TIMI Major Bleeding Research Articles

Optimal antithrombotic strategy for patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention: updated meta-analysis of randomised controlled trials

Abstract Background The optimal antithrombotic strategy for the growing proportion of patients with indications for both dual antiplatelet therapy and long-term anticoagulation remains controversial, with recent randomized trials published and mixed recommendations in guidelines. We meta-analysed bleeding and cardiovascular outcomes comparing dual versus triple and non-vitamin K oral anticoagulants (NOAC) versus vitamin K oral anticoagulants (VKA) antithrombotic regimens. Methods MEDLINE, Embase and Cochrane databases were searched for original randomised trials with relevant search terms from January 1980-December 2019. Two authors evaluated studies for inclusion and extracted data to pool efficacy and safety endpoints. Results The search yielded 331 articles, with 22 full-texts reviewed and six randomised trials totalling 12,146 patients included. Dual antithrombotic strategies had reduced TIMI major and minor bleeding (odds ratios 0.59, 95% confidence interval 0.44–0.80), as well as all, major, and minor bleeding (odds ratios 0.55–0.59, all P<0.05), with no differences in mortality, myocardial infarction, stroke, stent thrombosis or composite cardiovascular events (odds ratio 0.91–1.26, all P>0.05), compared with triple antithrombotic strategies in six trials. NOAC regimens had lower TIMI major and minor bleeding (odds ratio 0.64, 0.49–0.85), as well as major, minor and intracranial bleeding (odds ratios 0.36–0.66, all P<0.05), and similar no differences in mortality or all cardiovascular endpoints (odds ratios 0.85–1.13, all P>0.05), compared with VKA regimens in four trials. Conclusion Dual antithrombotic therapy with NOAC had significantly reduced bleeding without increase in cardiovascular events and mortality compared to their counterparts, and should generally be recommended in patients needing dual antiplatelet and long term anticoagulation therapy. Funding Acknowledgement Type of funding source: None

Comparing clinical outcomes following 1 year of dual antiplatelet therapy in patients risk stratified by the PRECISE-DAPT and DAPT scores

Abstract Background Dual antiplatelet therapy (DAPT) is the standard of care following PCI. DAPT reduces ischemic events but increases bleeding risk. Duration of DAPT following PCI remains controversial. Current guidelines recommend duration be individualized based on risk of ischemia and bleeding. Although multiple strategies exist to risk stratify patients, including application of the PRECISE-DAPT and DAPT scores, there is currently no standardized risk assessment protocol. Purpose To determine if the PRECISE-DAPT and DAPT scores can identify patients at increased risk of ischemia or bleeding in a cohort prescribed 12 months of DAPT following PCI. Methods We calculated the PRECISE-DAPT and DAPT scores for 469 consecutive patients at baseline after PCI. Patients were grouped based on score treatment recommendation; PRECISE-DAPT prolonged or shortened (PRECISE DAPT <25 vs. ≥25) and DAPT prolonged or shortened (DAPT ≥2 vs <2). End points included 1-year rates of major adverse cardiovascular events (MACE) and TIMI major or minor bleeding. Results Among 469 patients, mean age was 64.4 (SD 12.2); 102 (21.7%) were women. Index presentation consisted of a STEMI in 207 (44.1%), NSTEMI in 99 (21.1%), and UA in 60 (12.8%). At presentation, 174 (37.1%) were current smokers, 115 (24.5%) had a prior MI, 118 (25.2%) had diabetes, 249 (53.1%) had dyslipidemia and 281 (60.0%) were previously diagnosed as hypertensive. Overall, there was an increase in bleeding and no difference in MACE for patients with a PRECISE-DAPT score ≥25 (13.3% vs. 4.1% P<0.001). No difference in bleeding or MACE was present in patients stratified by the DAPT score. Conclusion A PRECISE-DAPT score ≥25 was associated with an increased rate of bleeding and no difference in MACE in patients prescribed 12 months of DAPT. This supports the use of the PRECISE-DAPT as a prospective tool in clinical practice. Funding Acknowledgement Type of funding source: None

Real world risk of major outcomes for type 2 diabetes with stable coronary artery disease without prior MI or stroke and THEMIS-like patients using the SNDS French nationwide claims database

Abstract Background The THEMIS randomized controlled trial showed that patients with stable coronary artery disease and type 2 diabetes mellitus (CAD-T2DM), without a history of myocardial infarction (MI) or stroke, and who received ticagrelor plus aspirin, had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. After 3 years of follow-up, the incidence of major outcomes in the placebo arm was 1.8% for ischemic stroke, 3.3% for MI, 4.9% for all-cause death, 9.2% for a composite of all-cause-death, MI or stroke, and 0.38 per 100 patients-years for TIMI major bleedings. The risk of these outcomes is not well known in current practice. Purpose To estimate the incidence of major outcomes for CAD-T2DM patients without prior MI-stroke and more specifically for THEMIS-like patients in a real world setting. Methods Cohort within the main scheme of the SNDS (Système National des Données de Santé), the French nationwide claims database, representing about 86% of 66 million people. All CAD-T2DM prevalent patients without prior MI-stroke were identified on January 1st, 2014 (inclusion date), based on a 5-year database history, and followed for two years. The THEMIS-like population included CAD-T2DM patients without prior MI-stroke ≥50 years at inclusion date without renal failure with dialysis, cirrhosis or liver cancer history, as well as no intracranial and gastro-intestinal bleeding for the last 6 months, or anticoagulant or antiplatelet agent 2 months before and after inclusion date. The Kaplan-Meier method was used to estimate the 2-year cumulative incidence of all-cause death and a composite of all-cause death, MI and stroke, and the cumulative incidence function, taking into account death as competing risk for other clinical outcomes. Results From 258,260 CAD-T2DM patients without prior MI-stroke, 64,334 were included in the THEMIS-like population (24.9%) with the same median age of 72 years, with 68.3% and 65.7% men, respectively. The 2-year cumulative incidence for the CAD-T2DM without prior MI-stroke and THEMIS-like populations was 1.7% and 1.5% for ischemic stroke, 1.7% and 1.3% for MI, 9.5% and 5.3% for heart failure, 4.9% and 3.2% for major bleeding, 13.6% and 9.7% for all-cause death, and 16.2% and 12.0% for the composite outcome, respectively. Conclusions In current practice, the median age of the THEMIS-like population was 6 years older than in the THEMIS trial (i.e. 66 years), with an observed risk after 2 years of follow-up, about double for the composite outcome, triple for deaths and quadruple for major bleedings than those of the placebo arm of the trial (estimation after 2 years of follow-up in the THEMIS trial placebo arm assuming constant risk across time according to Kaplan-Meier graph). Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Study performed with unconditional funding from AstraZeneca

Clinical outcomes of patients treated using very short duration dual antiplatelet therapy after implantation of biodegradable-polymer drug-eluting stents: rationale and design of a prospective multicenter REIWA registry.

Several studies have demonstrated the safety and feasibility of short (3-6months) and very short duration (< 2months) dual antiplatelet therapy (DAPT) in patients with a durable-polymer drug-eluting stent (DP-DES). However, the clinical importance of using very short duration DAPT has yet to be established in patients with a biodegradable polymer drug-eluting stent (BP-DES). The aim of this REIWA registry (multicenter and prospective registry; investigation of clinical outcomes of patients treated with short duration dual antiplatelet therapy after implantation of biodresorbable-polymer drug-eluting stent: a multicenter, prospective registry from Iwate medical university affiliated hospitals) is to determine the safety and feasibility of using 1-month DAPT followed by P2Y12 inhibitor monotherapy in patients after BP-DES implantation. This study is an observational, prospective, multicenter registry encompassing the entire local medical region of Iwate Prefecture (northern area of mainland Japan). A total of 1200 patients who underwent successful PCI with a novel thin strut BP-DES (Synergy, Ultimaster or Orsiro) and are considered to be appropriate patients for very short DAPT, are registered and subsequently administered 1-month DAPT followed by P2Y12 inhibitor monotherapy (clopidogrel 75mg/day or prasugrel 3.75mg/day). The primary endpoint was a composite of cardiovascular and bleeding events, which included cardiovascular death, spontaneous myocardial infarction, definite stent thrombosis, ischemic or hemorrhagic stroke, or TIMI major or minor bleeding at 12months. The REIWA registry (UMIN000037321) will demonstrate both the safety and feasibility of using 1-month DAPT in patients with BP-DES. Furthermore, results of this study will also be able to provide supportive evidence for P2Y12 inhibitor monotherapy after 1-month DAPT following BP-DES implantation.

Benefit of dual antithrombotic therapy with direct oral anticoagulants in patients with atrial fibrillation undergoing percutaneous coronary intervention: a systematic review and metaanalysis of randomized clinical trials.

Antithrombotic treatment in patients with atrial fibrillation undergoing percutaneous coronary intervention is still debated. We conducted a meta-analysis of recent randomized controlled trials to evaluate the benefit of different antithrombotic strategies. Data were analyzed between May and September 2019. Efficacy outcomes were trial-defined major adverse cardiovascular events (MACE); its individual components; stent thrombosis. Safety outcomes were trial-defined primary bleeding outcome; TIMI and ISTH major bleeding; clinically relevant non-major bleeding; intracranial hemorrhage. Differences in outcomes among groups were expressed as pooled odds ratio (OR) and corresponding 95% confidence interval (CI). Four randomized studies were included (10,969 patients). The mean age ranged from 69 to 72years, prevalence of acute coronary syndrome (ACS) varied from 48 to 62%. Comparing dual antithrombotic therapy (DAT) with a direct oral anticoagulant (DOAC) versus triple antithrombotic therapy (TAT) with vitamin K antagonist (VKA), OR for trial-defined MACE and primary bleeding outcome were 1.03 (95% CI, 0.86-1.24) and 0.59 (95% CI, 0.41-0.86), respectively. There was a 68% lower risk of intracranial hemorrhage and a non-statistically significant higher risk of stent thrombosis with DAT. DAT wasas effective and safer than TAT in patients with stable coronary artery disease, while a trend towards increased ischemic events was seen in ACS patients. DAT with a DOAC showed similar efficacy and less bleeding than TAT with a VKA. However, increased stent thrombosis with DAT may be present, and TAT should be considered in patients at high ischemic risk, such as ACS patients.

403-P: Impact of Diabetes-Related Factors and Background Antihyperglycemic Therapy on the Efficacy and Safety of Ticagrelor Added to Aspirin: Insights from the THEMIS Trial

In the THEMIS trial of 19,220 patients with stable CAD and T2DM without prior MI or stroke followed for a median of 39.9 months, ticagrelor plus aspirin (ASA) lowered ischemic CV events but increased major bleeding events compared with placebo plus ASA, with a more favorable net clinical benefit in those with prior PCI. We now report the efficacy and safety by diabetes-related factors and background antihyperglycemic therapy. While the incidence of the primary efficacy outcome (CV death, MI, stroke; MACE) event rates (overall 8.1%) was higher with increasing diabetes duration (11.1% &amp;gt;20 years vs. 6.7% ≤5 years) and A1c (11.8% &amp;gt;10% vs. 6.4% ≤6%), the relative benefits of ticagrelor on MACE reduction (overall HR 0.90; p=0.04) did not differ across these various subgroups (p-values for interaction=0.83 and 0.16, respectively). In contrast, the primary safety outcome (TIMI major bleeding) event rate (overall 1.6%) did not vary by diabetes duration or A1c and was similarly increased by ticagrelor in all of these subgroups (overall HR=2.32 [1.82,2.94]; p&amp;lt;0.01). The impact of diabetes duration and A1c were similar in the prior PCI subgroup. Regardless of treatment assignment, patients treated with insulin vs. not had a higher risk for MACE (HR=1.65 [1.49, 1.83]; p&amp;lt;0.01) with no difference in major bleeding (HR=0.92 [0.71, 1.19]; p=0.52), while those treated with sulfonylurea vs. not had no difference in risk for MACE (HR=1.00 [0.91,1.11]; p=0.93) or major bleeding (HR=1.12 [0.89,1.41]; p=0.34) endpoints. The efficacy and safety of ticagrelor did not differ based on background antihyperglycemic therapy. These data suggest that, in general, the relative benefits and risks of ticagrelor added to aspirin are consistent regardless of T2DM duration, A1c, or background antihyperglycemic therapy. NCT01991795. Disclosure L.A. Leiter: Advisory Panel; Self; Abbott, Amgen, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Amgen, AstraZeneca, Kowa Pharmaceuticals America, Inc., Medicines Company. Speaker’s Bureau; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Medscape, Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi, Servier. D.L. Bhatt: Research Support; Self; Abbott, Afimmune, Amarin Corporation, Amgen, AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Cardax, Chiesi USA, Inc., CSL Behring, Ferring Pharmaceuticals, Fractyl Laboratories, Inc., Idorsia, Ironwood Pharmaceuticals, Ischemix, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PLx Pharma Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis, Synaptic. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp &amp; Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. K. Fox: Other Relationship; Self; AstraZeneca, Servier. T. Simon: Advisory Panel; Self; Novartis Pharmaceuticals Corporation, Servier. Board Member; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc. Consultant; Self; Air Liquide, Sanofi. S. Mehta: Research Support; Self; AstraZeneca. E. Lev: None. R.G. Kiss: Speaker’s Bureau; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp., Pfizer Inc. A.J. Dalby: None. H. Bueno: Advisory Panel; Self; AstraZeneca, Bayer AG, Novartis AG. Consultant; Self; Amgen, Bristol-Myers Squibb, Pfizer Inc. Research Support; Self; AstraZeneca, Novartis AG. W. Ridderstråle: Employee; Self; AstraZeneca. A. Himmelmann: Employee; Self; AstraZeneca. J. Prats: Other Relationship; Self; AstraZeneca. Y. Liu: None. J.J. Lee: None. J. Amerena: None. M.N. Kosiborod: Consultant; Self; Amarin Corporation, Amgen, Applied Therapeutics, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., Eli Lilly and Company, GlaxoSmithKline plc., Glytec, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi US, Vifor Pharma Group. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. P.G. Steg: Consultant; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Idorsia, Mylan, Novartis AG, Pfizer Inc., Sanofi, Servier. Research Support; Self; Amarin Corporation. Speaker’s Bureau; Self; Novo Nordisk A/S.

Antithrombotic treatment in patients with atrial fibrillation undergoing coronary angioplasty: rational convincement and supporting evidence

BackgroundThe management of antithrombotic therapy in patients undergoing percutaneous coronary intervention (PCI) with an indication for long-term oral anticoagulant therapy (OAT) is still a matter of debate. We aim to evaluate the safety and the efficacy of dual therapy (DT) compared to triple therapy (TT) in this clinical setting. MethodsA study level meta-analysis and a review of randomized trials selected using PubMed, Embase, EBSCO, Cochrane database of systematic reviews, Web of Science, and abstract from major cardiology congresses. Six randomized trials with 12,156 patients evaluating the strategy of DT vs. TT in patients treated with PCI with indication for long-term OAT were included. ResultsPatients treated with DT demonstrated a 45% relative reduction in the risk of TIMI major bleeding (1.71% vs. 2.99%; OR 0.55, 95% CI 0.41–0.71; P<0.0001) and TIMI minor bleeding compared to TT arm (4.67% vs 7.83%, OR 0.55 95% CI 0.39–0.78, P = 0.0007). All-cause mortality was similar in two arms (3.95% vs 3.77%, P = 0.92), as well as cardiovascular mortality (2.21% vs 2.19%, P = 0.97). DT was associated with a borderline increase of ST (1.02% vs 0.67%, P = 0.07). No significant differences were observed in occurrence of MI and stroke. ConclusionsOur findings suggest that DT is safer than TT with regard to occurrence of major bleeding. DT with a direct oral anticoagulant plus clopidogrel at discharge could be effective in most patients, maintaining aspirin in periprocedural phase and as longer “tailored” treatment for patients at higher ischemic risk.

ST-Segment– Elevation Myocardial Infarction for Pharmacoinvasive Strategy or Primary Percutaneous Coronary Intervention in Gaza (STEPP- PCI)

Background A primary percutaneous coronary intervention (PCI) Primary PCI continues to be the optimal reperfusion therapy in patients with ST elevation myocardial infarction however, in areas where PCI centers are not readily available, a pharmacoinvasive strategy has been proposed. This study investigated the safety and efficacy of a pharmacoinvasive strategy compared with primary (PCI) strategy for ST-segment elevation myocardial infarction (STEMI) in Gaza. Methods: We randomized 145 patients presenting within 2 hours of symptom onset of acute ST elevation myocardial infarction to primary CPI (PCI) or for pharmaco-invasive PCI 2-24 hours after streptokinase, except in the event of failed reperfusion, in which case, emergency angiography was recommended. The primary endpoint a composite of death, shock and congestive heart failure at 30 days. Results: Total 145 patients with mean age 56.5+10.48 years. (The mean age of patients is) The primary endpoint in primary PCI (17%) and in pharmaco-invasive PCI (16.1%) p = 0.24.???? There was no difference in 30-day mortality (4.7 % in primary PCI and 4.9% in pharmacoinvasive strategy (P=0.94). Secondary endpoints:Emergency angiography was required in 39.5% of the patients in the pharmaco-invasive strategy and the median time for underwent angiography was 6 hours after randomization. TIMI major bleeding occurred among 4 patients ( 4.9 % ) in the pharmacoinvasive group and in 2 patients (3.1%) of the primary PCI group (P = 0.59).The pharmacoinvasive group had 1.9 times the odds of having TIMI major bleed compared with the primary PCI group Conclusions In this randomized trial, early-presenting STEMI patients unable to undergo primary PCI within 1 hour (median, 75±20 minutes) were randomized to primary PCI or a pharmaco-invasive strategy with streptokinase followed by PCI. At 1 month follow-up, there was no statistical difference in all-cause mortality, heart failure or shock. This study suggests that, if primary PCI cannot be performed within 1 hour of presentation, a pharmaco-invasive strategy may be as good as primary PCI.

P2816Antithrombotic strategy for patients with anticoagulation indication undergoing percutaneous coronary intervention: meta-analysis of randomised controlled trials

Abstract Background A significant proportion of patients having acute coronary syndrome and/or undergoing percutaneous coronary intervention (PCI) have indications for long-term anticoagulation such as atrial fibrillation. Their optimal antithrombotic strategy despite recent randomised trials. We meta-analysed outcomes comparing dual versus triple, and non-vitamin K oral anticoagulants (NOAC) versus vitamin K oral anticoagulants (VKA) antithrombotic regimens. Methods MEDLINE, Embase and Cochrane databases were searched for original randomised trials with relevant search terms. Two authors evaluated these studies for inclusion and extracted data pooling bleeding and cardiovascular events. Results The search yielded 308 articles, with 19 full-texts reviewed and 4 randomised trials totalling 6,029 patients included. Dual antithrombotic strategies were associated with significant reductions in TIMI major and minor bleeding (odds ratios 0.55, 95% confidence interval 0.36–0.83), and other bleeding endpoints including all, major, minor and intracranial bleeding (odds ratios 0.45–0.62, all P&lt;0.05), compared with triple antithrombotic strategies in four trials, with no differences in mortality, myocardial infarction, stroke, stent thrombosis or composite cardiovascular events (odds ratio 0.79–1.13, all P&gt;0.05). NOAC regimens were associated with significant reductions in TIMI major and minor bleeding odds ratio 0.49 (0.37–0.65), as well as major, minor and intracranial bleeding (odds ratios 0.29–0.52, all P&lt;0.05), but again no differences in mortality or all cardiovascular endpoints (odds ratios 0.98–1.49, all P&gt;0.05). Conclusion Antithrombotic strategies involving dual instead of triple agents, and NOAC instead of VKA had significantly less bleeding without increasing mortality and cardiovascular events, and are therefore preferred options in patients undergoing PCI who also require long-term anticoagulation.

P2801Hard events after orsiro sirolimus-eluting stent (HEROES) in STEMI: a multicenter registry

Abstract Background Primary percutaneous coronary intervention (pPCI) using drug-eluting stents (DES) is the treatment of choice for the ST segment elevation Myocardial infarction (STEMI). Specific DES platforms, as well the strategies used to control drug release, may influence mid-to-long term pPCI success rate. Orsiro, a third generation hybrid sirolimus eluting stent with a biodegradable polymer, may potentially cause less stent malapposition, stent-induced inflammation and mechanical damage, ultimately reducing the thrombogenicity of the stent. Purpose The aim of the HEROES Registry is: 1) to evaluate the safety and efficacy of the Orsiro stent in STEMI patients undergoing pPCI; 2) to capture data that reflect the “real-world” use of Orsiro stents in pPCI and provide insights into patient characteristics, comorbid conditions, patterns of care, quality of care and performance measurements. Methods From January 2012 to March 2018 we prospectively enrolled all patients diagnosed with STEMI who have received one or more Orsiro stents in the target vessel of pPCI at 9 Italian centres. The primary end-point of the study was a device-oriented composite end-point (DOCE) of cardiac death, any myocardial infarction (MI) clearly attributable to the intervention culprit vessel (TVMI) and ischemic-driven target lesion revascularization (ID-TLR) at 1-year follow up. Secondary end-points were: 1) DOCE at 6-month and 3-year follow-ups; 2) any definite/probable stent thrombosis; 3) any TIMI major bleeding (in-hospital, within 7 days after pPCI and at follow-up). Results Study cohort comprised 338 patients with a mean age of 64.9±12.0 years; 255 (75.4%) were men, 69 (20.4%) had diabetes and 59 (17.5%) chronic kidney disease. Median follow-up was 10.5 (range 0–67) months. Culprit vessel was the left anterior descending (LAD) in 167 (49.4%), right coronary (RCA) in 97 (28.7%), left circumflex artery (LCX) in 42 (12.4%) and other vessels in 32 (9.5%). Multivessel disease was present in 178 (52.7%); 106 (31.4%) had bifurcation lesion as a culprit. In 155 (45.9%) the culprit lesion was proximal, in 154 (45.6%) mid-vessel. Stent per lesion ratio was 1.3±0.6. Thrombus grade was 0–2 in 236 (69.8%) and 3–5 in 102 (30.2%). At 1-year follow-up we observed a 4.4% cumulative incidence of DOCE, consisting of 13 (3.8%) cardiac deaths, 1 (0.3%) TVMI and 1 (0.3%) ID-TLR. Definite stent thrombosis occurred in only 1 (0.3%) patient during hospital stay. There were only 4 major bleedings (1.2%), all during follow-up. Kaplan-Meier analysis showed a DOCE-free survival at 6 months of 95.9%, and at 1 and 3 years of 95.6 and 95%, respectively. DOCE-free survival curve Conclusions Orsiro stent seems to be effective and safe in contemporary pPCI. The optimal features of Orsiro contribute to the few adverse events observed during follow-up and to an event-free survival that compares favorably with similar registries of modern DES.

P4635Long term risk and costs of bleeding in men and women treated with triple antithrombotic therapy

Abstract Background Triple antithrombotic therapy (TAT) is known to increase bleeds and its relevance is questioned. No study has observed the long-term risk of bleeding and health care costs from a sex perspective, in a total TAT population. We investigated the rate of all bleeds in patients receiving TAT at index hospitalization and within one year. We explored early discontinuation of TAT and potential sex disparities. We also assessed health care costs related to bleeding complications. Methods All patients discharged with TAT registered in SWEDEHEART in the County of Östergötland 2009–2015 were included. Information about bleeds during one-year follow-up were retrieved from the medical records. All bleeds receiving medical attention were included. Resource use associated with bleeds were assigned unit cost to estimate the health care costs associated with bleeding episodes. Results Among 272 identified patients, 156 bleeds occurred post-discharge, of which 28.8% were gastrointestinal. In total 54.4% had at least one bleed during or after the index event and 40.1% bled post discharge of whom 28.7% experienced a TIMI major or minor bleeding. Women discontinued TAT prematurely more often than men (52.9 vs 36.1%, p=0.01) and bled more (48.6 vs. 37.1%, p=0.09). One-year mean health care costs were EUR 575 and EUR 5787 in non-bleeding and bleeding patients, respectively. Conclusion The very high bleeding incidence in patients with TAT is a cause of concern, especially in women. There is a need for an adequately sized randomized, controlled trial to determine a safe but still effective treatment for these patients.

P1694Sex is not an independent predictor of ischemic outcomes or bleeding in NSTEMI patients undergoing percutaneous coronary intervention. Insights from the TAO trial

Abstract Background There is uncertainty regarding whether female sex is an independent predictor of adverse outcomes in acute coronary syndromes (ACS). Purpose We sought to describe and compare ischemic and bleeding outcomes between men and women with Non–ST-segment–Elevation (NSTE) ACS enrolled in the large Treatment of Acute coronary syndromes with Otamixaban (TAO) trial in which antithrombotic treatment was standardized and a systematic invasive approach was performed. Methods The TAO trial randomized moderate to high-risk NSTE-ACS patients with diagnostic coronary angiography planned in the first 72 hours to heparin plus eptifibatide versus otamixaban. This post-hoc analysis describes ischemic (all-cause death, new myocardial infarction, stent thrombosis within 180 days of randomization) and bleeding outcomes (TIMI major and minor bleeding within 30 days of randomization) according to sex. Results Of 13,229 patients with NSTE-ACS randomized in 55 countries, 3,980 (30.1%) were female and 9,249 (69.9%) were male. Mean age was 64.8±11.0 and 60.7±11.1 years, respectively. The prevalence of diabetes (34.0% vs. 25.8%), hypertension (80.8% vs. 67.0%), and hypercholesterolemia (55.9% vs. 52.2%) was higher among women compared with men but current smoking (21.5% vs. 38.7%) and history of previous MI were more frequent in males (15.5% vs. 20.7%). Females experienced a higher incidence of both ischemic outcomes (10.2% vs. 9.1%; OR=1.15; 95% CI, 1.01–1.30; p=0.034) and bleeding events (4.1% vs. 3.4%; OR=1.23; 95% CI, 1.02–1.49; p=0.029). Bleeding risk and CV death were particularly increased in women younger than 50 years, compared to males of the same age, at 5.5% vs. 1.4% (OR=4.00; 95% CI, 2.13–7.69; p=0.034) and 1.7% vs. 0.5% (OR=4.35; 95% CI, 1.02–20.00; p=0.02), respectively. No difference in either outcome was found between women and men between 50 and 80 years old. Above 80 years, women experienced a lower rate of bleeding (3.9% vs. 7.8%; OR=0.47; 95% CI, 0.23–0.88; p=0.024) but a similar rate of in ischemic events (16.0% vs. 17.2%; OR=0.92; 95% CI, 0.63–1.33; p=0.67). After adjustment for age, body weight, diabetes mellitus, prior PCI, serum creatinine, presenting systolic blood pressure, elevated biomarker at presentation, heart failure, the risk of ischemic (OR=1.03; 95% CI, 0.89–1.18; p=0.71) and bleeding events (OR=1.05; 95% CI, 0.85–1.33; p=0.65) were similar between men and women. Conclusions In this large international randomized trial of NSTE-ACS with standardized invasive management, women (particularly those younger than 50 years) experienced higher risks of ischemic and bleeding events than men, but the difference was not sustained after adjustment. In this population, sex was not an independent predictor of adverse outcomes in NSTE-ACS. The type of ACS (NSTE-ACS) and routine invasive management in women and men may explain this absence of difference. Acknowledgement/Funding The TAO trial was sponsored and funded by SANOFI. The present analysis was supported by the RHU iVASC grant “#ANR-16-RHUS-00010”

P6406Platelet reactivity in Hepatitis C virus infected patients on dual antiplatelet therapy for acute coronary syndrome

Abstract Background Coronary artery disease (CAD) has been recognized as a serious and potentially life-threatening complication of Hepatitis C Virus (HCV) infection. High on treatment platelet reactivity has been associated with high risk of ischemic events in patients with CAD, but data regarding the association with HCV infection are still lacking. Purpose We sought to assess platelet reactivity on dual anti-platelet therapy and long-term outcome of acute coronary syndrome (ACS) patients infected with HCV. Methods ACS patients infected with HCV were matched to ACS patients without HCV for age, sex, diabetes, hypertension and renal function. Primary and secondary study endpoints were the proportion of patients with high on treatment platelet reactivity (HTPR) and long-term outcomes, respectively. Results HCV-infected ACS patients had higher levels of platelet reactivity (ADP10-LTA: 56% ± 18% vs. 44% ± 22%; p=0.002; Arachidonic Acid-LTA: 25% ± 21% vs. 16% ± 15%; p=0.011) and higher rate of HTPR on clopidogrel and aspirin compared with non-HCV patients. Multivariable analysis demonstrated HCV-infection to be an independent predictor of HTPR. At follow-up, estimated major adverse clinical events (MACE: cardiac death, non fatal myocardial infarction and any revascularization) were 57% vs. 37%, p=0.006 in HCV-infected ACS and non-HCV, respectively. Also, TIMI major bleeding rates were higher in HCV-infected subjects (11% vs. 3%; p=0.043) as compared with non-infected patients. Platelet function according to HCV status Conclusions ACS patients with HCV infection have increased on treatment platelet reactivity, higher rate of HTPR, MACE and bleedings as compared with non-HCV patients.

Enhanced platelet inhibition by clopidogrel and risk of bleeding in patients requiring oral anticoagulation after drug-eluting stent implantation.

Clopidogrel is the P2Y12 inhibitor of choice in patients who undergo PCI and have an indication for oral anticoagulation (OAC). Prediction of the bleeding risk is of major interest in this population. The aim of this analysis was to investigate whether an enhanced platelet inhibition by clopidogrel measured by platelet function testing (PFT) with the Multiplate Analyzer is associated with an increased bleeding risk in patients on triple antithrombotic therapy. This investigation was performed in a cohort of 524 patients from the randomised ISAR-TRIPLE trial; 458 (87.4%) had PFT results available in the first 24 hours after PCI. Patients belonging to the lowest quintile according to PFT were considered as enhanced responders to clopidogrel. The primary endpoint was major bleeding according to TIMI criteria at nine months. The median of ADP-induced platelet aggregation in the whole population was 163 AU*min (107-241). Patients in the lowest quintile had values below 93 AU*min. These enhanced responders (92 patients) had a significantly higher risk of TIMI major bleeding (hazard ratio [HR] 3.13, 95% confidence interval [CI]: 1.38-7.09, p=0.01) and overall mortality (HR 3.42, 95% CI: 1.55-7.52, p=0.004) compared with the remaining patients (366 patients). No significant difference was observed for the secondary combined ischaemic endpoint (HR 1.27, 95% CI: 0.47-3.47, p=0.64). Enhanced platelet inhibition delivered by clopidogrel is associated with an increased risk for major bleeding and death in patients on OAC who undergo PCI. These results support the use of PFT to identify patients with an increased risk for bleeding.

Machine learning versus traditional risk stratification methods in acute coronary syndrome: a pooled randomized clinical trial analysis.

Traditional statistical models allow population based inferences and comparisons. Machine learning (ML) explores datasets to develop algorithms that do not assume linear relationships between variables and outcomes and that may account for higher order interactions to make individualized outcome predictions. To evaluate the performance of machine learning models compared to traditional risk stratification methods for the prediction of major adverse cardiovascular events (MACE) and bleeding in patients with acute coronary syndrome (ACS) that are treated with antithrombotic therapy. Data on 24,178 ACS patients were pooled from four randomized controlled trials. The super learner ensemble algorithm selected weights for 23 machine learning models and was compared to traditional models. The efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. The safety endpoint was a composite of TIMI major and minor bleeding or bleeding requiring medical attention. For the MACE outcome, the super learner model produced a higher c-statistic (0.734) than logistic regression (0.714), the TIMI risk score (0.489), and a new cardiovascular risk score developed in the dataset (0.644). For the bleeding outcome, the super learner demonstrated a similar c-statistic as the logistic regression model (0.670 vs. 0.671). The machine learning risk estimates were highly calibrated with observed efficacy and bleeding outcomes (Hosmer-Lemeshow p value = 0.692 and 0.970, respectively). The super learner algorithm was highly calibrated on both efficacy and safety outcomes and produced the highest c-statistic for prediction of MACE compared to traditional risk stratification methods. This analysis demonstrates a contemporary application of machine learning to guide patient-level antithrombotic therapy treatment decisions.Clinical Trial Registration ATLAS ACS-2 TIMI 46: https://clinicaltrials.gov/ct2/show/NCT00402597. Unique Identifier: NCT00402597. ATLAS ACS-2 TIMI 51: https://clinicaltrials.gov/ct2/show/NCT00809965. Unique Identifier: NCT00809965. GEMINI ACS-1: https://clinicaltrials.gov/ct2/show/NCT02293395. Unique Identifier: NCT02293395. PIONEER-AF PCI: https://clinicaltrials.gov/ct2/show/NCT01830543. Unique Identifier: NCT01830543.

The Role of Ticagrelor in STEMI Fibrinolytic and Its Rationale to Utilize for Indonesian Patients

Worldwide, ischemic heart disease is the most common cause of death and its frequency is increasing. ST-segment elevation myocardial infarction or STEMIis as form of ischemic heart disease with the highest mortality rate.&#x0D; Based on ESC (European Society of Cardiology) guideline 2017 for STEMI management, reperfusion therapywhich is primary PCI strategy is recommended over fibrinolysis within induced timeframes, but if timely primary PCI cannot be performed after STEMI diagnosis, fibrinolytic therapy is recommended within 12 hours of symptom onset in patients without contraindications. In fibrinolytic therapy, oral aspirin should be given, and Clopidogrel is indicated as an addition to aspirin. Although Clopidogrel is a recommended P2Y12receptor inhibitorin fibrinolytic therapy,PERKI guideline 2018 in ACS management also mention thatswitching to Ticagrelor can be considered in patients whowillundergo PCI treatmentafter fibrinolytic.&#x0D; In PLATO study, patients who have acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke. However, patients who received fibrinolytic therapy within 24 hours before randomization were excluded. WhileinSET-FAST study, Ticagrelor provides more prompt and potent platelet inhibition compared with Clopidogrel in patients undergoing PCI within 24 hours of receiving fibrinolysis for STEMI. TREAT study was conducted to evaluate the safety of ticagrelor in STEMI patients receiving fibrinolytic therapy within 24 hours.TREAT study concluded, at 30 days observation, in patients younger than 75 years with STEMI, delayed administration of Ticagrelor after fibrinolytic therapy was noninferior to Clopidogrel for TIMI major bleeding.&#x0D; Based on the result from PLATO study and preliminary TREAT study result on 30 days, the use of Ticagrelor within 24 hours after fibrinolytic therapy can be considered with comparable safety profile to Clopidogrel.&#x0D; &#x0D; Keywords: STEMI, fibrinolysis, ticagrelor

Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial

Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population). Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8-3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74-0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, pinteraction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78-1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75-1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48-2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36-3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74-1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75-0·95, p=0·005, in contrast to patients without PCI where it did not, pinteraction=0·012. Benefit was present irrespective of time from most recent PCI. In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk. AstraZeneca.

Resolute zotarolimus-eluting stent in ST-elevation myocardial infarction (resolute-STEMI): A prespecified prospective register from the DAPT-STEMI trial.

To evaluate the safety and efficacy outcomes after primary percutaneous coronary intervention (pPCI) with second-generation Resolute™ zotarolimus-eluting stent (R-ZES) in patients enrolled in the DAPT-STEMI Trial (NCT01459627). R-ZES is one of the most used drug eluting stents worldwide. To date, the safety and efficacy data of this stent in setting of STEMI is limited. The Resolute-STEMI is a prespecified prospective register that reports the safety and efficacy of R-ZES in setting of ST-Elevation Myocardial Infarction (STEMI) at 6 months for the following endpoints: a composite endpoint of all-cause mortality, any myocardial infarction (MI), any (unscheduled) revascularization, stroke and TIMI major bleeding, as well as target lesion failure and stent thrombosis (ST). From a total of 1,100 STEMI patients enrolled in the trial, 998 received a R-ZES. At 6 months the PE occurred in 42 (4.2%) patients. All-cause death, MI, revascularization, stroke and TIMI major bleeding was respectively 8 (0.8%), 9 (0.8%), 34 (3.4%), 2 (0.2%), and 4 (0.4%). The rate of target lesion revascularizations involving the culprit lesion was 1.1%. Target lesion failure was 1.5%. The rate of definite ST was 0.5%. The rate of both definite or probable ST was 0.7%. The present analysis is the largest to date reporting short-term and mid-term clinical outcomes with the R-ZES stent in setting of STEMI. At 30 days and 6-months R-ZES has an outstanding safety and efficacy even in this high-risk category of patients.

Tailored P2Y12 inhibitor treatment in patients undergoing non-urgent PCI-the POPular Risk Score study.

The POPular Risk Score was developed for the selective intensification of P2Y12 inhibitor treatment with prasugrel instead of clopidogrel in patients undergoing non-urgent percutaneous coronary intervention (PCI) with stent implantation. This score is based on platelet reactivity (VerifyNow P2Y12 assay), CYP2C19 genotyping, and clinical risk factors. Our aim was to determine if the use of this score in clinical practice is associated with a reduction in thrombotic events without increasing bleeding events. In a single-center prospective cohort study, patients with a high risk score were treated with prasugrel and patients with a low risk score with clopidogrel. The risk score-guided cohort was compared with a historic cohort of clopidogrel-treated patients. The endpoint consisted of all-cause death, myocardial infarction, stroke, or stent thrombosis during 1year of follow-up. TIMI major and minor bleeding events were also analyzed. The guided cohort contained 1127 patients, 26.9% of whom were switched to prasugrel according to the POPular Risk Score. The historic cohort contained 893 patients. The incidence of the combined thrombotic endpoint was significantly lower in the guided cohort as compared with the historic cohort (8.4% versus 3.7%, p < 0.001). This strategy was safe with respect to bleeding (4.0% versus 1.3%, p < 0.001, for TIMI major or minor bleeding). Results were comparable after multivariate and propensity score matched and weighted analysis. Selective intensification of P2Y12 inhibitor treatment after non-urgent PCI based on the POPular Risk Score is associated with a reduction in thrombotic events without an increase in bleeding events.

Incidence, predictors, and prognosis of premature discontinuation or switch of prasugrel or ticagrelor: the ATLANTIS - SWITCH study

Aim of the present study was to investigate the frequency and predictors of premature discontinuation or switch of ADP receptor blockers and its association with serious adverse events. For this purpose 571 consecutive ACS patients receiving ticagrelor (n = 258, 45%) or prasugrel (n = 313, 55%) undergoing PCI were enrolled in this prospective, observational, multicenter ATLANTIS-SWITCH substudy. Predictors of premature discontinuation or switch of antiplatelet therapy and their association with major adverse cardiovascular events and TIMI bleeding events were evaluated. Premature stop/switch was found in 72 (12.6%) patients: 34 (5.9%) stopped and 38 (6.7%) switched the ADP blocker. Ticagrelor treated patients were significantly more likely to stop/switch therapy as compared to prasugrel (15.9% vs. 9.2%, p = 0.016). We identified 4 independent predictors for stop/switch of ADP blocker: major surgery, need for oral anticoagulation (OAC), TIMI major bleeding and drug intolerance. TIMI major bleeding was a driver of stop/switch actions and occurred in 4.3% vs 0.2% in patients with vs without stop/switch (p = 0.001). The majority of stop/switch actions (75%) were physicians driven decisions. Importantly, stop/switch of therapy was not associated with increased risk of MACE (p = 0.936). In conclusion premature switch/stop of ADP blockers appears to be safe when mainly driven by physician’s decision and clinical indication.