Efficacy and Safety of Empagliflozin According to Background Diuretic Use in HFrEF: Post-Hoc Analysis of EMPEROR-Reduced.

BACKGROUND: The EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial established the efficacy of empagliflozin in reducing heart failure (HF) outcomes among patients with heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: The authors examined the outcomes of EMPEROR-Reduced as a function of background diuretic therapy. METHODS: The EMPEROR-Reduced trial was a double-blind, randomized controlled trial of placebo vs empagliflozin 10 mg among 3,730 HFrEF patients. Herein, the population was stratified into 4 groups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline. RESULTS: A total of 3,656 patients from the EMPEROR-Reduced trial were available for analysis. Of those patients, 482 (13.2%) were receiving no diuretic therapy, and 731 (20.0%), 1,411 (38.6%), and 1,032 (28.2%) were receiving <40 mg, 40 mg, and >40 mg, respectively. The efficacy of empagliflozin on the primary outcome (time to first event of hospitalization for HF or cardiovascular [CV] death) was consistent regardless of background diuretic therapy (>40 mg: HR: 0.88 [95% CI: 0.71-1.10]; 40 mg: HR: 0.65 [95% CI: 0.51-0.82]; <40 mg: HR: 0.65 [95% CI: 0.46-0.92]); no diuretic agents: HR: 0.78 [95% CI: 0.47-1.29]; Ptrend test = 0.192). Baseline diuretic doses did not influence the effect of empagliflozin on body weight, systolic blood pressure, NT-proBNP, or hematocrit at 52 weeks. The safety profile of empagliflozin vs placebo was unaffected by baseline diuretic dose; however, independently of treatment allocation, total rates of adverse events were higher among patients with higher baseline doses of diuretic agents. CONCLUSIONS: Empagliflozin exhibits a consistent effect on time to CV death or HF hospitalization and an unaltered safety profile regardless of baseline diuretic therapy. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Efficacy of empagliflozin in heart failure with preserved ejection fraction according to frailty status in EMPEROR-Preserved.

BACKGROUND: Frailty is a severe, common co-morbidity associated with heart failure (HF) with preserved ejection fraction (HFpEF). The impact of frailty on HFpEF outcomes may affect treatment choices in HFpEF. The impact of frailty on HFpEF patients and any impact on the clinical benefits of sodium glucose co-transporter 2 (SGLT2) inhibition in HFpEF have been described in only a limited number of trials. Whether the SGLT2 inhibitor empagliflozin would improve or worsen frailty status when given to HFpEF patients is also not known. The aims of this study were, therefore, to evaluate, in HFpEF patients enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), the impact of frailty on clinical outcomes, and on the effects of empagliflozin, as well as the effect of empagliflozin on frailty status during treatment period. METHODS: We calculated a cumulative deficit-derived frailty index (FI) using 44 variables including clinical, laboratory and quality of life parameters recorded in EMPEROR-Preserved. Patients were classified into four groups: non-frail (FI < 0.21), mild frailty (0.21 to <0.30), moderate frailty (0.30 to <0.40) and severe frailty (≥0.40). Clinical outcomes and health-related quality of life were evaluated according to baseline FI along with the effect of empagliflozin on chronological changes in FI (at 12, 32 and 52 weeks). RESULTS: The patient distribution was 1514 (25.3%), 2100 (35.1%), 1501 (25.1%) and 873 (14.6%) in non-frail, mild frailty, moderate frailty and severe frailty, respectively. Severe frailty patients tended to be female and have low Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, more co-morbidities and more polypharmacy. Incidence rates of the primary outcome of cardiovascular death or HF hospitalization increased as frailty worsened (hazard ratio [HR] of each FI category compared with the non-frail group: 1.10 [95% confidence interval, CI, 0.89-1.35], 2.00 [1.63-2.47] and 2.61 [2.08-3.27] in the mild frailty, moderate frailty and severe frailty groups, respectively; P trend < 0.001). Compared with placebo, empagliflozin reduced the risk for the primary outcome across the four FI categories, HR: 0.59 [95% CI 0.42-0.83], 0.79 [0.61-1.01], 0.77 [0.61-0.96] and 0.90 [0.69-1.16] in non-frail to severe frailty categories, respectively (P value for trend = 0.097). Empagliflozin also improved other clinical outcomes and KCCQ score across frailty categories. Compared with placebo, empagliflozin-treated patients had a higher likelihood of being in a lower FI category at Weeks 12, 32 and 52 (P < 0.05), odds ratio: 1.12 [95% CI 1.01-1.24] at Week 12, 1.21 [1.09-1.34] at Week 32 and 1.20 [1.09-1.33] at Week 52. CONCLUSIONS: Empagliflozin improved key efficacy outcomes with a possible diminution of effect in very frail patients. Empagliflozin also improved frailty status during follow-up.

Mineralocorticoid receptor antagonist use and the effects of empagliflozin on clinical outcomes in patients admitted for acute heart failure: Findings from EMPULSE.

AIMS: In patients hospitalized for acute heart failure (AHF) empagliflozin produced greater clinical benefit than placebo. Many patients with AHF are treated with mineralocorticoid receptor antagonists (MRAs). The interplay between empagliflozin and MRAs in AHF is yet to be explored. This study aimed to evaluate the efficacy and safety of empagliflozin versus placebo according to MRA use at baseline in the EMPULSE trial (NCT04157751). METHODS AND RESULTS: In this analysis all comparisons were performed between empagliflozin and placebo, stratified by baseline MRA use. The primary outcome included all-cause death, heart failure events, and a ≥5 point difference in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score at 90 days, assessed using the win ratio (WR). First heart failure hospitalization or cardiovascular death was a secondary outcome. From the 530 patients randomized, 276 (52%) were receiving MRAs at baseline. MRA users were younger, had lower ejection fraction, better renal function, and higher KCCQ scores. The primary outcome showed benefit of empagliflozin irrespective of baseline MRA use (WR 1.46, 95% confidence interval [CI] 1.08-1.97 and WR 1.27, 95% CI 0.93-1.73 in MRA users and non-users, respectively; interaction p = 0.52). The effect of empagliflozin on first heart failure hospitalization or cardiovascular death was not modified by MRA use (hazard ratio [HR] 0.58, 95% CI 0.30-1.11 and HR 0.85, 95% CI 0.47-1.52 in MRA users and non-users, respectively; interaction p = 0.39). Investigator-reported and severe hyperkalaemia events were infrequent (<6%) irrespective of MRA use. CONCLUSIONS: In patients admitted for AHF, initiation of empagliflozin produced clinical benefit and was well tolerated irrespective of background MRA use. These findings support the early use of empagliflozin on top of MRA therapy in patients admitted for AHF.

Safety, tolerability, pharmacodynamics and pharmacokinetics following once-daily doses of BI 187004, an inhibitor of 11 beta-hydroxysteroid dehydrogenase-1, over 28 days in patients with type 2 diabetes mellitus and overweight or obesity.

AIMS: To study the oral 11 beta-hydroxysteroid dehydrogenase-1 (11ß-HSD1) inhibitor BI 187004 (NCT02150824), as monotherapy and in combination with metformin, versus placebo in patients with type 2 diabetes mellitus (T2DM) affected by overweight or obesity. MATERIALS AND METHODS: This Phase II, randomized controlled trial investigated multiple rising doses of BI 187004 as monotherapy (Arm 1: 20, 80 or 240 mg) and in combination with metformin (Arm 2: 240 mg), in adults with T2DM and a body mass index of 28-40 kg/m2 . RESULTS: In total, 103 patients (Arm 1: n = 62, Arm 2: n = 41) were included in this study. BI 187004 was rapidly absorbed and exposure increased approximately dose-dependently. Target engagement of 11ß-HSD1 was observed with near-full inhibition of 11ß-HSD1 in the liver [decreased (5α-tetrahydrocortisol + 5ß-tetrahydrocortisol)/tetrahydrocortisone ratio]; hypothalamic-pituitary-adrenal axis activation was also seen (increased total urinary corticosteroids). No clinically relevant changes from baseline with BI 187004 treatment were observed for bodyweight or meal tolerance test parameters, or in most efficacy endpoints testing glucose and lipid metabolism; a significant increase was observed in weighted mean plasma glucose (p < .05 for 80 and 240 mg BI 187004) but not fasting plasma glucose. Drug-related adverse events were reported for 14 patients (22.6%) in Arm 1 and 10 patients (24.4%) in Arm 2, most frequently headache, diarrhoea, flushing and dizziness. A dose-dependent increase in heart rate was seen with BI 187004 treatment. CONCLUSIONS: BI 187004 was generally well tolerated in patients with T2DM. Despite complete 11ß-HSD1 inhibition, no clinically relevant effects were observed with BI 187004.

Cardiovascular disease in the elderly: proceedings of the European Society of Cardiology-Cardiovascular Round Table.

The growing elderly population worldwide represents a major challenge for caregivers, healthcare providers, and society. Older patients have a higher prevalence of cardiovascular (CV) disease, high rates of CV risk factors, and multiple age-related comorbidities. Although prevention and management strategies have been shown to be effective in older people, they continue to be under-used, and under-studied. In addition to hard endpoints, frailty, cognitive impairments, and patients' re-assessment of important outcomes (e.g. quality of life vs. longevity) are important aspects for older patients and emphasize the need to include a substantial proportion of older patients in CV clinical trials. To complement the often skewed age distribution in clinical trials, greater emphasis should be placed on real-world studies to assess longer-term outcomes, especially safety and quality of life outcomes. In the complex environment of the older patient, a multidisciplinary care team approach with the involvement of the individual patient in the decision-making process can help optimize prevention and management strategies. This article aims to demonstrate the growing burden of ageing in real life and illustrates the need to continue primary prevention to address CV risk factors. It summarizes factors to consider when choosing pharmacological and interventional treatments for the elderly and the need to consider quality of life and patient priorities when making decisions.

Empagliflozin in the treatment of heart failure with reduced ejection fraction in addition to background therapies and therapeutic combinations (EMPEROR-Reduced): a post-hoc analysis of a randomised, double-blind trial.

BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as ß blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; pinteraction=0·18). A similar result was seen for ß blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; pinteraction=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus ß blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; pinteraction=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.

Antithrombotic therapy according to baseline bleeding risk in patients with atrial fibrillation undergoing percutaneous coronary intervention: applying the PRECISE-DAPT score in RE-DUAL PCI.

AIMS: Patients with atrial fibrillation undergoing coronary intervention are at higher bleeding risk due to the concomitant need for oral anticoagulation and antiplatelet therapy. The RE-DUAL PCI trial demonstrated better safety with dual antithrombotic therapy (DAT: dabigatran 110 or 150 mg b.i.d., clopidogrel or ticagrelor) compared to triple antithrombotic therapy (TAT: warfarin, clopidogrel or ticagrelor, and aspirin). We explored the impact of baseline bleeding risk based on the PRECISE-DAPT score for decision-making regarding DAT vs. TAT. METHODS AND RESULTS: A score ≥25 points qualified high bleeding risk (HBR). Comparisons were made for the primary safety endpoint International Society of Thrombosis and Haemostasis major or clinically relevant non-major bleeding, and the composite efficacy endpoint of death, thrombo-embolic events, or unplanned revascularization, analysed by time-to-event analysis. PRECISE-DAPT was available in 2336/2725 patients, and 37.9% were HBR. Compared to TAT, DAT with dabigatran 110 mg reduced bleeding risk both in non-HBR [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.31-0.57] and HBR (HR 0.70, 95% CI 0.52-0.94), with a greater magnitude of benefit among non-HBR (Pint = 0.02). Dual antithrombotic therapy with dabigatran 150 mg vs. TAT reduced bleeding in non-HBR (HR 0.60, 95% CI 0.45-0.80), with a trend toward less benefit in HBR patients (HR 0.92, 95% CI 0.63-1.34; Pint = 0.08). The risk of ischaemic events was similar on DAT with dabigatran (both 110 and 150 mg) vs. TAT in non-HBR and HBR patients (Pint = 0.45 and Pint = 0.56, respectively). CONCLUSIONS: PRECISE-DAPT score appeared useful to identify AF patients undergoing PCI at further increased risk of bleeding complications and may help clinicians identifying the antithrombotic regimen intensity with the best benefit-risk ratio in an individual patient.

The effect of sex on the efficacy and safety of dual antithrombotic therapy with dabigatran versus triple therapy with warfarin after PCI in patients with atrial fibrillation (a RE-DUAL PCI subgroup analysis and comparison to other dual antithrombotic therapy trials).

BACKGROUND: The RE-DUAL PCI trial demonstrated that in patients with nonvalvular atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI), dual therapy with dabigatran and a P2Y12 inhibitor, either clopidogrel or ticagrelor, reduced the risk of bleeding without an increased risk of thromboembolic events as compared to triple therapy with warfarin in addition to a P2Y12 inhibitor and aspirin. What remains unclear is whether this effect is consistent between males and females undergoing PCI. HYPOTHESIS: The reduction in risk of bleeding without increased risk of thromboembolic events with dual therapy with dabigatran and a P2Y12 inhibitor in comparison to triple therapy with warfarin, a P2Y12 inhibitor and aspirin is consistent in females and males. METHODS: The primary safety endpoint was the first International Society on Thrombosis and Hemostasis (ISTH) major bleeding event (MBE) or clinically relevant non-major bleeding event (CRNMBE). The efficacy endpoint was the composite of death, thromboembolic event (stroke, myocardial infarction, and systemic embolism) or unplanned revascularization. Cox proportional hazard regression analyses were applied to calculate corresponding hazard ratios and interaction p values for each endpoint. RESULTS: A total of 655 women and 2070 men were enrolled. The risk of major or CRNM bleeding was lower with both dabigatran 110 mg dual therapy and dabigatran 150 mg dual therapy compared with warfarin triple therapy in female and male patients (for 110 mg: females: HR 0.69, 95% CI 0.47-1.01, males: HR 0.46, 95% CI 0.37-0.59, interaction p value: 0.084 and for 150 mg: females HR 0.74, 95% CI 0.48-1.16, males HR 0.71, 95% CI 0.56-0.90, interaction p value: 0.83). There was also no detectable difference in the composite efficacy endpoint of death, thromboembolic events or unplanned revascularization between dabigatran dual therapy and warfarin triple therapy, with no statistically significant interaction between sex and treatment (interaction p values: 0.73 and 0.72, respectively). CONCLUSIONS: Consistent with the overall study results, the risk of bleeding was lower with dabigatran 110 mg and 150 mg dual therapy compared with warfarin triple therapy, and risk of thromboembolic events was comparable with warfarin triple therapy independent of the patient's sex.

Evaluation of Dual Versus Triple Therapy by Landmark Analysis in the RE-DUAL PCI Trial.

OBJECTIVES: The aim of this study was to explore the early versus late benefits and risks of dabigatran dual therapy versus warfarin triple therapy in the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial. BACKGROUND: Patients with atrial fibrillation who undergo percutaneous coronary intervention are at increased risk for both bleeding and thrombotic events. METHODS: A total of 2,725 patients with atrial fibrillation underwent percutaneous coronary intervention and were randomized to receive dabigatran 110 mg, or dabigatran 150 mg plus a P2Y12 inhibitor (and no aspirin), or warfarin plus a P2Y12 inhibitor plus aspirin. Landmark analysis was performed at 30 and 90 days. RESULTS: There was a consistent and large reduction in major or clinically relevant nonmajor bleeding in patients randomized to dual therapy during the first 30 days (110 mg: hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.31 to 0.66; p < 0.0001; 150 mg: HR: 0.46; 95% CI: 0.30 to 0.72; p = 0.0006) compared with warfarin triple therapy. There was early net clinical benefit in both dabigatran groups versus warfarin (110 mg: HR: 0.65; 95% CI: 0.47 to 0.88; p = 0.0062; 150 mg: HR: 0.54; 95% CI: 0.37 to 0.79; p = 0.0015), due to larger reductions in bleeding than increased thrombotic events for dabigatran 110 mg and bleeding reduction without increased thrombotic risk for dabigatran 150 mg dual therapy versus warfarin triple therapy. After the removal of aspirin in the warfarin group, bleeding remained lower with dabigatran 110 mg and was similar with dabigatran 150 mg versus warfarin. CONCLUSIONS: In RE-DUAL PCI, in which patients in the dual-therapy arms were treated with aspirin for an average of only 1.6 days, there was early net clinical benefit with both doses of dabigatran dual therapy, without an increase in thrombotic events with dabigatran 150 mg. This could be helpful in the subset of patients with elevated risk for both bleeding and thrombotic events.

Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes.

AIMS: The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF). METHODS AND RESULTS: HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were -4.0 m (-16.0, 6.0; P = 0.42) and 4.0 m (-5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported. CONCLUSION: The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.

Dual antithrombotic therapy with dabigatran in patients with atrial fibrillation after percutaneous coronary intervention for ST-segment elevation myocardial infarction: a post hoc analysis of the randomised RE-DUAL PCI trial.

BACKGROUND: Little is known about the optimal antithrombotic therapy in patients with atrial fibrillation undergoing PCI for ST-elevation myocardial infarction (STEMI). AIMS: The aim of this study was to investigate the safety and efficacy of dabigatran dual therapy (110 or 150 mg twice daily, plus clopidogrel or ticagrelor) versus warfarin triple therapy in patients with atrial fibrillation and STEMI. METHODS: In the RE-DUAL PCI trial, 305 patients with STEMI were randomised to dabigatran 110 mg (n=113 versus 106 warfarin) or 150 mg (n=86 versus 84 warfarin). The primary endpoint was the time to first major/clinically relevant non-major bleeding event (MBE/CRNMBE). The thrombotic endpoint was a composite of death, thromboembolic events, or unplanned revascularisation. RESULTS: In STEMI patients, dabigatran 110 mg (HR 0.39, 95% CI: 0.20-0.74) and 150 mg (0.43, 0.21-0.89) dual therapy reduced the risk of MBE/CRNMBE versus warfarin triple therapy (p for interaction vs all other patients=0.31 and 0.16). The risk of thrombotic events for dabigatran 110 mg (HR 1.61, 95% CI: 0.85-3.08) and 150 mg (0.56, 0.20-1.51) had p interactions of 0.20 and 0.33, respectively. For net clinical benefit, the HRs were 0.74 (95% CI: 0.46-1.17) and 0.49 (0.27-0.91) for dabigatran 110 and 150 mg (p for interaction=0.80 and 0.12), respectively. CONCLUSIONS: After PCI for STEMI, patients on dabigatran dual therapy had lower risks of bleeding events versus warfarin triple therapy with similar risks of thromboembolic events, supporting dabigatran dual therapy even in patients with high thrombotic risk.

Dabigatran Dual Therapy vs Warfarin Triple Therapy Post-Percutaneous Coronary Intervention in Patients with Atrial Fibrillation With/Without a Proton Pump Inhibitor: A Pre-Specified Analysis of the RE-DUAL PCI Trial.

BACKGROUND AND OBJECTIVE: In patients with atrial fibrillation following percutaneous coronary intervention, if a proton pump inhibitor is used, could that allow the use of warfarin triple therapy, or is there additional reduction in bleeding while using it with dual therapy? METHODS: The RE-DUAL PCI trial randomized 2725 patients with atrial fibrillation post-percutaneous coronary intervention to dabigatran dual therapy (110 or 150 mg twice daily, with clopidogrel or ticagrelor) or warfarin triple therapy (with clopidogrel or ticagrelor, and aspirin for 1-3 months). This prespecified subgroup analysis evaluated risks of a first major bleeding event or clinically relevant non-major bleeding event, all gastrointestinal bleeding, and a composite efficacy endpoint of all-cause mortality/thromboembolic event or unplanned revascularization according to baseline use of a proton pump inhibitor. RESULTS: Of 2678 analyzed patients, 1641 (61.3%) were receiving a proton pump inhibitor at baseline. Dabigatran 110 and 150 mg dual therapy reduced the risk of major bleeding events or clinically relevant non-major bleeding events vs warfarin triple therapy regardless of proton pump inhibitor use, with comparable risk of the composite efficacy endpoint (all interaction p values > 0.05). For gastrointestinal bleeding, no interaction was observed between study treatment and proton pump inhibitor use (interaction p values 0.84 and 0.62 for dabigatran 110 and 150 mg dual therapy, respectively, vs warfarin triple therapy). CONCLUSIONS: Dabigatran 110 and 150 mg dual therapy reduced the risk of major bleeding events or clinically relevant non-major bleeding events vs warfarin triple therapy, regardless of proton pump inhibitor use at baseline, in patients with atrial fibrillation who underwent percutaneous coronary intervention. Risk of the composite efficacy endpoint appeared to be similar for dabigatran dual therapy vs warfarin triple therapy in patients receiving/not receiving a proton pump inhibitor. CLINICALTRIALS. GOV UNIQUE IDENTIFIER: NCT02164864.

Comparison of Dabigatran Plus a P2Y12 Inhibitor With Warfarin-Based Triple Therapy Across Body Mass Index in RE-DUAL PCI.

BACKGROUND: Body mass index (BMI) affects drug levels of nonvitamin K antagonist oral anticoagulants. We sought to assess whether BMI affected outcomes in the RE-DUAL PCI trial. METHODS: RE-DUAL PCI (NCT02164864) evaluated the safety and efficacy of a dual-antithrombotic-therapy regimen using dabigatran (110 mg or 150 mg twice daily and a P2Y12 platelet antagonist) in comparison with triple therapy of warfarin, aspirin, and a P2Y12 platelet inhibitor in 2725 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI). We compared the risk of first International Society on Thrombosis and Haemostasis (ISTH)-defined major or clinically relevant nonmajor bleeding events (primary endpoint) and the composite of death, myocardial infarction, stroke, systemic embolism, or unplanned revascularization (main efficacy endpoint) in relation to baseline BMI. RESULTS: Median (range) BMI was 28.1 (14-66) kg/m2. Dabigatran dual therapy versus warfarin triple therapy had relevantly and similarly lower rates of bleeding at both 110 mg and 150 mg twice-daily doses, irrespective of BMI. Thromboembolic event rates appeared consistent across categories of BMI, including those <25 and ≥35 kg/m2 (P for interaction: 0.806 and 0.279, respectively). CONCLUSIONS: The reduction in bleeding with dabigatran dual therapy compared with warfarin triple therapy in patients here evaluated appears consistent across BMI categories.

Effect of Lesion Complexity and Clinical Risk Factors on the Efficacy and Safety of Dabigatran Dual Therapy Versus Warfarin Triple Therapy in Atrial Fibrillation After Percutaneous Coronary Intervention: A Subgroup Analysis From the REDUAL PCI Trial.

BACKGROUND: The REDUAL PCI trial (Evaluation of Dual Therapy With Dabigatran vs Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting) demonstrated that, in patients with atrial fibrillation following percutaneous coronary intervention, bleeding risk was lower with dabigatran plus clopidogrel or ticagrelor (dual therapy) than warfarin plus clopidogrel or ticagrelor and aspirin (triple therapy). Dual therapy was noninferior for risk of thromboembolic events. Whether these results apply equally to patients at higher risk of ischemic events due to lesion complexity or clinical risk factors is unclear. METHODS: The primary end point was time to first major or clinically relevant nonmajor bleeding event. The composite efficacy end point was death, thromboembolic event, or unplanned revascularization. Our prespecified subgroup analysis categorized patients by presence of procedural complexity and/or clinical complexity factors at baseline. A modified dual antiplatelet therapy score categorized patients according to degree of clinical risk. RESULTS: Of 2725 patients, 43.1% had clinical complexity factors alone, 9.9% procedural factors alone, 10.0% both, and 37.0% neither. Risk of the primary bleeding end point was lower in both dabigatran dual therapy groups than warfarin triple therapy groups, regardless of procedural and/or clinical lesion complexity (interaction P values: 0.90 and 0.37, respectively). Importantly, a similar risk of the efficacy end point was observed between dabigatran dual and warfarin triple therapy, regardless of the presence of clinical or procedural complexity factors (interaction P values: 0.67 and 0.54, dabigatran 110 and 150 mg dual therapy, respectively). Similar benefit was seen for each dose of dabigatran dual therapy for bleeding events regardless of dual antiplatelet therapy score (interaction P values: 0.53 and 0.54, respectively), with similar risk of thromboembolic events (interaction P values: 0.20 and 0.08, respectively). CONCLUSIONS: In patients with atrial fibrillation undergoing percutaneous coronary intervention, dabigatran 110 and 150 mg dual therapy reduced bleeding risk compared with warfarin triple therapy, with a similar risk of thromboembolic outcomes, irrespective of procedural and/or clinical complexity and modified dual antiplatelet therapy score. Registration: URL: https://clinicaltrials.gov/; Unique identifier: NCT02164864.

Comparison of the Effect of Age (< 75 Versus ≥ 75) on the Efficacy and Safety of Dual Therapy (Dabigatran + Clopidogrel or Ticagrelor) Versus Triple Therapy (Warfarin + Aspirin + Clopidogrel or Ticagrelor) in Patients With Atrial Fibrillation After Percutaneous Coronary Intervention (from the RE-DUAL PCI Trial).

The RE-DUAL PCI trial reported that dabigatran dual therapy (110/150 mg twice daily, plus clopidogrel or ticagrelor) reduced bleeding events versus warfarin triple therapy (warfarin plus aspirin and clopidogrel or ticagrelor) in patients with atrial fibrillation who underwent percutaneous coronary intervention, with noninferiority in composite thromboembolic events. In this prespecified analysis, risks of first major or clinically relevant nonmajor bleeding event and composite end point of death, thromboembolic events, or unplanned revascularization were compared between dabigatran dual therapy and warfarin triple therapy in older (≥ 75 years) and younger (< 75 years) patients, using Cox proportional hazard regression. Of 2,725 patients randomized to treatment, 1,026 (37.7%) were categorized into older and 1,699 (62.3%) into younger age groups. Dabigatran 110 mg dual therapy lowered bleeding risk versus warfarin triple therapy in older (hazard ratio [HR] 0.67; 95% confidence interval [CI] 0.51 to 0.89) and younger patients (HR 0.40; 95% CI 0.30 to 0.54); interaction p value: 0.0125. Dabigatran 150 mg dual therapy lowered bleeding risk versus warfarin triple therapy in younger patients (HR 0.57; 95% CI 0.44 to 0.74), whereas no benefit could be observed in older patients (HR 1.21; 95% CI 0.83 to 1.77); interaction p value: 0.0013. For the thromboembolic end point, there was a trend for a higher risk with dabigatran 110 mg dual therapy in older patients, compared with warfarin triple therapy, whereas the risk was similar in younger patients. For dabigatran 150 mg dual therapy, the thromboembolic risk versus warfarin triple therapy was similar in older and younger patients. In conclusion, the benefits of dabigatran dual therapy differed in the 2 age groups, which may help dose selection when using dabigatran dual therapy.

Switching of Oral Anticoagulation Therapy After PCI in Patients With Atrial Fibrillation: The RE-DUAL PCI Trial Subanalysis.

OBJECTIVES: The aim of this study was to assess if prior oral anticoagulant agent (OAC) use modifies the lower bleeding risk observed with dabigatran dual therapy (dabigatran twice daily plus a P2Y12 inhibitor) versus warfarin triple therapy (warfarin plus a P2Y12 inhibitor plus aspirin) in patients with atrial fibrillation who underwent percutaneous coronary intervention (PCI). BACKGROUND: In the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial, the primary outcome of major bleeding or clinically relevant nonmajor bleeding was lower with dabigatran dual therapy versus warfarin triple therapy in patients with atrial fibrillation who underwent PCI. METHODS: A total of 2,725 patients were randomized to dual therapy with dabigatran (110 or 150 mg twice daily) plus clopidogrel or ticagrelor or triple therapy with warfarin plus aspirin and clopidogrel or ticagrelor. Subgroup analysis compared risk for major bleeding or clinically relevant nonmajor bleeding and a composite thromboembolic endpoint in patients with prior OAC use and in those who were OAC treatment naive. RESULTS: Risk for major bleeding or clinically relevant nonmajor bleeding was reduced with both dabigatran dual therapies compared with warfarin triple therapy in both the prior OAC use group (hazard ratios: 0.58 [95% confidence interval (CI): 0.42 to 0.81] and 0.61 [95% CI: 0.41 to 0.92] with 110 and 150 mg dabigatran, respectively) and the OAC-naive group (hazard ratios: 0.49 [95% CI: 0.38 to 0.63] and 0.76 [95% CI: 0.59 to 0.97] with 110 and 150 mg dabigatran) (p for interaction = 0.42 and 0.37, 110 and 150 mg dabigatran, respectively). The risk for thromboembolic events seemed similar with dabigatran dual therapy (both doses) and warfarin triple therapy across subgroups. CONCLUSIONS: Bleeding risk was reduced with dabigatran dual therapy versus warfarin triple therapy in patients with atrial fibrillation after PCI, regardless of whether they were prior OAC users or OAC treatment naive. These results suggest that it is also safe to switch patients on OAC pre-PCI to dabigatran dual therapy post-PCI.