Users Of Other Antihypertensive Drugs Research Articles

Re: Association of Inpatient Use of Angiotensin-converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients with Hypertension Hospitalized with COVID-19.

To the Editor: We read with interest the study by Zhang et al.,1 examining the association between inpatient use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) and mortality in patients hospitalized with coronavirus disease 2019 (COVID-19), published in Circulation Research. The use of ACEIs or ARBs was associated with an important 58% risk reduction in all-cause mortality (hazard ratio, 0.42; 95% confidence interval, 0.19, 0.92). The association was even stronger with the use of propensity score models, resulting in a risk reduction of almost 70%. We believe that these remarkable effects are mainly driven by immortal time bias. In this study, patients were deemed exposed to ACEIs or ARBs if they had received a prescription at any time during the hospitalization period. In contrast, patients who did not receive these drugs during the hospitalization period were categorized as nonusers. This method of identifying users and nonusers can introduce immortal time bias.2 Indeed, by design, ACEI or ARB users had to survive from the date of admission to the date of an ACEI or ARB prescription to be categorized as a user. This time period was both misclassified as exposed (instead of unexposed) and immortal, as it was impossible for patients to die during this time span. In contrast, it was possible for nonusers to die at any point during the hospitalization period. This is particularly evident in Zhang et al.’s1 Figures 2A and 2B, where there were no deaths in the first 7 days of follow-up for the ACEIs/ARBs group, whereas deaths occurred as early as the second day after admission in the non-user group. Given the maximum 28-day follow-up, even a small amount of misclassified exposed person–time could lead to important bias, as was shown previously with β-blockers for patients hospitalized for chronic obstructive pulmonary disease.3 The authors also compared the risk of death among users of ACEIs/ARBs versus users of other antihypertensive drugs. In this analysis, the authors first identified ACEI/ARB users and then users of other antihypertensive drugs. This hierarchical exposure definition introduced immortal time bias,4 as the time between hospital admission and first ACEI/ARB prescription was misclassified as exposed and immortal because no events could have occurred during that period. In summary, although residual confounding is always a concern in observational studies, immortal time bias can introduce severely skewed results, though it can be avoided using proper methods of analysis.2–4 It would be informative to repeat the analyses by modeling ACEI or ARB exposure using time-dependent methods.

Use of renin–angiotensin–aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study

SummaryBackgroundConcerns have been raised about the possibility that inhibitors of the renin–angiotensin–aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19.MethodsIn this case-population study, we consecutively selected patients aged 18 years or older with a PCR-confirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437.FindingsWe collected data for 1139 cases and 11 390 population controls. Among cases, 444 (39·0%) were female and the mean age was 69·1 years (SD 15·4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1·98, 95% CI 1·62–2·41) and risk factors (1·46, 1·23–1·73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0·94 (95% CI 0·77–1·15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0·80, 0·64–1·00) or angiotensin-receptor blockers (1·10, 0·88–1·37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0·53, 95% CI 0·34–0·80). The adjusted ORs were similar across severity degrees of COVID-19.InterpretationRAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19.FundingInstituto de Salud Carlos III.

Angiotensin‐Converting Enzyme Inhibitors and Alzheimer's Disease Progression in Older Adults: Results from the Réseau sur la Maladie d'Alzheimer Français Cohort

To assess whether angiotensin-converting enzyme inhibitor (ACE-I) treatment is associated with less cognitive decline in older adults with Alzheimer's disease (AD) than in those using other hypertensive or no drugs. Four-year prospective multicenter cohort study with a biannual assessment. Memory clinics from 16 university hospitals in France. Community-dwelling older adults with mild to moderate AD (N = 616). Participants were stratified into four groups according to type and duration of antihypertensive drug treatment. Cognitive decline was assessed using the Mini-Mental State Examination (MMSE). Linear mixed-effects models were used to assess differences in decline in MMSE score between the four groups. Hypertension at each visit was included in the model. Sixty-one participants had used ACE-Is continuously, 57 had used them intermittently, 189 had used other antihypertensive drugs, and 309 never used any antihypertensive drugs. Continuous ACE-Is users had a 4-year decline in MMSE of 6.4 ± 1.6 points (P < .001), intermittent ACE-Is users of 7.9 ± 1.1 points (P < .001), continuous or intermittent users of other antihypertensive drugs of 8.8 ± 0.7 points (P < .001), and never-users of 10.2 ± 0.6 points (P < .001). MMSE decline between the four groups was significantly different (adjusted P = .02). In subgroup analysis, the 118 (19.2%) participants who had continuously or intermittently used ACE-Is had a significant difference in 4-year MMSE decline from the 498 (80.8%) who had never used ACE-Is (7.5 ± 0.9 vs 9.7 ± 0.4; P = .03). The use of ACE-Is in older adults with AD is associated with a slower rate of cognitive decline independent of hypertension. Future research is needed to explore the role of ACE-Is in long-term AD progression.

Angiotensin‐Converting Enzyme Inhibitor Use by Older Adults Is Associated with Greater Functional Responses to Exercise

To assess the association between angiotensin converting enzyme inhibitors (ACEis) and improvements in the physical function of older adults in response to chronic exercise training. Secondary analysis of the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) study, a multisite randomized clinical trial to evaluate the effects of chronic exercise on the physical function of older adults at risk for mobility disability. Four academic research centers within the United States. Four hundred twenty-four individuals aged 70 to 89 with mild to moderate functional impairments categorized for this analysis as ACEi users, users of other antihypertensive drugs, or antihypertensive nonusers. A 12-month intervention of structured physical activity (PA) or health education promoting successful aging (SA). Change in walking speed during a 400-m test and performance on a battery of short-duration mobility tasks (Short Physical Performance Battery (SPPB)). Physical activity significantly improved the adjusted walking speed of ACEi users (P < .001) but did not of nonusers. PA improved the adjusted SPPB score of ACEi users (P < .001) and of persons who used other antihypertensive drugs (P = .005) but not of antihypertensive nonusers (P = .91).The percentage of ACEi users deriving clinically significant benefit from exercise training for walking speed (30%) and SPPB score (48%) was dramatically higher than for nonusers (14% and 12%, respectively). For older adults at risk for disability, exercise-derived improvements in physical function were greater for ACEi users than users of other antihypertensive drugs and antihypertensive nonusers.

Abstract 037: Ace Inhibitor Use by Older Adults is Associated with Improved Functional Responses to Exercise

Introduction: Functional status, assessed objectively by measures of physical performance, is a strong predictor of cardiovascular events in older adults. Angiotensin converting enzyme (ACE) inhibitors may further enhance the beneficial effects of exercise training on the functional status of older adults, but studies are lacking to confirm. The objective of this study was to assess the association of ACE inhibitor use with exercise-derived improvements in physical function among physically-limited older adults. Hypothesis: Older adults who used ACE inhibitors would have larger improvements in physical function in response to exercise than non-users. Methods: This study is a secondary analysis of the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) study. LIFE-P investigated the effects of 12-month interventions consisting of either structured physical activity or health education to promote successful aging on 424 adults aged 70-89 years at risk for becoming physically disabled. This analysis compared change in outcome measures at 6- and 12-months among participants who (1) did not use anti-hypertensive drugs, (2) used ACEi, and (3) used anti-hypertensive drugs excluding ACEi. The primary outcome measures were change in performance on a battery of short-duration mobility tasks (SPPB) and walking speed during a 400 meter test. Results: A significant medication by intervention interaction existed for SPPB (p=0.018). PA improved the adjusted SPPB score among ACEi users (p&lt;0.001) and users of other anti-hypertensive drugs (p=0.005) but not among anti-hypertensive non-users (p=0.911). Adjusted SPPB changes at 12 months were 0.95 points among ACEi users, 0.77 points among users of other anti-hypertensive drugs, and -0.08 points among anti-hypertensive non-users. For walking speed, the medication by intervention interaction was not significant (p=0.178), but a trend existed for the medication by intervention by visit interaction (p=0.094). PA significantly improved the adjusted walking speed of ACEi users (p&lt;0.001) but did not improve walking speed among the other two groups across study visits. At 12 months adjusted changes were 0.06 m/sec among ACEi users, 0.05 m/sec among anti-hypertensive non-users, and 0.02 m/sec among users of other anti-hypertensives. Conclusions: Among older adults at risk for disability, exercise-derived improvements in physical function were greatest among ACEi users. Future prospective studies are needed to confirm the true efficacy of ACE inhibitors in improving older adults’ functional responses to exercise.

Use of ACE inhibitors is associated with elevated levels of IGFBP-3 among hypertensive older adults: results from the IlSIRENTE study

Several studies in vitro or in rodent models have suggested a potential relationship between angiotensin-converting enzyme (ACE) inhibition and the insulin-like growth factor 1 (IGF-1) axis. However, this relationship has only rarely been investigated in humans. The aim of the present cross-sectional study was to assess the association of ACE inhibitors with free IGF-1 and IGFBP-3 in the blood of older hypertensive adults. Data are from the baseline evaluation of the IlSIRENTE study, which enrolled 364 subjects aged 80 or older. For the present study we selected a subpopulation of 264 hypertensive participants without congestive heart failure. Free IGF-1 and IGFBP-3 in the blood were measured by a radioimmunoassay method. Analyses of covariance were performed to evaluate the differences in free IGF-1 and IGFBP-3 levels according to the use of ACE inhibitors. The mean age of participants was 85.7 years (SD: 4.9), 170 (64%) were women and 123 (47%) were using an ACE inhibitor. Following adjustment for potential confounders, the concentration of free IGF-1 was slightly, but not significantly higher among ACE inhibitor users than among non-users (0.74 vs. 0.65 ng/mL; p=0.20). In contrast, ACE inhibitor users had a significantly higher IGFBP-3 serum levels than non-users (4821 vs. 4330 ng/mL; p=0.005). In addition, the concentration of IGFBP-3 was significantly higher among ACE inhibitors users than among non-users of antihypertensive drugs (p=0.02) and users of other antihypertensive drugs (p=0.01). Among hypertensive older adults, ACE inhibitors use is associated with higher IGFBP-3 levels.

Relation between use of angiotensin-converting enzyme inhibitors and muscle strength and physical function in older women: an observational study

Angiotensin-converting enzyme (ACE) inhibitors prevent decline in physical function in patients with congestive heart failure (CHF). We aimed to see whether ACE inhibitors also prevent reduction in physical performance and in muscle strength in older women who do not have CHF. We assessed 3-year rates of decline in both knee extensor muscle strength and walking speed in 641 women with hypertension who had participated in the Women's Health and Aging Study. Women were stratified into four groups according to type and duration of antihypertensive drug treatment. 61 had used ACE inhibitors continuously, 133 intermittently, 146 never, and 301 had used other hypertensive drugs either continuously or intermittently. Participants who had taken ACE inhibitors continuously had a lower mean 3-year decline in muscle strength of -1.0 kg (SE 1.1) compared with -3.7 (0.5) kg in continuous/intermittent users of other antihypertensive drugs (p=0.016) and with -3.9 kg in those who had never used antihypertensives (p=0.026). Muscle strength fell by 3.0 kg in 3 years in both continuous and intermittent users of ACE inhibitors (p=0.096). Mean 3-year decline in walking speed in continuous ACE inhibitor users was -1.7 cm/s compared with -13.6 cm/s in intermittent users of ACE inhibitors (p=0.015), -15.7 cm/s in continuous/intermittent users of other antihypertensive drugs (p=0.002), and -17.9 cm/s in never users of antihypertensive drugs (p=0.001). ACE inhibitor treatment may halt or slow decline in muscle strength in elderly women with hypertension and without CHF.

Use of calcium channel blockers as antihypertensives in relation to mortality. A population based observational study.

P51 The beneficial effect of pharmacological treatment of hypertension is well established. However, the outcome may depend on the specific antihypertensive drug used. This study, aimed to compare mortality in users of calcium channel blockers (CCBs) with that in users of other antihypertensive drugs (AHDs), includes 719 patients on antihypertensive drugs at an outpatient clinic in primary care in 1989-90. They were classified as users of CCBs (mostly felodipine) or users of other ADHs according to status at inclusion. Co-morbidity, systolic blood pressure, and smoking data were derived from standardised patient records. The Swedish mortality register was used to follow patients until death or until the end of 1995. Odds ratios were calculated by Cox regression analysis (the table). Although adjustment was made for confounders, mortality was higher in CCB users. This adds support to the view that CCBs may be inferior to other ADHs in reducing mortality when used to treat hypertension and should not be considered a first-line drug. Table 1.