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PLoS Medicine Apr 2023Antihypertensives are effective at reducing the risk of cardiovascular disease, but limited data exist quantifying their association with serious adverse events,...
BACKGROUND
Antihypertensives are effective at reducing the risk of cardiovascular disease, but limited data exist quantifying their association with serious adverse events, particularly in older people with frailty. This study aimed to examine this association using nationally representative electronic health record data.
METHODS AND FINDINGS
This was a retrospective cohort study utilising linked data from 1,256 general practices across England held within the Clinical Practice Research Datalink between 1998 and 2018. Included patients were aged 40+ years, with a systolic blood pressure reading between 130 and 179 mm Hg, and not previously prescribed antihypertensive treatment. The main exposure was defined as a first prescription of antihypertensive treatment. The primary outcome was hospitalisation or death within 10 years from falls. Secondary outcomes were hypotension, syncope, fractures, acute kidney injury, electrolyte abnormalities, and primary care attendance with gout. The association between treatment and these serious adverse events was examined by Cox regression adjusted for propensity score. This propensity score was generated from a multivariable logistic regression model with patient characteristics, medical history and medication prescriptions as covariates, and new antihypertensive treatment as the outcome. Subgroup analyses were undertaken by age and frailty. Of 3,834,056 patients followed for a median of 7.1 years, 484,187 (12.6%) were prescribed new antihypertensive treatment in the 12 months before the index date (baseline). Antihypertensives were associated with an increased risk of hospitalisation or death from falls (adjusted hazard ratio [aHR] 1.23, 95% confidence interval (CI) 1.21 to 1.26), hypotension (aHR 1.32, 95% CI 1.29 to 1.35), syncope (aHR 1.20, 95% CI 1.17 to 1.22), acute kidney injury (aHR 1.44, 95% CI 1.41 to 1.47), electrolyte abnormalities (aHR 1.45, 95% CI 1.43 to 1.48), and primary care attendance with gout (aHR 1.35, 95% CI 1.32 to 1.37). The absolute risk of serious adverse events with treatment was very low, with 6 fall events per 10,000 patients treated per year. In older patients (80 to 89 years) and those with severe frailty, this absolute risk was increased, with 61 and 84 fall events per 10,000 patients treated per year (respectively). Findings were consistent in sensitivity analyses using different approaches to address confounding and taking into account the competing risk of death. A strength of this analysis is that it provides evidence regarding the association between antihypertensive treatment and serious adverse events, in a population of patients more representative than those enrolled in previous randomised controlled trials. Although treatment effect estimates fell within the 95% CIs of those from such trials, these analyses were observational in nature and so bias from unmeasured confounding cannot be ruled out.
CONCLUSIONS
Antihypertensive treatment was associated with serious adverse events. Overall, the absolute risk of this harm was low, with the exception of older patients and those with moderate to severe frailty, where the risks were similar to the likelihood of benefit from treatment. In these populations, physicians may want to consider alternative approaches to management of blood pressure and refrain from prescribing new treatment.
Topics: Humans; Aged; Antihypertensive Agents; Cohort Studies; Frailty; Retrospective Studies; Hypotension; Syncope; Electrolytes
PubMed: 37075078
DOI: 10.1371/journal.pmed.1004223 -
Journal of Clinical Hypertension... Sep 2011KEY POINTS AND RECOMMENDATIONS: • In addition to hypertension, angiotensin-converting enzyme inhibitors are indicated for treatment of patients at high risk for... (Review)
Review
KEY POINTS AND RECOMMENDATIONS: • In addition to hypertension, angiotensin-converting enzyme inhibitors are indicated for treatment of patients at high risk for coronary artery disease, after myocardial infarction, with dilated cardiomypathy, or with chronic kidney disease. • The most familiar angiotensin-converting enzyme subtype, angiotensin-converting enzyme-1 (kininase II), cleaves the vasoconstrictor octapeptide angiotensin II from its inactive decapeptide precursor, angiotensin I, while simultaneously inactivating the vasodilator bradykinin. • Biochemical pathways within and around the renin-angiotensin system are highly species-specific; there is little evidence that "angiotensin-converting enzyme bypass pathways" have major clinical implications in humans. • Dietary sodium loading can diminish or abolish the antihypertensive effect of an angiotensin-converting enzyme inhibitor, while salt restriction or concomitant diuretic therapy enhances it. • Dose-response curves with angiotensin-converting enzyme inhibitors are quite flat but their peak effects vary in different individuals. • Increased serum creatinine (decreased glomerular filtration rate) during acute or chronic angiotensin-converting enzyme inhibition identifies individuals likely to experience long-term renal protective benefits. • Angiotensin-converting enzyme inhibitors are contraindicated in pregnancy due to fetal toxicity. • Use of angiotensin-converting enzymes can be limited by idiosyncratic reactions (cough or angioedema), hyperkalemia (usually in cardiac or renal failure or with combined renin-angiotensin blockade) or hypotension (usually with severe volume-depletion or cardiac failure).
Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cough; Humans; Hyperkalemia; Hypertension; Hypotension; Treatment Outcome
PubMed: 21896148
DOI: 10.1111/j.1751-7176.2011.00508.x -
Cardiovascular Therapeutics 2020It was indeed a Don Quixote-like pursuit of the mechanism of essential hypertension when we serendipitously discovered -adrenoceptors ( -ARs) in skin-lightening... (Review)
Review
It was indeed a Don Quixote-like pursuit of the mechanism of essential hypertension when we serendipitously discovered -adrenoceptors ( -ARs) in skin-lightening experiments in the frog. Now -ARs lurk on the horizon involving hypertension causality, renal denervation for hypertension, injury from falling in the elderly and prazosin's mechanism of action in anxiety states such as posttraumatic stress disorder (PTSD). Our goal here is to focus on this horizon and bring into clear view the role of -AR-mediated mechanisms in these seemingly unrelated conditions. Our narrative begins with an explanation of how experiments in isolated perfused kidneys led to the discovery of a sodium-retaining process, a fundamental mechanism of hypertension, mediated by -ARs. In this model system and in the setting of furosemide-induced sodium excretion, -AR activation inhibited adenylate cyclase, suppressed cAMP formation, and caused sodium retention. Further investigations led to the realization that renal -AR expression in hypertensive animals is elevated, thus supporting a key role for kidney -ARs in the pathophysiology of essential hypertension. Subsequent studies clarified the molecular pathways by which -ARs activate prohypertensive biochemical systems. While investigating the role of -adrenoceptors ( -ARs) versus -ARs in renal sympathetic neurotransmission, we noted an astonishing result: in the kidney -ARs suppress the postjunctional expression of -ARs. Here, we describe how this finding relates to a broader understanding of the role of -ARs in diverse disease states. Because of the capacity for qualitative and quantitative monitoring of -AR-induced regulatory mechanisms in the kidney, we looked to the kidney and found enlightenment.
Topics: Accidental Falls; Adrenergic alpha-2 Receptor Antagonists; Animals; Antihypertensive Agents; Anxiety; Autonomic Denervation; Blood Pressure; Diuretics; Essential Hypertension; Humans; Hypotension, Orthostatic; Kidney; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2; Renal Elimination; Renal Reabsorption; Signal Transduction; Sodium; Stress Disorders, Post-Traumatic
PubMed: 32426035
DOI: 10.1155/2020/2478781 -
European Geriatric Medicine Aug 2023The aim of this clinical review was to summarise the existing knowledge on the adverse effects of alpha-blockers and centrally acting antihypertensives, the effect these... (Review)
Review
PURPOSE
The aim of this clinical review was to summarise the existing knowledge on the adverse effects of alpha-blockers and centrally acting antihypertensives, the effect these may have on falls risk, and guide deprescribing of these medications.
METHODS
Literature searches were conducted using PubMed and Embase. Additional articles were identified by searching reference lists and reference to personal libraries. We discuss the place of alpha-blockers and centrally acting antihypertensives in the treatment of hypertension and methods for deprescribing.
RESULTS
Alpha-blockers and centrally acting antihypertensives are no longer recommended for the treatment of hypertension unless all other agents are contraindicated or not tolerated. These medications carry a significant falls risk and non-falls risk-associated side effects. Tools to aid and guide de-prescribing and monitoring of the withdrawal of these medication classes are available to assist the clinician including information on reducing the risk of withdrawal syndromes.
CONCLUSIONS
Centrally acting antihypertensives and alpha-blockers increase the risk of falls through a variety of mechanisms-principally by increasing the risk of hypotension, orthostatic hypotension, arrhythmias and sedation. These agents should be prioritised for de-prescribing in older frailer individuals. We identify a number of tools and a withdrawal protocol to aid the clinician in identifying and de-prescribing these medications.
Topics: Humans; Aged; Antihypertensive Agents; Accidental Falls; Hypertension; Hypotension; Adrenergic alpha-Antagonists
PubMed: 37436689
DOI: 10.1007/s41999-023-00813-x -
Report on Carcinogens : Carcinogen... 2011
Topics: Animals; Antihypertensive Agents; Carcinogens; Humans; Neoplasms; Phenoxybenzamine; Vasodilator Agents
PubMed: 21863081
DOI: No ID Found -
British Medical Journal Jul 1979
Topics: Aged; Antihypertensive Agents; Female; Humans; Hypertension, Malignant; Injections, Intravenous
PubMed: 476398
DOI: No ID Found -
Hypertension Research : Official... Aug 2023Maintaining medication adherence is important in treating hypertension, especially resistant hypertension (RH), and variable medication adherence can confound results in... (Clinical Trial)
Clinical Trial
Maintaining medication adherence is important in treating hypertension, especially resistant hypertension (RH), and variable medication adherence can confound results in blood pressure trials. This post-hoc analysis evaluated adherence at baseline and 3 months using available urine samples from the REQUIRE trial, comparing 24-h ambulatory systolic blood pressure (ASBP) lowering effects of ultrasound renal denervation (uRDN) versus sham in RH. At baseline, 45% (26/58) patients showed poor adherence. Among patients with good baseline adherence, adherence was unchanged at 3 months, and uRDN patients had a decreased ASBP whereas sham patients did not. In poorly adherent patients, sham patients showed a trend towards increased adherence and a significant ASBP reduction, whereas uRDN patients did not change. Accordingly, adherence changes and the resultant ASBP reduction in poorly adherent sham patients may explain the lack of between-group difference seen in REQUIRE. Monitoring and maintaining medication adherence is important for future interventional studies in RH.
Topics: Humans; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Hypertension; Hypotension; Kidney; Medication Adherence; Prospective Studies; Sympathectomy; Treatment Outcome
PubMed: 37264122
DOI: 10.1038/s41440-023-01333-8 -
Journal of the American Geriatrics... Apr 2018To determine predictors of serious adverse events (SAEs) involving syncope, hypotension, and falls, with particular attention to age, in the Systolic Blood Pressure... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To determine predictors of serious adverse events (SAEs) involving syncope, hypotension, and falls, with particular attention to age, in the Systolic Blood Pressure Intervention Trial.
DESIGN
Randomized clinical trial.
SETTING
Academic and private practices across the United States (N = 102).
PARTICIPANTS
Adults aged 50 and older with a systolic blood pressure (SBP) of 130 to 180 mmHg at high risk of cardiovascular disease events, but without diabetes, history of stroke, symptomatic heart failure or ejection fraction less than 35%, dementia, or standing SBP less than 110 mmHg (N = 9,361).
INTERVENTION
Treatment of SBP to a goal of less than 120 mmHg or 140 mmHg.
MEASUREMENTS
Outcomes were SAEs involving syncope, hypotension, and falls. Predictors were treatment assignment, demographic characteristics, comorbidities, baseline measurements, and baseline use of cardiovascular medications.
RESULTS
One hundred seventy-two (1.8%) participants had SAEs involving syncope, 155 (1.6%) hypotension, and 203 (2.2%) falls. Randomization to intensive SBP control was associated with greater risk of an SAE involving hypotension (hazard ratio (HR) = 1.67, 95% confidence interval (CI) = 1.21-2.32, P = .002), and possibly syncope (HR = 1.32, 95% CI = 0.98-1.79, P = .07), but not falls (HR = 0.98, 95% CI = 0.75-1.29, P = .90). Risk of all three outcomes was higher for participants with chronic kidney disease or frailty. Older age was also associated with greater risk of syncope, hypotension, and falls, but there was no age-by-treatment interaction for any of the SAE outcomes.
CONCLUSIONS
Participants randomized to intensive SBP control had greater risk of hypotension and possibly syncope, but not falls. The greater risk of developing these events associated with intensive treatment did not vary according to age.
Topics: Accidental Falls; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Comorbidity; Female; Humans; Hypertension; Hypotension; Male; Middle Aged; Risk Factors; Syncope; Time Factors
PubMed: 29601076
DOI: 10.1111/jgs.15236 -
JAMA Cardiology May 2023Ultrasound renal denervation (uRDN) was shown to lower blood pressure (BP) in patients with uncontrolled hypertension (HTN). Establishing the magnitude and consistency...
IMPORTANCE
Ultrasound renal denervation (uRDN) was shown to lower blood pressure (BP) in patients with uncontrolled hypertension (HTN). Establishing the magnitude and consistency of the uRDN effect across the HTN spectrum is clinically important.
OBJECTIVE
To characterize the effectiveness and safety of uRDN vs a sham procedure from individual patient-level pooled data across uRDN trials including either patients with mild to moderate HTN on a background of no medications or with HTN resistant to standardized triple-combination therapy.
DATA SOURCES
A Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN SOLO and TRIO) and A Study of the ReCor Medical Paradise System in Stage II Hypertension (RADIANCE II) trials.
STUDY SELECTION
Trials with similar designs, standardized operational implementation (medication standardization and blinding of both patients and physicians to treatment assignment), and follow-up.
DATA EXTRACTION AND SYNTHESIS
Pooled analysis using individual patient-level data using linear regression models to compare uRDN with sham across the trials.
MAIN OUTCOMES AND MEASURES
The primary outcome was baseline-adjusted change in 2-month daytime ambulatory systolic BP (dASBP) between groups.
RESULTS
A total of 506 patients were randomized in the 3 studies (uRDN, 293; sham, 213; mean [SD] age, 54.1 [9.3]; 354 male [70.0%]). After a 1-month medication stabilization period, dASBP was similar between the groups (mean [SD], uRDN, 150.3 [9.2] mm Hg; sham, 150.8 [10.5] mm Hg). At 2 months, dASBP decreased by 8.5 mm Hg to mean (SD) 141.8 (13.8) mm Hg among patients treated with uRDN and by 2.9 mm Hg to 147.9 (14.6) mm Hg among patients treated with a sham procedure (mean difference, -5.9; 95% CI, -8.1 to -3.8 mm Hg; P < .001 in favor of uRDN). BP decreases from baseline with uRDN vs sham were consistent across trials and across BP parameters (office SBP: -10.4 mm Hg vs -3.4 mm Hg; mean difference, -6.4 mm Hg; 95% CI, -9.1 to -3.6 mm Hg; home SBP: -8.4 mm Hg vs -1.4 mm Hg; mean difference, -6.8 mm Hg; 95% CI, -8.7 to -4.9 mm Hg, respectively). The BP reductions with uRDN vs sham were consistent across prespecified subgroups. Independent predictors of a larger BP response to uRDN were higher baseline BP and heart rate and the presence of orthostatic hypertension. No differences in early safety end points were observed between groups.
CONCLUSIONS AND RELEVANCE
Results of this patient-level pooled analysis suggest that BP reductions with uRDN were consistent across HTN severity in sham-controlled trials designed with a 2-month primary end point to standardize medications across randomized groups.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02649426 and NCT03614260.
Topics: Humans; Male; Middle Aged; Antihypertensive Agents; Sympathectomy; Treatment Outcome; Hypertension; Kidney; Hypotension
PubMed: 36853627
DOI: 10.1001/jamacardio.2023.0338 -
Circulation Jul 2019Drug effects can be investigated through natural variation in the genes for their protein targets. The present study aimed to use this approach to explore the potential...
BACKGROUND
Drug effects can be investigated through natural variation in the genes for their protein targets. The present study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are among the most commonly used medications worldwide.
METHODS
Genetic proxies for the effect of antihypertensive drug classes were identified as variants in the genes for the corresponding targets that associated with systolic blood pressure at genome-wide significance. Mendelian randomization estimates for drug effects on coronary heart disease and stroke risk were compared with randomized, controlled trial results. A phenome-wide association study in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University biobank (BioVU) and in observational analysis of the UK Biobank.
RESULTS
Suitable genetic proxies for angiotensin-converting enzyme inhibitors, β-blockers, and calcium channel blockers (CCBs) were identified. Mendelian randomization estimates for their effect on coronary heart disease and stroke risk, respectively, were comparable to results from randomized, controlled trials against placebo. A phenome-wide association study in the UK Biobank identified an association of the CCB standardized genetic risk score with increased risk of diverticulosis (odds ratio, 1.02 per standard deviation increase; 95% CI, 1.01-1.04), with a consistent estimate found in BioVU (odds ratio, 1.01; 95% CI, 1.00-1.02). Cox regression analysis of drug use in the UK Biobank suggested that this association was specific to nondihydropyridine CCBs (hazard ratio 1.49 considering thiazide diuretic agents as a comparator; 95% CI, 1.04-2.14) but not dihydropyridine CCBs (hazard ratio, 1.04; 95% CI, 0.83-1.32).
CONCLUSIONS
Genetic variants can be used to explore the efficacy and side effects of antihypertensive medications. The identified potential effect of nondihydropyridine CCBs on diverticulosis risk could have clinical implications and warrants further investigation.
Topics: Antihypertensive Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenomic Variants
PubMed: 31234639
DOI: 10.1161/CIRCULATIONAHA.118.038814