Drug Combinations

ImportanceTransitioning from metered-dose inhalers to propellant-free dry-powder inhalers could reduce health care-related greenhouse gas emissions, but the clinical difference in outcomes that may be associated with this switch is uncertain.ObjectiveTo evaluate the clinical difference in outcomes associated with a July 2021 Veterans Health Administration (VHA) formulary change that replaced budesonide-formoterol metered-dose inhaler with fluticasone-salmeterol dry-powder inhaler for the treatment of chronic obstructive pulmonary disease and asthma.Design, setting, and participantsThis within-person, self-controlled case series (SCCS) and matched observational cohort study (cohort study) used data from the US Veterans Affairs health care system from January 2018 through December 2022. Veterans who were prescribed a combination inhaler before and after the formulary change were included in both the SCCS and cohort study. Data were analyzed between April 19, 2024, and April 4, 2025.ExposuresTreatment with budesonide-formoterol metered-dose inhaler vs fluticasone-salmeterol dry-powder inhaler.Main outcomes and measuresRescue medication use (albuterol and prednisone fills), emergency department visits, and hospitalizations (all-cause, respiratory-related, and pneumonia-specific) were assessed.ResultsFollowing the VHA formulary change, 260 268 patients switched from budesonide-formoterol metered-dose therapy to fluticasone-salmeterol dry-powder therapy. In the SCCS (median [IQR] age, 71 [62-75] years; 91% male), among patients who switched inhalers and experienced the adverse outcomes of interest, treatment with fluticasone-salmeterol dry-powder inhaler therapy was associated with a 10% decrease in albuterol fills (incidence rate ratio [IRR], 0.90 [95% CI, 0.90-0.91]), a 2% increase in prednisone fills (IRR, 1.02 [95% CI, 1.01-1.03]), a 5% increase in all-cause emergency department visits (IRR, 1.05 [95% CI, 1.04-1.06]), an 8% increase in all-cause hospitalizations (IRR, 1.08 [95% CI, 1.06-1.09]), a 10% increase in respiratory-related hospitalizations (IRR, 1.10 [95% CI, 1.07-1.14]), and a 24% increase in pneumonia-specific hospitalizations (IRR, 1.24 [95% CI, 1.17-1.31]). In the cohort study of 258 557 patients (mean [SD] age, 68.9 [11.3] years; 94% male), those who switched to a fluticasone-salmeterol dry-powder inhaler had no difference in mortality (1.89% vs 1.90%; adjusted absolute difference, -0.01 percentage points [95% CI, -0.12 to 0.10 percentage points]) but had increases in all-cause hospitalizations (16.14% vs 15.64%; adjusted absolute difference, 0.49 percentage points [95% CI, 0.21-0.78 percentage points]), respiratory-related hospitalizations (3.15% vs 2.74%; adjusted absolute difference, 0.41 percentage points [95% CI, 0.27-0.55 percentage points]), and pneumonia-related hospitalizations (1.15% vs 1.03%; adjusted absolute difference, 0.12 percentage points [95% CI, 0.04-0.21 percentage points]) at 180 days after the switch compared with matched patients who did not switch.Conclusions and relevanceThe study found that the VHA formulary transition from budesonide-formoterol metered-dose inhaler to fluticasone-salmeterol dry-powder inhaler was associated with increased health care utilization, suggesting potential harm and the need to reevaluate this policy change.

Background and aimsThe efficacy and safety of early sacubitril/valsartan (Sac/Val) initiation after acute heart failure (AHF) has not been demonstrated outside North America. The present study aimed to evaluate the effect of in-hospital Sac/Val therapy initiation after an AHF episode on N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in Japanese patients.MethodsThis was an investigator-initiated, multicentre, prospective, randomized, open-label, blinded-endpoint pragmatic trial. After haemodynamic stabilization within 7 days after hospitalization, eligible inpatients were allocated to switch from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to Sac/Val (Sac/Val group) or to continue angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (control group). The primary efficacy endpoint was the 8-week proportional change in geometric means of NT-proBNP levels.ResultsA total of 400 patients were equally randomized, and 376 (median age 75 years, 31.9% women, de novo heart failure rate 55.6%, and median left ventricular ejection fraction 37%) were analysed. The per cent changes in NT-proBNP level geometric means at Weeks 4/8 were -35%/-45% (Sac/Val group) and -18%/-32% (control group), and their group ratio (Sac/Val vs. control) was 0.80 (95% confidence interval 0.68-0.94; P = .008) at Week 4 and 0.81 (95% confidence interval 0.68-0.95; P = .012) at Week 8, respectively. In the pre-specified subgroup analyses, the effects of Sac/Val were confined to patients with a left ventricular ejection fraction ConclusionsIn-hospital Sac/Val therapy initiation in addition to contemporary recommended therapy triggered a greater NT-proBNP level reduction in Japanese patients hospitalized for AHF. These findings may expand the evidence on Sac/Val therapy in this clinical situation outside North America.Clinical trial registrationClinicalTrial.gov (NCT05164653) and Japan Registry of Clinical Trials (jRCTs021210046).

ImportanceRandomized clinical trials have shown that sacubitril-valsartan reduces the risks of mortality and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF), but patients with kidney failure requiring dialysis were excluded.ObjectiveTo investigate the comparative effectiveness of sacubitril-valsartan vs angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs or ARBs) in patients with HFrEF requiring hemodialysis.Design, setting, and participantsThis retrospective, 1:1 propensity score-matched comparative effectiveness study included patients who were 18 years or older with HFrEF, enrolled in Medicare Parts A, B, and D, and survived at least 90 days receiving in-center hemodialysis from July 8, 2015, to December 31, 2020. Patients were excluded for less than 180 days of continuous Medicare Parts A, B, and D primary payer coverage or prior dispensing of sacubitril-valsartan. Data analysis was conducted from September 23, 2023, to June 25, 2024.ExposuresNew use of sacubitril-valsartan vs new or continued use of ACEIs or ARBs.Main outcomes and measuresThe associations between initiation of sacubitril-valsartan therapy and all-cause mortality, cardiovascular mortality, all-cause hospitalization, and HF hospitalization were assessed using Cox proportional hazards regression models in a propensity score-matched sample.ResultsParticipants included 1:1 matched pairs of 1434 sacubitril-valsartan users and 1434 ACEI or ARB users (mean [SD] age, 64 [13] years). Of the 2868 matched participants, 996 (65%) were male; 987 (34%) were Black or African American and 1677 (58%) were White; and median dialysis vintage was 3.8 (IQR, 1.8-6.3) years. The median follow-up was 0.9 (IQR, 0.4-1.7) years. Sacubitril-valsartan (vs ACEI or ARB) therapy was associated with a reduction in all-cause mortality (hazard ratio [HR], 0.82 [95% CI, 0.73-0.92]) and all-cause hospitalization (HR, 0.86 [95% CI, 0.79-0.93]) but not cardiovascular mortality (HR, 1.01 [95% CI, 0.86-1.19]) or HF hospitalization (HR, 0.91 [95% CI, 0.82-1.02]). There was a decrease in hyperkalemia (HR, 0.71 [95% CI, 0.62-0.81]) and no difference in hypotension (HR, 0.99 [95% CI, 0.83-1.19]). Only 195 participants (14%) ever received the maximum combination dose of sacubitril (97 mg twice daily) and valsartan (103 mg twice daily).Conclusions and relevanceIn this comparative effectiveness study of patients with HFrEF requiring hemodialysis, sacubitril-valsartan therapy was associated with beneficial effects in all-cause mortality and all-cause hospitalization.