1AbstractThe OPTIMIST trial aims to determine whether low-intensity monitoring is at least as effective (“non-inferior”) to standard monitoring, on the functional recovery of patients who have received recombinant tissue plasminogen activator or equivalent lytic reperfusion treatment for acute ischaemic stroke. It is designed as an international, multicenter, stepped-wedge (4 periods/3 steps) cluster randomized trial. This statistical analysis plan pre-specifies the method of analysis for every outcome and key variable collected in the trial.The primary outcome is an “unfavourable outcome” at Day 90, defined as a score of 2 to 6 on the modified Rankin scale. The primary analysis will consist in a log-binomial regression adjusted for the effect of time and for clustering by site using a random effect. The non-inferiority margin was pre-specified as a relative risk of 1.15 for a bad outcome; thus, non-inferiority will be declared if the upper bound of the 95% confidence interval around the relative risk is lower than 1.15.The primary analysis will adjust for calendar time (6-month intervals) and will be based on imputed data. The analysis plan also includes planned sensitivity analyses including covariate adjustments and subgroup analyses.2Administrative information2.1Study identifiersProtocol Number: GI-AU-NMH-2019-CA Version: 3.0, Date: 3 March 2021ClinicalTrials.gov register Identifier:NCT03734640Australian New Zealand Clinical Trial Registry: ACTRN 126190015561342.2Revision history2.3Contributors to the statistical analysis planLB – Main author; developed the initial draft and prepared subsequent versions. SB - Prepared initial draft and reviewed subsequent versions. MO, CA - Reviewed every draft and approved final version. LX - Prepared economic analysis section and approved final version. SJ - Comments on economic analysis plan; approved final draft. XW, AM, BJ, DS, PK, PM-V, DD, YS, LS, WAWZ, NHT, CD, TR, RIL - Approved final draft.

Background Function after acute stroke using the modified Rankin Scale (mRS) is usually assessed at a point in time. The analytical implications of serial mRS measurements to evaluate functional recovery over time is not completely understood. We compare repeated‐measures and single‐measure analyses of the mRS from a randomized clinical trial. Methods and Results Serial mRS data from AFFINITY (Assessment of Fluoxetine in Stroke Recovery), a double‐blind placebo randomized clinical trial of fluoxetine following stroke (n=1280) were analyzed to identify demographic and clinical associations with functional recovery (reduction in mRS) over 12 months. Associations were identified using single‐measure (day 365) and repeated‐measures (days 28, 90, 180, and 365) partial proportional odds logistic regression. Ninety‐five percent of participants experienced a reduction in mRS after 12 months. Functional recovery was associated with age at stroke <70 years; no prestroke history of diabetes, coronary heart disease, or ischemic stroke; prestroke history of depression, a relationship partner, living with others, independence, or paid employment; no fluoxetine intervention; ischemic stroke (compared with hemorrhagic); stroke treatment in Vietnam (compared with Australia or New Zealand); longer time since current stroke; and lower baseline National Institutes of Health Stroke Scale & Patient Health Questionnaire‐9 scores. Direction of associations was largely concordant between single‐measure and repeated‐measures models. Association strength and variance was generally smaller in the repeated‐measures model compared with the single‐measure model. Conclusions Repeated‐measures may improve trial precision in identifying trial associations and effects. Further repeated‐measures stroke analyses are required to prove methodological value. Registration URL: http://www.anzctr.org.au; Unique identifier: ACTRN12611000774921.

Objective: To describe the pattern of acute illness and 6-month mortality and health-related quality-of-life outcomes for a cohort of Aboriginal and Torres Strait Islander patients presenting with septic shock. Design: Nested cohort study of Aboriginal and Torres Strait Islander participants recruited to a large randomised controlled trial of corticosteroid treatment in patients with septic shock. Setting: Royal Darwin Hospital, Northern Territory. Participants: All Aboriginal and Torres Strait Islander patients recruited to the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) trial at Royal Darwin Hospital were compared with a non-Indigenous cohort drawn from the same site, and a cohort matched for age, sex and severity of disease. Main outcome measures: Mortality at 90 days and 6 months, time to shock resolution, mechanical ventilation requirement, renal replacement therapy requirement, and five-domain, five-level EuroQol questionnaire (EQ-5D-5L) score at 6 months. Results: Aboriginal and Torres Strait Islander patients had significantly reduced risk of death at 90 days when compared with non-Indigenous patients recruited to ADRENAL at Royal Darwin Hospital (12/60 v 23/62; adjusted odds ratio, 0.40 [95% CI, 0.17 to 0.94]) which was robust to additional adjustment for baseline covariates (odds ratio, 0.35 [95% CI, 0.14 to 0.90]). When compared with the matched population drawn from the broader ADRENAL cohort, there was no significant difference in 90-day mortality (12/60 v 16/61; adjusted odds ratio, 1.43 [95% CI, 0.60 to 3.39]; P = 0.42). Only nine Aboriginal and Torres Strait Islander patients provided 6-month health-related quality-of-life data. Conclusions: Aboriginal and Torres Strait Islander patients had reduced risk of death at 90 days when compared with non- Indigenous patients recruited to the ADRENAL trial at Royal Darwin Hospital, which was robust to adjustment for covariates, but similar outcomes when compared with a cohort matched for age, sex and severity of disease.

Background Several trials have demonstrated protective effects from inhibition of sodium‐glucose cotransporter 2 among patients with type 2 diabetes mellitus. There is uncertainty about the consistency of the cardiovascular benefits achieved across patient subsets. Methods and Results We included 4 large‐scale trials of sodium‐glucose cotransporter 2 inhibition compared with placebo in patients with diabetes mellitus that reported effects on cardiovascular outcomes overall and for participant subgroups defined at baseline by cardiovascular disease, reduced kidney function, and heart failure. Fixed effects models with inverse variance weighting were used to estimate summary hazard ratios and 95% CIs . There were 38 723 patients from 4 trials, with a mean 2.9 years of follow‐up. Of the patients, 22 870 (59%) had cardiovascular disease, 7754 (20%) had reduced kidney function, and 4543 (12%) had heart failure. There were 3828 major adverse cardiac events. There was overall benefit for major adverse cardiac events (0.88; 95% CI , 0.82–0.94; P <0.001) and no evidence that the effects of sodium‐glucose cotransporter 2 inhibition varied across patient subgroups, defined by the presence of cardiovascular disease or heart failure at baseline (all P interaction >0.252; I 2 <25%). All patient subgroups benefited with respect to hospitalization for heart failure (all P interaction>0.302; I 2 <10%), cardiovascular death (all P interaction>0.167; I 2 <50%), and death from any cause (all P interaction>0.354; I 2 =0%). The only difference in effects across subgroups was for stroke, with protection observed among those with reduced kidney function but not those with preserved kidney function ( P interaction=0.020; I 2 =81%). Conclusions Sodium‐glucose cotransporter 2 inhibitors protect against cardiovascular disease and death in diverse subsets of patients with type 2 diabetes mellitus regardless of cardiovascular disease history.

Background The effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on kidney failure, particularly the need for dialysis or transplantation or death due to kidney disease, is uncertain. Additionally, previous studies have been underpowered to robustly assess heterogeneity of effects on kidney outcomes by different levels of estimated glomerular filtration rate (eGFR) and albuminuria. We aimed to do a systematic review and meta-analysis to assess the effects of SGLT2 inhibitors on major kidney outcomes in patients with type 2 diabetes and to determine the consistency of effect size across trials and different levels of eGFR and albuminuria. Methods We did a systematic review and meta-analysis of randomised, controlled, cardiovascular or kidney outcome trials of SGLT2 inhibitors that reported effects on major kidney outcomes in people with type 2 diabetes. We searched MEDLINE and Embase from database inception to June 14, 2019, to identify eligible trials. The primary outcome was a composite of dialysis, transplantation, or death due to kidney disease. We used random-effects models to obtain summary relative risks (RRs) with 95% CIs and random-effects meta-regression to explore effect modification by subgroups of baseline eGFR, albuminuria, and use of renin-angiotensin system (RAS) blockade. This review is registered with PROSPERO (CRD42019131774). Findings From 2085 records identified, four studies met our inclusion criteria, assessing three SGLT2 inhibitors: empagliflozin (EMPA-REG OUTCOME), canagliflozin (CANVAS Program and CREDENCE), and dapagliflozin (DECLARE-TIMI 58). From a total of 38 723 participants, 252 required dialysis or transplantation or died of kidney disease, 335 developed end-stage kidney disease, and 943 had acute kidney injury. SGLT2 inhibitors substantially reduced the risk of dialysis, transplantation, or death due to kidney disease (RR 0.67, 95% CI 0.52-0.86, p=0.0019), an effect consistent across studies (I-2 =0%, P-heterogeneity=0.53), SGLT2 inhibitors also reduced end-stage kidney disease (0.65, 0.53-0.81, p<0.0001), and acute kidney injury (0.75, 0.66-0.85, p<0.0001), with consistent benefits across studies. Although we identified some evidence that the proportional effect of SGLT2 inhibitors might attenuate with declining kidney function (P-trend=0.073), there was clear, separate evidence of benefit for all eGFR subgroups, including for participants with a baseline eGFR 30-45 mL/min per 1.73 m(2) (RR 0.70, 95% CI 0.54-0.91, p=0.0080). Renoprotection was also consistent across studies irrespective of baseline albuminuria (P-trend=0.66) and use of RAS blockade (P-heterogeneity=0. 31). Interpretation SGLT2 inhibitors reduced the risk of dialysis, transplantation, or death due to kidney disease in individuals with type 2 diabetes and provided protection against acute kidney injury. These data provide substantive evidence supporting the use of SGLT2 inhibitors to prevent major kidney outcomes in people with type 2 diabetes. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease.

BACKGROUND:Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS:In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS:The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS:In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).

This project measured population salt intake in Samoa by integrating urinary sodium analysis into the World Health Organization's (WHO's) STEPwise approach to surveillance of noncommunicable disease risk factors (STEPS). A subsample of the Samoan Ministry of Health's 2013 STEPS Survey collected 24-hour and spot urine samples and completed questions on salt-related behaviors. Complete urine samples were available for 293 participants. Overall, weighted mean population 24-hour urine excretion of salt was 7.09 g (standard error 0.19) to 7.63 g (standard error 0.27) for men and 6.39 g (standard error 0.14) for women (P=.0014). Salt intake increased with body mass index (P=.0004), and people who added salt at the table had 1.5 g higher salt intakes than those who did not add salt (P=.0422). A total of 70% of the population had urinary excretion values above the 5 g/d cutoff recommended by the WHO. A reduction of 30% (2 g) would reduce average population salt intake to 5 g/d, in line with WHO recommendations. While challenging, integration of salt monitoring into STEPS provides clear logistical and cost benefits and the lessons communicated here can help inform future programs.

IMPORTANCE:Cardiovascular disease prevention, including lifestyle modification, is important but underutilized. Mobile health strategies could address this gap but lack evidence of therapeutic benefit.OBJECTIVE:To examine the effect of a lifestyle-focused semipersonalized support program delivered by mobile phone text message on cardiovascular risk factors.DESIGN AND SETTING:The Tobacco, Exercise and Diet Messages (TEXT ME) trial was a parallel-group, single-blind, randomized clinical trial that recruited 710 patients (mean age, 58 [SD, 9.2] years; 82% men; 53% current smokers) with proven coronary heart disease (prior myocardial infarction or proven angiographically) between September 2011 and November 2013 from a large tertiary hospital in Sydney, Australia.INTERVENTIONS:Patients in the intervention group (n = 352) received 4 text messages per week for 6 months in addition to usual care. Text messages provided advice, motivational reminders, and support to change lifestyle behaviors. Patients in the control group (n=358) received usual care. Messages for each participant were selected from a bank of messages according to baseline characteristics (eg, smoking) and delivered via an automated computerized message management system. The program was not interactive.MAIN OUTCOMES AND MEASURES:The primary end point was low-density lipoprotein cholesterol (LDL-C) level at 6 months. Secondary end points included systolic blood pressure, body mass index (BMI), physical activity, and smoking status.RESULTS:At 6 months, levels of LDL-C were significantly lower in intervention participants, with concurrent reductions in systolic blood pressure and BMI, significant increases in physical activity, and a significant reduction in smoking. The majority reported the text messages to be useful (91%), easy to understand (97%), and appropriate in frequency (86%). [table: see text].CONCLUSIONS AND RELEVANCE:Among patients with coronary heart disease, the use of a lifestyle-focused text messaging service compared with usual care resulted in a modest improvement in LDL-C level and greater improvement in other cardiovascular disease risk factors. The duration of these effects and hence whether they result in improved clinical outcomes remain to be determined.TRIAL REGISTRATION:anzctr.org.au Identifier: ACTRN12611000161921.

Background Strategies to prevent pyrexia in patients with acute neurological injury may reduce secondary neuronal damage. The aim of this study was to determine the safety and efficacy of the routine administration of 6 grams/day of intravenous paracetamol in reducing body temperature following severe traumatic brain injury, compared to placebo. Methods A multicentre, randomised, blind, placebo-controlled clinical trial in adult patients with traumatic brain injury (TBI). Patients were randomised to receive an intravenous infusion of either 1g of paracetamol or 0.9% sodium chloride (saline) every 4 hours for 72 hours. The primary outcome was the mean difference in core temperature during the study intervention period. Results Forty-one patients were included in this study: 21 were allocated to paracetamol and 20 to saline. The median (interquartile range) number of doses of study drug was 18 (17–18) in the paracetamol group and 18 (16–18) in the saline group (P = 0.85). From randomisation until 4 hours after the last dose of study treatment, there were 2798 temperature measurements (median 73 [67–76] per patient). The mean ± standard deviation temperature was 37.4±0.5°C in the paracetamol group and 37.7±0.4°C in the saline group (absolute difference -0.3°C; 95% confidence interval -0.6 to 0.0; P = 0.09). There were no significant differences in the use of physical cooling, or episodes of hypotension or hepatic abnormalities, between the two groups. Conclusion The routine administration of 6g/day of intravenous paracetamol did not significantly reduce core body temperature in patients with TBI. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12609000444280

AIMS:Recent trials of cardiovascular polypills in high-risk populations show improvements in the use of cardiovascular preventive treatments, compared to usual care. We describe patterns of pill burden in Australian practice, define the impact of polypill therapy on pill burden, and explore how physicians add medication to polypill therapy.METHODS:The Kanyini Guidelines Adherence with the Polypill Study was an open-label trial involving 623 participants in Australia which randomized participants to a polypill strategy (containing a statin, antiplatelet agent, and two blood-pressure-lowering medications) or usual care. Participants either had established cardiovascular disease or were at high calculated risk (≥15% over 5 years). Current medications, daily pill burden, and self-reported use of combination treatment were recorded prior to randomization and at study end. Median pill burden at baseline and study end was compared in both arms. Subgroup analysis of the polypill strategy on trial primary outcomes was conducted by pill burden at baseline.RESULTS:Median total and cardiovascular pill burdens of the polypill group decreased from 7 to 5 and from 4 to 2, respectively (median change -2; IQR -3, 0), with no change in the usual care group (comparison of change; P < 0.001). No change was seen for noncardiovascular medications. Of those still using the polypill at study end, 43.8% were prescribed additional medications; 84.5% of these additional medications were blood-pressure-lowering medications. Within the polypill group, lower pill burden at baseline was associated with greater increases in the use of indicated cardiovascular preventive medications at study end compared to those with higher pill burdens. No trend was observed between the level of baseline pill burden and the effect of poylpill treatment on systolic blood pressure or total cholesterol.CONCLUSION:A cardiovascular polypill in contemporary Australian practice reduces cardiovascular and total pill burdens, despite frequent prescription of additional medications.

Panic disorder has been associated with altered serotonin metabolism in the brainstem raphe. The aim of study was to evaluate the BR echogenicity on transcranial sonography (TCS) in panic disorder. A total of 96 healthy volunteers were enrolled in the "derivation" cohort, and 26 healthy volunteers and 26 panic disorder patients were enrolled in the "validation" cohort. TCS echogenicity of brainstem raphe and substantia nigra was assessed on anonymized images visually and by means of digitized image analysis. Significantly reduced brainstem raphe echogenicity was detected more frequently in panic disorder patients than in controls using both visual (68% vs. 31%) and digitized image analysis (52% vs. 12%). The optimal cut-off value of digitized brainstem raphe echogenicity indicated the diagnosis of panic disorder with a sensitivity of 64% and a specificity of 73%, and corresponded to the 30th percentile in the derivation cohort. Reduced brainstem raphe echogenicity was associated with shorter treatment duration, and, by trend, lower severity of anxiety. No relationship was found between echogenicity of brainstem raphe or substantia nigra and age, gender, severity of panic disorder, or severity of depression. Patients with panic disorder exhibit changes of brainstem raphe on TCS suggesting an alteration of the central serotonergic system.

Early smoking onset age (SOA) is a public health concern with scant empirical evidence of its role in health outcomes. The study had two aims: i) to assess whether an early SOA was associated with the risk of fatal and non-fatal CVD and all-cause and CVD mortality and ii) to explore the linear and non-linear association between SOA and the outcomes of interest. Data from 4499 current or former smokers, recruited from 1995 to 2005, aged 25 to 79 years, and with a median 7.02 years of follow-up, were obtained from the REGICOR population-based cohort. In the present analysis, performed in 2018, the independent variable was SOA and the dependent variables were CVD events, CVD mortality, and all-cause mortality. Penalized smoothing spline methods were used to assess the linear and non-linear association. During follow-up, 361 deaths and 210 CVD events were recorded. A significant non-linear component was identified in the association between SOA and CVD outcomes with a cut-off point at 12 years: In the group aged ≤12 years, each year of delay in SOA was inversely associated with CVD risk (HR = 0.71; 95%CI = 0.53–0.96) and CVD mortality (HR = 0.58; 95%CI = 0.37–0.90). No association was observed in the older SOA group. A linear association was observed between SOA and all-cause mortality, and each year of delay was associated with 4% lower risk of mortality (HR = 0.96; 95%CI = 0.93–0.98). The associations were adjusted for lifelong exposure to tobacco and cardiovascular risk factors. These results reinforce the value of preventing tobacco use among teenagers and adolescents.

IMPORTANCE Most patients with cardiovascular disease (CVD) do not take recommended medications long-term. The use of fixed-dose combinations (FDCs) improves adherence in several clinical areas. Previous trials of cardiovascular FDCs have assessed short-term effects compared with placebo or no treatment. OBJECTIVE To assess whether FDC delivery of aspirin, statin, and 2 blood pressure-lowering agents vs usual care improves long-term adherence to indicated therapy and 2 major CVD risk factors, systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C). DESIGN, SETTING, AND PARTICIPANTS The UMPIRE trial, a randomized, open-label, blinded-end-point trial among 2004 participants with established CVD or at risk of CVD enrolled July 2010-July 2011 in India and Europe. The trial follow-up concluded in July 2012. INTERVENTIONS Participants were randomly assigned (1:1) to an FDC-based strategy (n=1002) containing either (1) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 50 mg atenolol or (2) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 12.5 mg hydrochlorothiazide or to usual care (n=1002). MAIN OUTCOMES AND MEASURES Adherence to medication (defined as self-reported use of antiplatelet, statin, and ≥2 BP-lowering medications) and changes in SBP and LDL-C from baseline. RESULTS At baseline, mean BP was 137/78 mm Hg, LDL-C was 91.5 mg/dL, and 1233 (61.5%) of 2004 participants reported use of antiplatelet, statin, and 2 or more BP-lowering medications. Median follow-up was 15 months (interquartile range, 12-18 months). The FDC group had improved adherence vs usual care (86% vs 65%; relative risk [RR] of being adherent, 1.33; 95% CI, 1.26-1.41; P < .001) with concurrent reductions in SBP (-2.6 mm Hg; 95% CI, -4.0 to -1.1 mm Hg; P < .001) and LDL-C (-4.2 mg/dL; 95% CI, -6.6 to -1.9 mg/dL; P < .001) at the end of the study. Although there was consistency of effects across predefined subgroups, evidence existed of larger benefits in patients with lower adherence at baseline. In this subgroup of 727 participants (36%), adherence at the end of study was 77% vs 23% (RR, 3.35; 95% CI, 2.74-4.09; P < .001 for interaction), SBP was reduced by 4.9 mm Hg (95% CI 7.3-2.6 mm Hg; P = .01 for interaction), and LDL-C was reduced by 6.7 mg/dL (95% CI, 10.5-2.8 mg/dL; P = .11 for interaction). There were no significant differences in serious adverse events or cardiovascular events (50 [5%] in the FDC group and 35 [3.5%] in the usual care group; RR, 1.45; 95% CI, 0.94-2.24; P=.09) between the groups. CONCLUSIONS AND RELEVANCE Among patients with or at high risk of CVD, use of an FDC strategy for blood pressure, cholesterol, and platelet control vs usual care resulted in significantly improved medication adherence at 15 months and statistically significant but small improvements in SBP and LDL-C. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01057537.

Objectives The ADVANCE trial was designed to determine the effects of routine blood pressure lowering using a fixed combination of perindopril–indapamide on major vascular outcomes in patients with type 2 diabetes, regardless of initial blood pressure levels or the use of other blood pressure-lowering drugs, including angiotensin-converting enzyme inhibitors. Methods After a 6-week run-in period, 11 140 high-risk individuals with type 2 diabetes were randomized to fixed combination perindopril–indapamide or matching placebo, in addition to current therapy. The two primary outcomes were composites of major macrovascular and major microvascular events, analysed jointly and separately by intention to treat. Results The reduction in blood pressure in participants assigned to active treatment was 5.6/2.2 mmHg greater than that observed in the control group. Active treatment reduced the risk of the combined primary outcome, a major macrovascular or microvascular event by 9% (P = 0.041) and resulted in a 14% (P = 0.025) reduction in all-cause mortality and an 18% (P = 0.027) reduction in cardiovascular mortality. There were reductions of 14% (P = 0.02) in total coronary events and 21% (P < 0.0001) in total renal events. The treatment was well tolerated, with 73% and 74% of patients in the active treatment and placebo groups still adherent to randomized therapy after an average of 4.3 years of follow-up. Conclusions Routine treatment with the fixed combination of perindopril and indapamide was well tolerated and reduced the risk of death and major vascular events, regardless of the initial blood pressure level or concomitant treatments received. The results suggest that for every 79 patients treated in this manner, one death would be avoided over 5 years.

Objectives The ADVANCE trial was designed to determine the effects of routine blood pressure lowering using a fixed combination of perindopril–indapamide on major vascular outcomes in patients with type 2 diabetes, regardless of initial blood pressure levels or the use of other blood pressure-lowering drugs, including angiotensin-converting enzyme inhibitors. Methods After a 6-week run-in period, 11 140 high-risk individuals with type 2 diabetes were randomized to fixed combination perindopril–indapamide or matching placebo, in addition to current therapy. The two primary outcomes were composites of major macrovascular and major microvascular events, analysed jointly and separately by intention to treat. Results The reduction in blood pressure in participants assigned to active treatment was 5.6/2.2 mmHg greater than that observed in the control group. Active treatment reduced the risk of the combined primary outcome, a major macrovascular or microvascular event by 9% (P = 0.041) and resulted in a 14% (P = 0.025) reduction in all-cause mortality and an 18% (P = 0.027) reduction in cardiovascular mortality. There were reductions of 14% (P = 0.02) in total coronary events and 21% (P < 0.0001) in total renal events. The treatment was well tolerated, with 73% and 74% of patients in the active treatment and placebo groups still adherent to randomized therapy after an average of 4.3 years of follow-up. Conclusions Routine treatment with the fixed combination of perindopril and indapamide was well tolerated and reduced the risk of death and major vascular events, regardless of the initial blood pressure level or concomitant treatments received. The results suggest that for every 79 patients treated in this manner, one death would be avoided over 5 years.