BACKGROUND AND AIMS:Blood pressure (BP) lowering reduces cardiovascular disease (CVD) risk; however, the benefits of treating patients with normal systolic BP but elevated diastolic BP remain uncertain. METHODS:Data from 51 randomized controlled trials were pooled to compare BP-lowering effects in participants with and without isolated diastolic hypertension (IDH), defined as systolic BP < 130 mmHg and diastolic BP ≥ 80 mmHg. Treatment effects were stratified across baseline diastolic BP categories (range < 60 to ≥90 mmHg) among individuals with baseline systolic BP < 130 mmHg. Fixed-effect one-stage individual participant data meta-analyses were used, and Cox proportional hazard models, stratified by trial, were applied to analyse the data. RESULTS:Among 358 325 participants, 15 845 (4.4%) had IDH. At a median follow-up of 4.2 years, a 5 mmHg reduction in systolic BP reduced the risk of major cardiovascular events similarly in individuals with IDH [hazard ratio 0.91; 95% confidence interval (CI) 0.82-1.01] and those without IDH (hazard ratio 0.90; 95% CI 0.89-0.92; P for interaction = 1.00). Analyses by baseline diastolic BP showed no evidence of heterogeneity in treatment effects among individuals with baseline systolic BP < 130 mmHg (P for interaction = .26). Relative treatment effects were not statistically different by CVD history, age, prior medication use, and BP measurement methods. CONCLUSIONS:The study found no evidence to suggest that pharmacological BP-lowering therapy in individuals with IDH is less or more effective than in those without IDH. Relative risk reductions also did not diminish in those with lower diastolic BP, down to <60 mmHg at baseline. No meaningful differences across various clinical phenotypes were detected.

BACKGROUND:Individuals with chronic kidney disease (CKD), particularly those at more advanced stages, have been systematically under-represented in randomised controlled trials (RCTs) of blood-pressure-lowering treatment due to safety concerns, leading to a persistent paucity of evidence for cardiovascular risk management in this high-risk group. We investigated the effect of blood-pressure-lowering treatment on the risk of major cardiovascular disease and death across the full spectrum of CKD stages and by key clinical subgroups. METHODS:We conducted a one-stage meta-analysis of individual-participant data from RCTs in which participants were randomly assigned to a blood-pressure-lowering therapy versus a comparator. We used RCTs collated in the Blood Pressure Lowering Treatment Trialists' Collaboration dataset, published at any time in any language, which were eligible for inclusion if they had at least 1000 person-years of follow-up per arm, baseline blood-pressure and creatinine measurements, and time-to-event outcomes; those with unclear randomisation procedures or restricted to heart failure or acute care settings were excluded. Participants with a documented history of heart failure or extreme creatinine values were excluded. No age criteria were applied. The primary outcome was major cardiovascular events, defined as a composite of fatal or non-fatal stroke, ischaemic heart disease, or hospitalisation for, or death from, heart failure. Relative treatment effects were estimated with a stratified Cox proportional hazards model. Heterogeneity of treatment effects was evaluated across prespecified subgroups defined by CKD status, CKD stage (1-5), diabetes, proteinuria, and baseline blood pressure. A stratified network meta-analysis was performed to examine whether treatment effects differed by defined subgroups within each of five principal antihypertensive drug classes. The systematic review was registered in PROSPERO (CRD42018099283). FINDINGS:From 52 RCTs (363 684 participants), a total of 285 124 participants from 46 randomised trials met the eligibility criteria; 116 145 (40·7%) were women, 168 979 (59·3%) were men, 59 185 (20·7%) had CKD at baseline, and 86 067 (30·2%) had type 2 diabetes. During a median follow-up of 4·4 years (IQR 3·2-5·1), a 5 mm Hg reduction in systolic blood pressure reduced the risk of major cardiovascular disease in individuals with CKD (hazard ratio [HR] 0·91 [95% CI 0·87-0·94]) and without CKD (0·90 [0·88-0·93]; pinteraction>0·99). Furthermore, these observed relative risk reductions were consistent across all CKD stages, including severe stages 4-5 (pinteraction>0·99). Similar treatment effects were observed by proteinuria status and across blood-pressure categories, down to <120/70 mm Hg. However, the relative treatment effect in individuals with CKD was notably attenuated among those with coexisting diabetes (HR 0·96 [95% CI 0·90-1·02]) compared with those without (0·88 [0·84-0·93]; pinteraction=0·044). The stratified analysis within each drug class showed that the class-specific effects of antihypertensive agents versus placebo on cardiovascular disease risk remained unchanged across the investigated subgroups. INTERPRETATION:In the context of cardiovascular risk reduction, the relative benefit of blood-pressure lowering in patients with CKD is similar to that in individuals without CKD, with consistent efficacy across all CKD stages, blood-pressure thresholds, and proteinuria status. However, notably, this relative benefit is attenuated in patients with CKD and concomitant diabetes, underscoring the requirement for adapted therapeutic strategies in this high-risk subgroup. Moreover, the class-specific effects of principal antihypertensives in CKD mirror those observed in the broader population, independent of CKD stage or proteinuria status. FUNDING:British Heart Foundation.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack-Lipid-Lowering Trial (ALLHAT-LLT) was a pragmatic randomized trial conducted in 513 clinical centers across North America from 1994 to 2002. ALLHAT-LLT, which used standard of care (usual care) as the control treatment, did not find an effect of assignment to pravastatin on all-cause death. We aimed to use the trial data to estimate the effect of adhering to the assigned treatment, that is, the per-protocol effect. Moderately hypercholesterolemic (low-density lipoprotein cholesterol 100-189 mg/dL), hypertensive participants ≥55 years old were included and randomized to pravastatin (40 mg/day unless contraindicated) or usual care (lipid-lowering treatment discouraged unless clinically indicated). Of 10 355 individuals randomized, we included 9741 with complete baseline data. One-third of individuals in the pravastatin arm were non-adherent to the assigned treatment strategy at year 5. After adjusting for factors related to adherence, the 5 year risk difference comparing pravastatin to usual care was -3.0% (-4.9%, -1.3%), and the risk ratio was 0.79 (0.68, 0.91) for death. Findings were consistent across different definitions of treatment strategies. Our results suggest that the use of pravastatin under full adherence was protective against death, even if assignment to pravastatin was not clearly protective.

BACKGROUND:Pharmacologic blood pressure (BP) lowering is typically a lifelong treatment, and both clinicians and patients may have concerns about the long-term use of antihypertensive agents and the risk for cancer. However, evidence from randomized controlled trials (RCTs) regarding the effect of long-term pharmacologic BP lowering on the risk for new-onset cancer is limited, with most knowledge derived from observational studies. OBJECTIVES:The aim of this study was to assess whether long-term BP lowering affects the risk for new-onset cancer, cause-specific cancer death, and selected site-specific cancers. METHODS:Individual-level data from 42 RCTs were pooled using a one-stage individual participant data meta-analysis. The primary outcome was incident cancer of all types, and secondary outcomes were cause-specific cancer death and selected site-specific cancers. Prespecified subgroup analyses were conducted to assess the heterogeneity of the BP-lowering effect by baseline variables and over follow-up time. Cox proportional hazards regression, stratified by trial, was used for the statistical analysis. For site-specific cancers, analyses were complemented with Mendelian randomization, using naturally randomized genetic variants associated with BP lowering to mimic the design of a long-term RCT. RESULTS:Data from 314,016 randomly allocated participants without known cancer at baseline were analyzed. Over a median follow-up of 4 years (Q1-Q3: 3-5 years), 17,954 participants (5.7%) developed cancer, and 4,878 (1.5%) died of cancer. In the individual participant data meta-analysis, no associations were found between reductions in systolic or diastolic BP and cancer risk (HR per 5 mm Hg reduction in systolic BP: 1.03 [95% CI: 0.99-1.06]; HR per 3 mm Hg reduction in diastolic BP: 1.03 [95% CI: 0.98-1.07]). No changes in relative risk for incident cancer were observed over follow-up time, nor was there evidence of heterogeneity in treatment effects across baseline subgroups. No effect on cause-specific cancer death was found. For site-specific cancers, no evidence of an effect was observed, except a possible link with lung cancer risk (HR for systolic BP reduction: 1.17; 99.5% CI: 1.02-1.32). Mendelian randomization studies showed no association between systolic or diastolic BP reduction and site-specific cancers, including overall lung cancer and its subtypes. CONCLUSIONS:Randomized data analysis provided no evidence to indicate that pharmacologic BP lowering has a substantial impact, either increasing or decreasing, on the risk for incident cancer, cause-specific cancer death, or selected site-specific cancers.

Pharmacologic blood pressure (BP) lowering is typically a lifelong treatment, and both clinicians and patients may have concerns about the long-term use of antihypertensive agents and the risk for cancer. However, evidence from randomized controlled trials (RCTs) regarding the effect of long-term pharmacologic BP lowering on the risk for new-onset cancer is limited, with most knowledge derived from observational studies. The aim of this study was to assess whether long-term BP lowering affects the risk for new-onset cancer, cause-specific cancer death, and selected site-specific cancers. Individual-level data from 42 RCTs were pooled using a one-stage individual participant data meta-analysis. The primary outcome was incident cancer of all types, and secondary outcomes were cause-specific cancer death and selected site-specific cancers. Prespecified subgroup analyses were conducted to assess the heterogeneity of the BP-lowering effect by baseline variables and over follow-up time. Cox proportional hazards regression, stratified by trial, was used for the statistical analysis. For site-specific cancers, analyses were complemented with Mendelian randomization, using naturally randomized genetic variants associated with BP lowering to mimic the design of a long-term RCT. Data from 314,016 randomly allocated participants without known cancer at baseline were analyzed. Over a median follow-up of 4 years (Q1-Q3: 3-5 years), 17,954 participants (5.7%) developed cancer, and 4,878 (1.5%) died of cancer. In the individual participant data meta-analysis, no associations were found between reductions in systolic or diastolic BP and cancer risk (HR per 5 mm Hg reduction in systolic BP: 1.03 [95% CI: 0.99-1.06]; HR per 3 mm Hg reduction in diastolic BP: 1.03 [95% CI: 0.98-1.07]). No changes in relative risk for incident cancer were observed over follow-up time, nor was there evidence of heterogeneity in treatment effects across baseline subgroups. No effect on cause-specific cancer death was found. For site-specific cancers, no evidence of an effect was observed, except a possible link with lung cancer risk (HR for systolic BP reduction: 1.17; 99.5% CI: 1.02-1.32). Mendelian randomization studies showed no association between systolic or diastolic BP reduction and site-specific cancers, including overall lung cancer and its subtypes. Randomized data analysis provided no evidence to indicate that pharmacologic BP lowering has a substantial impact, either increasing or decreasing, on the risk for incident cancer, cause-specific cancer death, or selected site-specific cancers.

Background Hypoplastic left heart syndrome (HLHS) requires a series of 3-staged palliative operations, in which the right ventricle (RV) assumes systemic circulation under increased pressure-overload conditions. These patients have a shortened lifespan, often due to RV dysfunction. Neonatal cardiac progenitor cells (nCPCs) improve RV performance in animal models of pressure overload-induced RV dysfunction, as is experienced by HLHS patients. Objectives The authors conducted a phase 1 trial to assess the impact of autologous nCPCs injected into the RV myocardium during stage 2 operation. The primary endpoints were safety and feasibility, with efficacy assessed by evaluating RV size and function over a 1-year period. Methods The study enrolled HLHS patients in 2 groups. Group A consisted of 9 consecutive patients who received nCPC injections during their stage 2 operation. Group B involved a multicenter, randomized, double-blind trial comparing nCPC injections (n = 8) to standard-of-care (SOC) treatment (n = 8). The treatment arm received nCPC injections into the RV myocardium. All caregivers and cores except the surgeon were blinded to treatment. Results The trial met its primary safety and feasibility endpoints. However, the primary efficacy endpoint—changes in RV size or function measured by cardiac magnetic resonance and echocardiography—was not achieved. Despite this, secondary outcomes indicated potential clinical benefits. In group B, the mean major adverse cardiac events rates per 100 person-days were higher in the SOC arm (0.23) compared to the nCPC arm (0.00; P = 0.013) after stage 2 operation. The total 1-year in-hospital length of stay due to cardiac and vascular diseases was 15 days and 2 days per 100 person-days for the SOC and nCPC arms, respectively (P = 0.035). Mechanistic studies revealed that, on average, patients in the nCPC arm exhibited noticeable increases from baseline in plasma levels of VEGFC, VEGFD, TNF-α, and monocyte chemotactic protein-1 compared to the SOC arm by postoperative day 5, though the differences were not statistically significant after false discovery rate adjustment. Whereas subject numbers were insufficient to show significance for the composite endpoint of death or listed for transplantation for group B, when combining both groups A and B, no events were seen in the combined nCPC arms and 3 events were in the SOC arm (log-rank P = 0.005). Conclusions Injecting nCPCs into the RV during the stage 2 operation for HLHS patients appears to be safe but does not improve RV function. These findings warrant the initiation of a phase 2 trial. (The CHILD Trial: Hypoplastic Left Heart Syndrome Study [CHILD]; NCT03406884)

OBJECTIVE:To determine the effects of intensive blood pressure treatment on orthostatic hypertension. DESIGN:Systematic review and individual participant data meta-analysis. DATA SOURCES:MEDLINE, Embase, and Cochrane CENTRAL databases through 13 November 2023. INCLUSION CRITERIA:Population: ≥500 adults, age ≥18 years with hypertension or elevated blood pressure; intervention: randomized trials of more intensive antihypertensive drug treatment (lower blood pressure goal or active agent) with duration ≥6 months; control: less intensive antihypertensive drug treatment (higher blood pressure goal or placebo); outcome: measured standing blood pressure. MAIN OUTCOMES:Orthostatic hypertension, defined as an increase in systolic blood pressure ≥20 mm Hg or diastolic blood pressure ≥10 mm Hg after changing from sitting to standing. DATA SYNTHESIS:Two investigators independently abstracted articles. Individual participant data from nine trials identified during the systematic review were appended together as a single dataset. RESULTS:Of 31 124 participants with 315 497 standing blood pressure assessments, 9% had orthostatic hypotension (that is, a drop in blood pressure after standing of systolic ≥20 mm Hg or diastolic ≥10 mm Hg), 17% had orthostatic hypertension, and 3.2% had both a rise in systolic blood pressure and standing blood pressure ≥140 mm Hg at baseline. The effects of more intensive treatment were similar across trials with odds ratios for orthostatic hypertension ranging from 0.85 to 1.08 (I2=38.0%). During follow-up, 17% of patients assigned to more intensive treatment had orthostatic hypertension, whereas 19% of those assigned less intensive treatment had orthostatic hypertension. Compared with less intensive treatment, the risk of orthostatic hypertension was lower with more intensive blood pressure treatment (odds ratio 0.93, 95% confidence interval 0.90 to 0.96). Effects were greater among non-black versus black adults (odds ratio 0.86 v 0.97; P for interaction=0.003) and adults without diabetes versus those with diabetes (0.88 v 0.96; P for interaction=0.05) but did not differ by age ≥75 years, sex, baseline seated blood pressure ≥130/≥80 mm Hg, obesity, stage 3 kidney disease, stroke, cardiovascular disease, standing systolic blood pressure ≥140 mm Hg, or pre-randomization orthostatic hypertension (P for interactions ≥0.05). CONCLUSIONS:In this pooled cohort of adults with elevated blood pressure or hypertension, orthostatic hypertension was common and more intensive blood pressure treatment modestly reduced the occurrence of orthostatic hypertension. These findings suggest that approaches generally used for seated hypertension may also prevent hypertension on standing. STUDY REGISTRATION:Prospero CRD42020153753 (original proposal).

Abstract Background The current body of randomised evidence concerning the effect of blood pressure lowering on the risk of cancer remains limited. Purpose We leveraged the strengths of both randomised controlled trials (RCTs) and genomic information to examine this question. Methods Individual-level data from 314,016 participants from 42 RCTs were pooled to investigate the effect of blood pressure lowering on the risk of cancer through one-stage individual participant data (IPD) meta-analysis. The primary outcome was incident cancer, defined as the first occurrence of any cancer diagnosed after randomisation. Pre-specified subgroup analyses were conducted to assess heterogeneity in effect by follow-up time and baseline age groups, sex, body mass index categories, smoking status and previous use of antihypertensive drugs. Secondary outcomes were cause-specific cancer death and site-specific cancer risk comprising breast, colorectal, kidney, lung, prostate, and skin. Cox proportional hazard regression, stratified by trials, were used for statistical analyses. For site-specific cancers, analyses were complemented with Mendelian randomisation analyses using naturally randomised genetic variants associated with blood pressure lowering, retrieved from genome-wide association studies involving participants of European ancestry. Results Over a median of 4 years (interquartile range 2), 17,954 participants in RCTs were diagnosed with cancer of any type and 4,878 participants were reported to have died with cancer as the cause of death. In the IPD meta-analysis that compared the treatment arm with the comparator, no associations were identified between reductions in either systolic or diastolic blood pressure and the risk of incident cancer (hazard ratios [HRs] per 5 mmHg reduction in systolic and per 3 mmHg diastolic blood pressure were 1.03 (95% confidence interval [CI] 0.99-1.06) and 1.03 [0.98-1.07], respectively). We also found no pattern of increasing or decreasing relative risk for incident cancer during the follow-up period, nor was there evidence of heterogeneity in treatment effects across baseline subgroups. No effect on the risk of cause-specific cancer death was identified for either systolic or diastolic blood pressure lowering. Considering site-specific cancers, we also found no evidence of effect, except for a possible link with lung cancer risk, with HRs of 1.17 [99.5% CI 1.02-1.32] for systolic blood pressure and 1.17 [99.5% CI 0.98-1.36] for diastolic blood pressure lowering. In Mendelian randomisation studies, no association was observed for genetically determined systolic and diastolic blood pressure and all the considered site-specific cancers, including overall lung cancer and its subtypes. Conclusion We found no consistent randomised evidence to suggest that blood pressure-lowering has a substantial effect, whether increasing or decreasing, on incident cancer, cause-specific cancer death, or selected site-specific cancers.

Population enrichment designs can play a vital role in detecting treatment benefits, if present, by selecting a study population where the treatment is more likely to show a benefit compared to the unselected population. While population enrichment designs with one primary endpoint have been studied in the current literature, there are limited research on population enrichment with alternative primary endpoints. Many diseases have multiple sequelae and it can be sufficient to show treatment benefits on at least one of these consequences. In this manuscript, we provide the theoretical basis and development of a two-stage adaptive design with two binary alternative primary endpoints that simultaneously evaluates two subgroups for enrichment, selects one or both endpoints for efficacy assessments at the time of the interim analysis using pre-specified decision rules, and maintains an overall type I error rate. Treatment benefits can be declared in one or both endpoints in a selected subgroup or in the overall population at the time of interim or final analyses. We provide stage-wise boundary values for futility and efficacy and rejection probabilities under heterogeneous treatment effects in the subgroups. We further demonstrate the implementation of the proposed design and discuss venues for future development on this topic.

In modern clinical practice, less than half of patients with new-onset heart failure (HF) undergo ischemic evaluation and only a minority undergo revascularization. We aimed to assess the proportion of the effect of hypertension (antihypertensive treatment) on incident HF to be eliminated by prevention of coronary heart disease (CHD) event treated with or without revascularization, considering possible treatment-mediator interaction. The causal mediation analysis of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) included 42,418 participants (age 66.9 ± 7.7, 35.6% black, 53.2% men). A new CHD event (myocardial infarction or angina) that occurred after randomization but before the incident HF outcome was the mediator. Incident symptomatic congestive HF (CHF) and hospitalized/fatal HF (HHF) were the primary and secondary outcomes, respectively. Logistic regression (for mediator) and Cox proportional hazards regression (for outcome) were adjusted for demographics, cardiovascular disease history, and risk factors. During a median 4.5-year follow-up, 2,785 patients developed CHF, including 2,216 HHF events. Participants who developed CHD events had twice the higher incidence rate of CHF than CHD-free (28.5 vs 13.9 events/1,000 person-years). The proportion of reference interaction indicating direct harm because of a CHD event for lisinopril (234% for CHF, 355% for HHF) and amlodipine (244% for CHF, 468% for HHF) was greater than for chlortalidone (143% for CHF, 269% for HHF). In patients with revascularized CHD events, chlortalidone and amlodipine eliminated 21% to 24% and lisinopril eliminated -45% of HHF. Antihypertensive treatment could not eliminate harm from CHD events treated without revascularization. In conclusion, the antihypertensive drugs (chlortalidone, lisinopril, and amlodipine) prevent HF not principally by preventing CHD events but by way of other pathways. HF is moderated but not mediated by CHD events. Revascularization of CHD events is paramount for HF prevention.

Recurrent events can occur more than once in the same individual; such events may be of different types, known as multitype recurrent events. They are very common in longitudinal studies. Often there is a terminating event, after which no further events can occur. The risk of any event, including terminating events such as death or cure, is typically affected by prior events. We propose a flexible joint multitype recurrent-events model that explicitly provides estimates of the change in risk for each event due to subject characteristics, including number and type of prior events and the absolute risk for every event type (terminating and nonterminating), and predicts event-free survival probability over a desired time period. The model is fully parametric, and therefore a standard likelihood function and robust standard errors can be constructed. We illustrate the model with applications to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (1994-2002) and provide discussion of the results and model features.

BACKGROUND: Whether the relative effects of blood pressure (BP)–lowering treatment on cardiovascular outcomes differ by sex, particularly when BP is not substantially elevated, has been uncertain. METHODS: We conducted an individual participant-level data meta-analysis of randomized controlled trials of pharmacological BP lowering. We pooled the data and categorized participants by sex, systolic BP categories in 10-mm Hg increments from <120 to ≥170 mm Hg, and age categories spanning from <55 to ≥85 years. We used fixed-effect one-stage individual participant-level data meta-analyses and applied Cox proportional hazard models, stratified by trial, to analyze the data. RESULTS: We included data from 51 randomized controlled trials involving 358 636 (42% women) participants. Over 4.2 years of median follow-up, a 5-mm Hg reduction in systolic BP decreased the risk of major cardiovascular events both in women and men (hazard ratio [95% CI], 0.92 [0.89–0.95] for women and 0.90 [0.88–0.93] for men; P for interaction, 1). There was no evidence for heterogeneity of relative treatment effects by sex for the major cardiovascular disease, its components, or across the different baseline BP categories (all P for interaction, ≥0.57). The effects in women and men were consistent across age categories and the types of antihypertensive medications (all P for interaction, ≥0.14). CONCLUSIONS: The effects of BP reduction were similar in women and men across all BP and age categories at randomization and with no evidence to suggest that drug classes had differing effects by sex. This study does not substantiate sex-based differences in BP-lowering treatment.

Background: Orthostatic hypertension (OHTN) is associated with cardiovascular disease (CVD). We previously demonstrated how more intensive blood pressure (BP) treatment reduced orthostatic hypotension (OH) via a net increase in BP upon standing. Whether this effect also increased OHTN was not examined. Methods: We used pooled data from an individual participant data meta-analysis of 9 randomized BP pharmacologic treatment trials with seated and standing BP (search conducted through May 13, 2022). OHTN was defined as an increase in SBP ≥20 or DBP ≥10 mm Hg after changing from sitting to standing. Effects were examined overall and by baseline characteristics. Results: Of 31,124 participants with 315,497 standing BP assessments, 9% had OH, and 20% had OHTN at baseline. Trial effects were similar ( I 2 = 38.0%). During follow-up, 17% of those assigned more intensive treatment had OHTN, while 19% of those assigned less intensive treatment had OHTN. Intensive BP treatment significantly lowered OHTN risk (OR 0.93; 95% CI: 0.90, 0.96) ( Figure ). Effects were significantly greater among non-Black adults (OR 0.86 vs 0.97, P -interaction =0.003) and adults without diabetes (OR 0.88 vs 0.96; P -interaction =0.047). Effects did not differ by age≥75 years, sex, baseline seated BP≥130/≥80 mm Hg, obesity, stage 3 kidney disease, stroke, cardiovascular disease, standing SBP ≥140 mm Hg, or pre-randomization OHTN ( P -interactions ≥0.05). Conclusion: In this pooled cohort of adults with hypertension or higher CVD risk, OHTN was more common than OH and more intensive BP treatment reduced OHTN risk. The relationship between this effect with respect to CVD should be a focus of subsequent research.

Importance There are ongoing concerns about the benefits of intensive vs standard blood pressure (BP) treatment among adults with orthostatic hypotension or standing hypotension. Objective To determine the effect of a lower BP treatment goal or active therapy vs a standard BP treatment goal or placebo on cardiovascular disease (CVD) or all-cause mortality in strata of baseline orthostatic hypotension or baseline standing hypotension. Data Sources Individual participant data meta-analysis based on a systematic review of MEDLINE, EMBASE, and CENTRAL databases through May 13, 2022. Study Selection Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) with orthostatic hypotension assessments. Data Extraction and Synthesis Individual participant data meta-analysis extracted following PRISMA guidelines. Effects were determined using Cox proportional hazard models using a single-stage approach. Main Outcomes and Measures Main outcomes were CVD or all-cause mortality. Orthostatic hypotension was defined as a decrease in systolic BP of at least 20 mm Hg and/or diastolic BP of at least 10 mm Hg after changing position from sitting to standing. Standing hypotension was defined as a standing systolic BP of 110 mm Hg or less or standing diastolic BP of 60 mm Hg or less. Results The 9 trials included 29 235 participants followed up for a median of 4 years (mean age, 69.0 [SD, 10.9] years; 48% women). There were 9% with orthostatic hypotension and 5% with standing hypotension at baseline. More intensive BP treatment or active therapy lowered risk of CVD or all-cause mortality among those without baseline orthostatic hypotension (hazard ratio [HR], 0.81; 95% CI, 0.76-0.86) similarly to those with baseline orthostatic hypotension (HR, 0.83; 95% CI, 0.70-1.00; P = .68 for interaction of treatment with baseline orthostatic hypotension). More intensive BP treatment or active therapy lowered risk of CVD or all-cause mortality among those without baseline standing hypotension (HR, 0.80; 95% CI, 0.75-0.85), and nonsignificantly among those with baseline standing hypotension (HR, 0.94; 95% CI, 0.75-1.18). Effects did not differ by baseline standing hypotension ( P = .16 for interaction of treatment with baseline standing hypotension). Conclusions and Relevance In this population of hypertension trial participants, intensive therapy reduced risk of CVD or all-cause mortality regardless of orthostatic hypotension without evidence for different effects among those with standing hypotension.

PurposeThis study aimed to determine the 18-year risk of cancer, angioedema, insomnia, depression, and erectile dysfunction in association with antihypertensive drug use.MethodsThis is a post-trial passive follow-up study of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants between 1994 and 1998 that was conducted by linking their follow-up data with Medicare claims data until 2017 of subjects who were free of outcomes at baseline on 1 January 1999. The main outcomes were the occurrence of cancer (among n = 17,332), angioedema (among n = 17,340), insomnia (among n = 17,340), depression (among n = 17,330), and erectile dysfunction (among n = 7,444 men) over 18 years of follow-up.ResultsThe 18-year cumulative incidence rate of cancer other than non-melanoma skin cancer from Medicare inpatient claims was 23.9% for chlorthalidone, 23.4% for amlodipine, and 25.3% for lisinopril. There were no statistically significant differences in the 18-year risk of cancer, depression, and erectile dysfunction among the three drugs based on the adjusted hazard ratios. The adjusted 18-year risk of angioedema was elevated in those receiving lisinopril than in those receiving amlodipine (hazard ratio: 1.63, 95% CI: 1.14–2.33) or in those receiving chlorthalidone (1.33, 1.00–1.79), whereas the adjusted 18-year risk of insomnia was statistically significantly decreased in those receiving lisinopril than in those receiving amlodipine (0.90, 0.81–1.00).ConclusionsThe 18-year risk of angioedema was significantly higher in patients receiving lisinopril than in those receiving amlodipine or chlorthalidone; the risk of insomnia was significantly lower in patients receiving lisinopril than in those receiving amlodipine; and the risk of cancer, depression, and erectile dysfunction (in men) was not statistically significantly different among the three drug groups.

Key Points Question Is there a difference in the long-term risk of mortality and morbidity outcomes for adults with hypertension starting 1 of 3 antihypertensive treatments: thiazide-type diuretic, calcium channel blocker, or angiotensin-converting enzyme (ACE) inhibitor? Findings In this prespecified secondary analysis of outcomes of 32 804 participants in a randomized clinical trial and posttrial up to 23 years later, there was no significant difference in mortality due to cardiovascular disease among the 3 antihypertensive treatment groups. However, there was an increased risk of stroke outcomes for ACE inhibitors compared with diuretics; after accounting for multiple comparisons, this increased risk was no longer significant. Meaning Long-term follow-up supports the main findings that the diuretic group had similar cardiovascular outcomes and the ACE inhibitor group had higher stroke mortality risk.

ImportanceThe long-term relative risk of antihypertensive treatments with regard to mortality and morbidity is not well understood.ObjectiveTo determine the long-term posttrial risk of primary and secondary outcomes among trial participants who were randomized to either a thiazide-type diuretic, calcium channel blocker (CCB), or angiotensin-converting enzyme (ACE) inhibitor with up to 23 years of follow-up.Design, Setting, and ParticipantsThis prespecified secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a multicenter randomized, double-blind, active-controlled clinical trial, followed up with participants aged 55 years or older with a diagnosis of hypertension and at least 1 other coronary heart disease risk factor for up to 23 years, from February 23, 1994, to December 31, 2017. Trial participants were linked with administrative databases for posttrial mortality (N = 32 804) and morbidity outcomes (n = 22 754). Statistical analysis was performed from January 2022 to October 2023.InterventionsParticipants were randomly assigned to receive a thiazide-type diuretic (n = 15 002), a CCB (n = 8898), or an ACE inhibitor (n = 8904) for planned in-trial follow-up of approximately 4 to 8 years and posttrial passive follow-up for up to 23 years.Main Outcomes and MeasuresThe primary end point was mortality due to cardiovascular disease (CVD). Secondary outcomes included all-cause mortality, combined fatal and nonfatal (morbidity) CVD, and both mortality and morbidity for coronary heart disease, stroke, heart failure, end-stage renal disease, and cancer.ResultsA total of 32 804 participants (mean [SD] age, 66.9 [7.7] years; 17 411 men [53.1%]; and 11 772 Black participants [35.9%]) were followed up for all-cause mortality and a subgroup of 22 754 participants (mean [SD] age, 68.7 [7.2] years; 12 772 women [56.1%]; and 8199 Black participants [36.0%]) were followed up for fatal or nonfatal CVD through 2017 (mean [SD] follow-up, 13.7 [6.7] years; maximum follow-up, 23.9 years). Cardiovascular disease mortality rates per 100 persons were 23.7, 21.6, and 23.8 in the diuretic, CCB, and ACE inhibitor groups, respectively, at 23 years after randomization (adjusted hazard ratio [AHR], 0.97 [95% CI, 0.89-1.05] for CCB vs diuretic; AHR, 1.06 [95% CI, 0.97-1.15] for ACE inhibitor vs diuretic). The long-term risks of most secondary outcomes were similar among the 3 groups. Compared with the diuretic group, the ACE inhibitor group had a 19% increased risk of stroke mortality (AHR, 1.19 [95% CI, 1.03-1.37]) and an 11% increased risk of combined fatal and nonfatal hospitalized stroke (AHR, 1.11 [95% CI, 1.03-1.20]).Conclusions and RelevanceIn this secondary analysis of a randomized clinical trial in an adult population with hypertension and coronary heart disease risk factors, CVD mortality was similar between all 3 groups. ACE inhibitors increased the risk of stroke outcomes by 11% compared with diuretics, and this effect persisted well beyond the trial period.Trial RegistrationClinicalTrials.gov Identifier: NCT00000542

CCTRN is a Cardiovascular Cell Therapy Research Network. There were three randomized double blinded controlled stem cell clinical trials conducted in its first phase. The main results of these three clinical trials were published with conventional parametric models such as T test and nonparametric test such as Wilcoxon rank sum test without adjusting covariates. In this article, we conducted further analysis of the primary outcomes of these studies using a class of covariate adjusted nonparametric methods.