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Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis.
Yarmolinsky, J, Díez-Obrero, V, Richardson, TG, Pigeyre, M, Sjaarda, J, Paré, G, Walker, VM, Vincent, EE, Tan, VY, Obón-Santacana, M, et al
PLoS medicine. 2022;(2):e1003897
Abstract
BACKGROUND Epidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes. METHODS AND FINDINGS We performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), β-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 × 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = 0.035). There was little evidence of association of genetically proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94 to 1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92 to 1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99 to 1.13; P = 0.08). Genetically proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers. The primary limitations of this analysis include the modest statistical power for analyses of drug targets in relation to some less common histological subtypes of cancers examined and the restriction of the majority of analyses to participants of European ancestry. CONCLUSIONS In this study, we observed that genetically proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomized controlled trials for these medications.
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Association of Antihypertensives That Stimulate vs Inhibit Types 2 and 4 Angiotensin II Receptors With Cognitive Impairment.
Marcum, ZA, Cohen, JB, Zhang, C, Derington, CG, Greene, TH, Ghazi, L, Herrick, JS, King, JB, Cheung, AK, Bryan, N, et al
JAMA network open. 2022;(1):e2145319
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IMPORTANCE Use of antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, compared with those that do not stimulate these receptors, has been associated with a lower risk of dementia. However, this association with cognitive outcomes in hypertension trials, with blood pressure levels in the range of current guidelines, has not been evaluated. OBJECTIVE To examine the association between use of exclusively antihypertensive medication regimens that stimulate vs inhibit type 2 and 4 angiotensin II receptors on mild cognitive impairment (MCI) or dementia. DESIGN, SETTING, AND PARTICIPANTS This cohort study is a secondary analysis (April 2011 to July 2018) of participants in the randomized Systolic Blood Pressure Intervention Trial (SPRINT), which recruited individuals 50 years or older with hypertension and increased cardiovascular risk but without a history of diabetes, stroke, or dementia. Data analysis was conducted from March 16 to July 6, 2021. EXPOSURES Prevalent use of angiotensin II receptor type 2 and 4-stimulating or -inhibiting antihypertensive medication regimens at the 6-month study visit. MAIN OUTCOMES AND MEASURES The primary outcome was a composite of adjudicated amnestic MCI or probable dementia. RESULTS Of the 8685 SPRINT participants who were prevalent users of antihypertensive medication regimens at the 6-month study visit (mean [SD] age, 67.7 [11.2] years; 5586 [64.3%] male; and 935 [10.8%] Hispanic, 2605 [30.0%] non-Hispanic Black, 4983 [57.4%] non-Hispanic White, and 162 [1.9%] who responded as other race or ethnicity), 2644 (30.4%) were users of exclusively stimulating, 1536 (17.7%) inhibiting, and 4505 (51.9%) mixed antihypertensive medication regimens. During a median of 4.8 years of follow-up (95% CI, 4.7-4.8 years), there were 45 vs 59 cases per 1000 person-years of amnestic MCI or probable dementia among prevalent users of regimens that contained exclusively stimulating vs inhibiting antihypertensive medications (hazard ratio [HR], 0.76; 95% CI, 0.66-0.87). When comparing stimulating-only vs inhibiting-only users, amnestic MCI occurred at rates of 40 vs 54 cases per 1000 person-years (HR, 0.74; 95% CI, 0.64-0.87) and probable dementia at rates of 8 vs 10 cases per 1000 person-years (HR, 0.80; 95% CI, 0.57-1.14). Negative control outcome analyses suggested the presence of residual confounding. CONCLUSIONS AND RELEVANCE In this secondary analysis of SPRINT, prevalent users of regimens that contain exclusively antihypertensive medications that stimulate vs inhibit type 2 and 4 angiotensin II receptors had lower rates of incident cognitive impairment. Residual confounding cannot be ruled out. If these results are replicated in randomized clinical trials, certain antihypertensive medications could be prioritized to prevent cognitive decline.
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Analysis of Therapeutic Inertia and Race and Ethnicity in the Systolic Blood Pressure Intervention Trial: A Secondary Analysis of a Randomized Clinical Trial.
Zheutlin, AR, Mondesir, FL, Derington, CG, King, JB, Zhang, C, Cohen, JB, Berlowitz, DR, Anstey, DE, Cushman, WC, Greene, TH, et al
JAMA network open. 2022;(1):e2143001
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IMPORTANCE Therapeutic inertia may contribute to racial and ethnic differences in blood pressure (BP) control. OBJECTIVE To determine the association between race and ethnicity and therapeutic inertia in the Systolic Blood Pressure Intervention Trial (SPRINT). DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study was a secondary analysis of data from SPRINT, a randomized clinical trial comparing intensive (<120 mm Hg) vs standard (<140 mm Hg) systolic BP treatment goals. Participants were enrolled between November 8, 2010, and March 15, 2013, with a median follow-up 3.26 years. Participants included adults aged 50 years or older at high risk for cardiovascular disease but without diabetes, previous stroke, or heart failure. The present analysis was restricted to participant visits with measured BP above the target goal. Analyses for the present study were performed in from October 2020 through March 2021. EXPOSURES Self-reported race and ethnicity, mutually exclusively categorized into groups of Hispanic, non-Hispanic Black, or non-Hispanic White participants. MAIN OUTCOMES AND MEASURES Therapeutic inertia, defined as no antihypertensive medication intensification at each study visit where the BP was above target goal. The association between self-reported race and ethnicity and therapeutic inertia was estimated using generalized estimating equations and stratified by treatment group. Antihypertensive medication use was assessed with pill bottle inventories at each visit. Blood pressure was measured using an automated device. RESULTS A total of 8556 participants, including 4141 in the standard group (22 844 participant-visits; median age, 67.0 years [IQR, 61.0-76.0 years]; 1467 women [35.4%]) and 4415 in the intensive group (35 453 participant-visits; median age, 67.0 years [IQR, 61.0-76.0 years]; 1584 women [35.9%]) with at least 1 eligible study visit were included in the present analysis. Among non-Hispanic White, non-Hispanic Black, and Hispanic participants, the overall prevalence of therapeutic inertia in the standard vs intensive groups was 59.8% (95% CI, 58.9%-60.7%) vs 56.0% (95% CI, 55.2%-56.7%), 56.8% (95% CI, 54.4%-59.2%) vs 54.5% (95% CI, 52.4%-56.6%), and 59.7% (95% CI, 56.5%-63.0%) vs 51.0% (95% CI, 47.4%-54.5%), respectively. The adjusted odds ratios in the standard and intensive groups for therapeutic inertia associated with non-Hispanic Black vs non-Hispanic White participants were 0.85 (95% CI, 0.79-0.92) and 0.94 (95% CI, 0.88-1.01), respectively. The adjusted odds ratios for therapeutic inertia comparing Hispanic vs non-Hispanic White participants were 1.00 (95% CI, 0.90-1.13) and 0.89 (95% CI, 0.79-1.00) in the standard and intensive groups, respectively. CONCLUSIONS AND RELEVANCE Among SPRINT participants above BP target goal, this cross-sectional study found that therapeutic inertia prevalence was similar or lower for non-Hispanic Black and Hispanic participants compared with non-Hispanic White participants. These findings suggest that a standardized approach to BP management, as used in SPRINT, may help ensure equitable care and could reduce the contribution of therapeutic inertia to disparities in hypertension. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01206062.
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Oral Antihypertensives for Nonsevere Pregnancy Hypertension: Systematic Review, Network Meta- and Trial Sequential Analyses.
Bone, JN, Sandhu, A, Abalos, ED, Khalil, A, Singer, J, Prasad, S, Omar, S, Vidler, M, von Dadelszen, P, Magee, LA
Hypertension (Dallas, Tex. : 1979). 2022;(3):614-628
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BACKGROUND We aimed to address which antihypertensives are superior to placebo/no therapy or another antihypertensive for controlling nonsevere pregnancy hypertension and provide future sample size estimates for definitive evidence. METHODS Randomized trials of antihypertensives for nonsevere pregnancy hypertension were identified from online electronic databases, to February 28, 2021 (registration URL: https://www.crd.york.ac.uk/PROSPERO/; unique identifier: CRD42020188725). Our outcomes were severe hypertension, proteinuria/preeclampsia, fetal/newborn death, small-for-gestational age infants, preterm birth, and admission to neonatal care. A Bayesian random-effects model generated estimates of direct and indirect treatment comparisons. Trial sequential analysis informed future trials needed. RESULTS Of 1246 publications identified, 72 trials were included; 61 (6923 women) were informative. All commonly prescribed antihypertensives (labetalol, other β-blockers, methyldopa, calcium channel blockers, and mixed/multi-drug therapy) versus placebo/no therapy reduced the risk of severe hypertension by 30% to 70%. Labetalol decreased proteinuria/preeclampsia (odds ratio, 0.73 [95% credible interval, 0.54-0.99]) and fetal/newborn death (odds ratio, 0.54 [0.30-0.98]) compared with placebo/no therapy, and proteinuria/preeclampsia compared with methyldopa (odds ratio, 0.66 [0.44-0.99]) and calcium channel blockers (odds ratio, 0.63 [0.41-0.96]). No other differences were identified, but credible intervals were wide. Trial sequential analysis indicated that 2500 to 10 000 women/arm (severe hypertension or safety outcomes) to >15 000/arm (fetal/newborn death) would be required to provide definitive evidence. CONCLUSIONS In summary, all commonly prescribed antihypertensives in pregnancy reduce the risk of severe hypertension, but labetalol may also decrease proteinuria/preeclampsia and fetal/newborn death. Evidence is lacking for many other safety outcomes. Prohibitive sample sizes are required for definitive evidence. Real-world data are needed to individualize care.
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Management of hypertension and renin-angiotensin-aldosterone system blockade in adults with diabetic kidney disease: Association of British Clinical Diabetologists and the Renal Association UK guideline update 2021.
Banerjee, D, Winocour, P, Chowdhury, TA, De, P, Wahba, M, Montero, R, Fogarty, D, Frankel, AH, Karalliedde, J, Mark, PB, et al
BMC nephrology. 2022;(1):9
Abstract
People with type 1 and type 2 diabetes are at risk of developing progressive chronic kidney disease (CKD) and end-stage kidney failure. Hypertension is a major, reversible risk factor in people with diabetes for development of albuminuria, impaired kidney function, end-stage kidney disease and cardiovascular disease. Blood pressure control has been shown to be beneficial in people with diabetes in slowing progression of kidney disease and reducing cardiovascular events. However, randomised controlled trial evidence differs in type 1 and type 2 diabetes and different stages of CKD in terms of target blood pressure. Activation of the renin-angiotensin-aldosterone system (RAAS) is an important mechanism for the development and progression of CKD and cardiovascular disease. Randomised trials demonstrate that RAAS blockade is effective in preventing/ slowing progression of CKD and reducing cardiovascular events in people with type 1 and type 2 diabetes, albeit differently according to the stage of CKD. Emerging therapy with sodium glucose cotransporter-2 (SGLT-2) inhibitors, non-steroidal selective mineralocorticoid antagonists and endothelin-A receptor antagonists have been shown in randomised trials to lower blood pressure and further reduce the risk of progression of CKD and cardiovascular disease in people with type 2 diabetes. This guideline reviews the current evidence and makes recommendations about blood pressure control and the use of RAAS-blocking agents in different stages of CKD in people with both type 1 and type 2 diabetes.
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[Geriatric medicine: update 2020].
Germann, D, Cochet, C, Apostolova, Y, Fratangelo, L, Gagliano, M, Nguyen, S, Büla, C
Revue medicale suisse. 2021;(720-1):33-37
Abstract
Several studies published in 2020 showed new data supporting the prescription of statins in some old and very old patients. Despite the enthusiasm about SGLT-2 inhibitors, caution must remain in frail and dependent older diabetic patients who are not well represented in most studies. Antihypertensive treatment appears more beneficial when taken at night rather than in the morning but beware of the prescribing cascade of a diuretic when a new prescription of a calcium channel blocker. Biomarkers, including plasmatic biomarkers, are becoming increasingly important in the diagnostic strategy of neurocognitive disorders. Finally, fall prevention studies showed heterogeneous results but multimodal interventions remain mainstream.
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Antihypertensive medication use and ovarian cancer survival.
Huang, T, Townsend, MK, Dood, RL, Sood, AK, Tworoger, SS
Gynecologic oncology. 2021;(2):342-347
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OBJECTIVE Although experimental models suggest that use of beta-blockers, a common antihypertensive agent, may improve survival in ovarian cancer patients, results from clinical studies have been mixed. METHODS We evaluated the associations of pre-diagnostic (n = 950) and post-diagnostic (n = 743) use of antihypertensive medications with survival among patients with invasive, epithelial ovarian cancer in the Nurses' Health Study (NHS; 1994-2016) and NHSII (2001-2017), with follow-up until 2018 and 2019, respectively. Cox proportional hazards models were used to estimate hazard ratios (HR) for ovarian cancer mortality according to antihypertensive medication use before and after diagnosis, considering multiple drug classes (beta-blockers, calcium-channel blockers, thiazide diuretics, angiotensin-converting enzyme [ACE] inhibitors). RESULTS After adjusting for age, BMI, smoking status and tumor characteristics, pre-diagnostic use versus non-use of calcium-channel blockers was associated with higher ovarian cancer mortality (HR: 1.49; 95% CI: 1.13, 1.96), which was primarily due to polytherapy involving calcium-channel blockers (HR: 1.61; 95% CI: 1.15, 2.26). Pre-diagnostic use of beta-blockers, thiazide diuretics, or ACE inhibitors was not associated with ovarian cancer mortality. No association was observed for post-diagnostic antihypertensive medication use individually or in combination, except for lower mortality associated with polytherapy involving ACE inhibitors (HR: 0.53; 95% CI: 0.31, 0.91). CONCLUSION Overall, we did not find clear relationships between antihypertensive medication use and ovarian cancer mortality. However, given the limitation of the data, we cannot determine whether the association may differ by type of beta-blockers. The reasons underlying the observed associations with pre-diagnostic calcium-channel blocker use and post-diagnostic ACE inhibitor use require further investigation.
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Antihypertensive effects of rosuvastatin in patients with hypertension and dyslipidemia: A systemic review and meta-analysis of randomized studies.
Lee, S, Yang, S, Chang, MJ
PloS one. 2021;(11):e0260391
Abstract
Some studies have suggested the antihypertensive effects of statins, a class of lipid-lowering agents, particularly in patients with hypertension. However, the evidence for the role of statins in blood pressure (BP) lowering is controversial, and no meta-analysis of rosuvastatin therapy has been conducted to assess its BP-lowering effects. Therefore, the aim of this meta-analysis of randomized controlled trials (RCTs) was to investigate the effects of rosuvastatin on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with hypertension. We systematically searched the electronic databases MEDLINE, EMBASE, and Cochrane Library to identify RCTs in which patients were assigned to groups of rosuvastatin plus antihypertensive agents vs. antihypertensive agents. The three authors independently selected the studies, extracted data, and assessed methodological quality. We included five RCTs in this meta-analysis with 288 patients treated with rosuvastatin and 219 patients without rosuvastatin. The mean DBP in the rosuvastatin group was significantly lower than that in the non-rosuvastatin group by -2.12 mmHg (95% confidence interval (CI) -3.72 to -0.52; Pfixed-effects model = 0.009; I2 = 0%, Pheterogeneity = 0.97). Rosuvastatin treatment also lowered the mean SBP compared with the non-rosuvastatin treatment by -2.27 mmHg, but not significantly (95% CI - 4.75 to 0.25; Pfixed-effects model = 0.08; I2 = 0%, Pheterogeneity = 0.82). In this study, we reviewed the antihypertensive effects of rosuvastatin in patients with hypertension and dyslipidemia. We demonstrated a modest significant reduction of DBP and a trend toward a lowered SBP in patients with hypertension with rosuvastatin therapy. Rosuvastatin could be beneficial to control hypertension and, consequently, contribute toward reducing the risk of cardiovascular events in patients with hypertension and dyslipidemia.
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Effect of a Coordinated Community and Chronic Care Model Team Intervention vs Usual Care on Systolic Blood Pressure in Patients With Stroke or Transient Ischemic Attack: The SUCCEED Randomized Clinical Trial.
Towfighi, A, Cheng, EM, Ayala-Rivera, M, Barry, F, McCreath, H, Ganz, DA, Lee, ML, Sanossian, N, Mehta, B, Dutta, T, et al
JAMA network open. 2021;(2):e2036227
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IMPORTANCE Few stroke survivors meet recommended cardiovascular goals, particularly among racial/ethnic minority populations, such as Black or Hispanic individuals, or socioeconomically disadvantaged populations. OBJECTIVE To determine if a chronic care model-based, community health worker (CHW), advanced practice clinician (APC; including nurse practitioners or physician assistants), and physician team intervention improves risk factor control after stroke in a safety-net setting (ie, health care setting where all individuals receive care, regardless of health insurance status or ability to pay). DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial included participants recruited from 5 hospitals serving low-income populations in Los Angeles County, California, as part of the Secondary Stroke Prevention by Uniting Community and Chronic Care Model Teams Early to End Disparities (SUCCEED) clinical trial. Inclusion criteria were age 40 years or older; experience of ischemic or hemorrhagic stroke or transient ischemic attack (TIA) no more than 90 days prior; systolic blood pressure (BP) of 130 mm Hg or greater or 120 to 130 mm Hg with history of hypertension or using hypertensive medications; and English or Spanish language proficiency. The exclusion criterion was inability to consent. Among 887 individuals screened for eligibility, 542 individuals were eligible, and 487 individuals were enrolled and randomized, stratified by stroke type (ischemic or TIA vs hemorrhagic), language (English vs Spanish), and site to usual care vs intervention in a 1:1 fashion. The study was conducted from February 2014 to September 2018, and data were analyzed from October 2018 to November 2020. INTERVENTIONS Participants randomized to intervention were offered a multimodal coordinated care intervention, including hypothesized core components (ie, ≥3 APC clinic visits, ≥3 CHW home visits, and Chronic Disease Self-Management Program workshops), and additional telephone visits, protocol-driven risk factor management, culturally and linguistically tailored education materials, and self-management tools. Participants randomized to the control group received usual care, which varied by site but frequently included a free BP monitor, self-management tools, and linguistically tailored information materials. MAIN OUTCOMES AND MEASURES The primary outcome was change in systolic BP at 12 months. Secondary outcomes were non-high density lipoprotein cholesterol, hemoglobin A1c, and C-reactive protein (CRP) levels, body mass index, antithrombotic adherence, physical activity level, diet, and smoking status at 12 months. Potential mediators assessed included access to care, health and stroke literacy, self-efficacy, perceptions of care, and BP monitor use. RESULTS Among 487 participants included, the mean (SD) age was 57.1 (8.9) years; 317 (65.1%) were men, and 347 participants (71.3%) were Hispanic, 87 participants (18.3%) were Black, and 30 participants (6.3%) were Asian. A total of 246 participants were randomized to usual care, and 241 participants were randomized to the intervention. Mean (SD) systolic BP improved from 143 (17) mm Hg at baseline to 133 (20) mm Hg at 12 months in the intervention group and from 146 (19) mm Hg at baseline to 137 (22) mm Hg at 12 months in the usual care group, with no significant differences in the change between groups. Compared with the control group, participants in the intervention group had greater improvements in self-reported salt intake (difference, 15.4 [95% CI, 4.4 to 26.0]; P = .004) and serum CRP level (difference in log CRP, -0.4 [95% CI, -0.7 to -0.1] mg/dL; P = .003); there were no differences in other secondary outcomes. Although 216 participants (89.6%) in the intervention group received some of the 3 core components, only 35 participants (14.5%) received the intended full dose. CONCLUSIONS AND RELEVANCE This randomized clinical trial of a complex multilevel, multimodal intervention did not find vascular risk factor improvements beyond that of usual care; however, further studies may consider testing the SUCCEED intervention with modifications to enhance implementation and participant engagement. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01763203.
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The effects of capsinoids and fermented red pepper paste supplementation on blood pressure: A systematic review and meta-analysis of randomized controlled trials.
Amini, MR, Sheikhhossein, F, Bazshahi, E, Hajiaqaei, M, Shafie, A, Shahinfar, H, Azizi, N, Eghbaljoo Gharehgheshlaghi, H, Naghshi, S, Fathipour, RB, et al
Clinical nutrition (Edinburgh, Scotland). 2021;(4):1767-1775
Abstract
BACKGROUND & AIMS The present systematic review and meta-analysis were conducted to investigate the effects of capsinoids and fermented red pepper paste (FRPP) supplementation on Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP). METHODS Relevant studies, published up to May 2020, were searched through PubMed/Medline, Scopus, ISI Web of Science, Embase, and Google Scholar. All randomized clinical trials investigating the effect of capsinoids and FRPP supplementation on blood pressure including SBP and DBP were included. RESULTS Out of 335 citations, 7 trials that enrolled 363 subjects were included. Capsinoids and FRPP resulted in significant reduction in DBP (Weighted mean differences (WMD): -1.90 mmHg; 95% CI, -3.72 to -0.09, P = 0.04) but no significant change in SBP (WMD: 0.55 mmHg, 95% CI: -1.45, 2.55, P = 0.588). FRPP had a significant reduction in SBP. Greater effects on SBP were detected in trials, lasted ≥12 weeks, and sample size >50. Capsinoids with dosage ≤200 and FRPP with dosage of 11.9 g significantly decreased DBP. CONCLUSION Overall, these data suggest that supplementation with FRPP may play a role in improving SBP and DBP but for capsinoids no effects detected in this analysis on SBP and DBP.