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Background Hereditary angioedema (HAE) is characterized by unpredictable and often severe cutaneous and mucosal swelling that affects the extremities, face, larynx, gastrointestinal tract, or genitourinary area. Introduction of novel long-term prophylactic treatment options (lanadelumab, berotralstat, and C1-esterase inhibitor SC [human]) into the treatment armamentarium has substantially reduced HAE attacks, allowing patients to be attack free for longer with improvements to their quality of life. Using data drawn from a wide-ranging survey of patients with HAE, we examined the relationship between duration of time attack free and health-related quality of life (HRQoL), exploring the possibility that there is an association between observed improvement in HRQoL and attack-free duration. Methods A survey among patients with HAE on long-term prophylaxis (LTP) in six countries (the US, Australia, Canada, UK, Germany, and Japan) assessed the relationship between attack-free duration and mean Angioedema Quality of Life (AE-QoL) scores, quality of life benefits, and rescue medication used. Analysis of covariance (ANCOVA) was used to assess the roles of LTP and attack-free period (< 1 month, 1– < 6 months, ≥ 6 months) on total AE-QoL scores. Results include descriptive p -values for strength of association, without control for multiplicity. Descriptive statistics were used to show the relationship between time attack free and quality of life benefits. Results Longer durations of time for which participants reported being attack free at the time of the survey correlated with better AE-QoL scores and less use of rescue medication. The mean total AE-QoL scores were 51.8, 33.2, and 19.9 for those who reported having been attack free for < 1 month, 1– < 6 months, and ≥ 6 months, respectively, with higher scores reflecting more impairment. The ANCOVA results showed a strong association between attack-free duration and AE-QoL total score. Conclusion This study shows that longer attack-free duration has an influential role for better HRQoL in patients receiving LTP. Prolonging the attack-free period is an important goal of therapy and recent advances in LTP have increased attack-free duration. However, opportunities exist for new treatments to further increase attack-free duration and improve HRQoL for all patients with HAE.

Insomnia and poor sleep are associated with an increased risk of developing cardiovascular disease (CVD) and its precursors, including hypertension. In 2022, the American Heart Association (AHA) added inadequate sleep to its list of health behaviors that increase the risk for CVD. It remains unknown, however, whether the successful treatment of insomnia and inadequate sleep can reduce heightened CVD risk. SLEEPRIGHT is a single‐site, prospective clinical trial designed to evaluate whether the successful treatment of insomnia results in improved markers of CVD risk in patients with untreated hypertension and comorbid insomnia disorder. Participants ( N  = 150) will undergo baseline assessments, followed by a 6‐week run‐in period after which they will receive cognitive behavior therapy for insomnia (CBT‐I), comprised of 6 hourly sessions with an experienced CBT‐I therapist over a 6‐week period. In addition to measures of insomnia severity, as well as both subjective and objective measures of sleep, the primary outcome measures are nighttime blood pressure (BP) and BP dipping assessed by 24‐h ambulatory BP monitoring (ABPM). Secondary outcomes include several CVD risk biomarkers, including clinic BP, lipid profile, vascular endothelial function, arterial stiffness, and sympathetic nervous system (SNS) activity. Data analysis will evaluate the association between improvements in insomnia and sleep with primary and secondary CVD risk biomarker outcomes. The SLEEPRIGHT trial (ClinicalTrials.Gov NCT04009447) will utilize CBT‐I, the current gold standard treatment for insomnia disorder, to evaluate whether reducing insomnia severity and improving sleep are accompanied by improved biomarkers of CVD risk in patients with untreated hypertension.

In this randomized noninferiority trial involving patients with rheumatoid arthritis, cardiovascular events and cancers occurred more frequently with tofacitinib than with a TNF inhibitor, and noninferiority of tofacitinib with respect to these end points was not established.

ObjectivesCompare the risk of extended major adverse cardiovascular (CV) event (MACE) composite outcomes and component events in patients with rheumatoid arthritis (RA) treated with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in Oral Rheumatoid Arthritis Trial (ORAL) Surveillance.MethodsPatients with RA aged ≥50 years and with ≥1 additional CV risk factor received tofacitinib 5 mg or 10 mg two times per day or TNFi. MACE (non-fatal myocardial infarction (MI), non-fatal stroke or CV death (MACE-3)) was extended by sequential addition of CV events (hospitalisation for unstable angina (MACE-4), coronary revascularisation (MACE-5), transient ischaemic attack (MACE-6), peripheral vascular disease (MACE-7)), heart failure (HF) hospitalisation (MACE-8) and venous thromboembolism (VTE; (MACE-8 plus VTE)). HRs (tofacitinib vs TNFi) were evaluated for MACE and individual components.ResultsHRs for MACE-4 to MACE-8 with combined and individual tofacitinib doses versus TNFi were similar. Risk of MACE-8 plus VTE appeared similar with tofacitinib 5 mg two times per day versus TNFi (HR 1.12 (0.82 to 1.52)), but higher with tofacitinib 10 mg two times per day versus TNFi (HR 1.38 (1.02 to 1.85)). Risk of MI was higher with tofacitinib versus TNFi, but difference in risk of other individual CV events was not suggested. Across extended MACE definitions, risk appeared higher with tofacitinib versus TNFi in those with atherosclerotic CV disease or age ≥65 years.ConclusionIn ORAL Surveillance, risk of composite CV endpoints combining all ischaemic CV events and HF did not appear different with tofacitinib versus TNFi. The totality of CV risk was higher with tofacitinib 10 mg two times per day versus TNFi, driven by an increase in VTE.Trial registration number NCT02092467.

Background/Aim DARE-19 (NCT04350593) was a randomized trial studying the effects of dapagliflozin, an SGLT2 inhibitor, in hospitalized patients with COVID-19 pneumonia and cardiometabolic risk factors. The conduct of DARE-19 offered the opportunity to define an innovative and clinically meaningful endpoint in a new disease that would best reflect the known profile of dapagliflozin, accompanied by the statistical challenges of analysis and interpretation of such a novel endpoint.MethodsHierarchical composite endpoints (HCEs) are based on clinical outcomes which, unlike traditional composite endpoints incorporate ranking of components according to clinical importance. Design of an HCE requires the clinical considerations specific to the therapeutic area under study and the mechanism of action of the investigational treatment. Statistical aspects for the clinical endpoints include the proper definition of the estimand as suggested by ICH E9(R1) for the precise specification of the treatment effect measured by an HCE.ResultsWe describe the estimand of the DARE-19 trial, where an HCE was constructed to capture the treatment effect of dapagliflozin in hospitalized patients with COVID-19, and was analyzed using a win odds. Practical aspects of designing new studies based on an HCE are described. These include sample size, power, and minimal detectable effect calculations for an HCE based on the win odds analysis, as well as handling of missing data and the clinical interpretability of the win odds in relation to the estimand.ConclusionsHCEs are flexible endpoints that can be adapted for use in different therapeutic areas, with win odds as the analysis method. DARE-19 is an example of a COVID-19 trial with an HCE as one of the primary endpoints for estimating a clinically interpretable treatment effect in the COVID-19 setting.

Background Although several previous studies tested SGLT2 inhibitors in the setting of an acute, non-cardiovascular illness, detailed information on their efficacy and safety among participants with and without type 2 diabetes (T2D) from double-blind randomized trials is lacking. In this secondary prespecified analysis of the Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19) trial, we sought to evaluate the safety and efficacy of initiating dapagliflozin during acute illness with COVID-19 in patients with and without T2D. Methods The DARE-19 trial randomized 1250 patients hospitalized with COVID-19 and cardiometabolic risk factors to dapagliflozin or placebo. T2D was present in 636/1250 (50.9%) of the cohort. Dual primary outcomes were evaluated: prevention (time to new or worsened organ dysfunction or death) and a hierarchical composite outcome of recovery (change in clinical status by day 30). Key biomarkers (serum bicarbonate, estimated glomerular filtration rate [eGFR], hematocrit, and glucose) and safety were assessed in participants with and without T2D during index hospitalization. Results Among patients with T2D, the prevention outcome occurred in 10.9% receiving dapagliflozin versus 13.9% receiving placebo (hazard ratio [HR] 0.76, 95% CI 0.49–1.18). In patients without diabetes, the event rate was 11.5% with dapagliflozin versus 13.3% with placebo (HR 0.86, 95% CI 0.55–1.35; interaction p  = 0.668). For the primary recovery outcome, no significant differences were observed between dapagliflozin and placebo groups regardless of diabetes status (interaction p  = 0.222). Close laboratory monitoring revealed similarities in serum bicarbonate, eGFR, or hematocrit for the dapagliflozin and placebo groups, irrespective of T2D status. Any serious adverse event was reported in 12·7% of patients in the dapagliflozin group, 14·3% in the placebo group among patients with T2D, and in 8·5% of patients in the dapagliflozin group, and 11·9% in the placebo group in patients without T2D. Diabetes ketoacidosis was reported in two patients with T2D in the dapagliflozin group. Conclusions Initiating dapagliflozin in patients hospitalized for acute COVID-19 was well tolerated and safe, irrespective of T2D status. Serum biomarker levels remained stable and comparable between treatment groups, indicating no increased risk of adverse metabolic or renal effects with dapagliflozin in this clinical scenario. Trial registration The trial was registered on ClinicalTrials.gov (NCT04350593).

ObjectivesEvaluate risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) with or without a history of atherosclerotic cardiovascular disease (ASCVD) in ORAL Surveillance.MethodsPatients with RA aged ≥50 years with ≥1 additional CV risk factor received tofacitinib 5 mg or 10 mg two times per day or TNFi. Hazard rations (HRs) were evaluated for the overall population and by history of ASCVD (exploratory analysis).ResultsRisk of MACE, myocardial infarction and sudden cardiac death were increased with tofacitinib versus TNFi in ORAL Surveillance. In patients with history of ASCVD (14.7%; 640/4362), MACE incidence was higher with tofacitinib 5 mg two times per day (8.3%; 17/204) and 10 mg two times per day (7.7%; 17/222) versus TNFi (4.2%; 9/214). HR (combined tofacitinib doses vs TNFi) was 1.98 (95% confidence interval (CI) 0.95 to 4.14; interaction p values: 0.196 (for HR)/0.059 (for incidence rate difference)). In patients without history of ASCVD, MACE HRs for tofacitinib 5 mg two times per day (2.4%; 30/1251) and 10 mg two times per day (2.8%; 34/1234) versus TNFi (2.3%; 28/1237) were, respectively, 1.03 (0.62 to 1.73) and 1.25 (0.76 to 2.07).ConclusionsThis post hoc analysis observed higher MACE risk with tofacitinib versus TNFi in patients with RA and history of ASCVD. Among patients without history of ASCVD, all with prevalent CV risk factors, MACE risk did not appear different with tofacitinib 5 mg two times per day versus TNFi. Due to the exploratory nature of this analysis and low statistical power, we cannot exclude differential MACE risk for tofacitinib 5 mg two times per day versus TNFi among patients without history of ASCVD, but any absolute risk excess is likely low.Trial registration number NCT02092467.

ObjectivesTo examine the validity and statistical limitations of exploratory analyses of clinical trial data commonly requested by agencies responsible for determining which medical products may be financed or reimbursed by a healthcare system.DesignThis was a retrospective review of efficacy and safety analyses conducted for German Health Technology Assessment (HTA) evaluations with a decision date between 2015 and 2020, and an illustrative safety-related exploratory analysis of data from two phase III clinical trials of verubecestat (an anti-amyloid drug whose development was stopped for lack of efficacy) as would be mandated by the German HTA agency.ResultsWe identified 422 HTA evaluations of 404 randomised controlled clinical trials. For 140 trials (34.7%), the evaluation was based on subpopulations of participants in the originating confirmatory trial (175 subpopulations were assessed). In 57% (100 of 175), the subpopulation sample size was 50% or less of the original study population. Detailed analysis of five evaluations based on subpopulations of the original trial is presented. The safety-related exploratory analysis of verubecestat led to 206 statistical analyses for treatments and 812 treatment-by-subgroup interaction tests. Of 31 safety endpoints with an elevated HR (suggesting association with drug treatment), the HR for 81% of these (25 of 31) was not elevated in both trials. Of the 812 treatment-by-subgroup interactions evaluated, 26 had an elevated HR for a subgroup in one trial, but only 1 was elevated in both trials.ConclusionsMany HTA evaluations rely on subpopulation analyses and numerous post hoc statistical hypothesis tests. Subpopulation analysis may lead to loss of statistical power and uncontrolled influences of random imbalances. Multiple testing may introduce spurious findings. Decisions about benefits of medical products should therefore not rely on exploratory analyses of clinical trial data but rather on prospective clinical studies and careful synthesis of all available evidence based on prespecified criteria.

Aims The objective of this study was to examine associations between elevated depressive symptoms and increased risk of adverse clinical events patients with heart failure and reduced ejection fraction (HFrEF), as well as the potential contribution of health behaviours. Methods and results One hundred forty‐two men and women with HFrEF were enrolled through heart failure (HF) clinics and followed over time. At baseline and 6 months, depressive symptoms were assessed by the Beck Depression Inventory‐II (BDI‐II) and HFrEF disease activity by B‐type natriuretic peptide (BNP). The Self‐Care of Heart Failure Index (SCHFI) was used to assess HF self‐care behaviours. Proportional hazards regression models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. Over a median follow‐up period of 4 years, 42 patients (30%) died, and 84 (60%) had cardiovascular hospitalizations. A 10‐point higher baseline BDI‐II score was associated with a 35% greater risk of death or cardiovascular hospitalization. Higher baseline BDI‐II scores were associated with poorer HF self‐care maintenance behaviours (R = −0.30, P < 0.001) and fewer daily steps (R = −0.19, P = 0.04), suggesting that elevated depressive symptoms may diminish important health behaviours. Increases in plasma BNP over 6 months were associated with worse outcomes. Changes in BDI‐II and plasma BNP over 6 months were positively related (R = 0.25, P = 0.004). Conclusions This study confirms that elevated depressive symptoms are associated with an increased likelihood of adverse clinical outcomes in patients with HFrEF. Poor health behaviours may contribute to the adverse association of elevated depressive symptoms with the increased hazard of adverse clinical outcomes.

Insulin-resistant subjects develop more severe and diffuse coronary artery atherosclerosis than insulin-sensitive controls but the mechanisms that mediate this atherosclerosis phenotype are unknown. To determine the metabolic parameters that associate with the severity of coronary atherosclerosis in insulin resistant pigs fed a high fat/high NaCl diet. The primary endpoint was severity of coronary atherosclerosis in adult pigs (Sus scrofa, n = 37) fed a high fat diet that also contained high NaCl (56% above recommended levels) for 1 year. Twenty pigs developed severe and diffuse distal coronary artery atherosclerosis (i.e., severe = intimal area as a percent medial area > 200% in at least 2 coronary artery cross sections and diffuse distal = intimal area as a percent medial area ≥ 150% over 3 sections separated by 2 cm in the distal half of the coronary artery). The other 17 pigs had substantially less coronary artery atherosclerosis. All 37 pigs had blood pressure in a range that would be considered hypertensive in humans and developed elevations in total and LDL and HDL cholesterol, weight gain, increased backfat, and increased insulin resistance (Bergman Si) without overt diabetes. Insulin resistance was not associated with atherosclerosis severity. Five additional pigs fed regular pig chow also developed increased insulin resistance but essentially no change in the other variables and little to no detectible coronary atherosclerosis. Most importantly, the 20 high fat/high NaCl diet-fed pigs with severe and diffuse distal coronary artery atherosclerosis had substantially greater increases (p< 0.05) in oxidized LDL (oxLDL) and fructosamine consistent with increased protein glycation. In pigs fed a high fat/high NaCl diet, glycated proteins are induced in the absence of overt diabetes and this degree of increase is associated with the development of severe and diffuse distal coronary artery atherosclerosis.