Effects of Antihypertensive Drug Treatment on Cognitive Function and the Risk of Dementia
Hypertension has been associated with an increased risk of stroke, vascular dementia, and Alzheimer’s disease.1-10 Cerebral infarcts, lacunae, and white matter changes are implicated in the pathogenesis of vascular dementia, but also may lead to the development of Alzheimer’s disease.11 Microcirculatory disorders and endothelial dysfunction also may cause a deterioration in cognitive function in persons with hypertension.11 The Epidemiology of Vascular Aging study showed that hypertension is a major risk factor for severe white matter hyperintensities diagnosed by cerebral magnetic resonance imaging (MRI).12 Persons taking antihypertensive drugs to control their blood pressure had a reduced risk of severe white matter hyperintensities.12 Cognitive function is an important determinant of the ability to live independently in the community and of quality of life.13 Cognitive function itself can predict incidence of cardiovascular disease.14 This review article discusses the effect of hypertension treatment on cognitive function and the risk of dementia.
Numerous studies have demonstrated that treatment with antihypertensive drugs reduces the incidence of all strokes in men, women, elderly persons (including those older than 80 years), younger persons, persons with systolic and diastolic hypertension, persons with isolated systolic hypertension, and persons with a history of stroke or transient ischemic attack (TIA)15-27(Table25,28-35). The overall data suggest that reduction of stroke in persons with hypertension is related more to a reduction in blood pressure than to the type of antihypertensive drugs used.36 Reduction of stroke by antihypertensive drugs reduces the incidence of dementia. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS),25 treatment with perindopril plus indapamide reduced stroke-related dementia by 34% and cognitive decline as assessed by the Mini-Mental State Examination (MMSE) by 45%.
The Medical Research Council trial28 and the Systolic Hypertension in the Elderly Program (SHEP) trial29 did not find any significant difference in the incidence of cognitive decline between persons randomized to antihypertensive drug treatment with diuretics as the primary drug or to placebo. However, a selective dropout in the Medical Research Council and SHEP trials due to nonfatal events might have impaired the recognition of a benefit of antihypertensive treatment on dementia and disability outcomes.37 At 2-year median follow-up in the European Trial on Isolated Systolic Hypertension in the Elderly (Syst-Eur),30 compared with placebo, antihypertensive drug treatment using the calcium channel blocker nitrendipine as the primary drug reduced the incidence of dementia by 50%. Based on this study, if 1000 patients with hypertension were treated with antihypertensive drugs for 5 years, 19 cases of dementia would be prevented.30 Randomized patients in the Syst-Eur trial were offered active study medication for a further period of observation.31 At 3.9-year median follow-up, compared with the control group, antihypertensive drug therapy reduced the risk of dementia by 55%. This study showed that if 1000 patients with hypertension were treated with antihypertensive drugs for 5 years, 20 cases of dementia (95% confidence interval [CI], 7-33) would be prevented. The investigators of this study attributed the benefit of antihypertensive drug treatment on cognitive function primarily to the prevention of degenerative dementia rather than dementia occurring in association with cerebrovascular events such as stroke or TIA.31 At 3.7-years mean follow-up of patients ages 70-89 years in the Study on Cognition and Prognosis in the Elderly (SCOPE),32 there was no significant difference in cognitive decline or development of dementia in patients using candesartan as antihypertensive therapy compared with placebo. The reduction in blood pressure in this study was 3.2/1.6 mm Hg greater in patients treated with candesartan than in patients treated with placebo. In addition, the persons included in this study had good cognitive function.
In a longitudinal survey of the effect of antihypertensive medication on cognitive function in 1900 African Americans ages 65 years and older who showed no evidence of cognitive impairment at baseline, antihypertensive drug therapy reduced the risk of cognitive impairment by 38% (95% CI, 16%-55%) at 5-year follow-up.33 The incidence of cognitive impairment was 14.7% in patients treated with any antihypertensive drug versus 20.5% in patients not treated with antihypertensive drugs. There was no significant difference between types of antihypertensive drugs in reducing cognitive impairment. In the Cardiovascular Health Study, users of antihypertensive drug regimens, which included calcium channel blockers or loop diuretics, had more severe white matter hyperintensities on MRI and worse performance on the Modified MMSE than users of beta blockers.38 In an observational study of 993 persons with hypertension, mean age 77 years, diuretics (P = 0.007), angiotensin-converting enzyme inhibitors (P = 0.016), beta blockers (P = 0.014), and angiotensin receptor blockers (P = 0.016) improved cognitive scores.34 Patients taking dihydropyridine calcium channel blockers, non-dihydropyridine calcium channel blockers, alpha blockers, and clonidine had no difference in the development of cognitive impairment.34 At 2.2-year follow-up of 6416 persons older than age 55 years in the Rotterdam Study,35 those taking antihypertensive drugs at baseline had a 70% reduction in the development of vascular dementia.
In 81 patients with hypertension, antihypertensive drug therapy with the beta blocker bisoprolol and the thiazide diuretic bendrofluazide caused no significant change in quality of life at 8-week follow-up.39 In a prospective cohort study of elderly persons, those with poorly controlled hypertension had increased rates of subcortical white matter and periventricular white matter lesions diagnosed by MRI than persons with successfully treated hypertension.40 The investigators of this study concluded that adequate treatment of hypertension may prevent white matter lesions and the associated cognitive decline. On the basis of the available data, we recommend that the choice of antihypertensive drug therapy to prevent dementia be based on the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines.41 There remains an urgent need for further blinded, long-term comparative hypertension trials, including follow-up evaluation of cognitive function in relation to the course of hypertension treatment.42
On the basis of the available data, antihypertensive drug treatment reduces stroke and vascular dementia. There also may be effects from antihypertensive drug therapy on lowering the rates of other degenerative dementias. The overall data would suggest that antihypertensive drug therapy can reduce cognitive impairment, although some studies have shown no significant change in cognitive function with treatment. There are also conflicting data as to which antihypertensive drugs should be used for preventing cognitive impairment. On the basis of the available data, we recommend that the choice of antihypertensive drug therapy to prevent dementia be based on the JNC 7 guidelines. The authors report no relevant financial relationships.