Summary Background Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor prevents ischaemic events after coronary stenting, but increases bleeding. Guidelines support weighting ...bleeding risk before the selection of treatment duration, but no standardised tool exists for this purpose. Methods A total of 14 963 patients treated with DAPT after coronary stenting—largely consisting of aspirin and clopidogrel and without indication to oral anticoagulation—were pooled at a single-patient level from eight multicentre randomised clinical trials with independent adjudication of events. Using Cox proportional hazards regression, we identified predictors of out-of-hospital Thrombosis in Myocardial Infarction (TIMI) major or minor bleeding stratified by trial, and developed a numerical bleeding risk score. The predictive performance of the novel score was assessed in the derivation cohort and validated in patients treated with percutaneous coronary intervention from the PLATelet inhibition and patient Outcomes (PLATO) trial (n=8595) and BernPCI registry (n=6172). The novel score was assessed within patients randomised to different DAPT durations (n=10 081) to identify the effect on bleeding and ischaemia of a long (12–24 months) or short (3–6 months) treatment in relation to baseline bleeding risk. Findings The PRECISE-DAPT score (age, creatinine clearance, haemoglobin, white-blood-cell count, and previous spontaneous bleeding) showed a c-index for out-of-hospital TIMI major or minor bleeding of 0·73 (95% CI 0·61–0·85) in the derivation cohort, and 0·70 (0·65–0·74) in the PLATO trial validation cohort and 0·66 (0·61–0·71) in the BernPCI registry validation cohort. A longer DAPT duration significantly increased bleeding in patients at high risk (score ≥25), but not in those with lower risk profiles (pinteraction =0·007), and exerted a significant ischaemic benefit only in this latter group. Interpretation The PRECISE-DAPT score is a simple five-item risk score, which provides a standardised tool for the prediction of out-of-hospital bleeding during DAPT. In the context of a comprehensive clinical evaluation process, this tool can support clinical decision making for treatment duration. Funding None.
Abstract Background Optimal upfront dual antiplatelet therapy (DAPT) duration after complex percutaneous coronary intervention (PCI) with drug-eluting stents (DES) remains unclear. Objectives This ...study investigated the efficacy and safety of long- (≥12 months) versus short-term (3 or 6 months) DAPT with aspirin and clopidogrel according to PCI complexity. Methods We pooled patient-level data from 6 randomized controlled trials investigating DAPT durations after PCI. Complex PCI was defined as having at least 1 of the following features: 3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, or chronic total occlusion. The primary efficacy endpoint was major adverse cardiac events (MACE), defined as the composite of cardiac death, myocardial infarction, or stent thrombosis. The primary safety endpoint was major bleeding. Intention-to-treat was the primary analytic approach. Results Of 9,577 patients included in the pooled dataset for whom procedural variables were available, 1,680 (17.5%) underwent complex PCI. Overall, 85% of patients received new-generation DES. At a median follow-up time of 392 days (interquartile range: 366 to 710 days), patients who underwent complex PCI had a higher risk of MACE (adjusted hazard ratio HR: 1.98; 95% confidence interval CI: 1.50 to 2.60; p < 0.0001). Compared with short-term DAPT, long-term DAPT yielded significant reductions in MACE in the complex PCI group (adjusted HR: 0.56; 95% CI: 0.35 to 0.89) versus the noncomplex PCI group (adjusted HR: 1.01; 95% CI: 0.75 to 1.35; pinteraction = 0.01). The magnitude of the benefit with long-term DAPT was progressively greater per increase in procedural complexity. Long-term DAPT was associated with increased risk for major bleeding, which was similar between groups (pinteraction = 0.96). Results were consistent by per-treatment landmark analysis. Conclusions Alongside other established clinical risk factors, procedural complexity is an important parameter to take into account in tailoring upfront duration of DAPT.
Abstract Background The incidence, predictors, and prognostic impact of post-discharge bleeding (PDB) after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation are ...unclear. Objectives This study sought to characterize the determinants and consequences of PDB after PCI. Methods The prospective ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) study was used to determine the incidence and predictors of clinically relevant bleeding events occurring within 2 years after hospital discharge. The effect of PDB on subsequent 2-year all-cause mortality was estimated by time-adjusted Cox proportional hazards regression. Results Among 8,582 “all-comers” who underwent successful PCI with DES in the ADAPT-DES study, PDB occurred in 535 of 8,577 hospital survivors (6.2%) at a median time of 300 days (interquartile range: 130 to 509 days) post-discharge. Gastrointestinal bleeding (61.7%) was the most frequent source of PDB. Predictors of PDB included older age, lower baseline hemoglobin, lower platelet reactivity on clopidogrel, and use of chronic oral anticoagulation therapy. PDB was associated with higher crude rates of all-cause mortality (13.0% vs. 3.2%; p < 0.0001). Following multivariable adjustment, PDB was strongly associated with 2-year mortality (hazard ratio HR: 5.03; p < 0.0001), with an effect size greater than that of post-discharge myocardial infarction (PDMI) (HR: 1.92; p = 0.009). Conclusions After successful PCI with DES in an unrestricted patient population, PDB is not uncommon and has a strong relationship with subsequent all-cause mortality, greater that that associated with PDMI. Efforts to reduce PDB may further improve prognosis after successful DES implantation. (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents ADAPT-DES; NCT00638794 )
The objective of this article is to review the contemporary literature on optimal dual antiplatelet therapy (DAPT) duration after drug-eluting stent (DES) implantation. Relevant studies were searched ...through MEDLINE, the Cochrane database, and the EMBASE database. Of the 6852 publications retrieved, 23 were considered relevant, including 11 randomized controlled trials (RCTs) and 12 meta-analyses. Initially prescribed for 3-6 months after first-generation DES, the recommended duration of DAPT was subsequently prolonged to at least 1 year, a response to reports of late stent thrombosis after DAPT discontinuation. Seven RCTs subsequently suggested that 1-year DAPT may not be necessary after DES implantation, and that a 6-month or even a 3-month course of DAPT may be as effective and safer. In contrast, four RCTs examining the benefit of DAPT beyond 1 year reached conflicting conclusions. In the DAPT trial, 30-month compared with 12-month DAPT after DES resulted in reduced rates of stent thrombosis and major adverse cardiovascular events, but greater rates of major bleeding with increased non-cardiac mortality. Several meta-analyses have subsequently been performed collectively demonstrating increased rates of all-cause mortality with prolonged DAPT compared with shorter DAPT after DES, due to greater non-cardiovascular mortality with prolonged DAPT not offset by a concomitant reduction in cardiac mortality. The benefit-risk ratio of prolonged DAPT appears to be better in patients with myocardial infarction (MI) than in those without prior MI. On the basis of these findings, a personalized approach is advisable when deciding upon the optimal duration of DAPT after DES, wherein the individualized risks of ischaemic vs. bleeding events are carefully considered for each patient.
Abstract Background Although some randomized controlled trials (RCTs) and meta-analyses have suggested that prolonged dual-antiplatelet therapy (DAPT) may be associated with increased mortality, the ...mechanistic underpinnings of this association remain unclear. Objectives The aim of this study was to analyze the associations among bleeding, mortality, and DAPT duration after drug-eluting stent implantation in a meta-analysis of RCTs. Methods RCTs comparing different DAPT durations after drug-eluting stent placement were sought through the MEDLINE, Embase, and Cochrane databases and the proceedings of international meetings. Deaths were considered possibly bleeding related if occurring within 1 year of the episodes of bleeding. Primary analysis was by intention-to-treat. Secondary analysis was performed in a modified intention-to-treat population in which events occurring when all patients were on DAPT were excluded. Results Individual patient data were obtained for 6 RCTs, and aggregate data were available for 12 RCTs. Patients with bleeding had significantly higher rates of mortality compared with those without, and in a time-adjusted multivariate analysis, bleeding was an independent predictor of mortality occurring within 1 year of the bleeding episode (hazard ratio: 6.93; 95% confidence interval: 4.53 to 10.60; p < 0.0001). Shorter DAPT was associated with lower rates of all-cause death compared with longer DAPT (hazard ratio: 0.85; 95% confidence interval: 0.73 to 1.00; p = 0.05), which was driven by lower rates of bleeding-related deaths with shorter DAPT compared with prolonged DAPT (hazard ratio: 0.65; 95% confidence interval: 0.43 to 0.99; p = 0.04). Mortality unrelated to bleeding was comparable between the 2 groups. Similar results were apparent in the modified intention-to-treat population. Conclusions Bleeding was strongly associated with the occurrence of mortality within 1 year after the bleeding event. Shorter compared with longer DAPT was associated with lower risk for bleeding-related death, a finding that may underlie the lower all-cause mortality with shorter DAPT in the RCTs of different DAPT durations after DES.
Although platelet reactivity during P2Y12-inhibitors is associated with stent thrombosis (ST) and bleeding, standardized and clinically validated thresholds for accurate risk stratification after ...percutaneous coronary intervention (PCI) are lacking. We sought to determine the prognostic value of low platelet reactivity (LPR), optimal platelet reactivity (OPR), or high platelet reactivity (HPR) by applying uniform cut-off values for standardized devices.
Authors of studies published before January 2015, reporting associations between platelet reactivity, ST, and major bleeding were contacted for a collaborative analysis using consensus-defined, uniform cut-offs for standardized platelet function assays. Based on best available evidence for each device (exploratory studies), LPR-OPR-HPR categories were defined as <95, 95-208, and >208 PRU for VerifyNow, <19, 19-46, and >46 U for the Multiplate analyser and <16, 16-50, and >50% for VASP assay. Seventeen studies including 20 839 patients were used for the analysis; 97% were treated with clopidogrel and 3% with prasugrel. Patients with HPR had significantly higher risk for ST risk ratio (RR) and 95% CI: 2.73 (2.03-3.69), P < 0.00001, yet a slight reduction in bleeding RR: 0.84 (0.71-0.99), P = 0.04 compared with those with OPR. In contrast, patients with LPR had a higher risk for bleeding RR: 1.74 (1.47-2.06), P < 0.00001, without any further benefit in ST RR: 1.06 (0.68-1.65), P = 0.78 in contrast to OPR. Mortality was significantly higher in patients with HPR compared with other categories (P < 0.05). Validation cohorts (n = 14) confirmed all results of exploratory studies (n = 3).
Platelet reactivity assessment during thienopyridine-type P2Y12-inhibitors identifies PCI-treated patients at higher risk for mortality and ST (HPR) or at an elevated risk for bleeding (LPR).
Summary Background Despite recent studies, the optimum duration of dual antiplatelet therapy (DAPT) after coronary drug-eluting stent placement remains uncertain. We performed a meta-analysis with ...several analytical approaches to investigate mortality and other clinical outcomes with different DAPT strategies. Methods We searched Medline, Embase, Cochrane databases, and proceedings of international meetings on Nov 20, 2014, for randomised controlled trials comparing different DAPT durations after drug-eluting stent implantation. We extracted study design, inclusion and exclusion criteria, sample characteristics, and clinical outcomes. DAPT duration was categorised in each study as shorter versus longer, and as 6 months or shorter versus 1 year versus longer than 1 year. Analyses were done by both frequentist and Bayesian approaches. Findings We identified ten trials published between Dec 16, 2011, and Nov 16, 2014, including 31 666 randomly assigned patients. By frequentist pairwise meta-analysis, shorter DAPT was associated with significantly lower all-cause mortality compared with longer DAPT (HR 0·82, 95% CI 0·69–0·98; p=0·02; number needed to treat NNT=325), with no significant heterogeneity apparent across trials. The reduced mortality with shorter compared with longer DAPT was attributable to lower non-cardiac mortality (0·67, 0·51–0·89; p=0·006; NNT=347), with similar cardiac mortality (0·93, 0·73–1·17; p=0.52). Shorter DAPT was also associated with a lower risk of major bleeding, but a higher risk of myocardial infarction and stent thrombosis. We noted similar results in a Bayesian framework with non-informative priors. By network meta-analysis, patients treated with 6-month or shorter DAPT and 1-year DAPT had higher risk of myocardial infarction and stent thrombosis but lower risk of mortality compared with patients treated with DAPT for longer than 1 year. Patients treated with DAPT for 6 months or shorter had similar rates of mortality, myocardial infarction, and stent thrombosis, but lower rates of major bleeding than did patients treated with 1-year DAPT. Interpretation Although treatment with DAPT beyond 1 year after drug-eluting stent implantation reduces myocardial infarction and stent thrombosis, it is associated with increased mortality because of an increased risk of non-cardiovascular mortality not offset by a reduction in cardiac mortality. Funding None.
Summary Background The relative safety of drug-eluting stents and bare-metal stents, especially with respect to stent thrombosis, continues to be debated. In view of the overall low frequency of ...stent thrombosis, large sample sizes are needed to accurately estimate treatment differences between stents. We compared the risk of thrombosis between bare-metal and drug-eluting stents. Methods For this network meta-analysis, randomised controlled trials comparing different drug-eluting stents or drug-eluting with bare-metal stents currently approved in the USA were identified through Medline, Embase, Cochrane databases, and proceedings of international meetings. Information about study design, inclusion and exclusion criteria, sample characteristics, and clinical outcomes was extracted. Findings 49 trials including 50 844 patients randomly assigned to treatment groups were analysed. 1-year definite stent thrombosis was significantly lower with cobalt-chromium everolimus eluting stents (CoCr-EES) than with bare-metal stents (odds ratio OR 0·23, 95% CI 0·13–0·41). The significant difference in stent thrombosis between CoCr-EES and bare-metal stents was evident as early as 30 days (OR 0·21, 95% CI 0·11–0·42) and was also significant between 31 days and 1 year (OR 0·27, 95% CI 0·08–0·74). CoCr-EES were also associated with significantly lower rates of 1-year definite stent thrombosis compared with paclitaxel-eluting stents (OR 0·28, 95% CI 0·16–0·48), permanent polymer-based sirolimus-eluting stents (OR 0·41, 95% CI 0·24–0·70), phosphorylcholine-based zotarolimus-eluting stents (OR 0·21, 95% CI 0·10–0·44), and Resolute zotarolimus-eluting stents (OR 0·14, 95% CI 0·03–0·47). At 2-year follow-up, CoCr-EES were still associated with significantly lower rates of definite stent thrombosis than were bare-metal (OR 0·35, 95% CI 0·17–0·69) and paclitaxel-eluting stents (OR 0·34, 95% CI 0·19–0·62). No other drug-eluting stent had lower definite thrombosis rates compared with bare-metal stents at 2-year follow-up. Interpretation In randomised studies completed to date, CoCr-EES has the lowest rate of stent thrombosis within 2 years of implantation. The finding that CoCr-EES also reduced stent thrombosis compared with bare-metal stents, if confirmed in future randomised trials, represents a paradigm shift. Funding The Cardiovascular Research Foundation.
Abstract
Background
Prolonged dual anti-platelet therapy (DAPT) is intended to reduce ischaemic events, at the cost of an increased bleeding risk in patients undergoing percutaneous coronary ...intervention (PCI). In this study, we evaluated whether race influences the ischaemia/bleeding risk trade-off.
Methods
We searched for randomized clinical trials (RCTs) comparing DAPT duration after PCI. To compare the benefit or harm between DAPT duration by race, individual patient-level landmark meta-analysis was performed after discontinuation of the shorter duration DAPT group in each RCT. The primary ischaemic endpoint was major adverse cardiac events (MACEs), and the primary bleeding endpoint was major bleeding events (clinicaltrials.gov NCT03338335).
Results
Seven RCTs including 16,518 patients (8,605 East Asians, 7,913 non-East Asians) were pooled. MACE occurred more frequently in non-East Asians (0.8% vs. 1.8%,
p
< 0.001), while major bleeding events occurred more frequently in East Asians (0.6% vs. 0.3%,
p
= 0.001). In Cox proportional hazards model, prolonged DAPT significantly increased the risk of major bleeding in East Asians (hazard ratio HR, 2.843, 95% confidence interval CI, 1.474–5.152,
p
= 0.002), but not in non-East Asians (HR, 1.375, 95% CI, 0.523–3.616,
p
= 0.523). East Asians had a higher median probability risk ratio of bleeding to ischaemia (0.66 vs. 0.15), and the proportion of patients with higher probability of bleeding than ischaemia was significantly higher in East Asians (32.3% vs. 0.4%,
p
< 0.001).
Conclusion
We suggest that the ischaemia/bleeding trade-off may be different between East Asians and non-East Asians. In East Asians, prolonged DAPT may have no effect in reducing the ischaemic risk, while significantly increases the bleeding risk.
Risk stratification after percutaneous coronary intervention (PCI) is mainly based on demographics and clinical presentation (stable coronary artery disease CAD vs. acute coronary syndromes ACS). We ...investigated the impact of PCI extent and complexity on 2-year clinical outcomes after successful implantation of drug-eluting stents (DES) and whether this effect is influenced by clinical presentation and/or high platelet reactivity (HPR) on clopidogrel.
Patients from the prospective, multicenter Assessment of Dual Antiplatelet Therapy with Drug-Eluting Stents study were stratified according to PCI complexity, with complex PCI (C-PCI) defined as ≥3 stents implanted, bifurcation PCI with 2 stents, rotational atherectomy use for severely calcified lesions, or left main or saphenous vein graft (SVG) PCI. Major adverse cardiac events (MACE; cardiac death, myocardial infarction, and stent thrombosis) were compared at 2-year follow-up in patients with and without C-PCI. Successful DES PCI was performed in 8582 patients—2255 (26.3%) with C-PCI. C-PCI was independently associated with higher 2-year risk of MACE (adjusted HR adjHR: 1.56; 95%CI: 1.29–1.89; p<0.0001), MI (adjHR: 1.71; 95%CI: 1.37–2.14; p<0.0001), and ST (adjHR: 2.26; 95%CI: 1.42–3.59; p=0.0006). The association between C-PCI vs. non–C-PCI and the risk of MI and ST was greater in stable CAD than in ACS (Pinteraction=0.04 and 0.03, respectively). SVG PCI, 2-stent bifurcation treatment, and implantation of ≥3 stents were independently associated with MACE.
Patients undergoing extensive and more complex PCI experienced worse outcomes after successful PCI. Considering the extent and complexity of PCI revascularization may improve risk stratification.
•Percutaneous coronary intervention (PCI) complexity is associated with the risk of adverse events after successful PCI.•The risk of high platelet reactivity is additive to that of PCI complexity.•Procedural complexity should be considered when risk stratifying patients after PCI.
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