This trial compared the efficacy and safety of oral dabigatran, a direct thrombin inhibitor, versus subcutaneous enoxaparin for extended thromboprophylaxis in patients undergoing total hip ...arthroplasty. A total of 2,055 patients were randomised to 28-35 days treatment with oral dabigatran, 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery. The primary efficacy outcome was a composite of total venous thromboembolism VTE (venographic or symptomatic) and death from all-causes. The main secondary composite outcome was major VTE (proximal deep-vein thrombosis or non-fatal pulmonary embolism) plus VTE-related death. The main safety outcome was major bleeding. In total, 2,013 were treated, of whom 1,577 operated patients were included in the primary efficacy analysis. The primary efficacy outcome occurred in 7.7% of the dabigatran group versus 8.8% of the enoxaparin group, risk difference (RD) -1.1% (95%CI -3.8 to 1.6%); p<0.0001 for the pre-specified non-inferiority margin. Major VTE plus VTE-related death occurred in 2.2% of the dabigatran group versus 4.2% of the enoxaparin group, RD -1.9% (-3.6% to -0.2%); p=0.03. Major bleeding occurred in 1.4% of the dabigatran group and 0.9% of the enoxaparin group (p=0.40). The incidence of adverse events, including liver enzyme elevations and cardiac events, during treatment was similar between the groups. Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as subcutaneous enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty, and superior to enoxaparin for reducing the risk of major VTE. The risk of bleeding and safety profiles were similar.
Mechanisms underlying kidney benefits with sodium-glucose cotransporter-2 (SGLT2) inhibition in heart failure and/or type 2 diabetes (T2D) with established cardiovascular disease are currently ...unclear.
We evaluated post hoc the factors mediating the effect of empagliflozin on a composite kidney outcome (first sustained estimate glomerular filtration rate ≥40% reduction from baseline, initiation of renal replacement therapy, or death due to kidney disease) in EMPA-REG OUTCOME. Variables, calculated as change from baseline or updated mean, were evaluated as time-dependent covariates and using a landmark approach (at Week 12) in Cox regression analyses. In multivariable analyses, variables with the greatest mediating effect were added using a step-up procedure.
In univariable time-dependent updated mean covariate analyses, the strongest mediator was hematocrit (99.5% mediation). Hemoglobin, uric acid, and urine albumin-to-creatinine ratio mediated 79.4%, 33.2%, and 31.0%, respectively. Multivariable analyses were not performed due to the very strong mediation effect of hematocrit. In univariable Week 12 landmark change from baseline analyses, the strongest mediators included hematocrit (40.7%), glycated hemoglobin (28.3%), systolic blood pressure (16.8%), and free fatty acids (16.5%), which yielded a combined mediation of 78.9% in multivariable analysis.
Changes in hematocrit and hemoglobin were the strongest mediators of empagliflozin's kidney benefits in EMPA-REG OUTCOME participants with T2D and cardiovascular disease.
In EMPA-REG OUTCOME, empagliflozin reduced the composite of total events leading to/prolonging hospitalisation for any cause and all-cause mortality by 24 % versus placebo in patients with T2DM and ...ASCVD, with 67.7 events prevented/1000 patient-years and a low NNT. Effects were sustained and were consistent regardless of the reason for hospitalisation.
Patients with type 2 diabetes and atherosclerotic cardiovascular disease are at high clinical risk. We assessed the effect of the sodium-glucose co-transporter-2 inhibitor, empagliflozin, on total ...cardiovascular events and admissions to hospital in the EMPA-REG OUTCOME trial.
The EMPA-REG OUTCOME trial was a randomised, double-blind, non-inferiority trial of patients (aged ≥18 years) with type 2 diabetes and atherosclerotic cardiovascular disease done between August, 2010, and April, 2015. Participants were randomly assigned (1:1:1) to empagliflozin 10 mg or 25 mg, or placebo. The primary outcome was major adverse cardiovascular events: a composite of cardiovascular death, non-fatal stroke, or non-fatal myocardial infarction. As prespecified, the effects of pooled empagliflozin versus placebo were assessed on total (first plus recurrent) events of major adverse cardiovascular events, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, and admission to hospital for heart failure. We also did post-hoc analyses on additional cardiovascular and admission to hospital outcomes. We used statistical models that preserve randomisation and account for correlation of recurrent events, including negative binomial regression, as prespecified for the primary analyses. The EMPA-REG OUTCOME trial is registered with ClinicalTrials.gov, NCT01131676, and is closed to accrual.
In the EMPA-REG OUTCOME trial, 7020 patients were randomly assigned and treated with empagliflozin 10 mg (n=2345), empagliflozin 25 mg (n=2342), or placebo (n=2333) and followed up for a median of 3·2 years (IQR 2·2 to 3·6) in the pooled empagliflozin group and 3·1 years (2·2 to 3·5) in the placebo group. Analysing total (first plus recurrent) events, empagliflozin versus placebo reduced the risk of major adverse cardiovascular events (rate ratio RR 0·78 95% CI 0·67 to 0·91; p=0·0020; 12·88 95% CI 3·74 to 22·02 events prevented per 1000 patient-years); fatal or non-fatal myocardial infarction (0·79 0·62 to 0·998; p=0·049; 4·97 -0·68 to 10·61 events prevented per 1000 patient-years); the composite of fatal or non-fatal myocardial infarction, or coronary revascularisation (0·80 0·67 to 0·95; p=0·012; 11·65 1·25 to 22·05 events prevented per 1000 patient-years); admission to hospital for heart failure (0·58 0·42 to 0·81; p=0·0012; 9·67 3·07 to 16·28 events prevented per 1000 patient-years); and all-cause admission to hospital (0·83 0·76 to 0·91; p<0·0001; 50·41 26·20 to 74·63 events prevented per 1000 patient-years). For outcomes significantly reduced with empagliflozin, risk reductions were numerically larger for total events than for first events. Total fatal or non-fatal stroke was not significantly different between treatment groups (RR 1·10 95% CI 0·82 to 1·49; p=0·52).
Empagliflozin reduced the total burden of cardiovascular complications and all-cause admission to hospital in patients with type 2 diabetes and atherosclerotic cardiovascular disease.
The Boehringer Ingelheim and Lilly Alliance.
Abstract Dabigatran, an oral once-daily unmonitored thrombin inhibitor, has been tested elsewhere using enoxaparin 40 mg once daily. We used the North American enoxaparin 30 mg BID regimen as the ...comparator. This was a double-blind, centrally randomized trial. Unilateral total knee arthroplasty patients were randomized to receive oral dabigatran etexilate 220 or 150 mg once daily, or enoxaparin 30 mg SC BID after surgery, blinded. Dosing stopped at contrast venography, 12 to 15 days after surgery. Among 1896 patients, dabigatran 220 and 110 mg showed inferior efficacy to enoxaparin (venous thromboembolism rates of 31% P = .02 vs enoxaparin, 34% P < .001 vs enoxaparin, and 25%, respectively). Bleeding rates were similar, and no drug-related hepatic illness was recognized. Dabigatran, effective compared to once-daily enoxaparin, showed inferior efficacy to the twice-daily North American enoxaparin regimen, probably because of the latter's more intense and prolonged dosing.
Empagliflozin (EMPA) reduces weight and HbA1c in patients with T2DM, but it is not known if it leads to reductions in elevated liver enzymes reflective of liver fat. We investigated the effect of ...EMPA on liver transaminases in the EMPA-REG OUTCOME trial.
Patients with T2DM and established CV disease were randomized to receive EMPA 10 mg, EMPA 25 mg, or placebo (PBO) in addition to standard of care. Changes from baseline in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assessed in all treated patients (N=7020) and in tertiles by baseline ALT or AST.
In the EMPA group, ALT decreased from baseline to week 28 and then remained stable. In the PBO group, ALT declined steadily to a lesser extent. Reductions in ALT were greatest in the highest tertile of baseline ALT (tertile 3). In the lowest tertile, changes in ALT were similar between EMPA and PBO. AST decreased from baseline to week 28 and then remained stable with EMPA; there were no relevant changes with PBO. Changes from baseline in AST were generally similar between EMPA and PBO at weeks 28 and 164 in the second and third tertiles, but were greater with EMPA than PBO in the highest tertile by baseline AST. Similar patterns were observed in analysis of pooled Phase III trial data and a trial of EMPA vs. glimepiride.
In conclusion, EMPA reduced ALT and AST vs. PBO in the EMPA-REG OUTCOME trial, with greater reductions in ALT than AST, in a pattern consistent with a reduction in liver fat.
Table. Changes in ALT and AST in the EMPA-REG OUTCOME trial.ALT (U/L)AST (U/L)Week 28PBOEMPAPBOEMPAAll patientsChange from baseline-0.73 (0.25)-2.96 (0.18)-0.31 (0.20)-1.32 (0.14)Difference vs PBO-2.22 (-2.83, -1.62)***-1.01 (-1.48, -0.54)***Tertile 1Change from baseline1.57 (0.51)1.51 (0.36)1.88 (0.38)1.72 (0.27)Difference vs PBO-0.06 (-1.27, 1.15)-0.16 (-1.08. 0.75)Tertile 2Change from baseline0.29 (0.51)-1.15 (0.35)0.70 (0.36)-0.03 (0.26)Difference vs PBO-1.45 (-2.65, -0.24)*-0.73 (-1.61, 0.14)Tertile 3Change from baseline-3.96 (0.48)-8.33 (0.35)-3.15 (0.34)-4.69 (0.24)Difference vs PBO-4.36 (-5.51, -3.21)***-1.53 (-2.35, -0.72)***Week 164All patientsChange from baseline-1.80 (0.36)-3.(0.25)-0.51 (0.33)-1.17 (0.23)Difference vs PBO-1.26 (-2.12, -0.40)**-0.66 (-1.45, 0.13)Tertile 1Change from baseline2.46 (0.72)2.32 (0.49)2.69 (0.67)2.51 (0.45)Difference vs PBO-0.13 (-1.84, 1.58)-0.18 (-1.75, 1.39)Tertile 2Change from baseline0.04 (0.71)-0.86 (0.48)1.17 (0.61)0.73 (0.42)Difference vs PBO-0.91 (-2.59, 0.77)-0.44 (-1.88, 1.00)Tertile 3Change from baseline-7.33 (0.65)-9.54 (0.46)-4.51 (0.57)-5.50 (0.39)Difference vs PBO-2.22 (-3.78, -0.66)**-0.99 (-2.34, 0.36)Mixed model repeated measures analysis in patients treated with ≥1 dose of study drug based on observed cases. Changes from baseline are adjusted mean (standard error). Differences vs PBO are adjusted mean (95% confidence interval). Tertile 3 indicates the highest tertile by baseline value. All patients: N=2333 for PBO; N=4686 for EMPA. *p<0.05; **p<0.01; ***p<0.001
Disclosure
N. Sattar: Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, Medscape, Sanofi-Aventis Deutschland GmbH. D.H. Fitchett: Advisory Panel; Self; Boehringer Ingelheim GmbH, Eli Lilly and Company. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Amgen Inc., Sanofi. S. Hantel: Employee; Self; Boehringer Ingelheim GmbH. J.T. George: Employee; Self; Boehringer Ingelheim GmbH. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck & Co., Inc., Abbott.
Objective:
It is well established that higher low-density lipoprotein (LDL)-cholesterol levels are associated with increased cardiovascular risk. We analyzed whether effects of empagliflozin on ...cardiovascular outcomes varied by different LDL-cholesterol levels at baseline in EMPA-REG OUTCOME.
Methods:
Participants with type 2 diabetes and high cardiovascular risk received empagliflozin (10/25 mg) or placebo in addition to standard of care. We investigated the time to first 3P-MACE, cardiovascular death, hospitalization for heart failure (HHF) and all-cause mortality for empagliflozin versus placebo between baseline LDL-cholesterol categories <1.8, 1.8–<2.2, 2.2– <2.6, 2.6–3.0, and > 3.0 mmol/L, by a Cox regression including the interaction of baseline LDL-cholesterol category and treatment.
Results:
Of the 7020 participants randomized and treated, 81.0% received lipid lowering therapy (77.0% statins). Mean ± SD LDL-cholesterol was 2.2 ± 0.9 mmol/L, and 38%/18%, had LDL-cholesterol <1.8/>3.0 mmol/L. Age, BMI, and HbA1c levels were balanced between the LDL-cholesterol subgroups, but those in the lowest versus highest group, had more coronary artery disease (83.0% vs 59.9%) and statin treatment (88.2% vs 50.9%). Empagliflozin consistently reduced all outcomes across LDL-cholesterol categories (all interaction p-values > 0.05).
Conclusion:
The beneficial cardiovascular effects of empagliflozin was consistent across higher and lower LDL-cholesterol levels at baseline.
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