Risk of Early Bleeding with Dual Antiplatelet Therapy in Acute Stroke and Transient Ischemic Attack Regardless of NIHSS Admission.

BACKGROUND: Dual antiplatelet therapy (DAT) is a therapeutic option for patients with minor ischemic stroke (IS) or transient ischemic attack (TIA). No study has evaluated the incidence of early bleeding in patients with moderate to major ischemic stroke. The current study aimed to analyze both the frequency of early bleeding and hospital morbidity related to DAT for either acute IS or TIA regardless of admission National Institute of Health Stroke Scale (NIHSS) score. METHODS: This was a retrospective analysis based on data collected from a prospective data bank of a single center. We included patients who underwent DAT in the first 24 hours of symptom onset with a loading dose (aspirin 300 mg + clopidogrel 300 mg) on the first day, followed by a maintenance dose (aspirin 100 mg + clopidogrel 75 mg). We analyzed intracranial and/or extracranial hemorrhage that had occurred during the hospital admission, symptomatic bleeding, modified Rankin Scale (mRS) score at discharge, and death rates as outcomes. RESULTS: Of the 119 patients analyzed, 94 (79 %) had IS and 25 (21 %) had TIA. Hemorrhage occurred in 11 (9.2 %) and four (3.4 %) patients with TIA or NIHSS ≤ 3, respectively, although none were symptomatic. Patients with bleeding as a complication had higher admission NIHSS [4 (3-7) vs. 2 (1-4), p = 0.044] and had higher mRS at discharge (mRS 2 [1-5] vs. mRS 1 [0-2], p = 0.008). These findings did not indicate increased mortality, as one (9 %) patient died from bleeding and two (1.8 %) patients died without bleeding (p = 0.254). CONCLUSION: DAT seems to be a safe therapy in patients regardless of admission NIHSS if started within the first 24 h after symptom onset because only 1.6 % of patients had symptomatic bleeding.

Risk definition and outcomes with the application of the PEGASUS-TIMI 54 trial inclusion criteria to a "real world" STEMI population: results from the Italian "CARDIO-STEMI SANREMO" registry.

BACKGROUND: The PEGASUS-TIMI 54 trial inclusion criteria effectively identified high-risk patients with recent myocardial infarction (MI) who would benefit from continuing dual antiplatelet therapy (DAPT) with ticagrelor for more than 12 months. It is unknown how many real-world patients meet these criteria during the acute phase of ST-elevation MI (STEMI), or the extent to which these criteria predict a patient's risk and prognosis. Study objectives were: (1) determine the proportion of PEGASUS-TIMI 54-like patients (PG-l) in a real-world cohort of patients hospitalized with STEMI and to assess their ischemic and hemorrhagic risk; (2) examine their ischemic and hemorrhagic in-hospital events (major adverse cardiovascular and cerebrovascular events [MACCE] and clinically relevant bleeding); (3) evaluate their long-term outcomes and the impact on the long-term prognosis of the type of DAPT prescribed at discharge. METHODS: This observational study was conducted in 1086 patients admitted to hospital with a diagnosis of STEMI between February 2011 and March 2018 and enrolled in the CARDIO-STEMI Sanremo registry. Patients' demographic and clinical characteristics, procedural variables, and individual ischemic and hemorrhagic risk scores were assessed in-hospital. Four-year survival was also analyzed. RESULTS: The proportion of PG-I patients was 69.2%. Compared with non-PG-l patients, PG-l patients were older, had more multivessel disease and comorbidities, and experienced more frequent MACCE (8.3% vs. 3.6%, p = 0.005) and clinically significant bleeding events (6.7% vs. 2.7%, p = 0.008), a higher rate of in-hospital death (6.5% vs. 1.5%, p < 0.001), and higher follow-up mortality rate (14.8% vs. 7.7%; p = 0.002). Four-year survival was significantly lower in the PG-l group (83.9% vs. 91.8%; Log-rank = 0.001) and was related to the cumulative number of concurrent risk factors. In the unadjusted analysis, survival was greater in patients discharged on ticagrelor than on another P2Y12 inhibitor (90.2% vs. 76.7%, Log-rank = 0.001), and the difference was particularly evident in PG-l patients. CONCLUSIONS: The risk of MACCE for PG-l patients increased with the number of concurrent PEGASUS-TIMI 54 risk features. Treatment with ticagrelor on discharge was associated with improved survival rates during 4 years of follow-up.

Risk of Stroke vs. Intracerebral Hemorrhage in Patients with Non-Valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Comparing Dual vs. Triple Antithrombotic Therapy.

BACKGROUND: About 15% of patients with non-valvular atrial fibrillation might require percutaneous coronary interventions (PCIs) with stent placement to treat obstructive coronary artery disease. Dual antiplatelet therapy (DAPT) with acetylsalicylic acid (aspirin) and P2Y12 antagonist is recommended after PCI. Patients requiring DAPT also require treatment with oral anticoagulation for atrial fibrillation. We conducted a meta-analysis to identify the antithrombotic regimen associated with the lowest rate of bleeding and thromboembolic events in non-valvular atrial fibrillation after PCI. METHODS: We searched PubMed, Embase, Scopus and Cochrane databases to identify randomized trials that investigated the use of dual antiplatelet therapy and vitamin K antagonist and/or Non-vitamin K antagonist oral anticoagulants (NOAC) (triple antithrombotic therapy (TAT)) against single antiplatelet agent and NOAC (dual antithrombotic therapy (DAT)) in the setting of coronary artery disease (CAD) requiring PCI and non-valvular atrial fibrillation. Random-effect models were used to pool data. We used the I2 statistic to measure heterogeneity between trials. RESULTS: We found 4 randomized clinical trials (ENTRUST, AUGUSTUS, PIONEER, REDUAL) using different NOACs. Overall, 9241 patients (median age 70 years, 41.4% female, mean CHADS2VASC Score 3.5) were included. We excluded patients in the very low dose rivaroxaban group from the PIONEER AF-PCI trial and low dose dabigatran group from the REDUAL PCI trial as these are not available in the United States. Our metanalysis showed that dual therapy was associated with less risk of intracranial hemorrhage (RR 0.55, 95% CI 0.31-0.99; p = 0.045; I2 = 42%) and major bleeding (RR 0.66; 95% CI 0.55-0.79; p < 0.0001; I2 = 27%) as compared to triple therapy. Further risk of ischemic stroke (RR 0.94, 95% CI 0.63-1.39; p = 0.75; I2=0%), myocardial infarction (RR 1.18, 95% CI 0.94-1.47; p = 0.16; I2 = 0), or stent thrombosis (RR 0.50, 95% CI 0.93-2.41; p = 0.10; I2 = 0%) were unchanged. Similar findings were also noted on analysis of NOAC specific DAT vs VKA based TAT. CONCLUSIONS: The combination of an antiplatelet and NOACs (dual therapy) is associated with less risk of major bleeding and intracranial hemorrhage, with no significant difference in ischemic events (stroke myocardial infarction or stent thrombosis).

Comparative Effectiveness of Dual Antiplatelet Therapy With Aspirin and Clopidogrel Versus Aspirin Monotherapy in Mild-to-Moderate Acute Ischemic Stroke According to the Risk of Recurrent Stroke: An Analysis of 15 000 Patients From a Nationwide, Multicenter Registry.

BACKGROUND: This study compared the effectiveness of dual antiplatelet therapy (DAPT) with clopidogrel-aspirin with that of aspirin monotherapy (AM) in mild-to-moderate acute ischemic stroke considering the risk of recurrent stroke using the Stroke Prognosis Instrument II (SPI-II) score. METHODS: This study is a retrospective analysis of data from a prospective, nationwide, multicenter stroke registry database between January 2011 and July 2018. We included patients with mild-to-moderate (National Institutes of Health Stroke Scale score ≤10), acute (within 24 hours of onset), noncardioembolic ischemic stroke. The primary outcome was a 3-month composite of stroke (either hemorrhagic or ischemic), myocardial infarction, and all-cause mortality. Propensity scores using the inverse probability of treatment weighting method were used to mitigate baseline imbalances between the DAPT and AM groups and within each subgroup considering SPI-II scores. RESULTS: Among the 15 430 patients (age, 66±13 years; men, 62.0%), 45.1% (n=6960) received DAPT and 54.9% (n=8470) received AM. Primary outcome events were significantly more frequent in the AM group (16.7%) than in the DAPT group (15.5%; P=0.03). Weighted Cox proportional hazards models showed a reduced risk of 3-month primary vascular events in the DAPT group versus the AM group (hazard ratio, 0.84 [0.78-0.92]; P<0.001), with no interaction between acute treatment type and SPI-II risk subgroups (Pinteraction=0.44). However, among the high-risk patients with SPI-II scores >7, a substantially larger absolute benefit was observed for 3-month composite vascular events in the DAPT group (weighted absolute risk differences, 5.4%), whereas smaller absolute benefits were observed among patients in the low- or medium-risk SPI-II subgroups (1.7% and 2.4%, respectively). CONCLUSIONS: Treatment with clopidogrel-aspirin was associated with a reduction in 3-month vascular events compared with AM in mild-to-moderate acute noncardioembolic ischemic stroke patients. Larger magnitudes of the effects of DAPT with clopidogrel-aspirin were observed in the high-risk subgroup by SPI-II risk scores.

Higher neutrophil-to-lymphocyte ratio (NLR) increases the risk of suboptimal platelet inhibition and major cardiovascular ischemic events among ACS patients receiving dual antiplatelet therapy with ticagrelor.

BACKGROUND: Neutrophil to lymphocyte ratio (NLR) has emerged as a useful and easy-to-assess prognostic tool and biomarker of cardiovascular risk. However, few studies have evaluated its role on platelet inhibition among patients on dual antiplatelet therapy (DAPT), and especially in the settings of acute coronary syndromes (ACS). We aimed at assessing the impact of NLR on platelet reactivity and the risk of major ischemic events at long-term follow-up among ACS patients on DAPT with ticagrelor. METHODS: Patients on dual antiplatelet therapy with ASA + ticagrelor (90 mg/twice a day) after percutaneous coronary revascularization for ACS were scheduled for platelet function assessment 30-90 days post-discharge. Aggregation tests were performed by Multiple Electrode Aggregometry (MEA). Suboptimal platelet inhibition (HRPR-high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min). The primary study endpoint was defined as the occurrence of major cardiovascular events (a composite of cardiovascular death, recurrent acute coronary syndrome, target vessel revascularization) at longest available follow-up. RESULTS: We included 397 patients, that were divided according to NLR tertiles. Patients with higher NLR were older (p < .001), less frequently smokers (p = .03), with higher rates of renal failure (p = .001), previous bypass surgery (p = .05) and use of statins (p = .03) and diuretics (p = .01). Higher white blood cells count and C-reactive protein (p < .001) and lower haemoglobin (p = .001) were associated with NLR. Mean platelet reactivity and the prevalence of high platelet reactivity (HRPR) on ticagrelor were significantly associated to higher NLR tertiles values (7% vs 12% vs 14.3%, p = .04), with a significant relationship between NLR and platelet reactivity being confirmed for all the different activating stimuli. At a mean follow-up of 939 ± 581.4 days, 21.2% of the patients experienced the primary composite endpoint, with a trend for a higher risk of events across NLR tertiles (15.4% vs 24.2% vs 24.4%, p = .09), that became statistically significant after correction for baseline confounders (adjusted HR[95%CI] = 1.13[1.008-1.26], p = .036). Moreover, NLR was significantly associated to overall mortality and recurrent ACS (adjusted p = .008, p = .06 and p = .02 respectively). CONCLUSIONS: In the present study we found that among ACS patients treated with ASA and ticagrelor after PCI, suboptimal platelet inhibition despite DAPT was significantly increased for higher values of Neutrophil-to-Lymphocyte Ratio. Moreover, mortality and the risk of recurrent major ischemic events at long-term were associated to NLR.

Dual antiplatelet therapy prolongation in high-risk patients with prior myocardial infarction: insights from the post-PCI registry.

BACKGROUND: Patients surviving a myocardial infarction (MI) are at a heightened risk for recurrent ischemic events that can be reduced with the long-term addition of a second antithrombotic drug to aspirin. However, data about real prescription of this therapy are lacking and sometimes controversial. METHODS: We aimed to describe the incidence and the determinants of a dual antiplatelet therapy (DAPT) prolongation beyond 12 months in a cohort of consecutive patients undergoing percutaneous coronary intervention (PCI) with prior MI undergoing PCI and features of high ischemic risk intended as age more than 65 years, second MI, type 2 diabetes mellitus, multivessel coronary artery disease (MVCAD) and chronic kidney disease (CKD). We analysed patients enrolled in the prospective 'Post-PCI' registry that included patients treated with PCI for stable coronary artery disease (CAD) or acute coronary syndromes. At 12 months' follow-up, we collected data about DAPT prolongation in patients with prior MI and at least one of the previous features of high risk who did not experience ischemic and bleeding events during the follow-up. RESULTS: Among 1113 patients included in the registry, 778 (72%) presented the inclusion criteria for the present study: 434 (66%) were more than 65 years old, 245 (37%) had a second MI, 189 (29%) diabetes mellitus, 480 (73%) MVCAD and 216 (33%) CKD. Despite a DAPT being prescribed for 1 year in 86% of the patients, it was prolonged for over 12 months in 105 (16%) of them. At multivariable analysis, only second MI and MVCAD were independent predictors of DAPT prolongation in a model including age more than 65 years, diabetes mellitus, CKD and PCI on left main/left anterior descending coronary artery. We found no significant difference in DAPT prolongation according to a DAPT-score value at least 2 or based on the physician who actually performed the follow-up (clinical cardiologist, interventional cardiologist or other). CONCLUSION: In patients with prior MI and features of high ischemic risk undergoing PCI, the rate of DAPT prolongation beyond 12 months was low; recurrent MI and MVCAD appeared as its main determinants.

Major Bleeding after Surgical Revascularization with Dual Antiplatelet Therapy.

OBJECTIVE: Patients with acute coronary syndrome are treated with dual antiplatelet therapy containing acetylsalicylic acid (ASA) and P2Y12 antagonists. In case of urgent coronary artery bypass grafting this might be associated with increasing risks of bleeding complications. METHODS: Data from 1200 consecutive urgent operations between 2010 and 2018 were obtained from our institutional patient database. For this study off-pump surgery was excluded. The primary composite end point major bleeding consisted of at least one end point: transfusion ≥ 5 packed red blood cells within 24 hours, rethoracotomy due to bleeding, chest tube output >2000 mL within 24 hours. Demographic data, peri-, and postoperative variables and outcomes were compared between patients treated with mono antiplatelet therapy, ASA + clopidogrel (ASA-C) +ticagrelor (ASA-T) or +prasugrel (ASA-P) < 72 hours before surgery. Furthermore, we compared patients with dual antiplatelet therapy with ASA monotherapy. RESULTS: From 1,086 patients, 475 (44%) received dual antiplatelet therapy. Three-hundred seventy-two received ASA-C (77.7%), 72 ASA-T (15%), and 31 ASA-P (6.5%). Major bleeding (44 vs. 23%, p < 0.0001) was more frequently in patients receiving dual therapy with higher rates of massive drainage loss within 24 hours (23 vs. 11%, p < 0.0001) of mass transfusion (34 vs. 16%, p < 0.0001) and rethoracotomy (10 vs. 5%, p = 0.002) when compared with ASA. In this analysis, ASA-T and ASA-P were not associated with higher bleeding complications compared with ASA-C. CONCLUSION: Dual antiplatelet therapy is associated with higher rates of major bleeding. Further studies should examine the difference in the prevalence of major bleeding complications in the different dual antiplatelet therapy regimes in patients requiring urgent surgery.

Relationship Between Platelet Reactivity and Ischemic and Bleeding Events After Percutaneous Coronary Intervention in East Asian Patients: 1-Year Results of the PENDULUM Registry.

Background The balance between ischemic and bleeding events and their association with platelet reactivity in patients receiving antiplatelet therapy after percutaneous coronary intervention (PCI), which differs among regions, is not fully evaluated for East Asians. We examined ischemic/bleeding events and platelet reactivity in Japanese patients undergoing PCI and determined associations between high/low platelet reactivity and clinical outcomes. Methods and Results PENDULUM (Platelet Reactivity in Patients with Drug Eluting Stent and Balancing Risk of Bleeding and Ischemic Event) is a prospective, multicenter registry of Japanese patients with PCI. Primary end points were incidence of first major adverse cardiac and cerebrovascular events (MACCE) and first major bleeding events at 12 months post-PCI. Platelet reactivity (P2Y12 reaction unit [PRU] value) was measured at 12 to 48 hours post-PCI; patients were grouped as having high PRU (>208), optimal PRU (>85 to ≤208), and low PRU (≤85). MACCE and major bleeding occurred in 4.4% and 2.8% of 6267 patients, respectively. The mean±SD PRU value was 182.1±77.1. MACCE was significantly higher in the high PRU (5.7%; n=2227) versus the optimal PRU group (3.6%; n=3002). The hazard ratio (HR) for high PRU versus optimal PRU level was significantly higher for MACCE (adjusted HR, 1.53; 95% CI, 1.14-2.06 [P=0.004]); stent thrombosis followed the same trend. Incidence of major bleeding did not differ significantly between groups. A high PRU level was significantly associated with MACCE in both patients with and patients without acute coronary syndrome. Conclusions These real-world data suggest an association between high platelet reactivity and cardiovascular events in Japanese patients undergoing PCI. The trend was the same in both patients with and patients without acute coronary syndrome. REGISTRATION URL: https://www.umin.ac.jp/ctr. Unique identifier: UMIN 000020332.

Safety of direct oral anticoagulant - and antiplatelet therapy in patients with atrial fibrillation treated by carotid artery stenting.

BACKGROUND: The periprocedural administration of dual antiplatelet therapy has been recommended in patients treated by carotid artery stenting. However, some patients with concurrent disease have been prescribed anticoagulants. We compared the post-operative incidence of hemorrhagic and thromboembolic events in two patient groups treated by different regimens of multi-antithrombotic agents. METHODS: As our 31 patients had a history of nonvalvular atrial fibrillation, they had received anticoagulants; they were also treated with aspirin and clopidogrel before carotid artery stenting. The prior anticoagulant therapy was continued in 17 patients and they received vitamin K antagonist plus dual antiplatelet therapy after the procedure (group 1). Other 14 patients underwent direct oral anticoagulant plus aspirin or clopidogrel (group 2). Post-procedural hemorrhagic and thromboembolic events were compared between two groups. RESULTS: Carotid artery stenting was angiographically successful in all patients. Complications were encountered in two group 1 patients. Post-operative image revealed a silent subarachnoid hemorrhage in one. The other presented with superior mesenteric artery occlusion 6 months after the procedure. No hemorrhagic or thromboembolic events occurred in group 2. CONCLUSION: We concluded that the administration of a direct oral anticoagulant plus an antiplatelet agent reduced the risk for periprocedural hemorrhagic and embolic events in patients with concurrent nonvalvular atrial fibrillation who underwent carotid artery stenting.

Pharmacodynamic Effects of Vorapaxar in Prior Myocardial Infarction Patients Treated With Potent Oral P2Y12 Receptor Inhibitors With and Without Aspirin: Results of the VORA-PRATIC Study.

Background Vorapaxar as an adjunct to dual antiplatelet therapy (DAPT) reduces thrombotic events in patients with prior myocardial infarction at the expense of increased bleeding. Withdrawal of aspirin has emerged as a bleeding reduction strategy. The pharmacodynamic effects of vorapaxar with potent P2Y12 inhibitors as well as the impact of dropping aspirin is unexplored and represented the aim of the VORA-PRATIC (Vorapaxar Therapy in Patients With Prior Myocardial Infarction Treated With Newer Generation P2Y12 Receptor Inhibitors Prasugrel and Ticagrelor) study. Methods and Results Post-myocardial infarction patients (n=130) on standard DAPT (aspirin+prasugrel or ticagrelor) were randomized to 1 of 3 arms: (1) triple therapy: aspirin+prasugrel/ticagrelor+vorapaxar; (2) dual therapy (drop aspirin): prasugrel/ticagrelor+vorapaxar; (3) DAPT: aspirin+prasugrel/ticagrelor. Pharmacodynamic assessments were performed at 3 time points (baseline and 7 and 30 days). Vorapaxar reduced CAT (collagen-ADP-TRAP)-induced platelet aggregation, a marker of platelet-mediated global thrombogenicity (triple therapy versus DAPT at 30 days: mean difference=-27; 95% CI,-35 to -19; P<0.001; primary end point). This effect was attenuated but still significant in the absence of aspirin (dual therapy versus DAPT at 30 days: mean difference=-15; 95% CI,-23 to -7; P<0.001; between-group comparisons, P<0.05). Vorapaxar abolished TRAP-induced aggregation (P<0.001), without affecting thrombin generation and clot strength. There were no differences in markers of P2Y12 reactivity. Markers sensitive to aspirin-induced effects increased (P<0.001) in the dual-therapy arm. Conclusions In post-myocardial infarction patients treated with potent P2Y12 inhibitors, vorapaxar reduces platelet-driven global thrombogenicity, an effect that persisted, albeit attenuated, in the absence of aspirin and without affecting markers of P2Y12 reactivity or clot kinetics. The clinical implications of these PD observations warrant future investigation. Registration URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT02545933.

Safety and efficacy of antiplatelet regimens after percutaneous coronary intervention using drug eluting stents: A network meta-analysis of randomized controlled trials.

AIMS: We aimed to determine the efficacy and safety of different anti-platelet regimens after percutaneous coronary intervention (PCI) with drug eluting stent (DES) implantation using a network meta-analysis of randomized controlled trials (RCTs). METHODS: RCTs comparing shorter duration (≤6 months) of dual antiplatelet therapy (S-DAPT) with either aspirin (ASA) or P2Y12 inhibitor monotherapy against longer duration (≥12 months) DAPT (L-DAPT) after PCI were searched in the MEDLINE, EMBASE and COCHRANE databases. End-points of interest were all-cause death, cardiovascular (CV) death, myocardial infarction (MI), stent thrombosis (ST), major bleeding and major or minor bleeding. Network meta-analyses were performed using frequentist approach. RESULTS: Eighteen RCTs with total of 57,942 patients met the inclusion and exclusion criteria. This included 14 RCTs (N = 28,853) of S-DAPT with ASA monotherapy and 4 RCTs (N = 29,089) with P2Y12 inhibitor monotherapy. Compared with L-DAPT, the odds of MI were higher with S-DAPT with ASA monotherapy [OR 1.23; 95% CI 1.01-1.48], but not with P2Y12 inhibitor monotherapy [0.98; 0.85-1.14]. Both S-DAPT regimens lowered rates of major bleeding when compared with L-DAPT; ASA monotherapy [0.70; 0.49-1.00] and P2Y12 monotherapy [0.67; 0.45-0.98]. There were no differences in risks of all-cause or CV death between either regimen of S-DAPT and L-DAPT. However, in the acute coronary syndrome subgroup, ASA monotherapy was associated with increased risk of ST [1.55; 1.021-2.36] but P2Y12 monotherapy was not [0.93; 0.58-1.48]. CONCLUSION: Amongst patients undergoing DES implantation, S-DAPT with P2Y12 inhibitor monotherapy reduces bleeding without increased risk of MI or ST compared with L-DAPT. Prospective trials are needed to evaluate if S-DAPT with P2Y12 monotherapy is superior to S-DAPT with ASA monotherapy for ischemic protection.

Sex-Related Differences in Patients at High Bleeding Risk Undergoing Percutaneous Coronary Intervention: A Patient-Level Pooled Analysis From 4 Postapproval Studies.

Background Women have been associated with higher rates of recurrent events after percutaneous coronary intervention than men, possibly attributable to advanced age at presentation and greater comorbidities. These factors also put women at higher risk of bleeding, which may influence therapeutic strategies and clinical outcomes. Methods and Results We performed a patient-level pooled analysis of 4 postapproval registries to evaluate sex-related differences in patients at high bleeding risk (HBR) undergoing percutaneous coronary intervention. HBR required fulfillment of at least 1 major or 2 minor criteria of the Academic Research Consortium definition. Outcomes of interest were major bleeding and major adverse cardiac events (composite of cardiac death, myocardial infarction, or definite/probable stent thrombosis). Of the total 10 502 patients, 2832 (27.0%) were women. The prevalence of HBR was higher in women compared with men (29.0% versus 20.5%, P<0.0001). Women at HBR were older and had more comorbidities, while men at HBR were more often smokers, with prior myocardial infarction and more complex coronary lesions. At 4 years, women at HBR had significantly higher major bleeding compared with men at HBR (10.8% versus 6.2%, P<0.0001); however, this difference was attenuated after multivariable adjustment (hazard ratio, 0.92; 95% CI, 0.41-2.08). Major adverse cardiac event rates between groups were similar (12.2% versus 12.6%, P=0.82) and remained consistent after adjustment (hazard ratio, 0.64; 95% CI, 0.32-1.28). Conclusions The prevalence of HBR was higher in women compared with men, with considerable differences in the distribution of criteria. Women at HBR experienced higher rates of major bleeding but similar major adverse cardiac event rates compared with men at HBR at 4 years.

Real-World Dual Antiplatelet Therapy Following Polymer-Free Sirolimus-Eluting Stent Implantations to Treat Coronary Artery Disease.

OBJECTIVES: The objective of this post hoc analysis was to analyze real-world dual antiplatelet therapy (DAPT) regimens following polymer-free sirolimus-eluting stent (PF-SES) implantations in an unselected patient population. METHODS: Patient-level data from two all-comers observational studies (ClinicalTrials.gov Identifiers: NCT02629575 and NCT02905214) were pooled and analyzed in terms of their primary endpoint. During the data verification process, we observed substantial deviations from DAPT guideline recommendations. To illuminate this gap between clinical practice and guideline recommendations, we conducted a post hoc analysis of DAPT regimens and clinical event rates for which we defined the net adverse event rate (NACE) consisting of target lesion revascularization (TLR, primary endpoint of all-comers observational studies) all-cause death, myocardial infarction (MI), stent thrombosis (ST), and bleeding events. A logistic regression was utilized to determine predictors why ticagrelor was used in stable coronary artery disease (CAD) patients instead of the guideline-recommended clopidogrel. RESULTS: For stable CAD, the composite endpoint of clinical, bleeding, and stent thrombosis, i.e., NACE, between the clopidogrel and ticagrelor treatment groups was not different (5.4% vs. 5.1%, p = 0.745). Likewise, in the acute coronary syndrome (ACS) cohort, the NACE rates were not different between both DAPT strategies (9.2% vs. 9.3%, p = 0.927). There were also no differences in the accumulated rates for TLR, myocardial infarction ([MI], mortality, bleeding events, and stent thrombosis in elective and ACS patients. The main predictors for ticagrelor use in stable CAD patients were age < 65 years, smaller vessels, treatment of ostial and calcified lesions, and in-stent restenosis. CONCLUSION: Within the framework of a post hoc analysis based on a real-world, large cohort study, there were no differences in the combined endpoint of major adverse cardiac events (MACE), bleeding and thrombotic events for clopidogrel and ticagrelor in stable CAD or ACS patients. Despite the recommendation for clopidogrel by the European Society of Cardiology (ESC), real-world ticagrelor use was observed in subgroups of stable CAD patients that ought to be explored in future trials.

Real-world reasons and outcomes for 1-month versus longer dual antiplatelet therapy strategies with a polymer-free BIOLIMUS A9-coated stent.

BACKGROUND: A large trial established the favorable profile of a new polymer-free biolimus A9-eluting stent (PF-BES) with a 1-month dual antiplatelet therapy (DAPT) in high bleeding risk (HBR) patients. This is the first study comparing outcomes for a 1-month versus longer DAPT strategies following PF-BES-percutaneous coronary intervention (PCI). METHODS: All patients undergoing PF-BES-PCI (January 2016 to July 2018) were included in the multicenter CHANCE registry. Patients were stratified according to DAPT strategy at discharge (planned 1-month vs. planned >1-month). Primary outcomes were the 390-day estimates of a patient-oriented and of a device-oriented composite endpoints (POCE: death, myocardial infarction [MI] or target vessel revascularization; DOCE: cardiac death, target vessel-MI or ischemia-driven target lesion revascularization). Landmark analyses from 1-month post-PCI were carried. RESULTS: Following PF-BES-PCI, 328(40.3%) and 485(59.6%) patients were discharged with 1-month and longer DAPT (12 months [6-12]), respectively. Patients with a previous or index MI were less likely to be discharged on 1-month DAPT. Patients prescribed with 1-month DAPT were more likely to be at HBR than those with longer DAPT (90.2% vs. 69.9%, p = .001). No between-groups differences in the primary outcomes (planned 1-month vs. planned >1-month DAPT: POCE 11.9% vs. 13.2%, p = .747; DOCE: 4.8% vs. 8.1%, p = .500) were observed, also after adjusting for confoundings (POCE: adjusted-hazard ratio [adj-HR] 1.26, 95%CI 0.74-2.13; DOCE: adj-HR 1.00, 95%CI 0.49-1.99). Landmark analyses showed similar results. CONCLUSIONS: In a large all-comers registry of PF-BES PCI, no interaction of planned DAPT strategy (1-month vs. >1-month) with outcomes was found. This observation warrants investigation in adequately powered randomized studies (ClinicalTrials.gov NCT03622203).

Impact of extended dual antiplatelet therapy on clinical prognosis in acute coronary syndrome patients with intermediate or high ischemic risk defined by the GRACE score.

OBJECTIVES: To evaluate the impact of extended dual antiplatelet therapy (DAPT) beyond 12 months in acute coronary syndrome (ACS) patients with intermediate-risk to high-risk of developing ischemia according to the Global Acute Coronary Event Registration (GRACE) score. BACKGROUND: The duration of optimal DAPT remains controversial in patients at higher risk of developing ischemia. METHODS: Overall, 9,309 ACS patients in the Optimal antiPlatelet Therapy for Chinese patients with Coronary Artery Disease (OPT-CAD) study were stratified as low-risk ( n = 5,112) or intermediate-risk to high-risk (n = 4,197) according to the GRACE score on hospital discharge. Clinical outcomes at 12-24 months in patients with intermediate-to-high risk who completed 1-year DAPT without any adverse events were analyzed. The primary endpoint was 24-month net adverse clinical events (NACEs). RESULTS: Patients at intermediate-to-high-risk had significantly higher incidence of NACE (10.2 vs. 4.9%, p < .01) and ischemic events (8.3 vs. 3.8%, p < .01) than low-risk patients at 24 months. For patients at intermediate-to-high-risk, extended DAPT beyond 12 months was associated with lower risk of NACE (3.0 vs. 5.1%, p = .012), all-cause death (1.1 vs. 2.6%, p = .01), and cardiac death (0.6 vs. 1.8%, p = .01), without excessive risk of major bleeding events (0.3 vs. 0.5%, p = .47). Clinical outcomes in the propensity-matched cohort were consistent. CONCLUSIONS: ACS patients with intermediate-risk or high-ischemic risk may benefit from extended DAPT beyond 1 year, an outcome than requires further confirmation in large-scale randomized trials.

Platelet function testing guided antiplatelet therapy reduces cardiovascular events in Chinese patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention: The PATROL study.

BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor has become the standard of care to reduce thrombotic events in patients with acute coronary syndrome or after percutaneous coronary intervention (PCI). The role of routine platelet function testing (PFT) in patients treated with DAPT after PCI remains controversial and evidence of PFT-guided antiplatelet therapy for patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI is limited. METHODS: We analyzed 1,353 consecutive STEMI patients undergoing primary PCI. PFT was performed 72 hr postprocedure using a vasodilator-stimulated phosphoprotein assay. The primary endpoint of major adverse cardio-cerebral events (MACCEs) was defined as a composite of all-cause death, cardiac death, nonfatal myocardial infarction, target vessel revascularization, and ischemic stroke. Patients with high platelet reactivity (HPR) were randomized to receive an intensified antiplatelet strategy by switching from clopidogrel to ticagrelor (HPR switch group) or to continue on clopidogrel (HPR nonswitch group). One-year clinical outcomes were compared among the groups. RESULTS: The baseline clinical characteristics were comparable across all groups (all p > .05). At the 1-year clinical follow-up, the primary endpoint of MACCE was significantly higher in the HPR nonswitch group than in the non-HPR and HPR switch groups (19.49% vs. 10.20% or 8.57%, p < .05), which was mainly caused by higher mortality (14.87% vs. 4.51% or 5.71%, p < .05). Major bleeding events were comparable across the groups. CONCLUSIONS: In STEMI patients with HPR, identified by vasodilator stimulated phosphoprotein (VASP)-determined PFT, switching clopidogrel to ticagrelor could significantly improve 1-year clinical outcomes without increasing the risk of bleeding.

Long versus short dual antiplatelet therapy in acute coronary syndrome patients treated with prasugrel or ticagrelor and coronary revascularization: Insights from the RENAMI registry.

INTRODUCTION: The benefits of short versus long-term dual antiplatelet therapy (DAPT) based on the third generation P2Y12 antagonists prasugrel or ticagrelor, in patients with acute coronary syndromes treated with percutaneous coronary intervention remain to be clearly defined due to current evidences limited to patients treated with clopidogrel. METHODS: All acute coronary syndrome patients from the REgistry of New Antiplatelets in patients with Myocardial Infarction (RENAMI) undergoing percutaneous coronary intervention and treated with aspirin, prasugrel or ticagrelor were stratified according to DAPT duration, that is, shorter than 12 months (D1 group), 12 months (D2 group) and longer than 12 months (D3 group). The three groups were compared before and after propensity score matching. Net adverse clinical events (NACEs), defined as a combination of major adverse cardiac events (MACEs) and major bleedings (including therefore all cause death, myocardial infarction and Bleeding Academic Research Consortium (BARC) 3-5 bleeding), were the primary end points, MACEs (a composite of all cause death and myocardial infarction) the secondary one. Single components of NACEs were co-secondary end points, along with BARC 2-5 bleeding, cardiovascular death and stent thrombosis. RESULTS: A total of 4424 patients from the RENAMI registry with available data on DAPT duration were included in the model. After propensity score matching, 628 patients from each group were selected. After 20 months of follow up, DAPT for 12 months and DAPT for longer than 12 months significantly reduced the risk of NACE (D1 11.6% vs. D2 6.7% vs. D3 7.2%, p = 0.003) and MACE (10% vs. 6.2% vs. 2.4%, p < 0.001) compared with DAPT for less than 12 months. These differences were driven by a reduced risk of all cause death (7.8% vs. 1.3% vs. 1.6%, p < 0.001), cardiovascular death (5.1% vs. 1.0% vs. 1.2%, p < 0.0001) and recurrent myocardial infarction (8.3% vs. 5.2% vs. 3.5%, p = 0.002). NACEs were lower with longer DAPT despite a higher risk of BARC 2-5 bleedings (4.6% vs. 5.7% vs. 6.2%, p = 0.04) and a trend towards a higher risk of BARC 3-5 bleedings (2.4% vs. 3.3% vs. 3.9%, p = 0.06). These results were not consistent for female patients and those older than 75 years old, due to an increased risk of bleedings which exceeded the reduction in myocardial infarction. CONCLUSION: In unselected real world acute coronary syndrome patients treated with percutaneous coronary intervention, DAPT with prasugrel or ticagrelor prolonged beyond 12 months markedly reduces fatal and non-fatal ischaemic events, offsetting the increased risk deriving from the higher bleeding risk. On the contrary, patients >75 years old and female ones showed a less favourable risk-benefit ratio for longer DAPT due to excess of bleedings.

Clinical relevance of ticagrelor monotherapy following 1-month dual antiplatelet therapy after bifurcation percutaneous coronary intervention: Insight from GLOBAL LEADERS trial.

BACKGROUND: The aim of this study was to investigate the impact of ticagrelor monotherapy following 1-month dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) for bifurcation lesions. METHODS: GLOBAL LEADERS was a randomized, superiority, all-comers trial comparing 1-month DAPT with ticagrelor and aspirin followed by 23-month ticagrelor monotherapy (experimental treatment) with standard 12-month DAPT followed by 12-month aspirin monotherapy (reference treatment) in patients treated with a biolimus A9-eluting stent. The primary endpoint was a composite of all-cause death or new Q-wave myocardial infarction (MI) at 2 years. RESULTS: Among the 15,845 patients included in this subgroup analysis, 2,498 patients (15.8%) underwent PCI for at least one bifurcation lesion. The incidence of the primary endpoint was similar between the bifurcation and nonbifurcation groups (4.7 vs. 4.0%, p = .083). The experimental treatment had no significant effect on the primary endpoint according to the presence/absence of a bifurcation lesion (bifurcation: hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.51-1.07; nonbifurcation: HR: 0.90, 95% CI: 0.76-1.07, p for interaction = .343), but was associated with significant reduction in definite or probable stent thrombosis (p for interaction = .022) and significant excess of stroke (p for interaction = .018) when compared with the reference treatment. CONCLUSIONS: After PCI for bifurcation lesions using 1-month of DAPT followed by ticagrelor monotherapy for 23 months did not demonstrate explicit benefit regarding all-cause death or new Q-wave MI as in the overall trial.

Efficacy and Safety of Guideline-Recommended Risk Score-Directed Dual Antiplatelet Therapy After 2nd-Generation Drug-Eluting Stents.

BACKGROUND: Evaluate the safety and efficacy of guideline-recommended risk score-directed dual antiplatelet therapy (GD-DAPT) based on THE PRECISE-DAPT score after 2nd-generation drug-eluting stent (DES) implantation.Methods and Results:We analyzed 5,131 patients pooled from 4 clinical trials. Patients were divided into 3 groups according to current recommendations on the duration of DAPT and their actual DAPT duration: GD-DAPT (n=2,183), shorter DAPT (n=1,540), longer DAPT (n=1,408). The primary endpoint was the rate of net adverse clinical events (NACE) during the first 12 months. The secondary endpoints were ischemic or bleeding events. Overall, GD-DAPT did not affect NACE (1.2% vs. 1.2% for shorter DAPT and 1.7% for longer DAPT) or bleeding events (0.6% vs. 0.5% and 0.9%), and there were fewer ischemic events (2.8% vs. 4.4% and 4.0%, P=0.03) than with shorter DAPT. Especially in acute coronary syndrome (ACS) patients, GD-DAPT had fewer NACE (1.5% vs. 1.4% and 4.2%; P=0.006) and bleeding events (0.8% vs. 0.5% and 2.8%; P=0.001) than longer DAPT as well as fewer ischemic events (2.8% vs. 4.4% and 4.7%; P=0.03) than shorter DAPT. CONCLUSIONS: GD-DAPT did not affect NACE or bleeding events and reduced the number of ischemic events at 12 months compared with shorter DAPT. For ACS, GD-DAPT was associated with favorable outcomes compared with non-GD-DAPT. Therefore, GD-DAPT may optimize efficacy and safety.

Impact of high on-treatment platelet reactivity on outcomes following PCI in patients on hemodialysis: An ADAPT-DES substudy.

OBJECTIVES: We sought to compare clinical outcomes after percutaneous coronary intervention (PCI) in patients on versus not on hemodialysis (HD) and examine whether high on-treatment platelet reactivity (HPR) further impacts outcomes among patients on HD. BACKGROUND: Both chronic kidney disease (CKD) and HPR are predictors of major adverse cardiac events (MACE) after PCI. METHODS: Two-year outcomes of patients from the prospective, multicenter ADAPT-DES study (N = 8,582) were analyzed according to HD status at enrollment. All patients underwent platelet function testing with the VerifyNow assay; HPR on clopidogrel was defined as P2Y12 reaction units (PRU) >208. RESULTS: Compared with non-HD patients, patients on HD (n = 85) had significantly higher baseline PRU (median 254 vs. 188, p = .001) and more frequently had HPR (61.7% vs. 42.5%, p < .001). HD was associated with increased 2-year rates of MACE (death, myocardial infarction (MI) or definite stent thrombosis (ST); 23.4% vs. 10.7%, p < .001). HD was also strongly associated with 2-year overall mortality, cardiac death, MI, target vessel revascularization, major bleeding, stroke and ST. Following adjustment for HPR and other covariates, HD was independently associated with overall mortality, MI, ST, and major bleeding at 2 years. The relationship between HD status and 2-year MACE was consistent in patients with and without HPR (Pinteraction = .78). CONCLUSIONS: Nearly two-thirds of patients on HD exhibited HPR on clopidogrel, and both HD and HPR were independently associated with 2-year adverse outcomes after DES implantation. However, the deleterious impact of HD on clinical outcomes was present in both patients with and without HPR.