Abstract
Observational studies have suggested that angiotensin receptor blockers are associated with a unique cognitive protection. It is unclear if this is due to reduced blood pressure (BP) or angiotensin receptors type 1 blockade. To determine neurocognitive effects of candesartan vs lisinopril in older adults with mild cognitive impairment (MCI). This randomized clinical trial included participants aged 55 years or older with MCI and hypertension. Individuals were withdrawn from prior antihypertensive therapy and randomized in a 1 to 1 ratio to candesartan or lisinopril from June 2014 to December 2018. Participants underwent cognitive assessments at baseline and at 6 and 12 months. Brain magnetic resonance images were obtained at baseline and 12 months. This intent-to-treat study was double-blind and powered for a sample size accounting for 20% dropout. Data were analyzed from May to October 2019. Escalating doses of oral candesartan (up to 32 mg) or lisinopril (up to 40 mg) once daily. Open-label antihypertensive drug treatments were added as needed to achieve BP less than 140/90 mm Hg. The primary outcome was executive function (measured using the Trail Making Test, Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research tool) and secondary outcomes were episodic memory (measured using the Hopkins Verbal Learning Test-Revised) and microvascular brain injury reflected by magnetic resonance images of white matter lesions. Among 176 randomized participants (mean [SD] age, 66.0 [7.8] years; 101 [57.4%] women; 113 [64.2%] African American), 87 were assigned to candesartan and 89 were assigned to lisinopril. Among these, 141 participants completed the trial, including 77 in the candesartan group and 64 in the lisinopril group. Although the lisinopril vs candesartan groups achieved similar BP (12-month mean [SD] systolic BP: 130 [17] mm Hg vs 134 [20] mm Hg; P = .20; 12-month mean [SD] diastolic BP: 77 [10] mm Hg vs 78 [11] mm Hg; P = .52), candesartan was superior to lisinopril on the primary outcome of executive function measured by Trail Making Test Part B (effect size [ES] = -12.8 [95% CI, -22.5 to -3.1]) but not Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research score (ES = -0.03 [95% CI, -0.08 to 0.03]). Candesartan was also superior to lisinopril on the secondary outcome of Hopkins Verbal Learning Test-Revised delayed recall (ES = 0.4 [95% CI, 0.02 to 0.8]) and retention (ES = 5.1 [95% CI, 0.7 to 9.5]). These findings suggest that in older adults with MCI, 1-year treatment with candesartan had superior neurocognitive outcomes compared with lisinopril. These effects are likely independent of the BP-lowering effect of candesartan. ClinicalTrials.gov Identifier: NCT01984164.
Highlights
Clinical trials have suggested that lowering blood pressure (BP) using antihypertensive therapy provides cognitive protection in individuals without impaired cognition.[1,2] It is unclear if this is true in individuals who have symptoms of cognitive impairment
The lisinopril vs candesartan groups achieved similar BP (12-month mean [statistics including mean (SD)] systolic BP: 130 [17] mm Hg vs 134 [20] mm Hg; P = .20; 12-month mean [SD] diastolic BP: [10] mm Hg vs [11] mm Hg; P = .52), candesartan was superior to lisinopril on the primary outcome of executive function measured by Trail Making Test Part B but not Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research score (ES = −0.03 [95% CI, −0.08 to 0.03])
Candesartan was superior to lisinopril on the secondary outcome of Hopkins Verbal Learning Test-Revised delayed recall (ES = 0.4 [95% CI, 0.02 to 0.8]) and retention (ES = 5.1 [95% CI, 0.7 to 9.5])
Summary
Clinical trials have suggested that lowering blood pressure (BP) using antihypertensive therapy provides cognitive protection in individuals without impaired cognition.[1,2] It is unclear if this is true in individuals who have symptoms of cognitive impairment. Studies designed to compare the neurocognitive effects of antihypertensive classes in individuals who are cognitively impaired are limited. It is unclear if these effects are related to the reduction in BP or to possible pleiotropic BP-independent effects of certain antihypertensive medications. Comparing antihypertensive drug classes independent of the degree of BP lowering is critical to determine if these effects on cognition are only secondary to their BP or other non-BP effects. Such pleiotropic effects of antihypertensive drugs may be leveraged to repurpose drugs for cognitive disorders, including Alzheimer disease (AD)
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