Clinical trial results in context: comparison of baseline characteristics and outcomes of 38,510 RECOVERY trial participants versus a reference population of 346,271 people hospitalised with COVID-19 in England.

BACKGROUND: Randomised trials are essential to reliably assess medical interventions. Nevertheless, interpretation of such studies, particularly when considering absolute effects, is enhanced by understanding how the trial population may differ from the populations it aims to represent. METHODS: We compared baseline characteristics and mortality of RECOVERY participants recruited in England (n = 38,510) with a reference population hospitalised with COVID-19 in England (n = 346,271) from March 2020 to November 2021. We used linked hospitalisation and mortality data for both cohorts to extract demographics, comorbidity/frailty scores, and crude and age- and sex-adjusted 28-day all-cause mortality. RESULTS: Demographics of RECOVERY participants were broadly similar to the reference population, but RECOVERY participants were younger (mean age [standard deviation]: RECOVERY 62.6 [15.3] vs reference 65.7 [18.5] years) and less frequently female (37% vs 45%). Comorbidity and frailty scores were lower in RECOVERY, but differences were attenuated after age stratification. Age- and sex-adjusted 28-day mortality declined over time but was similar between cohorts across the study period (RECOVERY 23.7% [95% confidence interval: 23.3-24.1%]; vs reference 24.8% [24.6-25.0%]), except during the first pandemic wave in the UK (March-May 2020) when adjusted mortality was lower in RECOVERY. CONCLUSIONS: Adjusted 28-day mortality in RECOVERY was similar to a nationwide reference population of patients admitted with COVID-19 in England during the same period but varied substantially over time in both cohorts. Therefore, the absolute effect estimates from RECOVERY were broadly applicable to the target population at the time but should be interpreted in the light of current mortality estimates. TRIAL REGISTRATION: ISRCTN50189673- Feb. 04, 2020, NCT04381936- May 11, 2020.

Effect of Fenofibrate on Progression of Diabetic Retinopathy.

BACKGROUND: Findings from cardiovascular outcome trials suggest that fenofibrate therapy may reduce the progression of diabetic retinopathy. METHODS: We recruited and followed adults with nonreferable diabetic retinopathy or maculopathy using the national Diabetic Eye Screening (DES) program in Scotland. We randomly assigned participants to receive 145-mg fenofibrate tablets or placebo (taken daily or, in those with impaired renal function, on alternate days). The primary outcome was a composite of developing referable diabetic retinopathy or maculopathy (based on Scotland's DES grading scheme) or treatment (intravitreal injection, retinal laser, vitrectomy) for retinopathy or maculopathy. RESULTS: A total of 1151 participants were randomly assigned to treatment. During a median of 4.0 years, progression to referable diabetic retinopathy or maculopathy, or treatment thereof, occurred in 131 (22.7%) of 576 participants in the fenofibrate group and 168 (29.2%) of 575 in the placebo group (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.91; P=0.006). In the fenofibrate group compared with the placebo group, the frequencies for any progression of retinopathy or maculopathy were 185 (32.1%) vs. 231 (40.2%); hazard ratio, 0.74; 95% CI, 0.61 to 0.90 and for the development of macular edema were 22 (3.8%) vs. 43 (7.5%); hazard ratio, 0.50; 95% CI, 0.30 to 0.84. Seventeen (3.0%) participants assigned fenofibrate and 28 (4.9%) assigned placebo were given treatment for retinopathy (hazard ratio, 0.58; 95% CI, 0.31 to 1.06). There was no effect on visual function, quality of life, or visual acuity. Trial-averaged estimated glomerular filtration rate was 7.9 (95% CI, 6.8 to 9.1) ml/min/1.73 m2 lower in participants in the fenofibrate group compared with the placebo group. Serious adverse events occurred in 208 (36.1%) participants allocated fenofibrate and 204 (35.5%) participants allocated placebo. CONCLUSIONS: Fenofibrate reduced progression of diabetic retinopathy compared with placebo among participants with early retinal changes. (Funded by the National Institute for Health and Care Research; ClinicalTrials.gov number, NCT03439345; ISRCTN number, ISRCTN15073006.).

Empagliflozin in Patients with Chronic Kidney Disease.

BACKGROUND: The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. METHODS: We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 ml per minute per 1.73 m2, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes. RESULTS: A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P<0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P = 0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. CONCLUSIONS: Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110; EudraCT number, 2017-002971-24.).

Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus.

BACKGROUND: Diabetes mellitus is associated with an increased risk of cardiovascular events. Aspirin use reduces the risk of occlusive vascular events but increases the risk of bleeding; the balance of benefits and hazards for the prevention of first cardiovascular events in patients with diabetes is unclear. METHODS: We randomly assigned adults who had diabetes but no evident cardiovascular disease to receive aspirin at a dose of 100 mg daily or matching placebo. The primary efficacy outcome was the first serious vascular event (i.e., myocardial infarction, stroke or transient ischemic attack, or death from any vascular cause, excluding any confirmed intracranial hemorrhage). The primary safety outcome was the first major bleeding event (i.e., intracranial hemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or other serious bleeding). Secondary outcomes included gastrointestinal tract cancer. RESULTS: A total of 15,480 participants underwent randomization. During a mean follow-up of 7.4 years, serious vascular events occurred in a significantly lower percentage of participants in the aspirin group than in the placebo group (658 participants [8.5%] vs. 743 [9.6%]; rate ratio, 0.88; 95% confidence interval [CI], 0.79 to 0.97; P=0.01). In contrast, major bleeding events occurred in 314 participants (4.1%) in the aspirin group, as compared with 245 (3.2%) in the placebo group (rate ratio, 1.29; 95% CI, 1.09 to 1.52; P=0.003), with most of the excess being gastrointestinal bleeding and other extracranial bleeding. There was no significant difference between the aspirin group and the placebo group in the incidence of gastrointestinal tract cancer (157 participants [2.0%] and 158 [2.0%], respectively) or all cancers (897 [11.6%] and 887 [11.5%]); long-term follow-up for these outcomes is planned. CONCLUSIONS: Aspirin use prevented serious vascular events in persons who had diabetes and no evident cardiovascular disease at trial entry, but it also caused major bleeding events. The absolute benefits were largely counterbalanced by the bleeding hazard. (Funded by the British Heart Foundation and others; ASCEND Current Controlled Trials number, ISRCTN60635500 ; ClinicalTrials.gov number, NCT00135226 .).

Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus.

BACKGROUND: Increased intake of n-3 fatty acids has been associated with a reduced risk of cardiovascular disease in observational studies, but this finding has not been confirmed in randomized trials. It remains unclear whether n-3 (also called omega-3) fatty acid supplementation has cardiovascular benefit in patients with diabetes mellitus. METHODS: We randomly assigned 15,480 patients with diabetes but without evidence of atherosclerotic cardiovascular disease to receive 1-g capsules containing either n-3 fatty acids (fatty acid group) or matching placebo (olive oil) daily. The primary outcome was a first serious vascular event (i.e., nonfatal myocardial infarction or stroke, transient ischemic attack, or vascular death, excluding confirmed intracranial hemorrhage). The secondary outcome was a first serious vascular event or any arterial revascularization. RESULTS: During a mean follow-up of 7.4 years (adherence rate, 76%), a serious vascular event occurred in 689 patients (8.9%) in the fatty acid group and in 712 (9.2%) in the placebo group (rate ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.55). The composite outcome of a serious vascular event or revascularization occurred in 882 patients (11.4%) and 887 patients (11.5%), respectively (rate ratio, 1.00; 95% CI, 0.91 to 1.09). Death from any cause occurred in 752 patients (9.7%) in the fatty acid group and in 788 (10.2%) in the placebo group (rate ratio, 0.95; 95% CI, 0.86 to 1.05). There were no significant between-group differences in the rates of nonfatal serious adverse events. CONCLUSIONS: Among patients with diabetes without evidence of cardiovascular disease, there was no significant difference in the risk of serious vascular events between those who were assigned to receive n-3 fatty acid supplementation and those who were assigned to receive placebo. (Funded by the British Heart Foundation and others; Current Controlled Trials number, ISRCTN60635500 ; ClinicalTrials.gov number, NCT00135226 .).

The longitudinal course of bipolar disorder as revealed through weekly text messaging: a feasibility study.

OBJECTIVES: To examine the feasibility of collecting course of illness data from patients with bipolar I and II disorder, using weekly text-messaged mood ratings, and to examine the time trajectory of symptom ratings based on this method of self-report. METHODS: A total of 62 patients with bipolar I (n = 47) or II (n = 15) disorder provided mood data in response to weekly cell phone text messages (n = 54) or e-mail prompts (n = 8). Participants provided weekly ratings using the Altman Self-Rating Mania Scale and the Quick Inventory of Depressive Symptoms-Self Report. Patients with bipolar I and II disorder, and men and women, were compared on percentages of time in depressive or manic mood states over up to two years. RESULTS: Participants provided weekly ratings over an average of 36 (range 1-92) weeks. Compliance with the procedure was 75%. Overall, participants reported depressive symptoms 47.7% of the time compared to 7% of entries reflecting manic symptoms, 8.8% reflecting both depressive and manic symptoms, and 36.5% reflecting euthymic mood. Participants with bipolar I disorder reported more days of depression and were less likely to improve with time than participants with bipolar II disorder. Gender differences observed at the beginning of the study were not observed at follow-up. CONCLUSIONS: The results are similar to those of other longitudinal studies of bipolar disorder that use traditional retrospective, clinician-gathered mood data. Text-message-based symptom monitoring during routine follow-up may be a reliable alternative to in-person interviews.