornerstone of pharmacological treatment to optimize clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Intravenous anticoagulant drugs available for PPCI include the indirect thrombin inhibitors unfractionated heparin and low-molecular-weight heparin, and the direct thrombin inhibitor bivalirudin. Intravenous antiplatelet drugs mainly include glycoprotein IIb/IIIa inhibitors and the P2Y 12 -receptor inhibitor cangrelor. Dual antiplatelet therapy with aspirin and an oral P2Y 12 -receptor inhibitor is pivotal for the acute and long-term treatment of patients with STEMI undergoing PPCI. Prasugrel and ticagrelor provide a more prompt, potent, and predictable antiplatelet effect compared with clopidogrel, which translates into better clinical outcomes. Therefore, these agents are the first-line treatment in PPCI. However, patients can still experience adverse ischaemic events, which might be in part attributed to alternative pathways triggering thrombosis. Thrombin has an important role, suggesting the need for strategies directly targeting circulating thrombin or other factors of the coagulation cascade, such as oral anticoagulants (rivaroxaban), and the thrombin receptor on the platelet membrane (vorapaxar). In this Review, we provide an overview of currently available antithrombotic therapies used in patients with STEMI undergoing PPCI, results from pivotal clinical trials and their implications for guidelines, as well as recommendations for clinical practice.