Sodium-glucose co-transporter-2 inhibitors for hospitalised patients with COVID-19: a prospective meta-analysis of randomised trials.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been proposed as a potential treatment for adults hospitalised with COVID-19, due to their potential anti-inflammatory and endothelial protective effects. Published evidence from randomised control trials (RCTs) does not provide evidence of benefit. We aimed to estimate the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo in adults hospitalised with COVID-19. METHODS: Eligible RCTs that estimated the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo on 28-day all-cause mortality (primary outcome) were included in this prospective meta-analysis. The primary safety outcome was ketoacidosis by 28 days. Trials were identified through systematic searches of ClinicalTrials.gov, EudraCT, and the WHO ISRCTN registry between Nov 1, 2022 and Jan 31, 2023. The search terms were "random*" AND "COVID" AND each SGLT2i, not restricted by trial status or language. Individual searches were then combined. Prespecified summary outcome data, overall and within subgroups of interest, were provided by each trial. The primary analyses were inverse variance weighted meta-analysis of odds ratios (ORs). Risk of bias was assessed using the Cochrane Risk of Bias tool. This study was registered with PROSPERO, CRD42023406442. FINDINGS: Three eligible trials randomly assigned 6096 participants (3025 to the SGLT2 inhibitor group and 3071 to the usual care or placebo group). 2381 (39%) patients were women and 1547 (25%) had type 2 diabetes at randomisation. By 28 days, there were 351 deaths in the SGLT2 inhibitor group and 382 deaths in the usual care or placebo group (summary OR 0·93 [95% CI 0·79-1·08]; p=0·33, I2 for inconsistency across trials 0%). The risk of bias was assessed as being low. Ketoacidosis was observed in seven participants in the SGLT2 inhibitor group and two patients in the usual care or placebo group. INTERPRETATION: Although administration of SGLT2 inhibitor was safe, we found no clear evidence that adding SGLT2 inhibitor therapy improved outcomes in patients hospitalised with COVID-19 compared with usual care or placebo. These data do not support the use of SGLT2 inhibitors as standard treatment in adults hospitalised for COVID-19. FUNDING: None.

An international survey assessing the effects of the duration of attack-free period on health-related quality of life for patients with hereditary angioedema.

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.

Depressive symptoms are associated with clinical outcomes in heart failure with reduced ejection fraction.

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.

Angiogenic Gene Therapy for Refractory Angina: Results of the EXACT Phase 2 Trial.

BACKGROUND: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina. METHODS: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×1011 viral particles) via transepicardial delivery. RESULTS: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months. CONCLUSIONS: XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732.

Risk of extended major adverse cardiovascular event endpoints with tofacitinib versus TNF inhibitors in patients with rheumatoid arthritis: a post hoc analysis of a phase 3b/4 randomised safety study.

OBJECTIVES: Compare 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. METHODS: Patients 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. RESULTS: HRs 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. CONCLUSION: In 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.

Risk of Venous Thromboembolism With Tofacitinib Versus Tumor Necrosis Factor Inhibitors in Cardiovascular Risk-Enriched Rheumatoid Arthritis Patients.

OBJECTIVE: The ORAL Surveillance trial found a dose-dependent increase in venous thromboembolism (VTE) and pulmonary embolism (PE) events with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to assess VTE incidence over time and explore risk factors of VTE, including disease activity, in ORAL Surveillance. METHODS: Patients with rheumatoid arthritis (RA) aged 50 years or older with at least one additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily (BID) or TNFi. Post hoc, cumulative probabilities and incidence rates (patients with first events/100 patient-years) by 6-month intervals were estimated for adjudicated VTE, deep vein thrombosis, and PE. Cox regression models identified risk factors. Clinical Disease Activity Index leading up to the event was explored in patients with VTE. RESULTS: Cumulative probabilities for VTE and PE were higher with tofacitinib 10 mg BID, but not 5 mg BID, versus TNFi. Incidence rates were consistent across 6-month intervals within treatments. Across treatments, risk factors for VTE included prior VTE, body mass index greater than or equal to 35 kg/m2, older age, and history of chronic lung disease. At the time of the event, most patients with VTE had active disease as defined by Clinical Disease Activity Index. CONCLUSION: Incidences of VTE and PE were higher with tofacitinib (10 > 5 mg BID) versus TNFi and were generally consistent over time. Across treatments, VTE risk factors were aligned with previous studies in the general RA population. These data highlight the importance of assessing VTE risk factors, including age, body mass index, and VTE history, when considering initiation of tofacitinib or TNFi in patients with active RA.

Cognitive behavior therapy for insomnia for untreated hypertension with comorbid insomnia disorder: The SLEEPRIGHT clinical trial.

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.

Association of Depression Symptoms and Biomarkers of Risk on Clinical Outcomes in HFrEF.

BACKGROUND: Prior studies have demonstrated an association of depression with adverse clinical outcomes in patients with HFrEF, but the possible mechanisms responsible for the association are not unserstood. METHODS: 142 men and women with HFrEF were enrolled through HF clinics and followed over time. At baseline and 6-months, depression was assessed by the Beck Depression Inventory (BDI-II) and disease activity by B-type natriuretic peptide (BNP). Proportional Hazards Regression Models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. RESULTS: 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% higher hazard of death or cardiovascular hospitalization. Greater baseline BDI-II scores were associated with poorer HF self-care maintenance (R=-0.30, p<0.001) and fewer daily steps (R=-0.19, p=0.04), suggesting that depression may adversely affect important health behaviors. Increases in plasma BNP over 6 months were associated with worse outcomes. Changes in BDI-II score and plasma BNP over 6 months were positively correlated (R=0.25, p=0.004). CONCLUSIONS: This study underscores the importance of elevated depression symptoms and their association with an increased likelihood of adverse clinical outcomes in patients with HFrEF. Health behaviors may play a greater role than direct biobehavioral pathways in the adverse effects of depression on the HF disease trajectory and resultant clinical outcomes.

Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance.

OBJECTIVES: Evaluate 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. METHODS: Patients 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). RESULTS: Risk 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). CONCLUSIONS: This 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.

Exploratory analyses of clinical trial data used for health technology assessments: a retrospective evaluation.

OBJECTIVES: To 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. DESIGN: This 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. RESULTS: We 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. CONCLUSIONS: Many 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.

Design and Analysis of Studies Based on Hierarchical Composite Endpoints: Insights from the DARE-19 Trial.

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. METHODS: Hierarchical 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. RESULTS: We 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. CONCLUSIONS: HCEs 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.

Dapagliflozin and Kidney Outcomes in Hospitalized Patients with COVID-19 Infection: An Analysis of the DARE-19 Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Patients who were hospitalized with coronavirus disease 2019 (COVID-19) infection are at high risk of AKI and KRT, especially in the presence of CKD. The Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19) trial showed that in patients hospitalized with COVID-19, treatment with dapagliflozin versus placebo resulted in numerically fewer participants who experienced organ failure or death, although these differences were not statistically significant. We performed a secondary analysis of the DARE-19 trial to determine the efficacy and safety of dapagliflozin on kidney outcomes in the overall population and in prespecified subgroups of participants defined by baseline eGFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The DARE-19 trial randomized 1250 patients who were hospitalized (231 [18%] had eGFR <60 ml/min per 1.73 m2) with COVID-19 and cardiometabolic risk factors to dapagliflozin or placebo. Dual primary outcomes (time to new or worsened organ dysfunction or death, and a hierarchical composite end point of recovery [change in clinical status by day 30]), and the key secondary kidney outcome (composite of AKI, KRT, or death), and safety were assessed in participants with baseline eGFR <60 and ≥60 ml/min per 1.73 m2. RESULTS: The effect of dapagliflozin versus placebo on the primary prevention outcome (hazard ratio, 0.80; 95% confidence interval, 0.58 to 1.10), primary recovery outcome (win ratio, 1.09; 95% confidence interval, 0.97 to 1.22), and the composite kidney outcome (hazard ratio, 0.74; 95% confidence interval, 0.50 to 1.07) were consistent across eGFR subgroups (P for interaction: 0.98, 0.67, and 0.44, respectively). The effects of dapagliflozin on AKI were also similar in participants with eGFR <60 ml/min per 1.73 m2 (hazard ratio, 0.71; 95% confidence interval, 0.29 to 1.77) and ≥60 ml/min per 1.73 m2 (hazard ratio, 0.69; 95% confidence interval, 0.37 to 1.29). Dapagliflozin was well tolerated in participants with eGFR <60 and ≥60 ml/min per 1.73 m2. CONCLUSIONS: The effects of dapagliflozin on primary and secondary outcomes in hospitalized participants with COVID-19 were consistent in those with eGFR below/above 60 ml/min per 1.73 m2. Dapagliflozin was well tolerated and did not increase the risk of AKI in participants with eGFR below or above 60 ml/min per 1.73 m2.

Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis.

BACKGROUND: Increases in lipid levels and cancers with tofacitinib prompted a trial of major adverse cardiovascular events (MACE) and cancers in patients with rheumatoid arthritis receiving tofacitinib as compared with a tumor necrosis factor (TNF) inhibitor. METHODS: We conducted a randomized, open-label, noninferiority, postauthorization, safety end-point trial involving patients with active rheumatoid arthritis despite methotrexate treatment who were 50 years of age or older and had at least one additional cardiovascular risk factor. Patients were randomly assigned in a 1:1:1 ratio to receive tofacitinib at a dose of 5 mg or 10 mg twice daily or a TNF inhibitor. The coprimary end points were adjudicated MACE and cancers, excluding nonmelanoma skin cancer. The noninferiority of tofacitinib would be shown if the upper boundary of the two-sided 95% confidence interval for the hazard ratio was less than 1.8 for the combined tofacitinib doses as compared with a TNF inhibitor. RESULTS: A total of 1455 patients received tofacitinib at a dose of 5 mg twice daily, 1456 received tofacitinib at a dose of 10 mg twice daily, and 1451 received a TNF inhibitor. During a median follow-up of 4.0 years, the incidences of MACE and cancer were higher with the combined tofacitinib doses (3.4% [98 patients] and 4.2% [122 patients], respectively) than with a TNF inhibitor (2.5% [37 patients] and 2.9% [42 patients]). The hazard ratios were 1.33 (95% confidence interval [CI], 0.91 to 1.94) for MACE and 1.48 (95% CI, 1.04 to 2.09) for cancers; the noninferiority of tofacitinib was not shown. The incidences of adjudicated opportunistic infections (including herpes zoster and tuberculosis), all herpes zoster (nonserious and serious), and adjudicated nonmelanoma skin cancer were higher with tofacitinib than with a TNF inhibitor. Efficacy was similar in all three groups, with improvements from month 2 that were sustained through trial completion. CONCLUSIONS: In this trial comparing the combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk-enriched population, risks of MACE and cancers were higher with tofacitinib and did not meet noninferiority criteria. Several adverse events were more common with tofacitinib. (Funded by Pfizer; ORAL Surveillance ClinicalTrials.gov number, NCT02092467.).

Power and sample size calculation for the win odds test: application to an ordinal endpoint in COVID-19 trials.

The win odds is a distribution-free method of comparing locations of distributions of two independent random variables. Introduced as a method for analyzing hierarchical composite endpoints, it is well suited to be used in the analysis of ordinal scale endpoints in COVID-19 clinical trials. For a single outcome, we provide power and sample size calculation formulas for the win odds test. We also provide an implementation of the win odds analysis method for a single ordinal outcome in a commonly used statistical software to make the win odds analysis fully reproducible.

Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: COVID-19 can lead to multiorgan failure. Dapagliflozin, a SGLT2 inhibitor, has significant protective benefits for the heart and kidney. We aimed to see whether this agent might provide organ protection in patients with COVID-19 by affecting processes dysregulated during acute illness. METHODS: DARE-19 was a randomised, double-blind, placebo-controlled trial of patients hospitalised with COVID-19 and with at least one cardiometabolic risk factor (ie, hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease). Patients critically ill at screening were excluded. Patients were randomly assigned 1:1 to dapagliflozin (10 mg daily orally) or matched placebo for 30 days. Dual primary outcomes were assessed in the intention-to-treat population: the outcome of prevention (time to new or worsened organ dysfunction or death), and the hierarchial composite outcome of recovery (change in clinical status by day 30). Safety outcomes, in patients who received at least one study medication dose, included serious adverse events, adverse events leading to discontinuation, and adverse events of interest. This study is registered with ClinicalTrials.gov, NCT04350593. FINDINGS: Between April 22, 2020 and Jan 1, 2021, 1250 patients were randomly assigned with 625 in each group. The primary composite outcome of prevention showed organ dysfunction or death occurred in 70 patients (11·2%) in the dapagliflozin group, and 86 (13·8%) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·58-1·10; p=0·17). For the primary outcome of recovery, 547 patients (87·5%) in the dapagliflozin group and 532 (85·1%) in the placebo group showed clinical status improvement, although this was not statistically significant (win ratio 1·09, 95% CI 0·97-1·22; p=0·14). There were 41 deaths (6·6%) in the dapagliflozin group, and 54 (8·6%) in the placebo group (HR 0·77, 95% CI 0·52-1·16). Serious adverse events were reported in 65 (10·6%) of 613 patients treated with dapagliflozin and in 82 (13·3%) of 616 patients given the placebo. INTERPRETATION: In patients with cardiometabolic risk factors who were hospitalised with COVID-19, treatment with dapagliflozin did not result in a statistically significant risk reduction in organ dysfunction or death, or improvement in clinical recovery, but was well tolerated. FUNDING: AstraZeneca.

Noninvasive measure of treatment response in non-alcoholic steatohepatitis: Insights from EMMINENCE and meta-analysis.

BACKGROUND AND AIM: Liver histology changes are the current gold standard for evaluating non-alcoholic steatohepatitis (NASH), but are limited by their invasiveness and variability for sampling and interpretation. We evaluated noninvasive biomarkers as an indication of histologic changes in NASH. METHODS: Associations between 12-month biomarker and NASH Clinical Research Network histologic score changes in 339 patients with NASH in the EMMINENCE trial was examined with multivariable models and partial canonical correlation. A meta-analysis of 17 NASH trials including 3717 patients examined associations between these same changes and histologic response within treatment groups, and treatment effects on biomarkers and on liver histology. Biopsy measures assessed were changes in ballooning, steatosis, inflammation, and fibrosis, NASH improvement without worsening of fibrosis, and fibrosis improvement without worsening of NASH. All analytic methods suggest that a combination of aspartate aminotransferase (AST), cytokeratin-18 (CK-18 [M30 or M65]), and hemoglobin A1C (HbA1c) changes best predicts overall liver biopsy changes in response to interventions. RESULTS: The weighted average of standardized mean changes (0.403 × AST, 0.314 × CK-18, 0.283 × HbA1c) facilitated comparisons of within-group responses and treatment effects among studies included in the meta-analysis. This composite in EMMINENCE discriminated between patients with and without NASH resolution without worsening fibrosis with area under the receiver-operator characteristic curve of 0.7880, and for fibrosis improvement without NASH worsening of 0.7553. CONCLUSION: A composite score based on changes in AST, HbA1c, and CK-18 could serve as a surrogate for liver histologic improvement and an effective objective, noninvasive tool for comparative assessment of treatment effects of novel interventions.

On kernel machine learning for propensity score estimation under complex confounding structures.

Post marketing data offer rich information and cost-effective resources for physicians and policy-makers to address some critical scientific questions in clinical practice. However, the complex confounding structures (e.g., nonlinear and nonadditive interactions) embedded in these observational data often pose major analytical challenges for proper analysis to draw valid conclusions. Furthermore, often made available as electronic health records (EHRs), these data are usually massive with hundreds of thousands observational records, which introduce additional computational challenges. In this paper, for comparative effectiveness analysis, we propose a statistically robust yet computationally efficient propensity score (PS) approach to adjust for the complex confounding structures. Specifically, we propose a kernel-based machine learning method for flexibly and robustly PS modeling to obtain valid PS estimation from observational data with complex confounding structures. The estimated propensity score is then used in the second stage analysis to obtain the consistent average treatment effect estimate. An empirical variance estimator based on the bootstrap is adopted. A split-and-merge algorithm is further developed to reduce the computational workload of the proposed method for big data, and to obtain a valid variance estimator of the average treatment effect estimate as a by-product. As shown by extensive numerical studies and an application to postoperative pain EHR data comparative effectiveness analysis, the proposed approach consistently outperforms other competing methods, demonstrating its practical utility.

Is acute heart failure a distinctive disorder? An analysis from BIOSTAT-CHF.

AIMS: This retrospective analysis sought to identify markers that might distinguish between acute heart failure (HF) and worsening HF in chronic outpatients. METHODS AND RESULTS: The BIOSTAT-CHF index cohort included 2516 patients with new or worsening HF symptoms: 1694 enrolled as inpatients (acute HF) and 822 as outpatients (worsening HF in chronic outpatients). A validation cohort included 935 inpatients and 803 outpatients. Multivariable models were developed in the index cohort using clinical characteristics, routine laboratory values, and proteomics data to examine which factors predict adverse outcomes in both conditions and to determine which factors differ between acute HF and worsening HF in chronic outpatients, validated in the validation cohort. Patients with acute HF had substantially higher morbidity and mortality (6-month mortality was 12.3% for acute HF and 4.7% for worsening HF in chronic outpatients). Multivariable models predicting 180-day mortality and 180-day HF readmission differed substantially between acute HF and worsening HF in chronic outpatients. Carbohydrate antigen 125 was the strongest single biomarker to distinguish acute HF from worsening HF in chronic outpatients, but only yielded a C-index of 0.71. A model including multiple biomarkers and clinical variables achieved a high degree of discrimination with a C-index of 0.913 in the index cohort and 0.901 in the validation cohort. CONCLUSIONS: This study identifies different characteristics and predictors of outcome in acute HF patients as compared to outpatients with chronic HF developing worsening HF. The markers identified may be useful in better diagnosing acute HF and may become targets for treatment development.