enalapril and Dementia

Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-β peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials.. In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with 'broad' and 'narrow' preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18-96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33-1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75-1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF.. We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted.

Topics: Aged; Aminobutyrates; Amnesia; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Confusion; Delirium; Dementia; Disorders of Excessive Somnolence; Drug Combinations; Enalapril; Female; Heart Failure; Humans; Male; Middle Aged; Neprilysin; Proportional Hazards Models; Stroke Volume; Tetrazoles; Valsartan

After the double-blind, placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial ended in February 1997, randomized patients were offered active study medication for a further period of observation.. To refine the estimates of the long-term effects of antihypertensive therapy on the incidence of dementia.. Eligible patients had no dementia and were at least 60 years old. Their systolic blood pressure at entry was 160 to 219 mm Hg, with diastolic blood pressure below 95 mm Hg. Antihypertensive therapy was started immediately after randomization in the active treatment group, but only after termination of the double-blind trial in the control patients. Treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d), hydrochlorothiazide (12.5-25 mg/d), or both add-on drugs.. Median follow-up increased from 2.0 years in the double-blind trial to 3.9 years overall. The incidence of dementia doubled from 32 to 64 cases, 41 of whom had Alzheimer disease. Throughout follow-up, systolic/diastolic blood pressure was 7.0/3.2 mm Hg higher in the 1417 control patients than in the 1485 subjects randomized to active treatment. At the last examination, the blood pressure difference was still 4.2/2.9 mm Hg; 48.1%, 26.4%, and 11.4% of the control patients were taking nitrendipine, enalapril, and/or hydrochlorothiazide, whereas in the active treatment group these proportions were 70.2%, 35.4%, and 18.4%, respectively. Compared with the controls, long-term antihypertensive therapy reduced the risk of dementia by 55%, from 7.4 to 3.3 cases per 1000 patient-years (43 vs 21 cases, P<.001). After adjustment for sex, age, education, and entry blood pressure, the relative hazard rate associated with the use of nitrendipine was 0.38 (95% confidence interval, 0.23-0.64; P<.001). Treatment of 1000 patients for 5 years can prevent 20 cases of dementia (95% confidence interval, 7-33).. The extended follow-up of Syst-Eur patients reinforces the evidence that blood pressure-lowering therapy initiated with a long-acting dihydropyridine protects against dementia in older patients with systolic hypertension.

Topics: Aged; Antihypertensive Agents; Calcium Channel Blockers; Dementia; Double-Blind Method; Drug Therapy, Combination; Enalapril; Europe; Female; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Incidence; Male; Middle Aged; Nitrendipine; Time Factors; Treatment Outcome

Hypertension is a risk factor for dementia, particularly vascular dementia. The objective of the "Vascular Dementia" project of the European multicentre Syst-Eur trial was to study the influence of antihypertensive therapy on the incidence of dementia in elderly patients with isolated systolic hypertension included in this trial. Patients were over the age of 60, with systolic blood pressure between 160 and 219 mmHg and diastolic blood pressure less than 95 mmHg in the sitting position and were not demented. After randomization, they were treated under double-blind conditions with nitrendipine associated with or replaced by enalapril or hydrochlorothiazide or an equivalent placebo. Cognitive functions were evaluated by the Mini-Mental State test (MMS) on inclusion then annually. When the MMS score was < or = 23, a complementary assessment was performed to establish the diagnosis of dementia according to DSM III-R criteria. The Modified Ischaemia score specified the aetiology of dementia. A total of 1180 and 1238 subjects were randomized to the placebo and active treatment groups, respectively. They presented comparable characteristics on inclusion. The median intent to treat duration of follow-up was 2.0 years. The incidence of dementia was decreased by 50%, from 7.7 per thousand patient-years in the placebo group to 3.8 per thousand patient-years in the active group (p = 0.05). There were 15 and 8 cases of dementia of the Alzheimer type, 4 and 3 cases of mixed dementia, 2 and 0 cases of vascular dementia in the placebo and active treatment groups, respectively. In conclusion, in subjects over the age of 60 years with isolated systolic HT, antihypertensive treatment initiated with nitrendipine can reduce the incidence of dementia.

Topics: Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Dementia; Diuretics; Double-Blind Method; Drug Therapy, Combination; Enalapril; Europe; Female; Follow-Up Studies; Humans; Hydrochlorothiazide; Hypertension; Incidence; Male; Mental Status Schedule; Nitrendipine; Risk Factors; Severity of Illness Index; Sodium Chloride Symporter Inhibitors; Treatment Outcome

Vascular factors have been shown to be associated with increased risk of dementia. However, clinical trials have so far been unsuccessful, suggesting new approaches are needed. The aim of this study was to use population-based real-world data to investigate risk factors and preventive factors for dementia, including the effects of traditional Chinese medicine (TCM).. This is a retrospective cohort study using LHID2000, a dataset randomly selected from Taiwan's National Health Insurance Research Database. Subjects with occlusion and stenosis of precerebral and cerebral arteries, cerebral atherosclerosis without mention of cerebral infarction, and transient cerebral ischemia were included. Subjects with dementia at baseline were excluded. The primary endpoint was dementia. Data for demographic and clinical comorbid status and treatments administered at baseline in 2000 and at the end of follow-up in 2013 were included.. A total of 4,207 subjects with cerebral vascular disease and no cognitive impairment were included, of whom 392 converted to dementia during an average 5.15-year (SD: 3.79) follow-up. Depression (adjusted HR: 1.54, 95% confidence interval [CI]: 1.13-2.09), osteoporosis (adjusted HR: 1.34, 95% CI: 1.04-1.74), and the use of enalapril (adjusted HR: 1.37, 95% CI: 1.09-1.73) were risk factors for dementia, while nitroglycerin (adjusted HR: 0.67, 95% CI: 0.53-0.85) was a protecting factor, in subjects with cerebrovascular diseases without mention of cerebral infarction. In total, statins were shown to be associated with decreased risk of dementia (HR: 0.73, 95% CI: 0.59-0.91); however, no one statin subtype or TCM had such an effect.. Depression, osteoporosis, and the use of enalapril were associated with a higher risk of dementia, while nitroglycerin might be a protecting factor for dementia, in subjects with cerebrovascular diseases without mention of cerebral infarction.

Topics: Cerebral Infarction; Cerebrovascular Disorders; Dementia; Enalapril; Humans; Nitroglycerin; Osteoporosis; Retrospective Studies; Risk Factors; Taiwan