Dabigatran dual therapy versus warfarin triple therapy post-PCI in patients with atrial fibrillation and diabetes

OBJECTIVES: The aim of this study was to evaluate dabigatran dual therapy versus warfarin triple therapy in patients with or without diabetes mellitus 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: It is unclear whether dual therapy is as safe and efficacious as triple therapy in patients with atrial fibrillation with diabetes following percutaneous coronary intervention.METHODS: In RE-DUAL PCI, 2,725 patients with atrial fibrillation (993 with diabetes) who had undergone PCI were assigned to warfarin triple therapy (warfarin, clopidogrel or ticagrelor, and aspirin) or dabigatran dual therapy (dabigatran 110 mg or 150 mg twice daily and clopidogrel or ticagrelor). Median follow-up was 13 months. The primary outcome was the composite of major bleeding or clinically relevant nonmajor bleeding, and the main efficacy outcome was the composite of death, thromboembolic events, or unplanned revascularization.RESULTS: Among patients with diabetes, the incidence of major bleeding or clinically relevant nonmajor bleeding was 15.2% in the dabigatran 110 mg dual therapy group versus 27.5% in the warfarin triple therapy group (hazard ratio [HR]: 0.48; 95% confidence interval [CI] 0.35 to 0.67) and 23.8% in the dabigatran 150 mg dual therapy group versus 25.1% in the warfarin triple therapy group (HR: 0.87; 95% CI: 0.62 to 1.22). Risk for major bleeding or clinically relevant nonmajor bleeding was also reduced with both dabigatran doses among patients without diabetes (dabigatran 110 mg dual therapy: HR: 0.54; 95% CI: 0.42 to 0.70; dabigatran 150 mg dual therapy: HR: 0.63; 95% CI: 0.48 to 0.83). Risk for the efficacy endpoint was comparable between treatment groups for both patients with and those without diabetes. No interaction between treatment and diabetes subgroup could be observed, either for bleeding or for composite efficacy endpoints.CONCLUSIONS: In this subgroup analysis, dabigatran dual therapy had a lower risk for bleeding and a comparable rate of the efficacy endpoint compared with warfarin triple therapy in patients with atrial fibrillation with or without diabetes following percutaneous coronary intervention.</p

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 P2Y(12) 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 P2Y(12) 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 P2Y(12) inhibitor in comparison to triple therapy with warfarin, a P2Y(12) 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

Risk of malnutrition in patients with systemic sclerosis-associated interstitial lung disease treated with nintedanib

International audienceOBJECTIVE: To assess adverse events in relation to baseline body mass index (BMI) and the risk of malnutrition in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) treated with nintedanib. METHODS: Among patients with SSc-ILD randomized to receive nintedanib or placebo in the SENSCIS trial, we assessed adverse events in subgroups by baseline BMI ≤20 and &gt;20 kg/m(2) , and the risk of malnutrition using a modified version of the Malnutrition Universal Screening Tool (MUST), over 52 weeks. RESULTS: The adverse event profile of nintedanib was similar between subgroups with baseline BMI ≤20 kg/m(2) (n=61) and &gt;20 kg/m(2) (n=515). In these subgroups, respectively, adverse events led to treatment discontinuation in 16.7% and 15.9% of the nintedanib group and 13.5% and 8.0% of the placebo group. Based on the modified MUST, the proportions of patients who had a low risk of malnutrition at baseline and at their last assessment were 74.0% in the nintedanib group and 78.1% in the placebo group, while the proportions who were classified as at low risk at baseline but at high risk by their last assessment were 4.5% in the nintedanib group and 1.0% in the placebo group. CONCLUSION: In the SENSCIS trial, most patients with SSc-ILD remained at low risk of malnutrition over 52 weeks, but the proportion at high risk was higher in patients treated with nintedanib than placebo. Management of disease manifestations and adverse events that may be associated with weight loss is important to reduce the risk of malnutrition in patients with SSc-ILD

Dyspnoea and cough in patients with systemic sclerosis-associated interstitial lung disease in the SENSCIS trial.

OBJECTIVE: The aim of these analyses was to investigate the rate of decline in forced vital capacity (FVC) in patients with SSc-associated interstitial lung disease (SSc-ILD) with and without cough or dyspnoea in the SENSCIS trial. METHODS: Patients in the SENSCIS trial were randomized to receive nintedanib or placebo. Subgroups with and without cough or dyspnoea at baseline were defined by responses to the St Georges Respiratory Questionnaire. RESULTS: At baseline, 114/575 patients (19.8%) did not have cough and 172/574 patients (30.0%) did not have dyspnoea. In the placebo group, the rate of FVC decline over 52 weeks was similar in patients with and without cough (-95.6 and -83.4 mL/year, respectively) or dyspnoea (-95.8 and -87.7 mL/year, respectively). The effect of nintedanib vs placebo on reducing the rate of FVC decline was numerically more pronounced in patients without than with cough [difference: 74.4 (95% CI -11.1, 159.8) vs 31.5 (-11.1, 74.1)] and without than with dyspnoea [79.8 (9.8, 149.7) vs 25.7 (-19.9, 71.3)], but interaction P-values did not indicate heterogeneity in the treatment effect between these subgroups (P = 0.38 and P = 0.20, respectively). CONCLUSION: In the placebo group of the SENSCIS trial, the rate of FVC decline was similar irrespective of the presence of cough or dyspnoea at baseline. The effect of nintedanib on reducing the rate of FVC decline was numerically more pronounced in patients without than with cough or dyspnoea at baseline, but no statistically significant heterogeneity was observed between the subgroups. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02597933

Impact of lung function decline on time to hospitalisation events in systemic sclerosis-associated interstitial lung disease (SSc-ILD): a joint model analysis

Abstract Background Interstitial lung disease (ILD) is a common organ manifestation in systemic sclerosis (SSc) and is the leading cause of death in patients with SSc. A decline in forced vital capacity (FVC) is an indicator of ILD progression and is associated with mortality in patients with SSc-associated ILD (SSc-ILD). However, the relationship between FVC decline and hospitalisation events in patients with SSc-ILD is largely unknown. The objective of this post hoc analysis was to investigate the relationship between FVC decline and clinically important hospitalisation endpoints. Methods We used data from SENSCIS®, a phase III trial investigating the efficacy and safety of nintedanib in patients with SSc-ILD. Joint models for longitudinal and time-to-event data were used to assess the association between rate of decline in FVC% predicted and hospitalisation-related endpoints (including time to first all-cause hospitalisation or death; time to first SSc-related hospitalisation or death; and time to first admission to an emergency room [ER] or admission to hospital followed by admission to intensive care unit [ICU] or death) during the treatment period, over 52 weeks in patients with SSc-ILD. Results There was a statistically significant association between FVC decline and the risk of all-cause (n = 78) and SSc-related (n = 42) hospitalisations or death (both P < 0.0001). A decrease of 3% in FVC corresponded to a 1.43-fold increase in risk of all-cause hospitalisation or death (95% confidence interval [CI] 1.24, 1.65) and a 1.48-fold increase in risk of SSc-related hospitalisation or death (95% CI 1.23, 1.77). No statistically significant association was observed between FVC decline and admission to ER or to hospital followed by admission to ICU or death (n = 75; P = 0.15). The estimated slope difference for nintedanib versus placebo in the longitudinal sub-model was consistent with the primary analysis in SENSCIS®. Conclusions The association of lung function decline with an increased risk of hospitalisation suggests that slowing FVC decline in patients with SSc-ILD may prevent hospitalisations. Our findings also provide evidence that FVC decline may serve as a surrogate endpoint for clinically relevant hospitalisation-associated endpoints. Trial registration ClinicalTrials.gov NCT02597933 . Registered on 8 October 2015.http://deepblue.lib.umich.edu/bitstream/2027.42/173913/1/13075_2021_Article_2710.pd

Dural Arteriovenous Fistulae After Cerebral Venous Thrombosis

BACKGROUND AND PURPOSE: This analysis examined the frequency of dural arteriovenous fistulae (dAVF) after cerebral venous thrombosis (CVT) in patients included in a randomized controlled trial comparing dabigatran etexilate with dose-adjusted warfarin (RE-SPECT CVT [A Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate With Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis]), who had systematic follow-up magnetic resonance (MR) imaging. METHODS: RE-SPECT CVT was a Phase 3, prospective, randomized, parallel-group, open-label, multicenter, exploratory trial with blinded end point adjudication. We allocated patients with acute CVT to dabigatran 150 mg twice daily or dose-adjusted warfarin, for 24 weeks and obtained a standardized MR protocol including time-of-flight MR angiography, 3-dimensional phase-contrast venography, and 3-dimensional contrast-enhanced MR venography at the end of the treatment period. A blinded adjudication committee assessed the presence of dAVF in a predefined substudy of the trial. RESULTS: We analyzed development of dAVF in 112 of 120 randomized patients; 57 allocated to dabigatran and 55 to warfarin. For 3 (2.7%) of these 112 patients, quality of follow-up imaging was insufficient to evaluate dAVF. A dAVF (Borden I) was found in 1 patient (0.9%) allocated to warfarin; however, this dAVF was already present at baseline. The patient did not present with hemorrhage at baseline or during the trial and was asymptomatic at follow-up. CONCLUSIONS: Despite systematic imaging, we found no new dAVF 6 months after CVT. Routine follow-up cerebral MR angiography aiming to detect new dAVF 6 months after CVT has a very low yield. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02913326

Nintedanib in Patients With Systemic Sclerosis-Associated Interstitial Lung Disease: Subgroup Analyses by Autoantibody Status and Modified Rodnan Skin Thickness Score.

OBJECTIVE: Using data from the SENSCIS trial, these analyses were undertaken to assess the effects of nintedanib versus placebo in subgroups of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), based on characteristics previously identified as being associated with the progression of SSc-ILD. METHODS: Patients with SSc-ILD were randomized to receive either nintedanib or placebo, stratified by anti-topoisomerase I antibody (ATA) status. We assessed the rate of decline in forced vital capacity (FVC) (expressed in ml/year) over 52 weeks in subgroups based on baseline ATA status, modified Rodnan skin thickness score (MRSS) (&lt;18 versus ≥18), and SSc subtype (limited cutaneous SSc [lcSSc] versus diffuse cutaneous SSc [dcSSc]). RESULTS: At baseline, 60.8% of 576 patients who received treatment with either nintedanib or placebo were positive for ATA, 51.9% had dcSSc, and 77.5% of 574 patients with MRSS data available had an MRSS of &lt;18. The effect of nintedanib versus placebo on reducing the rate of decline in FVC (ml/year) was numerically more pronounced in ATA-negative patients compared to ATA-positive patients (adjusted difference in the rate of FVC decline, 57.2 ml/year [95% confidence interval (95% CI) -3.5, 118.0] versus 29.9 ml/year [95% CI -19.1, 78.8]), in patients with a baseline MRSS ≥18 compared to those with a baseline MRSS of &lt;18 (adjusted difference in the rate of FVC decline, 88.7 ml/year [95% CI 7.7, 169.8] versus 26.4 ml/year [95% CI -16.8, 69.6]), and in patients with dcSSc compared to those with lcSSc (adjusted difference in the rate of FVC decline, 56.6 ml/year [95% CI 3.2, 110.0] versus 25.3 ml/year [95% CI -28.9, 79.6]). However, all exploratory interaction P values were nonsignificant (all P &gt; 0.05), indicating that there was no heterogeneity in the effect of nintedanib versus placebo between these subgroups of patients. CONCLUSION: In patients with SSc-ILD, reduction in the annual rate of decline in FVC among patients receiving nintedanib compared to those receiving placebo was not found to be heterogenous across subgroups based on ATA status, MRSS, or SSc subtype

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 bid, 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 ISTH major or clinically relevant non-major bleeding, and the composite efficacy endpoint of death, thromboembolic events, or unplanned revascularization, analyzed by time-to-event analysis. PRECISE-DAPT was available in 2,336/2,725 patients, and 37.9% were HBR. Compared to TAT, DAT with dabigatran 110 mg reduced bleeding risk both in non-HBR (HR 0.42, 95%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). DAT 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). 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