NEJM original articles

Background. As-needed use of albuterol-budesonide has been shown to result in a significantly lower risk of severe asthma exacerbation than as-needed use of albuterol alone among patients with moderate-to-severe asthma. Data on albuterol-budesonide in mild asthma are needed.

Methods. We conducted a fully virtual, decentralized, phase 3b, multicenter, double-blind, event-driven trial involving persons 12 years of age or older with disease that was uncontrolled despite treatment for mild asthma with a short-acting β₂-agonist (SABA) with or without a low-dose inhaled glucocorticoid or leukotriene-receptor antagonist. Participants were randomly assigned in a 1:1 ratio to a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide (with each dose consisting of two inhaler actuations of 90 μg and 80 μg, respectively) or 180 μg of albuterol (with each dose consisting of two inhaler actuations of 90 μg) on an as-needed basis for up to 52 weeks. The primary end point was the first severe asthma exacerbation, assessed in a time-to-event analysis, in the on-treatment efficacy population, and the key secondary end point was the first severe exacerbation in the intention-to-treat population. Secondary end points included the annualized rate of severe asthma exacerbations and exposure to systemic glucocorticoids.

Results. A total of 2516 participants underwent randomization; 1797 (71.4%) completed the trial. Of 2421 participants in the full analysis population (1209 assigned to the albuterol-budesonide group and 1212 to the albuterol group), 97.2% were 18 years of age or older; 74.4% used a SABA alone at baseline. The trial was stopped for efficacy at a prespecified interim analysis. A severe exacerbation occurred in 5.1% of the participants in the albuterol-budesonide group and in 9.1% of those in the albuterol group in the on-treatment efficacy population (hazard ratio, 0.53; 95% confidence interval [CI], 0.39 to 0.73) and in 5.3% and 9.4%, respectively, in the intention-to-treat population (hazard ratio, 0.54; 95% CI, 0.40 to 0.73) (P<0.001 for both comparisons). The annualized rate of severe asthma exacerbations was lower with albuterol-budesonide than with albuterol (0.15 vs. 0.32; rate ratio, 0.47; 95% CI, 0.34 to 0.64), as was the mean annualized total dose of systemic glucocorticoids (23.2 vs. 61.9 mg per year). Adverse events were similar in the two treatment groups.

Conclusions. As-needed use of albuterol-budesonide resulted in a lower risk of a severe asthma exacerbation than as-needed use of albuterol alone among participants with disease that was uncontrolled despite treatment for mild asthma. (Funded by Bond Avillion 2 Development and AstraZeneca; BATURA ClinicalTrials.gov number, NCT05505734.)See also in NEJM Evidence: Participants as Partners in Decentralized Clinical Trials.

Background. Five risk factors account for approximately 50% of the global burden of cardiovascular disease. How the presence or absence of classic risk factors affects lifetime estimates of cardiovascular disease and death from any cause remains unclear.

Methods. We harmonized individual-level data from 2,078,948 participants across 133 cohorts, 39 countries, and 6 continents. Lifetime risk of cardiovascular disease and death from any cause was estimated up to 90 years of age according to the presence or absence of arterial hypertension, hyperlipidemia, underweight and overweight or obesity, diabetes, and smoking at 50 years of age. Differences in life span (in terms of additional life-years free of cardiovascular disease or death from any cause) according to the presence or absence of these risk factors were also estimated. Risk-factor trajectories were analyzed to predict lifetime differences according to risk-factor variation.

Results. The lifetime risk of cardiovascular disease was 24% (95% confidence interval [CI], 21 to 30) among women and 38% (95% CI, 30 to 45) among men for whom all five risk factors were present. In the comparison between participants with none of the risk factors and those with all the risk factors, the estimated number of additional life-years free of cardiovascular disease was 13.3 (95% CI, 11.2 to 15.7) for women and 10.6 (95% CI, 9.2 to 12.9) for men; the estimated number of additional life-years free of death was 14.5 (95% CI, 9.1 to 15.3) for women and 11.8 (95% CI, 10.1 to 13.6) for men. As compared with no changes in the presence of all risk factors, modification of hypertension at an age of 55 to less than 60 years was associated with the most additional life-years free of cardiovascular disease, and modification of smoking at an age of 55 to less than 60 years was associated with the most additional life-years free of death.

Conclusions. The absence of five classic risk factors at 50 years of age was associated with more than a decade greater life expectancy than the presence of all five risk factors, in both sexes. Persons who modified hypertension and smoking in midlife had the most additional life-years free of cardiovascular disease and death from any cause, respectively. (Funded by the German Center for Cardiovascular Research [DZHK]; ClinicalTrials.gov number, NCT05466825.).

Background. The safety and efficacy of treatment with intravenous tenecteplase before endovascular thrombectomy in patients with acute ischemic stroke due to large-vessel occlusion remain uncertain.

Methods. In this open-label trial conducted in China, we randomly assigned patients with acute ischemic stroke due to large-vessel occlusion who had presented within 4.5 hours after onset and were eligible for thrombolysis to receive either intravenous tenecteplase followed by endovascular thrombectomy or endovascular thrombectomy alone. The primary outcome was functional independence (a score of 0 to 2 on the modified Rankin scale; range, 0 to 6, with higher scores indicating more severe disability) at 90 days. Secondary outcomes included successful reperfusion before and after thrombectomy. Safety outcomes included symptomatic intracranial hemorrhage within 48 hours and death within 90 days.

Results. A total of 278 patients were randomly assigned to the tenecteplase-thrombectomy group and 272 to the thrombectomy-alone group. Functional independence at 90 days was observed in 147 patients (52.9%) in the tenecteplase-thrombectomy group and in 120 patients (44.1%) in the thrombectomy-alone group (unadjusted risk ratio, 1.20; 95% confidence interval, 1.01 to 1.43; P = 0.04). A total of 6.1% of the patients in the tenecteplase-thrombectomy group and 1.1% of those in the thrombectomy-alone group had successful reperfusion before thrombectomy, and 91.4% and 94.1%, respectively, had successful reperfusion after thrombectomy. Symptomatic intracranial hemorrhage within 48 hours occurred in 8.5% of the patients in the tenecteplase-thrombectomy group and in 6.7% of those in the thrombectomy-alone group; mortality at 90 days was 22.3% and 19.9%, respectively.

Conclusions. Among patients with acute ischemic stroke due to large-vessel occlusion who had presented within 4.5 hours after onset, the percentage of patients with functional independence at 90 days was higher with intravenous tenecteplase plus endovascular thrombectomy than with endovascular thrombectomy alone. (Funded by the Chongqing Science and Health Joint Medical Research Project and others; BRIDGE-TNK ClinicalTrials.gov number, NCT04733742.).

Background. In the phase 3, double-blind, randomized INAVO120 trial, treatment with inavolisib plus palbociclib-fulvestrant led to a significant progression-free survival benefit, as compared with placebo plus palbociclib-fulvestrant, among patients with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who had had relapse during or within 12 months after completion of adjuvant endocrine therapy.

Methods. We randomly assigned patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who had had disease recurrence or progression during or within 12 months after completion of adjuvant endocrine therapy to receive inavolisib plus palbociclib-fulvestrant (inavolisib group) or placebo plus palbociclib-fulvestrant (placebo group). In the current report, we provide the results of the final analysis of overall survival, including updated data on efficacy and safety.

Results. A total of 161 patients were assigned to the inavolisib group, and 164 to the placebo group. After a median follow-up of 34.2 months in the inavolisib group and 32.3 months in the placebo group, the median overall survival was 34.0 months (95% confidence interval [CI], 28.4 to 44.8) with inavolisib and 27.0 months (95% CI, 22.8 to 38.7) with placebo (hazard ratio for death, 0.67; 95% CI, 0.48 to 0.94; P = 0.02 [prespecified boundary for statistical significance, P<0.0469]). An objective response occurred in 62.7% (95% CI, 54.8 to 70.2) of patients in the inavolisib group and 28.0% (95% CI, 21.3 to 35.6) of those in the placebo group (P<0.001). The updated hazard ratio for disease progression or death was 0.42 (95% CI, 0.32 to 0.55). Adverse events led to discontinuation of inavolisib in 6.8% of patients and discontinuation of placebo in 0.6%. The incidence of hyperglycemia, stomatitis or mucosal inflammation, gastrointestinal toxic effects (e.g., diarrhea), and ocular toxic effects (e.g., dry eye and blurred vision) was higher with inavolisib than with placebo.

Conclusions. Treatment with inavolisib plus palbociclib-fulvestrant led to a significant overall survival benefit, as compared with placebo plus palbociclib-fulvestrant. Hyperglycemia, stomatitis or mucosal inflammation, gastrointestinal toxic effects, and ocular toxic effects were reported more frequently with inavolisib than with placebo. (Funded by F. Hoffmann-La Roche; INAVO120 ClinicalTrials.gov number, NCT04191499.).