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.
Dual antiplatelet therapy (DAPT) has represented for decades the cornerstone of treatment for the prevention of ischemic complications, including stent thrombosis, in patients undergoing percutaneous ...coronary intervention (PCI). Despite the evolution in stent technologies, which has allowed the reduction in the minimum required duration of DAPT, the optimal duration of DAPT to ensure the best safety and efficacy still remains largely debated. Indeed, the results from investigations regarding the optimal DAPT duration based on stent type is limited. Overall, DAPT duration should be defined as a minimal period needed to prevent the vulnerable phase of having stent thrombosis, which may indeed be more stent specific, from that required for secondary prevention of ischemic complications, which may depend on the general risk profile of the patient. The present manuscript is an overview on the optimal duration of DAPT after stent implantation, providing an overview on the evolution of stent technology over the past decades and how this has impacted considerations on DAPT duration as well providing future perspectives in the field.
Abstract Background Platelet inhibitory effects induced by oral P2Y12 receptor antagonists are delayed in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary ...percutaneous coronary intervention (PPCI), which may be attributed to impaired absorption affecting drug pharmacokinetics (PK) and pharmacodynamics (PD). Crushing tablets has been suggested to lead to more favorable PK/PD profiles. To date, no studies have investigated the PK/PD effects of crushing prasugrel. Objectives This study sought to determine whether crushing prasugrel is associated with more favorable drug bioavailability and platelet inhibitory effects compared with whole tablets in STEMI patients undergoing PPCI. Methods Our prospective, randomized, open-label study assessed STEMI patients undergoing PPCI (n = 52) who were treated with a prasugrel 60-mg loading dose (LD) either as whole or crushed tablets. PK/PD analyses were performed at 7 time points. PD effects were measured as P2Y12 reaction units and platelet reactivity index, and PK by plasma levels of prasugrel’s active metabolite. Results Compared with whole tablets, crushed prasugrel led to reduced P2Y12 reaction units by 30 min post-LD, which persisted at 1, 2 (164 vs. 95; least square mean difference = 68; 95% confidence interval: 10 to 126; primary endpoint), and 4 h post-LD. Significant differences were no longer present at 6 h post-LD. Parallel findings were shown with platelet reactivity index. Accordingly, high on-treatment platelet reactivity rates were reduced with crushed prasugrel. PK analyses showed a >3-fold faster absorption with crushed compared with whole prasugrel. Conclusions In STEMI patients undergoing PPCI, crushed prasugrel leads to faster drug absorption, and consequently, more prompt and potent antiplatelet effects compared with whole tablet ingestion. (Pharmacological Effects of Crushing Prasugrel in STEMI Patients; NCT02212028 )
Abstract Background Several studies have shown that patients with diabetes mellitus (DM) exhibit an impaired response to clopidogrel. This may contribute to their increased risk of recurrent ...atherothrombotic events, despite the use of dual-antiplatelet therapy. The mechanisms for impaired clopidogrel response in DM patients have not been fully elucidated. Objectives The aim of this study was to explore the mechanisms for impaired clopidogrel-mediated platelet inhibition in patients with DM using a comprehensive methodological approach embracing both pharmacokinetic (PK) and pharmacodynamic (PD) assessments as well as ex vivo and in vitro investigations. Methods Patients (DM, n = 30; non-DM, n = 30) with stable coronary artery disease taking aspirin 81 mg/day and P2Y12 antagonist naive were enrolled. Blood was collected before and at various times (0.5, 1, 2, 4, 6, and 24 h) after a 600-mg loading dose of clopidogrel. PD assessments included vasodilator-stimulated phosphoprotein, light transmission aggregometry, and VerifyNow P2Y12 ex vivo, before and after dosing and following in vitro incubation with escalating concentrations (1, 3, and 10 μM) of clopidogrel’s active metabolite (Clop-AM). Exposure to Clop-AM was also determined. Results PD assessments consistently showed that during the overall 24-h study time course, residual platelet reactivity was higher in DM patients compared with non-DM patients. In vitro incubation with Clop-AM revealed altered functional status of the P2Y12 signaling pathway in DM platelets as measured by vasodilator-stimulated phosphoprotein, but not with other PD assays. Clop-AM exposure was ∼40% lower in DM patients than in non-DM patients. Conclusions The present study suggests that among DM patients, impaired P2Y12 inhibition mediated by clopidogrel is largely attributable to attenuation of clopidogrel’s PK profile. This is characterized by lower plasma levels of Clop-AM over the sampling time course in DM patients compared with non-DM patients and only modestly attributed to altered functional status of the P2Y12 signaling pathway.
Prasugrel and ticagrelor are potent oral platelet P2Y
12
inhibitors and are recommended over clopidogrel in patients with acute coronary syndrome (ACS). Oral platelet P2Y
12
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 P2Y
12
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 Registration
http://www.clinicaltrials.gov
Unique Identifier: NCT04492423, registered July 2020 retrospectively registered.
Abstract Background The PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In ...Myocardial Infarction 54) trial studied 2 doses of ticagrelor, 90 mg twice a day (bid) and 60 mg bid, for long-term prevention of ischemic events in patients with prior myocardial infarction. Both doses similarly reduced the rate of ischemic events versus placebo. The pharmacokinetics and pharmacodynamics of ticagrelor 60 mg bid have not been studied. Objectives In this study, the authors sought to study the pharmacokinetics and pharmacodynamics for ticagrelor 60 mg compared with 90 mg bid. Methods A total of 180 patients who received >4 weeks of study medication had blood sampling in the morning pre-maintenance dose and again 2 h post-dose. All patients received aspirin. Plasma levels of ticagrelor and its active metabolite AR-C124910XX were determined. P2Y12 inhibition was assessed by the VerifyNow P2Y12 assay (Accumetrics, Inc., San Diego, California) (P2Y12 reaction units PRU), light transmittance aggregometry (adenosine diphosphate 5 and 20 μmol/l and arachidonic acid), and vasodilator-stimulated phosphoprotein phosphorylation assays. VerifyNow Aspirin assays and serum thromboxane B2 measurements were performed. Results Mean pre- and post-dose plasma levels of ticagrelor were 35% and 38% lower, respectively, with 60 mg versus 90 mg. Both doses achieved high levels of platelet inhibition pre- and post-dose, with numerically slightly more variability with 60 mg: mean (SD) pre-dose PRU values were 59 ± 63 and 47 ± 43 for ticagrelor 60 and 90 mg, respectively (p = 0.34). High platelet reactivity, determined as PRU >208, was rare with the 60-mg pre-dose and was absent post-dose. Platelet reactivity pre- and post-dose, as measured by light transmittance aggregometry or vasodilator-stimulated phosphoprotein assays, was numerically but not significantly lower with 90 mg than with 60 mg. Aspirin response was not affected by either dose. Conclusions Ticagrelor 60 mg bid achieved high levels of peak and trough platelet inhibition in nearly all patients, similar to that with 90 mg bid, helping to explain the efficacy of the lower ticagrelor dose in PEGASUS-TIMI 54.
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.
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.
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).
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.
Diabetes mellitus (DM) is a key risk factor for recurrent atherothrombotic events in patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI). The ...prothrombotic milieu that characterizes patients with DM underscores the importance of oral antithrombotic therapy for secondary prevention of recurrent events in these patients. Indeed, dual antiplatelet therapy (DAPT) with aspirin and the P2Y12inhibitor clopidogrel, which has represented the mainstay of treatment for many years, has significantly reduced the incidence of recurrent atherothrombotic events. However, recurrence rates in DM patients still remain high despite this treatment regimen, which may be partly related to inadequate platelet inhibition induced by standard DAPT with aspirin and clopidogrel. This underpins the need for more potent antithrombotic treatment regimens for secondary prevention of atherothrombotic events in DM patients following ACS or PCI. The development of antiplatelet therapies associated with more potent oral platelet P2Y12receptor inhibition, including prasugrel and ticagrelor, as well as platelet inhibitors blocking alternative pathways, such as thrombin-mediated platelet inhibition with vorapaxar, may represent potential treatment options in DM patients. Moreover, with the introduction of the target-specific oral anticoagulants, there has been a reappraisal of the use of anticoagulation in addition to antiplatelet therapy for secondary prevention in patients with ACS. This review provides an update on the recent advances and limitations of oral antithrombotic agents used for secondary prevention in DM patients following ACS or PCI. (Circ J 2016; 80: 791–801)
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