Rivaroxaban and usual care had similar rates of recurrent VTE and bleeding in symptomatic PE

QUESTION In patients with symptomatic pulmonary embolism (PE), what are the effects of rivaroxaban compared with usual care on recurrent venous thromboembolism (VTE) and bleeding? METHODS DESIGN Randomized controlled trial (EINSTEIN-Pulmonary Embolism Study). ClinicalTrials.gov NCT00439777. ALLOCATION Concealed.* BLINDING Blinded* (outcome adjudication committee and {data analysts}?). FOLLOW-UP PERIOD Mean 9 months. SETTING 263 sites in 38 countries. PATIENTS 4833 adults (mean age 58 y, 53% men) with acute, symptomatic, objectively verified PE with or without symptomatic deep venous thrombosis (DVT). Exclusion criteria included low-molecular-weight heparin, fondaparinux, or unfractionated heparin for >?48 hours, or >?1 dose of a vitamin K agonist (VKA) before randomization; or another indication for VKA treatment. INTERVENTION Oral rivaroxaban, 15 mg twice daily for 3 weeks and then 20 mg once daily (n =?2420); or usual care with enoxaparin, 1.0 mg/kg body weight twice daily (for ≥?5 d until international normalized ratio [INR] was ≥?2.0 for 2 consecutive d) plus a VKA (warfarin or acenocoumarol) started within 48 hours of randomization, with dose adjusted to maintain INR at 2.0 to 3.0 (n =?2413). OUTCOMES Primary efficacy outcome was symptomatic recurrent VTE (composite of fatal or nonfatal PE or DVT). Primary safety outcome was clinically relevant bleeding (composite of major or clinically relevant nonmajor bleeding). Secondary outcomes included major bleeding (clinically overt bleeding; decrease in hemoglobin level ≥?2.0 g/dL; transfusion of ≥?2 units of red cells; or if bleeding was intracranial or retroperitoneal, occurred in other critical sites, or contributed to death). PATIENT FOLLOW-UP 99.6% (intention-to-treat analysis). MAIN RESULTS The main results are in the Table. {Results are consistent with an absolute reduction in recurrent VTE with rivaroxaban of 5 per 1000 patients or an increase of 10 per 1000 patients, and a reduction in clinically relevant bleeding of 28 per 1000 patients or an increase of 7 per 1000 patients}?. CONCLUSION Rivaroxaban and usual care had similar rates of recurrent venous thromboembolism and clinically relevant bleeding in patients with symptomatic pulmonary embolism.Rivaroxaban vs usual care for symptomatic pulmonary embolism§OutcomesRivaroxabanUsual careAt a mean 9 moRRI (95% CI)NNH (CI)Recurrent VTE2.1%1.8%12% (-25 to 67)NSRRR (CI)NNT (CI)Clinically relevant bleeding||?10.3%11.4%9% (-7 to 23)NSMajor bleeding||**1.1%2.2%51% (21 to 69)92 (68 to 223)§NS = not significant; VTE = venous thromboembolism; other abbreviations defined in Glossary. RRI, RRR, NNH, NNT, and CI calculated from control event rates and hazard ratios in article. Analyses were adjusted for cancer at baseline.||Patients receiving ≥?1 dose of study drug (n =?4817).?Composite of major or clinically relevant nonmajor bleeding.**Clinically overt bleeding; decrease in hemoglobin level ≥?2.0 g/dL; transfusion of ≥?2 units of red cells; or if bleeding was intracranial or retroperitoneal, occurred in other critical sites, or contributed to death.     

Drotrecogin alfa (activated) did not reduce mortality at 28 or 90 days in patients with septic shock

QUESTION Does drotrecogin alfa (activated) (DrotAA) reduce mortality in patients with septic shock? METHODS DESIGN Randomized placebo-controlled trial (Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock [PROWESS-SHOCK] study). ClinicalTrials.gov NCT00604214. ALLOCATION Concealed.* BLINDING Blinded* (patients, clinicians, investigators, and sponsors). FOLLOW-UP PERIOD 90 days. SETTING 208 sites in Europe, North and South America, Australia, New Zealand, and India. PATIENTS 1697 patients ≥?18 years of age (mean age 63 y, 56% men) who had sepsis (infection and ≥?2 signs of systemic inflammation), shock (norepinephrine, ≥?5 μg/min, or equivalent dose of another vasopressor for ≥?4 h, and crystalloid, ≥?30 mL/kg body weight, or equivalent colloid volume within 8 h of vasopressor initiation), and evidence of hypoperfusion; were refractory to vasopressor weaning; and began the study drug ≤?24 hours after the first dose of a vasopressor. Patients with coexisting illness at high risk for death were excluded. INTERVENTION IV DrotAA (Xigris, Eli Lilly), 24 μg/kg body weight/h for 96 hours (n =?852), or placebo (0.9% saline) (n =?845). If study infusions were interrupted for procedures, they continued to day 6 to complete the 96-hour infusion. OUTCOMES Primary outcome was 28-day mortality. Secondary outcomes included 90-day mortality, serious adverse events, and bleeding events. 1500 patients were needed to detect a 7% absolute reduction from 35% in 28-day mortality (80% power, α =?0.05); sample size was increased to 1696 because mortality rate after recruitment of 750 patients was 28%. PATIENT FOLLOW-UP 98% at 90 days (intention-to-treat analysis). MAIN RESULTS DrotAA did not reduce mortality at 28 or 90 days (Table). Risk for nonserious bleeding events during treatment was higher with DrotAA (Table). CONCLUSION Drotrecogin alfa (activated) did not reduce mortality at 28 or 90 days in patients with septic shock.Drotrecogin alfa (activated) (DrotAA) vs placebo in patients with septic shock?OutcomesEvent ratesRRI (95% CI)NNH (CI)DrotAAPlacebo28-d mortality26%24%9% (-8 to 28)NS90-d mortality34%33%4% (-10 to 19)NS≥?1 serious adverse event at 28 d14%12%23% (-4 to 59)NS≥?1 nonserious bleeding event?8.6%4.8%80% (23 to 161)27 (13 to 91)≥?1 serious bleeding event?1.2%1.0%25% (-51 to 215)NS?NS = not significant; other abbreviations defined in Glossary. RRI, NNH, and CI calculated from control event rates and relative risks in article.?During treatment period.     

Optimal duration of dual antiplatelet therapy following treatment with the endeavor zotarolimus‐eluting stent in real‐world Japanese patients with coronary artery disease (OPERA): Study design and rationale

Background: In patients with coronary artery disease (CAD), there is an increasing therapeutic need among interventional cardiologists to conduct dual antiplatelet therapy (DAPT) whose duration is shorter than current guideline‐recommended 6–12 months after the implantation of drug‐eluting stents. However, no clinical grounds sufficient to rationalize the need are available. Objectives: To define the optimal duration of DAPT and to examine the safety and efficacy of the Endeavor zotarolimus‐eluting stent (E‐ZES) in real‐world Japanese patients with CAD. Study design: The present prospective, nonrandomized, multicenter, controlled study is uniquely designed to examine the analysis set to be formulated after integrating two different databases consisting of the following two study arms: the 3‐month DAPT arm, in which 1,210 patients were consecutively enrolled at 106 medical institutions; and the 12‐month DAPT arm, in which 1,210 patients will be consecutively extracted from the Endeavor Japan post‐marketing surveillance at 60 medical institutions. The primary endpoint is “net adverse cardiac and cerebrovascular events—death, myocardial infarction, cerebrovascular accident, and major bleeding)” at 12 months after implantation. The secondary endpoints are as follows: major adverse cardiac events at 1, 3, 6, 9, and 12 months after implantation; target vessel revascularization and target lesion revascularization at 9 and 12 months after implantation; and stent thrombosis, DAPT compliance, and bleeding events at 12 months after implantation. Noninferiority in the E‐ZES's profiles between the study arms will be investigated. Conclusions: The present study will provide insight into the optimal duration of DAPT after the E‐ZES implantation in individual, real‐world patients with CAD. © 2013 Wiley Periodicals, Inc.     

1-Month Dual-Antiplatelet Therapy Followed by Aspirin Monotherapy After Polymer-Free Drug-Coated Stent Implantation: One-Month DAPT Trial

ObjectivesThe aim of this study was to determine whether 1 month of dual-antiplatelet therapy (DAPT) followed by aspirin monotherapy after polymer-free drug-coated stent (PF-DCS) implantation is noninferior to 6 to 12 months of DAPT after biodegradable-polymer drug-eluting stent (BP-DES) implantation.BackgroundIt is necessary to determine the optimal minimal duration of DAPT followed by aspirin monotherapy after percutaneous coronary intervention (PCI).MethodsIn this trial, 3,020 patients with coronary artery disease considered for PCI for noncomplex lesions were randomized to 1-month DAPT after PF-DCS (n = 1,507) or 6- to 12-month DAPT after BP-DES (n = 1,513). The primary endpoint was the 1-year composite of cardiac death, nonfatal myocardial infarction, target vessel revascularization, stroke, or major bleeding (noninferiority hypothesis margin of 3%).ResultsThe primary endpoint occurred in 88 patients (5.9%) in the 1-month DAPT after PF-DCS group and 98 patients (6.5%) in the 6- to 12-month DAPT after BP-DES group (absolute difference −0.7%; upper limit of 1-sided 97.5% confidence interval: 1.33%; P < 0.001 for noninferiority). The occurrence of major bleeding was not different (1.7% vs 2.5%; P = 0.136). There was no difference in the occurrence of stent thrombosis (0.7% vs 0.8%; P = 0.842).ConclusionsAmong patients who underwent PCI for noncomplex lesions, 1-month DAPT followed by aspirin monotherapy after PF-DCS implantation was noninferior to 6- to 12-month DAPT after BP-DES implantation for the 1-year composite of cardiovascular events or major bleeding. The present findings need to be interpreted in the setting of different types of stents according to antiplatelet strategy. (A Randomized Controlled Comparison Between One Versus More Than Six Months of Dual Antiplatelet Therapy After Biolimus A9-Eluting Stent Implantation; NCT02513810)     

DAPT Score and the Impact of Ticagrelor Monotherapy During the Second Year After PCI

ObjectivesThis study assessed the ability of the dual-antiplatelet therapy (DAPT) score in stratifying ischemic and bleeding risk in a contemporary percutaneous coronary intervention (PCI) population.BackgroundThe DAPT score is recommended by guidelines as a tool to stratify ischemic and bleeding risk. Its utility in contemporary PCI is unknown.MethodsThe study studied patients in GLOBAL LEADERS (A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation) who were free of major ischemic and bleeding events and adhered to antiplatelet strategy during the first year after PCI. The primary ischemic endpoint was the composite of myocardial infarction or stent thrombosis. The primary bleeding endpoint was Bleeding Academic Research Consortium type 3 or 5. Outcomes from 12 to 24 months after PCI were compared according to the DAPT score.ResultsOf 11,289 patients that were event-free after the first year, 6,882 and 4,407 patients had low (<2) and high (≥2) DAPT scores, respectively. Compared with a low DAPT score, patients with a high DAPT score had a higher rate of the composites of myocardial infarction or stent thrombosis (0.70% vs. 1.55%; p < 0.0001). The rate of Bleeding Academic Research Consortium type 3 or 5 bleeding was 0.54% and 0.30% in the low and high DAPT score groups, respectively (p = 0.058). The effect of ticagrelor versus aspirin monotherapy on primary ischemic and bleeding endpoints during the second year were no different among the 2 groups.ConclusionsThe DAPT score can stratify ischemic but not bleeding risk in a contemporary PCI population during the second year. The score did not provide additional value for selection of antiplatelet strategy beyond the first year.     

Impact of prolonged dual antiplatelet therapy on patients after drug-eluting stents implantation

Background Impact of dual antiplatelet therapy beyond 12 months on patients implanted with DES remains unsolved.Methods From January 2010 to June 2011,1873 patients who have been taking DAPT and free from death,myocardial infarction,stroke,repeat coronary revascularization,stent thrombosis,and major or minor bleeding according to TIMI criteria for 12 months after implantation of DES were randomly assigned to continuous (prolonged DAPT group) or discontinuous (standard DAPT group) clopidogrel (75 mg/day).The primary outcome was major adverse cardiovascular events (MACEs) which compose of death,nonfatal myocardial infarction (MI),nonfatal stroke,target vessel revascularization (TVR) or stent thrombosis (ST) at 180 days.Results There was no significant difference in the incidence of 180-day MACEs between prolonged DAPT group and standard DAPT group (8.98 % versus 10.13 %,respectively,P=0.400).The frequency of major bleeding was 0.64 % in prolonged DAPT arm and 0.43% in standard DAPT arm (P=0.523),that of minor bleeding was 3.32 % versus 2.87 % (P=0.585),respectively.Conclusions Prolonged DAPT beyond 12 months neither improve prognosis nor increase risk of bleeding in patients implanted with DES.     

Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents

Background Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications, yet the benefits and risks of treatment beyond 1 year are uncertain.Methods Patients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed. After 12 months of treatment with a thienopyridine drug(clopidogrel or prasugrel) and aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another18 months; all patients continued receiving aspirin. The coprimary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events(a composite of death, myocardial infarction, or stroke) during the period from 12 to 30 months. The primary safety end point was moderate or severe bleeding.Results A total of 9961 patients were randomly assigned to continue thienopyridine treatment or to receive placebo.Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis(0.4% vs. 1.4%; hazard ratio, 0.29 [95% confidence interval {CI}, 0.17 to 0.48]; P 0.001) and major adverse cardiovascular and cerebrovascular events(4.3% vs. 5.9%; hazard ratio, 0.71 [95% CI, 0.59 to 0.85];P 0.001). The rate of myocardial infarction was lower with thienopyridine treatment than with placebo(2.1% vs. 4.1%; hazard ratio, 0.47; P 0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group(hazard ratio, 1.36 [95% CI, 1.00 to 1.85];P = 0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment(2.5% vs. 1.6%, P = 0.001). An elevated risk of stent thrombosis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment.Conclusions Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding.(Funded by a consortium of eight device and drug manufacturers and others; DAPT Clinical Trials.gov number, NCT00977938.)(From: N Engl J Med 2014; 371:2155-2166 December 4, 2014DOI: 10.1056 / NEJMoa1409312)     

Clinical Outcome of First‐ vs Second‐Generation DES According to DAPT Duration: Results of ARCTIC‐Generation

There is an apparent benefit with extension of dual antiplatelet therapy (DAPT) beyond 1 year after implantation of drug‐eluting stents (DES). Assessment by a Double Randomization of a Conventional Antiplatelet Strategy vs a Monitoring‐Guided Strategy for Drug‐Eluting Stent Implantation, and of Treatment Interruption vs Continuation One Year After Stenting (ARCTIC)‐Generation assessed whether there is a difference of outcome between first‐ vs second‐generation DES and if there is an interaction with DAPT duration in the ARCTIC‐Interruption study. ARCTIC‐Interruption randomly allocated 1259 patients 1 year after stent implantation to a strategy of interruption of DAPT (n = 624), in which aspirin antiplatelet treatment only was maintained, or DAPT continuation (n = 635) for 6 to 18 additional months. The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization. A total of 520 and 722 patients received a first‐ and a second‐generation DES, respectively. After a median follow‐up of 17 months (interquartile range, 15–18 months) after randomization, the primary endpoint occurred in 32 (6.2%) and 19 (2.6%) patients with first‐ and second‐generation DES, respectively (hazard ratio: 2.31, 95% confidence interval: 1.31‐4.07, P = 0.004). This was observed irrespective of the strategy of interruption or continuation of DAPT and timing of study recruitment. Major bleeding events occurred in 4 (0.8%) and 3 patients (0.4%) with first‐ and second‐generation DES, respectively (hazard ratio: 1.79, 95% confidence interval: 0.40‐8.02, P = 0.44). Results did not change after multiple adjustments for potential confounding variables. ARCTIC‐Generation showed worse clinical outcome with first‐ vs second‐generation DES, a difference that appeared to persist even with prolonged DAPT.     

Warfarin and aspirin did not differ for death or stroke in heart failure and sinus rhythm

QUESTION What are the relative efficacy and safety of warfarin and aspirin in patients with heart failure who are in sinus rhythm? METHODS DESIGN Randomized controlled trial (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction [WARCEF] trial). ClinicalTrials.gov NCT00041938. ALLOCATION {Concealed}*.? BLINDING Blinded? (patients, clinicians, {data collectors, safety committee}*, and outcome assessors). FOLLOW-UP PERIOD ≤?6 years (mean 3.5 y). SETTING 168 centers in the USA, Canada, Argentina, and Europe. PATIENTS 2305 adults ≥?18 years of age (mean age 61 y, 80% men) who had a left ventricular ejection fraction (LVEF) ≤?35% and normal sinus rhythm, and planned treatment with a β-blocker, angiotensin-converting enzyme inhibitor, or hydralazine and nitrates. Exclusion criteria included modified Rankin score >?4, medical conditions with high risk for cardiac embolism, clear indication for warfarin or aspirin, or contraindication to warfarin. Patients in New York Heart Association class I were eligible but could not comprise >?20% of randomized patients. INTERVENTION Active warfarin (with target international normalized ratio 2.0 to 3.5) plus aspirin placebo (n =?1142), or aspirin, 325 mg/d, plus warfarin placebo (n =?1163). OUTCOMES Primary composite endpoint of ischemic stroke, intracerebral hemorrhage (ICH), or death. Secondary outcome was a composite of ischemic stroke, ICH, death, myocardial infarction, or hospitalization for heart failure. The safety outcome was a composite of ischemic stroke, ICH, death, or intracranial hemorrhage. The trial had 69% power to detect a relative hazard reduction of 17.8% in the primary outcome and 83% power for the secondary outcome. PATIENT FOLLOW-UP {93%}* (96% for vital status; intention-to-treat analysis). MAIN RESULTS Enrolment was stopped early because of slow recruitment. Groups did not differ for the primary composite outcome or any of its components except for ischemic stroke (Table). Groups also did not differ for the secondary or safety composite endpoints (Table). CONCLUSION In patients with heart failure who are in sinus rhythm, warfarin and aspirin did not differ for a composite of death or ischemic or hemorrhage outcomes.Warfarin vs aspirin in patients with heart failure who are in sinus rhythm?OutcomesEvents / 100 patient-yAt a mean 3.5 yWarfarinAspirinRRR (95% CI)NNT (CI)Primary composite§7.57.9{4% (-10 to 16)}||Not significantSafety composite?7.68.0{3% (-11 to 15)}||Not significantRRI (CI)NNH (CI)Secondary composite**12.712.2{5% (-6 to 16)}||Not significant?Abbreviations defined in Glossary.§Ischemic stroke {0.7 vs 1.4, RRR 46%, 95% CI 16 to 65}||, intracerebral hemorrhage {0.12 vs 0.05, RRI 155%, CI -51 to 1210}||, or death {6.6 vs 6.5, RRI 4%, CI -11 to 20}||.||Estimates provided by author.?Ischemic stroke, intracerebral hemorrhage, death, or intracranial hemorrhage.**Ischemic stroke, intracerebral hemorrhage, death, myocardial infarction, or hospitalization for heart failure.     

Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation

Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is a widely accepted strategy in patients undergoing transcatheter aortic valve implantation (TAVI), but this approach is not evidence based. The goal of the present study was to determine whether DAPT in patients undergoing TAVI is associated with improved outcomes compared to aspirin alone. From May 2009 to August 2010, consecutive patients were randomized to receive a 300-mg loading dose of clopidogrel on the day before TAVI followed by a 3-month maintenance daily dose of 75 mg plus aspirin 100 mg lifelong (DAPT group) or aspirin 100 mg alone (ASA group). The primary end point was the composite of major adverse cardiac and cerebrovascular events, defined as death from any cause, myocardial infarction, major stroke, urgent or emergency conversion to surgery, or life-threatening bleeding. The cumulative incidence of major adverse cardiac and cerebrovascular events at 30 days and 6 months was 14% and 16%, respectively. No significant differences between the DAPT and ASA groups were noted at both 30 days (13% vs 15%, p = 0.71) and 6 months (18% vs 15%; p = 0.85). In conclusion, the strategy of adding clopidogrel to aspirin for 3 months after TAVI was not found to be superior to aspirin alone. These results must be confirmed in a larger randomized trial.     

Stent Thrombosis in Drug-Eluting or Bare-Metal Stents in Patients Receiving Dual Antiplatelet Therapy

ObjectivesThis study sought to compare rates of stent thrombosis and major adverse cardiac and cerebrovascular events (MACCE) (composite of death, myocardial infarction, or stroke) after coronary stenting with drug-eluting stents (DES) versus bare-metal stents (BMS) in patients who participated in the DAPT (Dual Antiplatelet Therapy) study, an international multicenter randomized trial comparing 30 versus 12 months of dual antiplatelet therapy in subjects undergoing coronary stenting with either DES or BMS.BackgroundDespite antirestenotic efficacy of coronary DES compared with BMS, the relative risk of stent thrombosis and adverse cardiovascular events is unclear. Many clinicians perceive BMS to be associated with fewer adverse ischemic events and to require shorter-duration dual antiplatelet therapy than DES.MethodsProspective propensity-matched analysis of subjects enrolled into a randomized trial of dual antiplatelet therapy duration was performed. DES- and BMS-treated subjects were propensity-score matched in a many-to-one fashion. The study design was observational for all subjects 0 to 12 months following stenting. A subset of eligible subjects without major ischemic or bleeding events were randomized at 12 months to continued thienopyridine versus placebo; all subjects were followed through 33 months.ResultsAmong 10,026 propensity-matched subjects, DES-treated subjects (n = 8,308) had a lower rate of stent thrombosis through 33 months compared with BMS-treated subjects (n = 1,718, 1.7% vs. 2.6%; weighted risk difference −1.1%, p = 0.01) and a noninferior rate of MACCE (11.4% vs. 13.2%, respectively, weighted risk difference −1.8%, p = 0.053, noninferiority p < 0.001).ConclusionsDES-treated subjects have long-term rates of stent thrombosis that are lower than BMS-treated subjects. (The Dual Antiplatelet Therapy Study [DAPT study]; NCT00977938)     

Dual Antiplatelet Therapy and Outcomes in Patients With Atrial Fibrillation and Acute Coronary Syndromes Managed Medically Without Revascularization: Insights From the TRILOGY ACS Trial

Associations between atrial fibrillation (AF), outcomes, and response to antiplatelet therapies in patients with acute coronary syndrome (ACS) managed medically without revascularization remain uncertain. We examined these associations for medically managed ACS patients randomized to dual antiplatelet therapy (DAPT) using patient data from the TRILOGY ACS trial. DAPT included aspirin plus clopidogrel 75 mg/d or prasugrel 10 mg/d (5 mg/d for those <60 kg or age ≥75 years). Patients receiving oral anticoagulants were excluded. Cox proportional hazards regression modeling was used to characterize associations between patients with AF (AF+) vs those without (AF?) and risk of ischemic and bleeding events, and to explore effects of randomized treatment on outcomes. Among 9101 patients with baseline AF status, 710 (7.8%) had AF. AF+ patients were older and had more comorbidities. Unadjusted associations of the composite of cardiovascular death/myocardial infarction/stroke were significantly higher among AF patients at 30 months (31.1% vs 18.4%; HR: 1.61, 95% CI: 1.35‐1.92, P < 0.001), but differences did not persist after adjustment (HR: 1.16, 95% CI: 0.97‐1.39, P = 0.11). When individual components of the composite endpoint were evaluated, 30‐month risk of events in AF+ patients was significantly higher. Thirty‐month risk of all‐cause death was significantly higher in AF+ patients: 18.1% vs 11.1% (HR: 1.62, 95% CI: 1.30‐2.02, P < 0.001). There was no significant interaction with randomized treatment and AF for the primary endpoint. Among medically managed high‐risk ACS patients receiving DAPT, AF was associated with higher unadjusted risks of ischemic and bleeding outcomes that were similar by treatment group.     

Thrombotic Complications Associated With Early and Late Nonadherence to Dual Antiplatelet Therapy

ObjectivesThis study sought to assess the frequency and clinical impact of dual antiplatelet therapy (DAPT) nonadherence.BackgroundThere are limited data on the impact of DAPT nonadherence during the first year after a second-generation drug-eluting stent placement.MethodsAfter successful Endeavor zotarolimus-eluting stent implantation, 2,265 patients were enrolled in a registry with limited exclusions and monitored during 12 months of prescribed DAPT. Predictors of any nonadherence (ANA) at 6 months were analyzed by multivariable analysis, and the association between ANA at 6 or 12 months with the endpoints of death, myocardial infarction, and stent thrombosis was assessed.ResultsThe study population included 30% female patients, 34% with diabetes and 36% with acute coronary syndromes. ANA occurred in 208 patients (9.6%) before 6 months and 378 patients (18.5%) before 1 year. Major bleeding (odds ratio [OR]: 12.83, 95% confidence interval [CI]: 7.55 to 21.80, p < 0.001) was the only predictor of ANA at 6 months. In time-dependent analyses, ANA before 6 months was associated with an increased risk of death or myocardial infarction (7.6% vs. 3.0%, p < 0.001) and a numerical increase in stent thrombosis (2.0% vs. 0.9%, p = 0.12). After adjustment for baseline differences, ANA within 6 months remained associated with death or MI (OR: 1.95, 95% CI: 1.02 to 3.75). ANA occurring after 6 months did not increase the risk of subsequent ischemic events.ConclusionsDAPT ANA occurs frequently and is associated with increased risk for thrombotic complications if it occurs within the first 6 months. Major bleeding was a significant correlate of DAPT ANA within 6 months. (EDUCATE: The MEDTRONIC Endeavor Drug Eluting Stenting: Understanding Care, Antiplatelet Agents and Thrombotic Events; NCT01069003)     

Review: Antiplatelet therapy does not reduce mortality in chronic kidney disease

QUESTION What are the effects of antiplatelet therapy on mortality and cardiovascular (CV) events in patients with chronic kidney disease (CKD)? REVIEW SCOPE Included studies compared antiplatelet agents with control (placebo, standard care, or no treatment) in adults with CKD. Trials with follow-up <?2 months in duration and those that did not provide data in an extractable format were excluded. Outcomes were mortality, CV events, and bleeding. REVIEW METHODS EMBASE/Excerpta Medica (1980 to Nov 2011), Cochrane Central Register of Controlled Trials (2011, Issue 4), Cochrane Renal Group's specialized register (Nov 2011), and reference lists of retrieved publications were searched for randomized controlled trials (RCTs). Investigators were contacted. 27 RCTs (n =?10?973) of patients with stable or no CV disease met the section criteria. Median follow-up was 12 months. Study quality was low to moderate as assessed by the Grading of Recommendations Assessment, Development, and Evaluation guidelines. MAIN RESULTS Meta-analysis showed that antiplatelet therapy reduced risk for myocardial infarction and increased minor bleeding (Table). Groups did not differ for all-cause mortality, CV mortality, stroke, or major bleeding (Table). CONCLUSION In patients with chronic kidney disease, antiplatelet therapy reduces myocardial infarction, but not mortality, and increases minor bleeding.Antiplatelet therapy vs control in patients with chronic kidney disease and stable or no cardiovascular disease*OutcomesNumber of trials (n)Weighted event ratesAt a median 12 moAntiplateletsControlRRR (95% CI)NNT (CI)All-cause mortality21 (10?632)6.2%7.2%13% (-24 to 39)Not significantCardiovascular mortality16 (8706)3.4%3.8%9% (-36 to 40)Not significantMyocardial infarction10 (9133)2.2%3.3%34% (13 to 49)89 (62 to 232)Stroke10 (9133)1.3%2.0%34% (-178 to 84)Not significantRRI (CI)NNH (CI)Major bleeding18 (10?230)1.6%1.3%29% (-31 to 142)Not significantMinor bleeding8 (7202)12%6.9%70% (44 to 102)21 (15 to 34)*Abbreviations defined in Glossary. RRR, RRI, NNT, NNH, and CI calculated from control event rates and relative risks in article using a random-effects model.     

Shortened dual antiplatelet therapy in contemporary percutaneous coronary intervention era

Percutaneous coronary intervention with stenting is followed by a duration of dual antiplatelet therapy (DAPT) to reduce stent thrombosis and avoid target lesion failure. The period of DAPT recommended in international guidelines following drug-eluting stent implantation is 12 mo for most patients with acute coronary syndrome, and 6 mo for patients with chronic coronary syndrome or high bleeding risk. The new generation of drug-eluting stents have metallic platforms with thinner struts, associated with significantly less stent thrombosis. Shortened DAPT has been investigated with these stents, with evidence from randomised clinical trials for some individual stents showing non-inferior safety and efficacy outcomes. This has to be balanced by the effect of DAPT on secondary prevention of systemic cardiovascular disease especially in high-risk populations. This review will outline the current evidence for individual stents with regards to DAPT duration for both acute coronary syndrome and chronic coronary syndrome and discuss further directions for research and personalised medicine in this contemporary percutaneous coronary intervention era.     

Prospective application of a bleeding and ischemic risks-adjusted antithrombotic protocol in elderly patients revascularized with everolimus-eluting stents: EPIC05-Sierra75 study

OBJECTIVESElderly patients show a higher incidence of ischemic and bleeding events after percutaneous transluminal coronary intervention (PCI). We sought to investigate outcomes in elderly patients treated with antithrombotic strategy guided by bleeding and ischemic risks after revascularization with last generation everolimus-eluting stent (EES).METHODSProspective multicenter registry including patients over 75 years revascularized with EES and antithrombotic therapy guided by clinical presentation, PCI complexity and PRECISE DAPT score. Co-primary safety endpoints were: (1) composite of cardiac death, myocardial infarction and stent thrombosis and; (2) bleeding (BARC 2-5). Primary efficacy endpoint was target lesion revascularization. A matched group of patients revascularized with current drug-eluting stents and no such tailored antithrombotic therapy was used as control.RESULTSFinally, 1064 patients were included in SIERRA-75 cohort, 80.8 ± 4.2 years, 36.6% women, 71% acute coronary syndromes (ACS) and 53.6% complex PCI. Co-primary safety endpoint of major adverse cardiovascular events was met in 6.2%, co-primary safety endpoint of bleeding in 7.8% and primary efficacy endpoint of TKLR in 1.5%. The multivariable adjusted model showed no significant association of the prescribed short/long dual antiplatelet therapy (DAPT) durations with any endpoint suggesting a well tailored therapy. No stent thrombosis reported in the subgroup with 1-3 months DAPT duration. As compared to control group, bleeding BARC 2-5 was significantly lower in SIERRA-75 group (7.4% vs. 10.2%, P = 0.04) as well as the net safety-efficacy endpoint (14.3% vs. 18.5%, P = 0.02). CONCLUSIONSIn elderly population, the application of this risks-adjusted antithrombotic protocol after revascularization with last generation EES seems to be associated with an improved prognosis in terms of ischemic and bleeding outcomes.     

Meta-Analysis of the Efficacy and Safety of P2Y12 Inhibitor Monotherapy After Short Course of Dual-Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention

BackgroundGuidelines recommend dual antiplatelet therapy (DAPT) following drug-eluting stent (DES) placement for ≥12 months in acute coronary syndrome or 6 months in stable coronary artery disease. However, with the advent of newer-generation stents, the optimal duration of DAPT to balance bleeding and thrombotic risks has been debated.ObjectivesWe aimed to perform a meta-analysis of randomized controlled trials (RCT) comparing P2Y₁₂ monotherapy in short-duration group (SDG) vs. standard treatment group (STG) course of DAPT in patients undergoing PCI.MethodsElectronic databases were searched for RCTs of patients undergoing percutaneous coronary intervention (PCI) with DES placement who received short (≤ 3 months) vs. standard DAPT course (≥12 months) and were followed for ≥12-months. Rates of major adverse cardiovascular events (a composite of cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke) were the primary outcome. Study-specific odds ratios (OR) and corresponding 95% confidence intervals were calculated using random-effects model.ResultsA total of 20,706 patients (10,344 in the SDG and 10,362 in the STG) were analysed from four studies. There was no significant difference observed for MACE (OR = 0.95, 95% CI: 0.81–1.08, P = .92, I² = 0%) myocardial infarction or stent thrombosis. However, lower rates of major bleeding were noted in the SDG (1.20 vs. 1.80%; OR: 0.61; 95% CI: 0.37–0.99; P = .04; I² = 71%) albeit with increased heterogeneity.ConclusionA short duration of DAPT followed by P2Y₁₂ inhibitor monotherapy was comparable to 12 months of DAPT with respect to MACE and thrombotic events, with lower rates of major bleeding events in select group of patients undergoing PCI. More data is needed to assess efficacy in patients with complex lesions and high risk ACS population including those with STEMI presentation.     

Prognostic implications of early and long-term bleeding events in patients on one-year dual antiplatelet therapy following drug-eluting stent implantation

Background : Bleeding has emerged as a predictor of early and late mortality after percutaneous coronary interventions. However, the prevalence and predictors of long‐term bleeding events in patients on prolonged dual antiplatelet therapy (DAPT) after drug‐eluting stent (DES) implantation has been poorly explored. Methods : A total of 1,437 patients undergoing DES implantation discharged on DAPT with aspirin and clopidogrel for 1 year were studied. Patients were followed for up to 4 years (34.3 ± 14.4 months) and the prevalence and predictors of in‐hospital and long‐term thrombolysis in myocardial infarction (TIMI) major and minor bleeding events evaluated. The impact of bleeding events on major adverse cardiac events (MACE), overall death, and stent thrombosis (ST) was also assessed. Results : The incidences of 30 days major and minor bleeding were 1.3 and 3.3%, respectively. The incidences of 1‐year major and minor bleeding were 3.0 and 5.6%, respectively. The incidences of major and minor bleeding up to 4‐year follow‐up were 3.6 and 6.9%, respectively. At multivariable analysis, 1‐year major bleeding was positively predicted by use of oral anticoagulants at hospital discharge [odds ratio (OR) = 13.4, 95% confidence interval (CI) 3.0–59.2, P = 0.001], anemia at admission (OR = 6.7, 95% CI = 2.7–16.5, P < 0.001) and use of glycoprotein IIb/IIIa inhibitors (OR = 2.7, 95% CI = 1.1–6.5, P = 0.03) and negatively predicted by male gender (OR = 0.39, 95% CI = 0.16–0.97, P = 0.042). Overall, major bleeding at 1 year and at long‐term follow‐up was associated with an increased risk of MACE, cardiac death and ST. Patients who had any bleeding event were more likely to prematurely discontinue antiplatelet therapy (50% vs. 9.6%, P < 0.001). Conclusions : In DES‐treated patients on prolonged DAPT, major bleeding occurring at 1 year and up to 4 years following DES implantation in patients on prolonged DAPT is associated with poor long‐term prognosis. © 2012 Wiley Periodicals, Inc.     

Optimal Duration of Dual Antiplatelet Therapy Following Percutaneous Coronary Intervention: An Umbrella Review

BackgroundThe optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention with stenting requires consideration of patient characteristics, and decision makers require a comprehensive overview of the evidence.MethodsWe performed an umbrella review of systematic reviews (SRs) of randomized controlled trials of extended DAPT (> 12 months) compared with DAPT for 6 to 12 months after percutaneous coronary intervention with stenting. Outcomes of interest were death, myocardial infarction (MI), stroke, stent thrombosis, major adverse cardiac and cerebrovascular events, bleeding, and urgent revascularization. We aimed to assess the evidence of benefits and harms among clinically important subgroups (eg, elderly patients, those with diabetes, prior MI, acute coronary syndrome). We assessed the quality of the included reviews by use of A Measurement Tool to Assess Systematic Reviews (AMSTAR).ResultsSixteen SRs involving 8 randomized controlled trials were included. Most scored 7 or more points on the AMSTAR checklist. There was no significant difference in outcomes with extended DAPT compared with 6 months of DAPT in most SRs, with the exception of an increased risk of major bleeding. Compared with 12 months, extended DAPT may reduce the risk of MI and stent thrombosis; however, the findings were not consistent across all reviews. There have been conflicting reports of an increased risk of death with extended DAPT. Few SRs assessed outcomes among patient subgroups.ConclusionsExtended DAPT may reduce the risk of MI and stent thrombosis but increase the risk of major bleeding and death. Whether the effects of extended DAPT are consistent across patient subgroups is unclear, and future SRs should address this knowledge gap.