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Background: Randomised evidence on the efficacy of blood pressure (BP)-lowering treatment to reduce cardiovascular risk in patients with atrial fibrillation (AF) is limited. Therefore, this study aimed to compare the effects of BP-lowering drugs in patients with and without AF at baseline., Methods and Findings: The study was based on the resource provided by the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC), in which individual participant data (IPD) were extracted from trials with over 1,000 patient-years of follow-up in each arm, and that had randomly assigned patients to different classes of BP-lowering drugs, BP-lowering drugs versus placebo, or more versus less intensive BP-lowering regimens. For this study, only trials that had collected information on AF status at baseline were included. The effects of BP-lowering treatment on a composite endpoint of major cardiovascular events (stroke, ischaemic heart disease or heart failure) according to AF status at baseline were estimated using fixed-effect one-stage IPD meta-analyses based on Cox proportional hazards models stratified by trial. Furthermore, to assess whether the associations between the intensity of BP reduction and cardiovascular outcomes are similar in those with and without AF at baseline, we used a meta-regression. From the full BPLTTC database, 28 trials (145,653 participants) were excluded because AF status at baseline was uncertain or unavailable. A total of 22 trials were included with 188,570 patients, of whom 13,266 (7%) had AF at baseline. Risk of bias assessment showed that 20 trials were at low risk of bias and 2 trials at moderate risk. Meta-regression showed that relative risk reductions were proportional to trial-level intensity of BP lowering in patients with and without AF at baseline. Over 4.5 years of median follow-up, a 5-mm Hg systolic BP (SBP) reduction lowered the risk of major cardiovascular events both in patients with AF (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.83 to 1.00) and in patients without AF at baseline (HR 0.91, 95% CI 0.88 to 0.93), with no difference between subgroups. There was no evidence for heterogeneity of treatment effects by baseline SBP or drug class in patients with AF at baseline. The findings of this study need to be interpreted in light of its potential limitations, such as the limited number of trials, limitation in ascertaining AF cases due to the nature of the arrhythmia and measuring BP in patients with AF., Conclusions: In this meta-analysis, we found that BP-lowering treatment reduces the risk of major cardiovascular events similarly in individuals with and without AF. Pharmacological BP lowering for prevention of cardiovascular events should be recommended in patients with AF., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: KR is an academic editor on PLOS Medicine’s editorial board and has in the past received personal fees as Speciality Consulting Editor for PLOS Medicine. KR is also in receipt of personal fees as Associate Editor for BMJ Heart.MW reports personal fees from Amgen, Kyowa Kirin, and Freeline outside the submitted work; JS reports ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer, Bayer, Pfizer and AstraZeneca, outside the submitted work. Group authors listed in the acknowledgements have no known competing interests.

Background: Although intensive blood pressure (BP)-lowering treatment reduces risk for cardiovascular disease, there are concerns that it might cause orthostatic hypotension (OH)., Purpose: To examine the effects of intensive BP-lowering treatment on OH in hypertensive adults., Data Sources: MEDLINE, EMBASE, and Cochrane CENTRAL from inception through 7 October 2019, without language restrictions., Study Selection: Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) that involved more than 500 adults with hypertension or elevated BP and that were 6 months or longer in duration. Trial comparisons were groups assigned to either less intensive BP goals or placebo, and the outcome was measured OH, defined as a decrease of 20 mm Hg or more in systolic BP or 10 mm Hg or more in diastolic BP after changing position from seated to standing., Data Extraction: 2 investigators independently abstracted articles and rated risk of bias., Data Synthesis: 5 trials examined BP treatment goals, and 4 examined active agents versus placebo. Trials examining BP treatment goals included 18 466 participants with 127 882 follow-up visits. Trials were open-label, with minimal heterogeneity of effects across trials. Intensive BP treatment lowered risk for OH (odds ratio, 0.93 [95% CI, 0.86 to 0.99]). Effects did not differ by prerandomization OH ( P for interaction = 0.80). In sensitivity analyses that included 4 additional placebo-controlled trials, overall and subgroup findings were unchanged., Limitations: Assessments of OH were done while participants were seated (not supine) and did not include the first minute after standing. Data on falls and syncope were not available., Conclusion: Intensive BP-lowering treatment decreases risk for OH. Orthostatic hypotension, before or in the setting of more intensive BP treatment, should not be viewed as a reason to avoid or de-escalate treatment for hypertension., Primary Funding Source: National Heart, Lung, and Blood Institute, National Institutes of Health. (PROSPERO: CRD42020153753).

Objectives: To investigate legacy effects at 14-year follow-up of all-cause and cardiovascular disease (CVD) mortality in 'treatment-naive' or 'previous treatment' groups based on blood pressure (BP)-lowering treatment status at baseline., Methods: A post-hoc observational study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. We excluded participants with a previous history of CVD events. Cox proportional hazard model and 95% confidence interval were used to estimate the effects of treatment naive on mortality outcomes. Moreover, a subgroup analysis by estimated 10-year Framingham risk score was performed., Results: In multivariable models adjusting for baseline and in-trial characteristics (BP values and number of BP medications as time-dependent variables), there was no statistically significant difference in 5 and 14-year all-cause mortality with a hazard ratio of 0.93 (95% confidence interval 0.80-1.09) and hazard ratio 0.95 (0.88-1.03) and in 5 and 14-year CVD mortality hazard ratio 0.94 (0.72-1.23) and hazard ratio 0.93 (0.80-1.08). In subgroup by absolute CVD risk, no heterogeneity of the association between treatment naive and short-term or long-term all-cause or CVD mortality were found. All comparisons are between the treatment-naive and previous treatment groups., Conclusion: Physicians are concerned about 'legacy effects' of not treating individuals with a BP of 140 mmHg or over and low absolute risk. When treatment intensification was taken into consideration in the primary prevention population in this study, no adverse legacy effect as a result of baseline BP 'treatment naivety' was evident in 14 years of follow-up. The nonsignificant associations were consistent across the CVD risk subgroups. However, the results may be biased due to unobserved residual confounding and therefore should be interpreted with caution.

We examined the association of orthostatic hypertension with all-cause mortality in the active treatment and placebo randomized groups of the Systolic Hypertension in the Elderly Program (SHEP). SHEP was a multicenter, randomized, double-blind, placebo-controlled clinical trial of the effect of chlorthalidone-based antihypertensive treatment on the rate of occurrence of stroke among older persons with isolated systolic hypertension (ISH). Men and women aged 60 years and above with ISH defined by a systolic blood pressure (SBP) of 160 mm Hg or higher and diastolic blood pressure lower than 90 mm Hg were randomized to chlorthalidone-based stepped care therapy or matching placebo. Among 4736 SHEP participants, 4073 had a normal orthostatic response, 203 had orthostatic hypertension, and 438 had orthostatic hypotension. Compared with normal response, orthostatic hypertension was associated with higher all-cause mortality at 4.5 and 17 years in analyses adjusted for age, gender, treatment, SBP, and pulse pressure (PP, HR 1.87, 95% CI 1.30-2.69, p = 0.0007; HR 1.40, 95% CI 1.17-1.68, p = 0.0003, respectively). These associations remained significant after additional adjustment for risk factors and comorbidities (HR 1.43, 95% CI 0.99-0.08, p = 0.0566 at 4.5 years, and HR 1.27, 95% CI 1.06-1.53, p = 0.0096 at 17 years). The increased risk of all-cause mortality associated with orthostatic hypertension was observed in both the active and placebo groups without significant interaction between randomization group and the effect on mortality. Orthostatic hypertension is associated with future mortality risk, is easily detected, and can be used in refining cardiovascular risk assessment.

Achieving blood pressure (BP) control is associated with lower cardiovascular disease (CVD) risk, but less is known about CVD risk associated with sustained BP control over time. This observational analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was restricted to participants with four to seven visits with systolic BP (SBP) measurements during a 22-month period (n = 24 309). The authors categorized participants as having sustained BP control (SBP < 140 mm Hg) at 100%, 75% to <100%, 50% to <75%, and <50% of visits during this period. Outcomes included fatal coronary heart disease (CHD)/nonfatal myocardial infarction (MI), stroke, heart failure (HF), a composite CVD outcome (fatal CHD/nonfatal MI, stroke, or HF), and mortality. Hazard ratios (HRs) for the association of category of sustained BP control for each outcome were obtained using proportional hazards models. SBP control was present among 20.0% of participants at 100%, 16.4% at 75% to less than 100%, 27.0% at 50% to less than 75%, and 36.6% at less than 50% of visits. Compared to those with SBP control at 100% visits, adjusted HR (95% CI) among those with SBP control at <50% of visits was 1.16 (0.93-1.44) for fatal CHD/nonfatal MI, 1.71 (1.26-2.32) for stroke, 1.63 (1.30-2.06) for HF, 1.39 (1.20-1.62) for the composite CVD outcome, and 1.14 (0.99-1.30) for mortality. Sustained SBP control may be beneficial for preventing stroke, HF, and CVD outcomes in adults taking antihypertensive medication., (©2019 Wiley Periodicals, Inc.)

Background: Clinical practice guidelines have traditionally recommended blood pressure treatment based primarily on blood pressure thresholds. In contrast, using predicted cardiovascular risk has been advocated as a more effective strategy to guide treatment decisions for cardiovascular disease (CVD) prevention. We aimed to compare outcomes from a blood pressure-lowering treatment strategy based on predicted cardiovascular risk with one based on systolic blood pressure (SBP) level., Methods and Findings: We used individual participant data from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) from 1995 to 2013. Trials randomly assigned participants to either blood pressure-lowering drugs versus placebo or more intensive versus less intensive blood pressure-lowering regimens. We estimated 5-y risk of CVD events using a multivariable Weibull model previously developed in this dataset. We compared the two strategies at specific SBP thresholds and across the spectrum of risk and blood pressure levels studied in BPLTTC trials. The primary outcome was number of CVD events avoided per persons treated. We included data from 11 trials (47,872 participants). During a median of 4.0 y of follow-up, 3,566 participants (7.5%) experienced a major cardiovascular event. Areas under the curve comparing the two treatment strategies throughout the range of possible thresholds for CVD risk and SBP demonstrated that, on average, a greater number of CVD events would be avoided for a given number of persons treated with the CVD risk strategy compared with the SBP strategy (area under the curve 0.71 [95% confidence interval (CI) 0.70-0.72] for the CVD risk strategy versus 0.54 [95% CI 0.53-0.55] for the SBP strategy). Compared with treating everyone with SBP ≥ 150 mmHg, a CVD risk strategy would require treatment of 29% (95% CI 26%-31%) fewer persons to prevent the same number of events or would prevent 16% (95% CI 14%-18%) more events for the same number of persons treated. Compared with treating everyone with SBP ≥ 140 mmHg, a CVD risk strategy would require treatment of 3.8% (95% CI 12.5% fewer to 7.2% more) fewer persons to prevent the same number of events or would prevent 3.1% (95% CI 1.5%-5.0%) more events for the same number of persons treated, although the former estimate was not statistically significant. In subgroup analyses, the CVD risk strategy did not appear to be more beneficial than the SBP strategy in patients with diabetes mellitus or established CVD., Conclusions: A blood pressure-lowering treatment strategy based on predicted cardiovascular risk is more effective than one based on blood pressure levels alone across a range of thresholds. These results support using cardiovascular risk assessment to guide blood pressure treatment decision-making in moderate- to high-risk individuals, particularly for primary prevention.

Background: Electrocardiographic (ECG) left ventricular hypertrophy (LVH) is a strong predictor of cardiovascular (CV) morbidity and mortality. However, the predictive value of ECG LVH in treated hypertensive patients remains unclear., Methods: A total of 33,357 patients (aged ≥ 55 years) with hypertension and at least 1 other coronary heart disease (CHD) risk factor were randomized to chlorthalidone, amlodipine, or lisinopril. The outcome of the present study was all-cause mortality; and secondary endpoints were CHD, nonfatal myocardial infarction (MI), stroke, angina, heart failure (HF), and peripheral arterial disease. Cornell voltage criteria (S in V3 + R in aVL > 28 [men] or >22 mm [women]) defined ECG LVH., Results: ECGs were available at baseline in 26,384 patients. Baseline Cornell voltage LVH was present in 1,741 (7%) patients, who were older (67.4 vs. 66.6 years, P < 0.001), more likely to be female (74 vs. 44%, P < 0001) with a higher systolic blood pressure (151 vs. 146 mm Hg, P < 0.001) than patients without ECG LVH. During 5.0 ± 1.4 years mean follow-up, baseline and in-study ECG LVH was significantly associated with 29 to 98% increased risks of all-cause mortality, MI, CHD, stroke, and HF in multivariable Cox analyses., Conclusions: Baseline Cornell voltage LVH is associated with increased CV morbidity and all-cause mortality in treated hypertensive patients independent of treatment modality and other CV risk factors., Clinical Trials Registration: Trial Number NCT00000542., (© American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: In this study, we aimed to translate the average relative effect of statin therapy from trial data to the individual patient with type 2 diabetes mellitus by developing and validating a model to predict individualized absolute risk reductions (ARR) of cardiovascular events., Methods and Results: Data of 2725 patients with type 2 diabetes mellitus from the Lipid Lowering Arm of the Anglo Scandinavian Cardiac Outcomes Trial (ASCOT-LLA) study (atorvastatin 10 mg versus placebo) were used for model derivation. The model was based on 8 clinical predictors including treatment allocation (statin/placebo). Ten-year individualized ARR on major cardiovascular events by statin therapy were calculated for each patient by subtracting the estimated on-treatment risk from the estimated off-treatment risk. Predicted 10-year ARR by statin therapy was <2% for 13% of the patients. About 30% had an ARR of >4% (median ARR, 3.2%; interquartile range, 2.5%-4.3%; 95% confidence interval for 3.2% ARR, -1.4% to 6.8%). Addition of treatment interactions did not improve model performance. Therefore, the wide distribution in ARR was a consequence of the underlying distribution in cardiovascular risk enrolled in these trials. External validation of the model was performed in data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT; pravastatin 40 mg versus usual care) and Collaborative Atorvastatin Diabetes Study (CARDS; atorvastatin 10 mg versus placebo) of 3878 and 2838 patients with type 2 diabetes mellitus, respectively. Model calibration was adequate in both external data sets, discrimination was moderate (ALLHAT-LLT: c-statistics, 0.64 [95% confidence interval, 0.61-0.67] and CARDS: 0.68 [95% confidence interval, 0.64-0.72])., Conclusions: ARRs of major cardiovascular events by statin therapy can be accurately estimated for individual patients with type 2 diabetes mellitus using a model based on routinely available patient characteristics. There is a wide distribution in ARR that may complement informed decision making., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00327418 (CARDS) and NCT00000542 (ALLHAT)., (© 2016 American Heart Association, Inc.)

Background and Objectives: Increased visit-to-visit variability of BP is associated with cardiovascular disease risk. We examined the association of visit-to-visit variability of BP with renal outcomes among 21,245 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial., Design, Setting, Participants, & Measurements: We measured mean BP and visit-to-visit variability of BP, defined as SD, across five to seven visits occurring 6-28 months after participants were randomized to chlorthalidone, amlodipine, or lisinopril. The composite outcome included incident ESRD after assessment of SD of systolic BP or ≥50% decline in eGFR between 24 months and 48 or 72 months after randomization. We repeated the analyses using average real variability and peak value of systolic BP and for visit-to-visit variability of diastolic BP., Results: Over a mean follow-up of 3.5 years, 297 outcomes occurred. After multivariable adjustment, including baseline eGFR and mean systolic BP, the hazard ratios for the composite end point were 1.29 (95% confidence interval [95% CI], 0.75 to 2.22), 1.76 (95% CI, 1.06 to 2.91), 1.46 (95% CI, 0.88 to 2.45), and 2.05 (95% CI, 1.25 to 3.36) for the second through fifth (SD of systolic BP =6.63-8.82, 8.83-11.14, 11.15-14.56, and >14.56 mmHg, respectively) versus the first (SD of systolic BP <6.63 mmHg) quintile of SD of systolic BP, respectively (P trend =0.004). The association was similar when ESRD and a 50% decline in eGFR were analyzed separately, for other measures of visit-to-visit variability of systolic BP, and for visit-to-visit variability of diastolic BP., Conclusions: Higher visit-to-visit variability of BP is associated with higher risk of renal outcomes independent of mean BP., (Copyright © 2016 by the American Society of Nephrology.)

Background: Variability of blood pressure (BP) across outpatient visits is frequently dismissed as random fluctuation around a patient's underlying BP., Objective: To examine the association of visit-to-visit variability (VVV) of systolic BP (SBP) and diastolic BP with cardiovascular disease (CVD) and mortality outcomes., Design: Prospective cohort study., Setting: Post hoc analysis of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial)., Participants: 25 814 ALLHAT participants., Measurements: The VVV of SBP was defined as the SD across SBP measurements obtained at 7 visits conducted from 6 to 28 months after ALLHAT enrollment. Participants without CVD events during the first 28 months of follow-up were followed from the 28-month visit through the end of active ALLHAT follow-up. Outcomes included fatal coronary heart disease (CHD) or nonfatal myocardial infarction, all-cause mortality, stroke, and heart failure., Results: During follow-up, 1194 fatal CHD or nonfatal MI events, 1948 deaths, 606 strokes, and 921 heart failure events occurred. After multivariable adjustment, including for mean SBP, the hazard ratio comparing participants in the highest versus lowest quintile of SD of SBP (≥14.4 mm Hg vs. <6.5 mm Hg) was 1.30 (95% CI, 1.06 to 1.59) for fatal CHD or nonfatal MI, 1.58 (CI, 1.32 to 1.90) for all-cause mortality, 1.46 (CI, 1.06 to 2.01) for stroke, and 1.25 (CI, 0.97 to 1.61) for heart failure. Higher VVV of diastolic BP was also associated with CVD events and mortality., Limitation: Long-term outcomes were not available., Conclusion: Higher VVV of SBP is associated with an increased risk for CVD and mortality. Future studies should examine whether reducing VVV of BP lowers this risk., Primary Funding Source: National Institutes of Health.

Few randomized trials have compared visit-to-visit variability (VVV) of systolic blood pressure (SBP) across drug classes. The authors compared VVV of SBP among 24,004 participants randomized to chlorthalidone, amlodipine, or lisinopril in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). VVV of SBP was calculated across 5 to 7 visits occurring 6 to 28 months following randomization. The standard deviation (SD) of SBP was 10.6 (SD=5.0), 10.5 (SD=4.9), and 12.2 (SD=5.8) for participants randomized to chlorthalidone, amlodipine, and lisinopril, respectively. After multivariable adjustment including mean SBP across visits and compared with participants randomized to chlorthalidone, participants randomized to amlodipine had a 0.36 (standard error [SE]: 0.07) lower SD of SBP and participants randomized to lisinopril had a 0.77 (SE=0.08) higher SD of SBP. Results were consistent using other VVV of SBP metrics. These data suggest chlorthalidone and amlodipine are associated with lower VVV of SBP than lisinopril., (©2014 Wiley Periodicals, Inc.)

Most studies of an association of visit-to-visit variability of blood pressure with increased risk of future adverse cardiovascular events are of short duration and rarely include a placebo group. Using data from the double-blind, placebo-controlled Systolic Hypertension in the Elderly Program, the authors examined mortality from cardiovascular causes up to 17 years of follow-up using the National Death Index. Visit-to-visit blood pressure variability was associated with cardiovascular death after adjustment for sex, age, serum creatinine, diabetes, body mass index, smoking status, left ventricular failure, and high-density lipoprotein cholesterol. The relationship was significantly stronger in the active treatment group compared with the placebo group. Although this could be the result of an effect of the medications used unrelated to visit-to-visit variability, the data are compatible with the hypothesis that inconsistent adherence leading to missing active medication doses may be an additional explanation for the relationship of visit-to-visit variability with cardiovascular death., (©2013 Wiley Periodicals, Inc.)

The debate over whether certain antihypertensive medications have benefits beyond what would be expected from their blood pressure lowering spurred the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, which randomized 42,418 participants to chlorthalidone (15,255), amlodipine (9048), lisinopril (9054), or doxazosin (9061). We compared chlorthalidone, the active control, with each of the other three agents with respect to the primary outcome, fatal coronary heart disease or nonfatal myocardial infarction, and several other clinical endpoints. The arms were similar with respect to the primary endpoint, although some differences were found for other endpoints, most notably heart failure. Although the desire was to achieve similar blood pressure reductions in the four arms, we found some systolic blood pressure and diastolic blood pressure differences. A natural question is to what degree can observed treatment group differences in cardiovascular outcomes be attributed to these blood pressure differences. The purpose of this paper was to delineate the problems inherent in attempting to answer this question, and to present analyses intended to overcome these problems., (Copyright © 2012 John Wiley & Sons, Ltd.)

A randomized, double-blind, active-controlled, multicenter trial assigned 32,804 participants aged 55 years and older with hypertension and ≥ 1 other coronary heart disease risk factors to receive chlorthalidone (n=15,002), amlodipine (n=8898), or lisinopril (n=8904) for 4 to 8 years, when double-blinded therapy was discontinued. Passive surveillance continued for a total follow-up of 8 to 13 years using national administrative databases to ascertain deaths and hospitalizations. During the post-trial period, fatal outcomes and nonfatal outcomes were available for 98% and 65% of participants, respectively, due to lack of access to administrative databases for the remainder. This paper assesses whether mortality and morbidity differences persisted or new differences developed during the extended follow-up. Primary outcome was cardiovascular mortality and secondary outcomes were mortality, stroke, coronary heart disease, heart failure, cardiovascular disease, and end-stage renal disease. For the post-trial period, data are not available on medications or blood pressure levels. No significant differences (P<.05) appeared in cardiovascular mortality for amlodipine (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.93-1.06) or lisinopril (HR, 0.97; CI, 0.90-1.03), each compared with chlorthalidone. The only significant differences in secondary outcomes were for heart failure, which was higher with amlodipine (HR, 1.12; CI, 1.02-1.22), and stroke mortality, which was higher with lisinopril (HR, 1.20; CI, 1.01-1.41), each compared with chlorthalidone. Similar to the previously reported in-trial result, there was a significant treatment-by-race interaction for cardiovascular disease for lisinopril vs chlorthalidone. Black participants had higher risk than non-black participants taking lisinopril compared with chlorthalidone. After accounting for multiple comparisons, none of these results were significant. These findings suggest that neither calcium channel blockers nor angiotensin-converting enzyme inhibitors are superior to diuretics for the long-term prevention of major cardiovascular complications of hypertension., (© 2011 Wiley Periodicals, Inc.)

The authors recruited a group of physicians from among the investigators participating in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) with a greater (more successful) or lesser (less successful) proportion of trial patients meeting blood pressure (BP) control goals. The authors utilized qualitative focus group methods to identify similarities and differences in practice behaviors. Successful and less successful physicians had similarities in knowledge and practice behaviors regarding awareness of treatment guidelines, approaches to diagnosis, use of pharmacologic management, and the opinion that systolic BP guidelines should consider a patient's age. However, there were discernible differences between the two physician groups in their views on doctor-patient relationships: physicians from the less successful group were more paternalistic with their patients, while physicians from the more successful group were more likely to use a patient-centered clinical approach to BP awareness and management.

Blood pressure (BP) control rates and number of antihypertensive medications were compared (average follow-up, 4.9 years) by randomized groups: chlorthalidone, 12.5-25 mg/d (n=15,255), amlodipine 2.5-10 mg/d (n=9048), or lisinopril 10-40 mg/d (n=9054) in a randomized double-blind hypertension trial. Participants were hypertensives aged 55 or older with additional cardiovascular risk factor(s), recruited from 623 centers. Additional agents from other classes were added as needed to achieve BP control. BP was reduced from 145/83 mm Hg (27% control) to 134/76 mm Hg (chlorthalidone, 68% control), 135/75 mm Hg (amlodipine, 66% control), and 136/76 mm Hg (lisinopril, 61% control) by 5 years; the mean number of drugs prescribed was 1.9, 2.0, and 2.1, respectively. Only 28% (chlorthalidone), 24% (amlodipine), and 24% (lisinopril) were controlled on monotherapy. BP control was achieved in the majority of each randomized group-a greater proportion with chlorthalidone. Over time, providers and patients should expect multidrug therapy to achieve BP <140/90 mm Hg in a majority of patients.

Background: Previous studies have reported that blood pressure response to antihypertensive medications is influenced by genetic variation in the renin-angiotensin-aldosterone system, but no clinical trails have tested whether the ACE insertion/deletion (I/D) polymorphism modifies the association between the type of medication and multiple cardiovascular and renal phenotypes., Methods and Results: We used a double-blind, active-controlled randomized trial of antihypertensive treatment that included hypertensives > or =55 years of age with > or =1 risk factor for cardiovascular disease. ACE I/D genotypes were determined in 37 939 participants randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatments and followed up for 4 to 8 years. Primary outcomes included fatal coronary heart disease (CHD) and/or nonfatal myocardial infarction. Secondary outcomes included stroke, all-cause mortality, combined CHD, and combined cardiovascular disease. Fatal and nonfatal CHD occurred in 3096 individuals during follow-up. The hazard rates for fatal and nonfatal CHD and the secondary outcomes were similar across antihypertensive treatments. ACE I/D genotype group was not associated with fatal and nonfatal CHD (relative risk of DD versus ID and II, 0.99; 95% CI, 0.91 to 1.07) or any secondary outcome. The 6-year hazard rate for fatal and nonfatal CHD in the DD genotype group was not statistically different from the ID and II genotype group by type of treatment. No secondary outcome measure was statistically different across antihypertensive treatment and ACE I/D genotype strata., Conclusions: ACE I/D genotype group was not a predictor of CHD, nor did it modify the response to antihypertensive treatment. We conclude that the ACE I/D polymorphism is not a useful marker to predict antihypertensive treatment response.

Background: The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial reported that treatment initiated with doxazosin compared with chlorthalidone doubled the risk for heart failure in high-risk hypertensive patients (relative risk, 2.04 [95% CI, 1.79 to 2.32]). Patients assigned to doxazosin therapy had a mean in-trial systolic/diastolic blood pressure 3/0 mm Hg higher than that in patients assigned to chlorthalidone. Sixty-eight percent (6167 of 9061) of the former patients and 59% (9081 of 15 256) of the latter patients were given additional medications to achieve a target blood pressure of less than 140/90 mm Hg., Objective: To ascertain the influence of open-label antihypertensive drugs and subsequent blood pressure on relative risk for heart failure., Design: Randomized, double-blind, active-controlled clinical trial., Setting: 623 sites in the United States and Canada., Patients: Hypertensive patients 55 years of age or older with at least one additional risk factor for cardiovascular disease., Intervention: Chlorthalidone (12.5 to 25 mg/d) or doxazosin (2 to 8 mg/d) for a planned follow-up of 4 to 8 years., Measurements: Data on blood pressure, medication, and incident heart failure (treated outside hospital, hospitalized, or fatal) from February 1994 through December 1999., Results: After the treatment groups were categorized as having no exposure to open-label medications (monotherapy) or exposure to open-label therapy, the relative risk for heart failure with doxazosin versus chlorthalidone was 3.10 (CI, 2.51 to 3.82) and 1.42 (CI, 1.20 to 1.69), respectively. After adjustment for follow-up systolic/diastolic blood pressure, the overall relative risk was 2.00 (CI, 1.72 to 2.32)., Conclusion: In high-risk patients with hypertension, the higher risk for heart failure while taking doxazosin compared with chlorthalidone is attenuated but not eliminated by adding other antihypertensive drugs. The small observed difference in systolic blood pressure does not explain this increased risk.

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. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does the effect of intensive blood pressure treatment on cardiovascular disease or all-cause mortality differ based on the presence or absence of orthostatic or standing hypotension? Findings: In this individual data meta-analysis of more than 29 000 participants in 9 hypertension trials, more intensive blood pressure treatment lowered risk of cardiovascular disease or all-cause mortality regardless of whether participants had orthostatic hypotension. Moreover, effects did not differ by the presence or absence of standing hypotension. Meaning: Asymptomatic orthostatic hypotension or standing hypotension among adults with hypertension should not be a deterrent to more intensive hypertension treatment. 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. This individual participant data meta-analysis assesses the effect of a lower blood pressure (BP) treatment goal or active therapy vs a standard BP treatment goal or placebo on cardiovascular disease or all-cause mortality among adults with orthostatic hypotension or standing hypotension. [ABSTRACT FROM AUTHOR]

Objective: Evidence from randomised trials of pharmacological treatments on long-term blood pressure (BP) reduction is limited. We investigated the antihypertensive drug effects on BP over time and across different participant characteristics.Methods: We conducted an individual patient-level data meta-analysis of 52 large-scale randomised clinical trials in the Blood Pressure Lowering Treatment Trialists' Collaboration using mixed models to examine treatment effects on BP over 4 years of mean follow-up.Results: There were 363 684 participants (42% women), with baseline mean age=65 years and mean systolic/diastolic BP=152/87 mm Hg, and among whom 19% were current smokers, 49% had cardiovascular disease, 28% had diabetes and 69% were taking antihypertensive treatment at baseline. Drugs were effective in lowering BP showing maximal effect after 12 months and gradually attenuating towards later years. Based on measures taken ≥12 months postrandomisation, mean systolic/diastolic BP difference (95% CI) between more and less intense BP-lowering treatment was -11.1 (-11.3 to -10.8)/-5.6 (-5.7 to -5.4) mm Hg; between active treatment and placebo was -5.1 (-5.3 to -5.0)/-2.3 (-2.4 to -2.2) mm Hg; and between active and control arms for drug comparison trials was -1.4 (-1.5 to -1.3)/-0.6 (-0.7 to -0.6) mm Hg. BP reductions were observed across different baseline BP values and ages, and by sex, history of cardiovascular disease and diabetes and prior antihypertensive treatment use.Conclusion: These findings suggest that BP-lowering pharmacotherapy is effective in lowering BP, up to 4 years on average, in people with different characteristics. Appropriate treatment strategies are needed to sustain substantive long-term BP reductions. [ABSTRACT FROM AUTHOR]

BACKGROUND/OBJECTIVES Due to the high costs and excess mortality associated with multimorbidity, there is a need to develop approaches for delaying its progression. High blood pressure (BP) is a common chronic condition and a risk factor for many additional chronic conditions, making it an ideal target for intervention. The purpose of this analysis was to determine the association between the level of sustained BP control and the progression of multimorbidity. DESIGN Retrospective cohort study. SETTING Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) linked to Medicare claims. PARTICIPANTS A total of 6,591 ALLHAT participants with Medicare who had systolic BP (SBP) measurements at eight or more study visits. MEASUREMENTS SBP control was categorized as lower than 140 mm Hg at less than 50%, 50% to less than 75%, 75% to less than 100%, and 100% of visits. Multimorbidity progression was defined by the number of incident chronic conditions, including arthritis, asthma, atrial fibrillation, cancer, chronic kidney disease, chronic obstructive pulmonary disease, coronary heart disease, dementia, depression, diabetes mellitus, heart failure, hyperlipidemia, osteoporosis, and stroke. Recurrent event survival analysis was used to calculate rate ratios (RRs) for the association of sustained SBP control with progression of multimorbidity. RESULTS: Rates of incident conditions per 10 person‐years (95% CIs) were 5.2 (5.1–5.4), 4.7 (4.5–4.8), 4.4 (4.2–4.5), and 4.0 (3.8–4.2) for participants with SBP control at less than 50%, 50% to less than 75%, 75% to less than 100%, and 100% of visits, respectively, over a median follow‐up of 9.0 years. Compared with participants with SBP control at less than 50% of visits, adjusted RRs (95% CIs) for multimorbidity progression were 0.90 (0.86–0.95), 0.85 (0.81–0.89), and 0.77 (0.72–0.82) for those with SBP control at 50% to less than 75%, 75% to less than 100%, and 100% of visits, respectively. CONCLUSIONS: Sustaining BP control may be an effective approach to slow multimorbidity progression and may reduce the population burden of multimorbidity. [ABSTRACT FROM AUTHOR]

BACKGROUND Elevations of fasting glucose (FG) levels are frequently encountered in people treated with thiazide diuretics. The risk is lower in people treated with ACE inhibitors (ACEi). To determine if genetic factors play a role in FG elevation, we examined the interaction of a diabetes gene risk score (GRS) with the use of 3 different antihypertensive medications. METHODS We examined 376 nondiabetic hypertensive individuals with baseline FG <100 mg/dl who were genotyped for 24 genes associated with risk of elevated glucose levels. All participants had ≥1 follow-up FG level over 6 years of follow-up. Participants were randomized to treatment with a thiazide-like diuretic (chlorthalidone), a calcium channel blocker (CCB; amlodipine), or an ACEi (lisinopril). Outcomes were an FG increase of ≥13 or ≥27 mg/dl, the upper 75% and 90% FG increase in the parent cohort from which the present cohort was obtained. Odds ratios were adjusted for factors that increase FG levels. RESULTS For every 1 allele increase in GRS, the adjusted odds ratios (ORs) were 1.06 (95% confidence interval (CI): 0.99, 1.14; P = 0.06) and 1.09 (95% CI: 0.99, 1.20; P = 0.08). When results were examined by randomized medications, participants randomized to amlodipine had statistically significant odds for either outcome (OR: 1.23; 95% CI: 1.03, 1.48; P = 0.01 and OR: 1.31; 95% CI: 1.06, 1.62; P = 0.01). No such risk increase was found in participants randomized to the other 2 medications. CONCLUSIONS A diabetes GRS predicts FG elevation in people treated with a CCB, but not with an ACEi or diuretic. These findings require confirmation. CLINICAL TRIALS REGISTRATION Trial number NCT00000542. [ABSTRACT FROM AUTHOR]

BACKGROUND Impaired renal function is a risk factor for cardiovascular disease, end-stage renal disease (ESRD), and mortality. The impact of short-term renal function decline on outcomes is less well studied. The association of antihypertensive medications with the impact of short-term estimated glomerular filtration rate (eGFR) decline is not known. METHODS We examined 20,207 hypertensive participants with baseline and 2-year creatinine levels from which eGFR changes were estimated. The associations between eGFR change with incident coronary heart disease (CHD), stroke, heart failure (HF), all-cause mortality, and ESRD during 2.9 years of in-trial follow up, and with mortality during in-trial and post-trial follow-up (7.6 years), were studied. Results were assessed by primary hypertension (HTN) treatment (chlorthalidone, lisinopril, and amlodipine) and adjusted for baseline eGFR levels. RESULTS In the short run, an eGFR decline below the cohort median (−1.28 ml/minute/1.73 m2/2 years) vs. above the median, or a 5 ml/min/1.73 m2/year decline vs. no decline, was associated with significant hazard risk for CHD (1.06–1.28), HF (1.24–1.91), ESRD (2.84–6.01), and mortality (1.08–1.19), but not with stroke risk. In the long term, there was a significant association with mortality (1.11–1.34). Interaction terms for outcomes by antihypertensive treatments were not statistically significant except for ESRD between amlodipine vs. chlorthalidone (hazard ratio: 3.17 [2.59, 3.88] vs. 2.41 [1.98, 2.97]; P interaction = 0.005) for a 5 ml/min/1.73 m2/year eGFR decline. CONCLUSION Decline in eGFR over 2 years is associated with increased risk of clinical outcomes beyond the effects of baseline eGFR. These risks were the same irrespective of the primary medication used to treat HTN. [ABSTRACT FROM AUTHOR]

Randomized trials of hypertension have seldom examined heterogeneity in response to treatments over time and the implications for cardiovascular outcomes. Understanding this heterogeneity, however, is a necessary step toward personalizing antihypertensive therapy. We applied trajectory-based modeling to data on 39 763 study participants of the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) to identify distinct patterns of systolic blood pressure (SBP) response to randomized medications during the first 6 months of the trial. Two trajectory patterns were identified: immediate responders (85.5%), on average, had a decreasing SBP, whereas nonimmediate responders (14.5%), on average, had an initially increasing SBP followed by a decrease. Compared with those randomized to chlorthalidone, participants randomized to amlodipine (odds ratio, 1.20; 95% confidence interval [CI], 1.10-1.31), lisinopril (odds ratio, 1.88; 95% CI, 1.73-2.03), and doxazosin (odds ratio, 1.65; 95% CI, 1.52-1.78) had higher adjusted odds ratios associated with being a nonimmediate responder (versus immediate responder). After multivariable adjustment, nonimmediate responders had a higher hazard ratio of stroke (hazard ratio, 1.49; 95% CI, 1.21-1.84), combined cardiovascular disease (hazard ratio, 1.21; 95% CI, 1.11-1.31), and heart failure (hazard ratio, 1.48; 95% CI, 1.24-1.78) during follow-up between 6 months and 2 years. The SBP response trajectories provided superior discrimination for predicting downstream adverse cardiovascular events than classification based on difference in SBP between the first 2 measurements, SBP at 6 months, and average SBP during the first 6 months. Our findings demonstrate heterogeneity in response to antihypertensive therapies and show that chlorthalidone is associated with more favorable initial response than the other medications. [ABSTRACT FROM AUTHOR]

Low adherence to antihypertensive medication has been hypothesized to increase visit-to-visit variability (VVV) of blood pressure (BP). We assessed the association between antihypertensive medication adherence and VVV of BP in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). VVV of BP was calculated using SD independent of mean, SD, and average real variability across study visits conducted 6 to 28 months after randomization. Participants who reported taking <80% of their antihypertensive medication at ≥1 study visits were categorized as nonadherent. Participants were followed up for cardiovascular events and mortality after the assessment of adherence and VVV of BP. SD independent of mean of BP was higher for nonadherent (n=2912) versus adherent (n=16 878) participants; 11.4±4.9 versus 10.5±4.5 for systolic BP; 6.8±2.8 versus 6.2±2.6 for diastolic BP (each P<0.001). SD independent of mean of BP remained higher among nonadherent than among adherent participants after multivariable adjustment (0.8 [95% confidence interval, 0.7-1.0] higher for systolic BP and 0.4 [95% confidence interval, 0.3-0.5] higher for diastolic BP]. SD and average real variability of systolic BP and diastolic BP were also higher among nonadherent than among adherent participants. Adjustment for nonadherence did not explain the association of VVV of BP with higher fatal coronary heart disease or nonfatal myocardial infarction, stroke, heart failure, or mortality risk. In conclusion, improving medication adherence may lower VVV of BP. However, VVV of BP is associated with cardiovascular outcomes independent of medication adherence. [ABSTRACT FROM AUTHOR]

Treatment resistant hypertension (TRH) is defined as uncontrolled hypertension (HTN) despite the use of ≥3 antihypertensive medication classes or controlled HTN while treated with ≥4 antihypertensive medication classes. Risk factors for TRH include increasing age, diminished kidney function, higher body mass index, diabetes, and African American (AA) race. Importantly, previous studies suggest a genetic role in TRH, although the genetics ofTRHare largely understudied. With 2203 treatment resistant cases and 2354 treatment responsive controls (36%AA) from the Genetics of Hypertension Associated Treatment Study (GenHAT), we assessed the association of 78 candidate gene polymorphisms with TRH status using logistic regression. After stratifying by race and adjusting for potential confounders, there were 2 genetic variants in the AGT gene (rs699, rs5051) statistically significantly associated with TRH among white participants.The Met allele of rs699 and the G allele of rs5051 were positively associated with TRH: OR = 1.27 (1.12–1.44), P = 0.0001, and OR = 1.36 (1.20–1.53), P < 0.0001, respectively. There was no similar association among AA participants (race interaction P = 0.0004 for rs699 and P = 0.0001 for rs5051).This research contributes to our understanding of the genetic basis of TRH, and further genetic studies of TRH may help reach the goal of better clinical outcomes for hypertensive patients. [ABSTRACT FROM AUTHOR]

The article presents a study on the impact of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial/Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (ALLHAT/JNC7) Dissemination Project on thiazide-type diuretic use. The study used IMS Health databases to compare prescribing practices of physicians before the project started in 2004 and after its completion in 2007. The study found that the project was associated with a small effect on the use of thiazide-type diuretic.

Presents a study that investigates antihypertensive drug treatment effects on incidence of stroke by type and subtype, timing of strokes, case-fatality rates, stroke residual effects and relationship of attained systolic blood pressure to stroke incidence. Context; Design, setting and participants; Results; Conclusions.

Background: Although hypertension guidelines define treatment-resistant hypertension as blood pressure uncontrolled by ≥3 antihypertensive medications, including a diuretic, it is unknown whether patient prognosis differs when a diuretic is included.Methods: Participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) were randomly assigned to first-step therapy with chlorthalidone, amlodipine, or lisinopril. At a Year 2 follow-up visit, those with average blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic on ≥3 antihypertensive medications, or blood pressure <140/90 mm Hg on ≥4 antihypertensive medications were identified as having apparent treatment-resistant hypertension. The prevalence of treatment-resistant hypertension and its association with ALLHAT primary (combined fatal coronary heart disease or nonfatal myocardial infarction) and secondary (all-cause mortality, stroke, heart failure, combined coronary heart disease, and combined cardiovascular disease) outcomes were identified for each treatment group.Results: Of participants assigned to chlorthalidone, amlodipine, or lisinopril, 9.6%, 11.4%, and 19.7%, respectively, had treatment-resistant hypertension. During mean follow-up of 2.9 years, primary outcome incidence was similar for those assigned to chlorthalidone compared with amlodipine or lisinopril (amlodipine- vs chlorthalidone-adjusted hazard ratio [HR] 0.86; 95% confidence interval [CI], 0.53-1.39; P = .53; lisinopril- vs chlorthalidone-adjusted HR = 1.06; 95% CI, 0.70-1.60; P = .78). Secondary outcome risks were similar for most comparisons except coronary revascularization, which was higher with amlodipine than with chlorthalidone (HR 1.86; 95% CI, 1.11-3.11; P = .02). An as-treated analysis based on diuretic use produced similar results.Conclusions: In this study, which titrated medications to a goal, participants assigned to chlorthalidone were less likely to develop treatment-resistant hypertension. However, prognoses in those with treatment-resistant hypertension were similar across treatment groups. [ABSTRACT FROM AUTHOR]

Background: Blood pressure lowering is an established strategy for preventing microvascular and macrovascular complications of diabetes, but its role in the prevention of diabetes itself is unclear. We aimed to examine this question using individual participant data from major randomised controlled trials.Methods: We performed a one-stage individual participant data meta-analysis, in which data were pooled to investigate the effect of blood pressure lowering per se on the risk of new-onset type 2 diabetes. An individual participant data network meta-analysis was used to investigate the differential effects of five major classes of antihypertensive drugs on the risk of new-onset type 2 diabetes. Overall, data from 22 studies conducted between 1973 and 2008, were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We included all primary and secondary prevention trials that used a specific class or classes of antihypertensive drugs versus placebo or other classes of blood pressure lowering medications that had at least 1000 persons-years of follow-up in each randomly allocated arm. Participants with a known diagnosis of diabetes at baseline and trials conducted in patients with prevalent diabetes were excluded. For the one-stage individual participant data meta-analysis we used stratified Cox proportional hazards model and for the individual participant data network meta-analysis we used logistic regression models to calculate the relative risk (RR) for drug class comparisons.Findings: 145 939 participants (88 500 [60·6%] men and 57 429 [39·4%] women) from 19 randomised controlled trials were included in the one-stage individual participant data meta-analysis. 22 trials were included in the individual participant data network meta-analysis. After a median follow-up of 4·5 years (IQR 2·0), 9883 participants were diagnosed with new-onset type 2 diabetes. Systolic blood pressure reduction by 5 mm Hg reduced the risk of type 2 diabetes across all trials by 11% (hazard ratio 0·89 [95% CI 0·84-0·95]). Investigation of the effects of five major classes of antihypertensive drugs showed that in comparison to placebo, angiotensin-converting enzyme inhibitors (RR 0·84 [95% 0·76-0·93]) and angiotensin II receptor blockers (RR 0·84 [0·76-0·92]) reduced the risk of new-onset type 2 diabetes; however, the use of β blockers (RR 1·48 [1·27-1·72]) and thiazide diuretics (RR 1·20 [1·07-1·35]) increased this risk, and no material effect was found for calcium channel blockers (RR 1·02 [0·92-1·13]).Interpretation: Blood pressure lowering is an effective strategy for the prevention of new-onset type 2 diabetes. Established pharmacological interventions, however, have qualitatively and quantitively different effects on diabetes, likely due to their differing off-target effects, with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers having the most favourable outcomes. This evidence supports the indication for selected classes of antihypertensive drugs for the prevention of diabetes, which could further refine the selection of drug choice according to an individual's clinical risk of diabetes.Funding: British Heart Foundation, National Institute for Health Research, and Oxford Martin School. [ABSTRACT FROM AUTHOR]

Background: Some studies have suggested a link between antihypertensive medication and cancer, but the evidence is so far inconclusive. Thus, we aimed to investigate this association in a large individual patient data meta-analysis of randomised clinical trials.Methods: We searched PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from Jan 1, 1966, to Sept 1, 2019, to identify potentially eligible randomised controlled trials. Eligible studies were randomised controlled trials comparing one blood pressure lowering drug class with a placebo, inactive control, or other blood pressure lowering drug. We also required that trials had at least 1000 participant years of follow-up in each treatment group. Trials without cancer event information were excluded. We requested individual participant data from the authors of eligible trials. We pooled individual participant-level data from eligible trials and assessed the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), β blockers, calcium channel blockers, and thiazide diuretics on cancer risk in one-stage individual participant data and network meta-analyses. Cause-specific fixed-effects Cox regression models, stratified by trial, were used to calculate hazard ratios (HRs). The primary outcome was any cancer event, defined as the first occurrence of any cancer diagnosed after randomisation. This study is registered with PROSPERO (CRD42018099283).Findings: 33 trials met the inclusion criteria, and included 260 447 participants with 15 012 cancer events. Median follow-up of included participants was 4·2 years (IQR 3·0-5·0). In the individual participant data meta-analysis comparing each drug class with all other comparators, no associations were identified between any antihypertensive drug class and risk of any cancer (HR 0·99 [95% CI 0·95-1·04] for ACEIs; 0·96 [0·92-1·01] for ARBs; 0·98 [0·89-1·07] for β blockers; 1·01 [0·95-1·07] for thiazides), with the exception of calcium channel blockers (1·06 [1·01-1·11]). In the network meta-analysis comparing drug classes against placebo, we found no excess cancer risk with any drug class (HR 1·00 [95% CI 0·93-1·09] for ACEIs; 0·99 [0·92-1·06] for ARBs; 0·99 [0·89-1·11] for β blockers; 1·04 [0·96-1·13] for calcium channel blockers; 1·00 [0·90-1·10] for thiazides).Interpretation: We found no consistent evidence that antihypertensive medication use had any effect on cancer risk. Although such findings are reassuring, evidence for some comparisons was insufficient to entirely rule out excess risk, in particular for calcium channel blockers.Funding: British Heart Foundation, National Institute for Health Research, Oxford Martin School. [ABSTRACT FROM AUTHOR]