2023-09-29 於2021月03月11日

Aspirin Non-Inferior to Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture

Date: Jan 19, 2023

Venous thromboembolism is a potentially fatal complication after orthopedic trauma. Clinical guidelines recommend low-molecular-weight heparin (LMWH) as thromboprophylaxis after a fracture while recent trials and meta-analyses suggested aspirin as an effective and safer alternative. Limited studies with head-to-head comparisons were however found.

In this pragmatic, multicenter, randomized, noninferiority PREVENT CLOT trial, the effectiveness and safety of thromboprophylaxis with aspirin were compared to LMWH in adults with an extremity fracture treated surgically or any pelvic or acetabular fracture treated surgically or nonsurgically. At 21 trauma centers located in the United States and Canada, a total of 12,211 patients were randomly assigned to receive 81 mg of oral aspirin (6101 patients) or 30 mg of subcutaneous enoxaparin (6110 patients), both groups received treatment twice daily while hospitalized. After hospital discharge, patients continued to receive thromboprophylaxis according to the clinical protocols of each hospital. The primary outcome was death from any cause at 90 days. Secondary outcomes included nonfatal pulmonary embolism, deep-vein thrombosis, and bleeding complications.

Patients received a mean of 8.8±10.6 in-hospital thromboprophylaxis doses and were prescribed a median 21-day supply of thromboprophylaxis at discharge. Death occurred in 47 (0.78%) and 45 (0.73%) patients in the aspirin and LMWH groups, respectively (difference, 0.05 percentage points; 96.2% confidence interval [CI], -0.27 to 0.38; P<0.001 for a noninferiority margin of 0.75 percentage points). Deep-vein thrombosis occurred in 2.51% and 1.71% of patients in the aspirin and LMWH groups, respectively (difference, 0.80 percentage points; 95% CI, 0.28 to 1.31). The incidence of pulmonary embolism, bleeding complications, and other serious adverse events were similar in the two groups.

The trial concluded that in patients with extremity fractures who had been treated operatively or with any pelvic or acetabular fracture, thromboprophylaxis with aspirin was noninferior to low-molecular-weight heparin in preventing death and was associated with a lower incidence of deep-vein thrombosis and pulmonary embolism and a lower 90-day mortality rate.

Source: www.nejm.org

Baxdrostat Demonstrated Substantial Reductions in Systolic and Diastolic Blood Pressure in Patients with Treatment-Resistant Hypertension

Date: Feb 2, 2023

Treatment-resistant hypertension is defined as elevated blood pressure despite of concurrent use of at least three antihypertensive drugs of different classes, including a diuretic. This condition is affecting approximately 10% of patients with hypertension in the United States (10 to 12 million people) and has a substantially increased risk of cardiovascular and renal adverse events. Pre-clinical and phase 1 studies on baxdrostat have shown high selectivity (selectivity ratio, 100:1) for aldosterone synthase inhibition, however, data on its efficacy and safety for patient use is warranted.

In this multicenter, placebo-controlled, randomized trial, patients who had treatment-resistant hypertension with a blood pressure of 130/80 mm Hg or higher and were receiving stable doses of at least three antihypertensive agents including a diuretic, were enrolled to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo. The primary endpoint was the change in systolic blood pressure from baseline to week 12 in each baxdrostat group as compared with the placebo group.

A total of 248 patients received either once-daily baxdrostat at a dose of 0.5 mg (65 patients), 1 mg (60 patients), or 2 mg (56 patients), or placebo (67 patients) completed the 12-week treatment period. At week 12, baxdrostat was associated with dose-dependent changes in systolic blood pressure of -20.3 mm Hg in the 2 mg group, -17.5 mm Hg in the 1 mg group, -12.1 mm Hg in the 0.5 mg group and -9.4 mm Hg in the placebo group. Significant changes in systolic blood pressure were observed between the 2 mg group and the placebo group (-11.0 mm Hg, 95% confidence interval [CI], -16.4 to -5.5; P<0.001) as well as between the 1 mg group and the placebo group (-8.1 mm Hg, 95% CI, -13.5 to -2.8; P=0.003). No deaths occurred during the trial, and baxdrostat had a generally tolerable side-effect profile. There were no instances of adrenocortical insufficiency.

In conclusion, aldosterone synthase inhibition with baxdrostat is effective for substantial reductions in systolic and diastolic blood pressure in patients with treatment-resistant hypertension.

Source: www.nejm.org

Bempedoic Acid Lowers the Incidence of Major Adverse Cardiovascular Events in Statin-Intolerant Patients

Date: Mar 4, 2023

Seven to twenty-nine percent of patients reported adverse musculoskeletal effects which lead to their avoidance to statins or intolerance to guideline-recommended doses. Bempedoic acid, an ATP citrate lyase inhibitor with similar mechanism to statins, increases clearance of LDL cholesterol from the circulation and is associated with a lower incidence of musculoskeletal adverse events. However, its effect on cardiovascular outcomes remains uncertain.

In this double-blind, randomized, placebo-controlled trial, patients who were unable or unwilling to take statins due to unacceptable adverse effects and had, or were at high risk for cardiovascular disease, were recruited across 1250 sites in 32 countries. A total of 13,970 patients were randomly assigned in a 1:1 ratio to receive oral bempedoic acid, 180 mg daily (n = 6992), or a matching placebo (n = 6978). The primary endpoint was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. Patients were followed for a median duration of 40.6 months.

The mean LDL cholesterol level for the participants in the both groups was 139.0 mg per deciliter at baseline. After 6 months, the level was 107.0 mg per deciliter with bempedoic acid compared to 136.0 mg per deciliter with placebo, with a difference of 29.2 mg per deciliter (0.76 mmol/L). The observed difference in the percent reductions was 21.1 percentage points (95% confidence interval [CI], 20.3 to 21.9) in favour of bempedoic acid. The incidence of a primary endpoint event was significantly lower in the bempedoic acid group than in the placebo group (819 patients [11.7%] vs 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI]. 0.79 to 0.96; P=0.004). The incidence of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction were also significantly lower with bempedoic acid than with placebo. The bempedoic acid group had however a higher incidence of gout, cholelithiasis, elevated hepatic enzymes, renal impairment, and hyperuricemia.

The study concluded that treatment with bempedoic acid among statin-intolerant patients was associated with a lower risk of major adverse cardiovascular events including death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.

                                                                                     Source: www.nejm.org

Noninferiority of Bedaquiline–Linezolid Regimen to Standard Treatment for Rifampin-Susceptible Tuberculosis

Date: Mar 09, 2023

A 24-week rifampin-based regimen is a common treatment practice for rifampin-susceptible pulmonary tuberculosis. Long-term adherence issue is a major concern that warrants investigation of new treatment approaches with shorter duration and compatible effectiveness.

In this phase 2 to 3, international, adaptive, randomized, open-label, noninferiority TRUNCATE-TB trial, patients with rifampin-susceptible tuberculosis were randomly assigned to receive either the standard treatment or a trial 8-week regimen. The trial regimen included four strategy groups: high dose rifampin-linezolid, high dose rifampin-clofazimine, rifapentine-linezolid, and bedaquiline-linezolid, each in combination with isoniazid, pyrazinamide, and ethambutol or levofloxacin for the rifapentine–linezolid group. After the 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment, and retreatment for relapse were done. The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. Noninferiority was assessed in high-dose rifampin–linezolid and bedaquiline–linezolid groups with complete enrollment and the margin was 12 percentage points.

A total of 674 participants with an age range of 18-65 years were enrolled. The strategy with an initial bedaquiline-linezolid regimen was noninferior to the standard treatment, in which the primary-outcome event occurred in 11 of the 189 participants (5.8%) (adjusted difference, 0.8 percentage points; 97.5% CI, −3.4 to 5.1; noninferiority met) as compared with 7 of the 181 participants (3.9%) in the standard-treatment group. The mean total duration of the bedaquiline–linezolid strategy group and the standard treatment group were 85 days and 180 days respectively. The incidence of grade 3 or 4 adverse events, serious adverse events, and respiratory disability did not differ significantly between the standard-treatment group and the two strategy groups.

A strategy involving initial treatment with a bedaquiline–linezolid regimen was noninferior to standard treatment for tuberculosis concerning clinical outcomes, which was also associated with a shorter total duration of treatment and with no apparent safety concerns.

Source: www.nejm.org