Vol.48 - Número 3, Julio/Septiembre 2019 Imprimir sólo la columna central

Effects of antihypertensive drugs treatment on cognitive function:
cognitive impairment, dementia and Alzheimer's disease

AUGUSTO VICARIO (1), GUSTAVO H. CEREZO (2), ANTONIO COCA (3), DARIUSZ
GASECK
(4), AUGUSTO ZANINELLI (5), DRAGAN LOVIC (6), EFSTATHIOS MANIOS(7), DAGMARA HERING (8), CRISTINA SIERRA (9), PEDRO CUNHA (10)
on behalf of the ESH WG on Hypertension and Brain.
1 Heart-Brain Unit ICBA Cardiovascular Institute, Buenos Aires, Argentina;
2
Cardiovascular and Epidemiology Depart. ICBA Cardiovascular Institute of Buenos Aires, Argentina; 3 Hospital Clinic, School of Medicine, University of Barcelona, Barcelona, Spain;
4 Depart. of Neurology for Adults, Medical University of Gdansk, Gdansk, Poland; 5 Depart. of General Practice, School of Medicine, University of Florence, Florence, Italy; 6 Clinic for Internal Disease Intermedica, Depart.of Cardiology, Hypertension Center, Nis, Serbia;
7 Depart.of Clinical Therapeutics, National and Kapodistrian, University of Athens, Alexandra Hospital, Greece; 8 Depart.of Hypertension and Diabetology, Medical University of Gdansk, Gdansk, Poland; 9 Depart.of Internal Medicine, University of Barcelona, Hospital Clinic, Barcelona, Spain; 10 Center for the Research and Treatment of Arterial Hypertension
and Cardiovascular Risk, Serviço de Medicina Interna do Hospital da Senhora da Oliveira, Guimarães; Life and Health Science Research Institute (ICVS), School of Medicine, University of Minho, Guimarães.
(1426) CABA, Buenos Aires, Argentina.
E-mail
Recibido 21-JUNIO-2019 – ACEPTADO el 09-JULIO-2019.
There are no conflicts of interest to disclose.

 

ABSTRACT

Over the past decades, a growing body of evidence supports the link between neurocognitive diseases and hypertension (HTN). Particularly, high blood pressure (BP) in midlife has been associated with an increased risk for cognitive decline and dementia in late-life. With increasing life expectancy, the prevalence of HTN increases and more people suffer from cognitive impairment, dementia or Alzheimer’s disease. Therefore, the Alzheimer’s disease International Association recognized HTN as the main modifiable vascular risk factor for cognitive decline and dementia. Given that the causes of dementia include a complex interplay between vascular and non-vascular risk factors, antihypertensive therapy could prevent cognitive decline or dementia risk beyond the presence of stroke. Given the growing incidence of worldwide dementia and its adverse impact on public health, it is likely that BP control can minimize the risk or delay the onset of cognitive impairment, thereby reducing the burden of dementia. For these reasons, the Working Group Hypertension and Brain of the European Hypertension Society has decided to write a brief non-systematic review on the topic.
Key words: Cognitive impairment. Dementia. Hypertension. Anti-hypertensive treatment.

 

In recent decades, medical evidence has gathered enough tests to support the relationship between hypertension (HTN) at medium age in life and the risk of dementia in the advanced stages of life [1], and the possibility for antihypertensive treatment to reduce the prevalence of dementia [2,3,4]. The prevalence of both pathologies, HTN and dementia, increases as life expectancy reached by people increases, and negatively impacts on public health. HTN, a non-communicable disease, leads the list of risk factors with the highest “load” in global diseases (7%), being responsible for the death of nearly 10 million people in the world every year [6]. However, although diagnosis, monitoring and treatment of HTN is simple, only 1 in 5 hypertensive patients have their HTN controlled. Meanwhile, dementia is considered a public health priority given its high prevalence and incidence projected to double every twenty years. So much so, that Alzheimer’s Disease International considers HTN as the main modifiable vascular risk factor to develop dementia and Alzheimer’s disease (AD) [6]. HTN causes subclinical vascular injury in the brain (small vessel disease, lacunar stroke and microbleeds), damaging subcortical white matter (WMD) and increasing the risk of stroke, cognitive impairment and dementia (probably both vascular dementia (VD) and AD). On the other hand, between 30 and 70% of patients suffering stroke presented cognitive impairment or post-stroke dementia, depending on the size, location and previous cognitive reserve of the individual. Medical evidence has shown that the treatment and control of blood pressure (BP) values by antihypertensive drugs, not only prevents stroke, but reduces the “load” and “progression” of WMD [7]. Thus, antihypertensive drugs are not just effective to prevent stroke, but may prevent or delay the appearance of cognitive impairment and dementia. Prospective tests that evaluated the effects of antihypertensive drugs on cognitive function, the incidence of dementia or AD are controversial, while some report benefits and others question its usefulness. Such discrepancy could lie in that most of them were not designed to evaluate cognitive results, its follow-up periods were short, and the aims, populations studied, the class of antihypertensive drugs used and the cognitive tests used were different. However, some randomized and controlled trials (RCT) and meta-analysis provide significant evidence on the beneficial effect that the antihypertensive treatment may have on cognitive function and the decrease in the incidence of dementia and AD.

Thus, considering the probable positive impact of antihypertensive treatment on public health, both delaying the start of cognitive impairment and decreasing the prevalence of dementia, our goal was to perform a brief non-systematic review on the topic. The MEDLINE database was consulted (using keywords: antihypertensive drugs, hypertension, cognitive impairment, dementia, and Alzheimer’s disease), as well as on the bibliography included in review articles, original papers, and epidemiological studies selected according to their relevance for the topic discussed according to the judgement of the authors.

 

EFFECT OF ANTIHYPERTENSIVE TREATMENT ON DEMENTIA
The first CRT that showed that antihypertensive treatment decreased the incidence of dementia was the Syst-Eur study (Systolic Hypertension in Europe) [8] (Table 1). This study, included in the European Dementia Prevention Initiative (EDPI), enrolled 2902 patients >60 years of age, with no diagnosis of dementia and using nitrendipine as antihypertensive drugs, with the chance of adding enalapril and/or hydrochlorothiazide. After 2 years of follow-up, the incidence of dementia was reduced by 50% (from 7.7 cases/1000 pts/year to 3.8 cases/1000 pts/year) and by 55% in 4 years in the extended phase (Syst-Eur 2) [9]. Although the aim of the study was to prevent vascular dementia, 64% of cases were diagnosed as type AD dementia (41/62 cases). Simultaneously, the results from the Rotterdam study were published, which included 7046 patients ≥55 years without dementia that were followed for 2.2 years [10]. It showed that the participants that were receiving antihypertensive treatment from the onset of the study significantly reduced the incidence of dementia (RR 0.30; CI 95%, 0.11-0.99) and in 13% the incidence of AD (with no statistical significance). The SHEP (Systolic Hypertension in the Elderly Program) study included 4736 individuals >60 years with diagnosis of isolated systolic HTN [11]. After 4.5 years of follow-up, using chlortalidone as antihypertensive agent, the total incidence of stroke was reduced by 36% without significant reduction on the incidence of dementia (37 cases in the treated group vs 44 cases in the placebo group).

Table 1. Prospective and controlled trials
  Trial Population/follow-up Drugs Cognitive results
  EFFECTS OF ANTI-HYPERTENSIVE TREATMENT ON DEMENTIA
  Systolic Hypertension in Europe (Syst-Eur) [8] n=2418, ≥60 y.o., no basal dementia, (2-year mean follow-up) Nitrendipine ± enalapril, HCTZ or both The incidence of dementia was reduced by 50% (7.7 in 3.8 cases/1000 pts/year). AD=23, VD=2 cases
  Systolic Hypertension in Europe (Syst-Eur 2) [9] n=2418, ≥60 y.o., (mean follow-up 3.9 years) Nitrendipine ± enalapril, HCTZ or both The incidence of dementia was reduced by 55% (7.4 in 3.3 cases/1000 pts/year). AD=41
  Rotterdam study [10] n=7046, ≥55 y.o., no basal dementia, (mean follow-up 2.2 years) Anti-hypertensive agents The incidence of VD was reduced (RR 0.30, 95% CI: 0.11-0.99) and 13% reduction in AD (not significant)
  Systolic Hypertension in the Elderly Program (SHEP) [11] n=4736, >60 y.o., isolated systolic HTN (follow-up. 2.2 years) Chlortalidone + atenolol Non-significant difference in the incidence of dementia (37 vs 44 cases)
  Systolic Blood Pressure Intervention Trial-MIND (SPRINT-MIND) [12] n=9361, >50 y.o., w/CV risk, no stroke or dementia (follow-up 5.1 years) Anti-hypertensive drugs The risk of CI was reduced (HR 0.81, 95% CI 0.69-0.95) and CI or dementia combined (HR 0.85, 95% CI 0.74-0.97)
  EFFECTS OF ANTI-HYPERTENSIVE TREATMENT ON COGNITION AND POST-STROKE DEMENTIA
  Heart Outcome Prevention Evaluation (HOPE) [14] n=9297, ≥55 y.o., vascular disease/diabetes (follow-up 4.5 years) Ramipril 41% CI reduction (RR 0.59, 95% CI 0.37 to 0.94)
  Perindopril Protection Against Recurrent Stroke Study (PROGRESS) [15] n=6105, mean 64 y.o., previous stroke or TIA, (follow-up. 3.94 years) Perindopril ± indapamide 45% post-stroke CI reduction (95% CI 21% to 61%) and 34% post-stroke dementia risk (95% CI 3% to 55%)
  EFFECTS OF ANTI-HYPERTENSIVE TREATMENT ON COGNITION IN VERY ELDERLY ADULTS
  Hypertension in Very Elderly Trial-Cognition (HYVET-COG) [17] n=1687, ≥80 y.o., no dementia, (follow-up 2.2 years Indapamide ± perindopril Non-significant difference in the incidence of dementia (38 vs 33 cases/1000 pts/y)
  New Castle 85+ study [18] ) n=238, >85 y.o., follow-up 3 years Calcium channel blockers Reduction of 1.29 MMSE points/year (95% CI 0.16-2,42, p=0.03)
  Leiden 85-plus study [19] n=204, >85 y.o., at least treated with one anti-hypertensive agent Anti-hypertensive drugs Only CCBs reduced CI yearly (0.4 MMSE-points/year)
  Leiden 85-plus study [20] n=249, >85 y.o., at least treated with one anti-hypertensive drug Anti-hypertensive drugs Total mortality increase (HR 1.29/10 mmHg decrease in SBP, 95% CI 1.15-1.46). and CI (-0.35 MMSE-points/10 mmHg; 95% CI -0.60, -0.11)
  The 90+ study [11] n=559, >90 y.o., no dementia (follow-up 2.8 years) Anti-hypertensive drugs Reduction in risk of dementia with HTN onset at 90 y+ (HR 0.37, 95% CI 0.19-0.73)
  Milan Geriatrics study [22] n=1587, >75 y.o., Anti-hypertensive drugs SBP and DBP correlated with mortality (J curve).
References. y.o.: years old; AD: Alzheimer’s disease; VS: vascular dementia; CI: cognitive impairment; TIA: transient ischemic attack; MMSE: Mini-mental Statement Examination; CCB: calcium channel blockers; CV: cardiovascular;
SBP: systolic blood pressure.


In the recent SPRINT-MIND (Systolic Blood Pressure Intervention Trial – Memory and Cognition in Decreased Hypertension) trial, a sub-study of the SPRINT, 9361 hypertensive patients (mean age 67.9 years) without diabetes, dementia or stroke but with increased cardiovascular risk were randomized to intensive treatment group (systolic BP <120 mmHg) and standard treatment group (systolic BP <140 mmHg). With an average of 5.1 years of follow-up, the intensive treatment arm reduced the incidence of mild cognitive impairment by 19% (14.6 cases/1000 per year vs 18.3 cases/1000 per year; HR 0.81; 95% CI, 0.69-0.95) and by 15% the incidence of composite end-point of mild cognitive impairment and probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR 0.85; 95% CI, 0.74-0.97) in comparison to the standard treatment arm [12]. On the other hand, the primary end-point of probable dementia was reduced by 17% without reaching a statistical significance (175 vs 147 new cases, HR 0.83; 95% CI, 0.67-1.04). further, a sub-group of 454 individuals belonging to the SPRINT trial underwent Magnetic Resonance tests to evaluate the “load” of WMD and total cerebral volume in relation to the antihypertensive treatment [13]. After 3.8 years of follow-up, although there were no differences seen in the total cerebral volume between groups, the WMD “load” progression was slower in the group with intensive treatment (0.28 cm3 vs 0.92 cm3).

 

EFFECT OF ANTIHYPERTENSIVE TREATMENT ON COGNITIVE FUNCTION AND POST-STROKE DEMENTIA
Two multicenter studies, one the HOPE (Heart Outcome Prevention Evaluation) study included 9297 patients >55 years with vascular disease or diabetes plus additional risk factors, followed for 4.5 years, showed a 32% reduction (95% CI; 0.56-0.84) in the total risk of stroke (using ramipril) [14]. The other one, the PROGRESS (Perindopril Protection against Recurrent Stroke Study) study enrolled 6105 patients with previous history of stroke or transient ischemic attack (mean age of 64 years and follow-up of 3.9 years), using perindopril plus indapamide prevented the recurrence of stroke in non-hypertensive and hypertensive patients by 28% (95% CI, 17-38) [15]. Although both studies were designed to evaluate cognitive function in hypertensive patients, the sub-analysis of the first study showed a reduction in cognitive decline linked to stroke of 41% (95% CI; 6-63) and 45% (95% CI; 21-61) in the second study. Moreover, a sub-analysis of the PROGRESS study proved that antihypertensive treatment reduces by 34% (95% CI; 3-55) the risk of dementia after stroke [16].

 

EFFECT OF ANTIHYPERTENSIVE TREATMENT ON COGNITION ON VERY ELDERLY ADULTS
The HYVET-COG (Hypertension in the Very Elderly Trial-Cognition) trial was designed to learn the risks and benefits of antihypertensive treatment in very elderly adults (≥80 years) [17]. A total of 3336 very elderly adults without dementia, treated with indapamide associated to perindopril (as required) were followed for 2.2 years (the study was interrupted due to internal results in terms of a strong reduction in the incidence of stroke, major cardiovascular events and all-cause mortality in the treated group). The incidence of dementia did not show statistically significant differences between the treated group and the placebo group (38 cases/1000 pts/year vs 33 cases/1000 pts/year).

The New Castle 85+ study (n=238 hypertensive patients >85 years of a population study cohort followed over 3 years) showed an association between the use of calcium channel blockers (CCBs) and less cognitive decline (1.29 points of the mini-mental statement examination (MMSE); 95% CI, 0.16-2-42, p=0.03) [18]. In a sub-group of 204 individuals belonging to the Leiden 85- plus study cohort (n=599, 85 years of age or more and followed until age 90), showed that only CCBs use slowed down cognitive decline measured by the MMSE score (-0.40 points per year; -0.72 points in the total group vs -0.32 points in the group treated with CCBs) [19]. This result raises a debate on the possibility of protective effects on cognition being attributed to class effect by CCBs plus BP decrease produced by them. However, a recent analysis of the same study concluded that systolic BP decrease in very elderly adults that receive antihypertensive treatment was associated with an increase in mortality (HR 1.29 per 10 mmHg decrease in systolic BP) and an accelerated decline of cognitive function (mean yearly change -0.35 MMSE points per 10 mmHg decrease in systolic BP) compared to patients that did not receive antihypertensive therapy drugs [20].

In agreement with these results, the 90+ study, which enrolled patients older than 90 years and were followed for 2.8 years, observed that HTN of late onset (between 80 and 89 years) may present a lower risk of dementia (HR 0.58, p=0.04) in comparison to individuals in whom HTN started at age 90 or more (HR 0.37, p=0.004) [21]. These findings added to the linear pressure-flow relation that the self-regulation curve of cerebral flow acquired in this age group, may suggest paradoxically, that high blood pressure in very advanced stages in life may exert a “cerebroprotective” effect.

In the Milan Geriatrics study (n=1587, age ≥75 years, followed for 10 years), the high BP values in individuals with cognitive function compromise (MMSE <25 points) were related to less mortality [22]. In such sense, Mosello et al, observed in 172 patients with a mean age of 79 years, that were hypertensive and receiving antihypertensive treatment, that the daily systolic BP values below 128 mmHg were associated with a greater cognitive decline in patients with dementia and more mild cognitive deterioration compared to those that were not receiving antihypertensive treatment [23]. Elderly individuals with ages of 80 or more constitute an age group with special characteristics: different incidence and prevalence of co-morbidities, fragility, loss of autonomy and motor skills, orthostatic hypotension and frequent falls. Even intensive HTN treatment, especially in the group of fragile patients is associated to higher mortality, impairment of cognitive functions and dementia [22]. So, the recommendations on HTN treatment in elderly patients and the possible cognitive results, probably do not apply to the group of very elderly patients, being necessary in this context to individualize the particular cases according to the scant current recommendations for very elderly patients, before implementing antihypertensive treatments with controversial results [24].

 

EFFECTS OF THE DIFFERENT CLASSES OF ANTIHYPERTENSIVE DRUGS ON COGNITION
The effect of the class of antihypertensive drugs on cognitive and dementia results is unclear. Nevertheless, some RCT and meta-analyses show that certain classes of antihypertensive drugs are more beneficial than others in the prevention of the appearance and/or progression of cognitive decline or decreasing the risk of dementia (Table 2).

Table 2. Effects of anti-hypertensive drugs according to class on cognition
  Trial Population/follow-up Drugs Cognitive results
  BETA BLOCKERS [11, 25-30]
  Fogari et al.[25] n=120, age 75-89 years Atenolol vs losartan Atenolol did not improve cognition. Losartan improved memory aspects.
  Pérez-Stable et al.[26] n=312, age 22-59 years (follow-up 12 months). Propranolol vs
placebo
No significant changes in the explored cognitive domains.
  Hajjar I et al [27] n=350,mean age 76.8 years BB and others BB less cognitive decline (p=.014)
  Rosenberg PB et al [28 n=216, with basal AD, follow-up 3 years. BB Reduction in yearly drop in Clinical Dementia Rate CDR (1.69 to 0.68, p=0.04)
  ] Honolulu-Asia Aging Study (HAAS) [30] n=2197, mean age 77 years (follow-up 5.8 years) BB Reduction in CI risk (RR 0.69; 95% CI 0.50-0.94). Better association in diabetes, >75 y.o. and PP ≥ 70 mmHg.
  DIURETICS [8,9,11,15,17,28,29-33]
  Kachaturian AS et al [29] n=3308, >65 years, with AD (follow-up 3 years) Diuretics, particularly K+ sparing ones Reduction in risk of AD. Diuretics (HR 0.57 95% CI 0.33-0.94), K+ sparing diuretics (HR 0.26; 95% CI 0.08-0.64).
  DeLoach T et al.[31] Review (Pubmed publications between 2000-15). Thiazides and/or K+ sparing diuretics Reduction in risk of AD (adjusted HR 0.63 95% CI; 0.42-0.94), K+ sparing diuretics alone (adjusted HR 0.09 95% CI; 0.01-0.41)
  Tully PJ et al [32] Meta-analysis (52,599, 3444 cases of dementia, mean age 71.6 years, follow-up 6.1 years. Diuretics Reduction in dementia risk (HR 0.83; 95% CI 0.76-0.91) and risk of AD (HR 0.82; 95% CI 0.71-0.94). K+ sparing diuretics better than thiazides/loop diuretics.
  CALCIUM CHANNEL BLOCKERS [8-9,18-19,33-36]
  Middelaar T et al [34] Review (1951 individuals, follow-up 6.7 years) CCB + other anti-hypertensive agents Reduction in dementia risk (HR 0.56; 95% CI, 0.36-0.87)
  Peters R [35] n=292, >80 y.o., follow-up 12 months CCB No relation between CBBs and changes in cognitive function.
  RENIN-ANGIOTENSIN SYSTEM MODULATORS (ACEI-ARBS) [37-43,47-50,52-55]
  ONTARGET (1) y TRANSCEND (2)
[39]
(1) n=26.620, CVD and Diabetes (2) n=5926 Ramipril, telmisartan, Ramipril + telmisartan Telmisartan vs placebo. No difference in cognitive results (incidence of dementia, cognitive dysfunction or MMSE ≤ 23 points).
  Study Cognition and Prognosis in the Elderly (SCOPE) [40-41] n=4937, 70-89 y.o., HTN and MMSE ≥ 24, (follow-up 3.7 years) Candesartan ± other anti-hypertensive agents Non-significant difference in CI or dementia. Reduction in MMSE score decrease in pts with basal MMSE 24-28 (-0.04 to -0.53, 95% CI 0.02-0.97).
  Antihypertensives and Vascular, Endothelial, and Cognitive Function (AVEC) [42] n=100, >60 y.o., follow-up 1 years, patients with mild CI. Candesartan or lisinopril or HCTZ Candesartan improved executive function (TMT-B p= 0.008).
  United States Veterans Affairs [47] n=819.491, age >65 y.o., nested database ARBs vs Lisinopril vs. other CV drugs Reduction in dementia incidence 55%, reduction in progression of dementia and AD 70%.
  Cardiovascular Health Study Cognition (CHS-Cognition)[52] n=1054, >75 y.o., follow-up 6 years. ACEI vs placebo Central ACEI reduction decline in MMSE 65%, non-central ACEI > risk incidence of dementia (adjusted HR 1.20 95% CI; 1.0-1.43/year exposition).

 

  • Beta blockers

In the process of consolidation and recovery of memory, adrenergic signal plays a significant role in structures such as the hippocampus. Gliebus and Lippa showed that in patients with cognitive impairment or dementia, using beta blockers (BBs) that go through the blood-brain barrier (BBB) (propranolol, metoprolol or carvedilol) worsens cognitive function in comparison to atenolol or others that do not go through the BBB [25].

In other propranolol [25] or atenolol [26] studies, used as monotherapy or in combination with diuretics (chlorthalidone) [11], they have not proven to improve cognitive tests scores.

On the other hand, other studies have shown the benefits of BB to prevent cognitive decline [27], and even to delay functional compromise in patients with AD [28]. Given that other classes of drugs were included in the studies (e.g.: diuretics, CCBs, or renin-angiotensin system modulators), it is not possible to evaluate the effect of BB in their full dimension. Kachaturian et al, showed that BB had a protective effect against the development of AD (adjusted HR 0.53; 95% CI, 0.22-1.09) [29]. On the other hand, a recent publication with data from the HAAS (Honolulu-Asia Aging Study) on 2197 men who entered the study with HTN and without dementia, showed that the patients receiving BB as monotherapy from the beginning of the study had less risk of cognitive impairment (RR 0.69; 95% CI, 0.50-0.94) than those receiving other antihypertensive drugs [30]. The association reached more significance >75 years in diabetic patients or with pulse pressure >70 mmHg. The authors attribute the neuroprotective effect of BBs in this group of vulnerable patients with hypertensive microvascular damage, to the improvement of cerebral blood perfusion.

  • Diuretics

In the study of Hajjar et al, using diuretics slowed down cognitive decline in elderly people, and even in people with diagnosis of AD [31]. Hydrochlorothiazide associated to CCBs has been effective to reduce the incidence of dementia in the Syst-Eur study [8,9]. In two significant RCTs, diuretics could not prove improvement in cognitive performance or decrease in the risk of dementia in hypertensive patients, both used as monotherapy and in combination with BBs [11] or ACEI [17]. However, diuretics associated with antihypertensive drugs proved to be effective in the prevention of stroke, and thus may have an important effect in reducing cognitive impairment and/or post-stroke dementia risk [15]. In the Dementia Progression Study of the Cache County Study on Memory Health and Ageing, it was shown in 216 individuals with AD, that using potassium-sparing diuretics, specifically spironolactone, was associated to a reduction in the incidence of AD of 70% (adjusted HR 0.26; 95% CI, 0.08-0.64) [29,32], and diuretics associated to statins delayed yearly functional decline (CDR – Clinical Dementia Rating 0.75 and 0.68 respectively) [28].

On the other hand, in the meta-analysis by Tully PJ et al, (including 15 articles, 52,599 individuals and a mean follow-up of 6.1 years), diuretics reduced between 15% and 17% the risk of dementia, and 18% the risk of AF [33]. When the analysis was stratified according to the different classes of diuretics, it was proven that potassium-sparing diuretics reduced the risk of dementia by 30%, while reduction was 14% for those with action on the glomerular ascending limb and 6% for the subclass of thiazide diuretics or with action with the distal convoluted tubule. The authors argue that neuroprotective mechanisms could be attributed to a decrease in potassium excretion, in contrast to the mechanism of action of other diuretics and in agreement with other drugs with effects similar to ACEI.

  • Calcium channel blockers

CCBs used in the Syst-Eur study (nitrendipine alone or in association with enalapril or hydrochlorothiazide) showed a potential reduction of 50% on the incidence of dementia [8,9]. CCBs used as antihypertensive drugs may maintain or improve cognitive function in hypertensive patients by mechanisms different from BP reduction, just like the results in studies performed in very elderly adults [18,19]. CCBs improve homeostasis of intracellular calcium (altered in ageing) and neuronal function. Moreover, its action on the smooth muscle inhibits the vascular contractility and improve cerebral flow. In the model of spontaneously hypertensive rat (SHR), hypertensive deterioration decreases cerebral volume and the frontal, occipital and hippocampus areas cellularity.

Using CCBs (lercanidipine) increased the volume and number of neurons in the frontal and occipital lobes [34]. In the review by Middelaar T et al, made on 1951 participants followed for 6.7 years, both CCBs (HR 0.56; 95% CI, 0.36-0.87) and ARBs were associated independently with dementia risk reduction (HR 0.60; 95% CI, 0.37-0.98) [35]. In another review, Peters R et al, did not find clear evidence that using CCBs decreases the risk of cognitive decline or dementia in very elderly adults [36]. Finally, the meta-analysis by Rouch L et al, (18 longitudinal studies, 11 RCT and 9 meta-analyses with more than 1 million patients), beyond proving a 9% reduction on the incidence of dementia with the antihypertensive treatment, concluded that CCBs and ARBs were better than other classes of drugs to prevent cognitive decline and dementia [37].

  • Renin-angiotensin system modulators (ACEI-ARB)

Basic investigation widely supports the key role of the renin-angiotensin system on HTN pathophysiology, cognitive function and the development of cognitive impairment, dementia and AD [38]. ACEI or ARBs could be extremely significant to preserve cognitive function. Brazsko JJ et al, showed that captopril improved and enalapril reverted cognitive deficits in untreated hypertensive patients [39].

Telmisartan was evaluated in three studies; two of them the PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes trials) and the TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Diseases), although without statistical significance, showed an improvement of cognitive impairment of 11% and 17% respectively. The third one, the ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) did not show clear cognitive results in patients with cardiovascular disease and diabetes [40].

The SCOPE study (Study Cognition and Prognosis in the Elderly) was a case-control randomized study that enrolled and followed 4964 hypertensive patients for 3.7 years [41]. Based on the MMSE score as cognitive measure, candesartan did not reduce the incidence of dementia or cognitive impairment; however, a sub-analysis observed reduction in cognitive decline only in individuals with basal MMSE score between 24-28 points; but without reaching statistical significance [42]. Two studies have shown the superiority of candesartan on cognitive function. The first, the AVEC study (Antihypertensives and Vascular, Endothelial, and Cognitive Function) a double-blind RCT that selected 100 hypertensive individuals >60 years old with diagnosis of early executive dysfunction (abnormal clock-drawing test) were followed for 12 months and candesartan proved to improve executive function [43]. In the second one, Hajjar et al, studied 53 hypertensive patients with executive dysfunction (Trial Making Test-part B) and showed that candesartan is better than Lisinopril and hydrochlorothiazide [44].

Executive function, cognitive domain more affected in hypertensive patients, depends on the integrity of the connection between the frontal lobe (dorsolateral prefrontal cortex) and subcortical nuclei (caudate, globus pallidus). Subcortical vascular damage produced by HTN demyelinates fibers, being responsible for disconnection syndrome. Three trials made in Argentina showed that executive dysfunction is more frequent in hypertensive patients than in those with normal pressure [45]; that such dysfunction advances (6-year follow-up) independently from BP control [46]; and its prevalence (using the clock-drawing test) reached 36-2% in the Corazón-Cerebro study, a multicenter study including 1281 patients with diagnosis of HTN [47].

The United States Veterans Affairs (a nested database that included 819,491 men) showed that using ARBs significantly reduced the incidence (55%) and progression (70%) of dementia and AD compared to the use of ACEI (lisinopril) or other non-ARB, non-ACEI cardiovascular medications [48].

The capacity of the different antihypertensive drugs of crossing the blood-brain barrier (BBB) depends on the liposolubility of drugs and its altered permeability. In this regard, ACEI (captopril, lisinopril, perindopril and ramipril) and ARBs (candesartan, ibersartan, valsartan and telmisartan) are drugs of central action given their greater capacity to penetrate cerebral tissues and exerting a positive effect on cognitive function [49-51].

On the other hand, ACEI and ARBs without central action (benazepril, enalapril, quinapril or losartan, olmesartan) seem to lack an effect on cognition [52]. The CHS-Cognition (Cardiovascular Health Study Cognition), a sub-study of CHS, demonstrated in a 6-year follow-up that ACEI of central action reduce the risk of cognitive decline by 65% per year, while the accumulated doses of ACEI without central action was associated to a greater incidence of dementia [53]. In agreement with this, perindopril (ACEI of central action) reduced 25% of cognitive decline in patients with mild to moderate AD [54]. Stuhec M et al’s review (15 RCT) suggested also that ARBs are better than other antihypertensive drugs; particularly in regard to improvement of episodic memory [55]. Likewise, in the review by Marpillat NL et al, ARBs presented more benefits on cognitive function than BBs, diuretics and ACEI [56].

 

META-ANALYSIS
The results of the previously mentioned RCT and others with less sound conclusions were included in different meta-analyses providing more evidence on the use of antihypertensive treatment on cognitive function (Table 3).

Table 3 . Meta-analysis
  Meta-analysis Number of trials Number of individuals Results
  PROGRESS, Syst-Eur, SHEP, HYVET meta-analysis [17] 4 RCT 14,946 Reduction in incidence of dementia (HR 0.87, 95% CI 0.76-1.0)
  Birns J et al. [57] 16 RCT 19,501 Heterogeneous effect on different cognitive functions
  Chang-Quan H et al. [58] 14 longitudinal 69,563 Reduction in VD incidence (RR 0.67, 95% CI 0.52-0.87)
  Levi Marpillat N et al. [56] 19 RCT + 11 trials 18,515 + 831,674 Reduction in risk of dementia incidence (HR 0.91, 95% CI 0.89-0.94).
  Rouch L et al. [38] 11 RCT + 9 MA 1,346,176 Reduction incidence and progression of CI and dementia (VD and AD)
  Guangli Xu et al. [59] 10 RCT 30,895 Reduction in incidence of dementia (RR 0.86, 95% CI 0.75-0.99). CCB and ARBs are superior.
  References. RCT: Randomized controlled trial; MA: meta-analysis; AD: Alzheimer’s disease; VD: vascular dementia; CI: cognitive impairment


While some meta-analyses showed the benefits of antihypertensive treatment on the different aspects of cognitive function, others reported decreasing the incidence of dementia. Unlike the PROGRESS and Syst-Eur trials, the HYVET-COG and SHEP trials did not yield conclusive results. However, the four studies included in a meta-analysis support using antihypertensive treatment to reduce the incidence of dementia (HR 0.87; 95% CI, 0.76-1.0) [17].

The review by Birns et al, concluded that antihypertensive treatment had a heterogeneous effect on different cognitive domains [57]. On 16 studies that gathered more than 19501 individuals, it was shown that antihypertensive treatment improves cortical cognitive functions (MMSE score and memory tasks); but did not observe an improvement on the functions involving subcortical structures, suggesting they continue to decline beyond BP reduction.

In this sense, a case-control study performed on hypertensive patients, showed the progressive compromise of executive functions (sub-cortical functions), even when BP values remained controlled for the 6 years of follow-up of the study [46]. The analysis made from 14 longitudinal studies that included more than 70,000 patients with follow-ups between 2.2 and 7.6 years, made by Chang-Quan H, et al, proved that antihypertensive treatment decreased the incidence of dementia (RR 0.67; 95% CI; 0.52-0.87), with no effect on cognitive compromise [58].

In a recent network meta-analysis on 19 RCT (n=18515 and follow-ups from 1 to 14 months), added to 11 studies (n=831674, 4 RCT and 7 observational studies), Marpillat NL et al, concluded that the antihypertensive treatment reduced 9% the risk of dementia (HR 0.91, 95% CI, 0.89-0.94) and presented benefits on all cognitive domains except language [56]. In the systematic review by Rouch et al, including more than 1.3 million individuals with an average age of 74 years in 38 publications (18 longitudinal studies, 11 RCT and 9 meta-analysis), it was shown that antihypertensive medication may decrease the risk of cognitive impairment, cognitive decline progression and dementia, not just vascular dementia but also AD [38]. On the other hand, the meta-analysis by Guangli-Xu et al, (10 cohort prospective studies, n=30895 and follow-up 2.2 to 32 years), showed that antihypertensive treatment only decreased the incidence of dementia (RR 0.86; 95% CI, 0.75-0.99), but not so the incidence of AD, cognitive impairment or cognitive decline [59].

 

CONCLUSIONS
As knowledge advances, increasingly investigations support the role of hypertension in the development and progression of neurocognitive diseases (cognitive impairment, dementia and AD). Antihypertensive treatment has proven to be effective not only in controlling BP, but also in slowing down the progression of cerebral vascular injury and decreasing the incidence of stroke, in such a manner that it is logical to think that the benefit may extend on clinical expression, delaying decline and cognitive impairment, as well as preventing dementia. However, the lack of studies designed specifically to evaluate the impact of antihypertensive treatment on cognitive function makes some results controversial.

In recent decades, randomized trials and meta-analysis have documented the benefits of antihypertensive drugs to preserve cognitive health, preventing its decline or deterioration and preventing dementia; but the benefits seem to differ according to the class of drugs. Among them, using drugs modulating the response of the renin-angiotensin system (ACEI or ARBs), CCBs and the property of some of them of crossing the BBB could be better than others to preserve cognitive function by a mechanism independent from BP decrease and control, suggesting a cerebroprotective effect.

From a statistical point of view there is evidence supporting the use of antihypertensive drugs to improve cognitive results; however, more studies are necessary to provide sound evidence that may enable reaching better recommendation levels. Nonetheless, and cautiously, current data should be accepted and infer them as evidence, because during the time that scientific investigation requires to reach sound conclusions, we may have missed the chance to revert the current situation and its subsequent negative impact on public health.

 

BIBLIOGRAPHY

  1. Launer LJ, Masaki K, Petrovitch H, et al. The association between mid-life blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. JAMA 1995; 274: 1846-51.
  2. Ruitenberg A, Skoog I, Ott A, et al. Blood pressure and risk of dementia: results from the Rotterdam Study and Gothenberg H-70 Study. Dementia Geriatr Cog Dis 2001; 12: 33-39.
  3. Qiu C, von Strauss E, Fastbom J, et al. Low blood pressure and risk of dementia in the Kungsholmen Project. Arch Neurol 2003; 60: 223-28.
  4. Stewart R, Xue QL, Masaki K, et al. Change in blood pressure and incident dementia: a 32-year prospective study. Hypertension 2009; 54: 233-40.
  5. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2224-60.
  6. Prince M, Albanese E, Guerchet M, et al. World Alzheimer’s Report 2014. Dementia and risk reduction. An analysis of protective and modifiable risk factors. Published by Alzheimer’s Disease International (ADI), London, September 2014. Disponible en: https://www.alz.co.uk/research/world-report-2014
  7. Verhaaren BF, Vernooij MW, de Boer R, et al. High blood pressure and cerebral white matter lesion progression in the general population. Hypertension 2013; 61: 1354-59.
  8. Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 1998; 352: 1347-51.
  9. Forette F, Seux ML, Staessen JA, et al. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Systolic Hypertension in Europe Investigators. Arch Intern Med 2002; 162: 2046-52.
  10. In’t Veld BA, Ruitenberg A, Hofman A, et al. Antihypertensive drugs and incidence of dementia: the Rotterdam Study. Neurobiol Aging 2001; 22: 407-12.
  11. SHEP Cooperative Reasearch Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the systolic hypertension in the elderly program (SHEP). JAMA 1991; 265: 3255-64.
  12. The SPRINT MIND Investigators for the SPRINT Research Group. Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. JAMA 2019; 321: 548-9.
  13. Kjeldsen SE, Narkiewicz K, Burnier M, et al. Intensive blood pressure lowering prevents mild cognitive impairment and possible dementia and slows development of white matter lesions in brain: the SPRINT Memory and Cognition IN Decreased Hypertension (SPRINT MIND) study. Blood Press 2018; 27: 247-48.
  14. Bosch J, Yusuf S, Pogue J, et al. Use of ramipril in preventing stroke: double blind randomisedtrial. Br. Med. J 2002; 324: 699702.
  15. PROGRESS collaborative group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack Lancet 2001; 358: 1033-41.
  16. Tzourio C, Anderson C, Chapman N, et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 2003; 163 (9):1069-75.
  17. Peters R, Beckett N, Forette F, et al. Incident dementia and blood pressure lowering in the hypertension in the very elderly trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. Lancet Neurol 2008; 7: 683-89.
  18. Peters R, Collerton J, Granic A, et al. Antihypertensive drugs use and risk of cognitive decline in the very oldman observational study- the Newcastle 85+ Study. J Hypertens 2015; 33: 2156-64.
  19. Trompet S, Westendorp RG, Kamper AM, et al. Use of calcium antagonists and cognitive decline in old age. The Leiden 85-plus study. Neurobiol Aging 2008; 29: 306-8.
  20. Streit S, Poortvliet RKE, Gussekloo J. Lower blood pressure during antihypertensive treatment is associated with higher all-cause mortality and accelerated cognitive decline in the oldest-old-data from the Leiden 85-plus Study. Age Ageing 2018; 47 (4): 545-550. doi: 10.1093/ageing/afy072.
  21. Corrada MM, Hayden KM, Paganini-Hill A, et al. Age of Onset of Hypertension and Risk of Dementia in the Oldest-Old: The 90+ Study. Alzheimers Dement 2017; 13: 103-110.
  22. Ogliari G, Westendorp RG, Muller M, et al. Blood pressure and 10-year mortality risk in the Milan Geriatrics 75+ Cohort Study: role of functional and cognitive status. Age Ageing 2015; 44: 932-37.
  23. Mossello E, Pieraccioli M, Nesti N, et al. Effects of low blood pressure in cognitively impaired elderly patients treated with antihypertensive drugs. JAMA 2015; 175: 578-85.
  24. Benetos A, Bulpitt CJ, Petrovic M, et al. An Expert Opinion From the European Society of Hypertension-European Union Geriatric Medicine Society Working Group on the Management of Hypertension in Very Old, Frail Subjects. Hypertension 2016; 67: 820-25.
  25. Fogari R, Mugellini A, Zoppi A, et al. Influence of losartan and atenolol on memory function in very elderly hypertensive patients. J Hum Hypertens 2003; 17: 781-85.
  26. Pérez-Stable, Halliday R, Gardiner PS et al. The effects of propranolol on cognitive function and quality of life: a randomized trial among patients with diastolic hypertension Am J Med 2000; 108: 359-65.
  27. Hajjar I, Catoe H, Sixta S, et al. Cross-sectional and longitudinal association between antihypertensive medications and cognitive impairment in an elderly population. J Gerontol A Biol Sci Med Sci 2005; 60: 67-73.
  28. Rosenberg PB, Mielke MM, Tschanz J, et al. Effects of cardiovascular medications on rate of functional decline in Alzheimer disease. Am J Geriatr Psychiatry 2008; 16: 883-92.
  29. Khachaturian AS, Zandi PP, Lyketsos CG, et al. for the Cache County Study Group. Antihypertensive Medication Use and Incident Alzheimer Disease. Arch Neurol 2006; 63: 689-92.
  30. Gelber RP, Webster Ross G, Petrovitch H, et al. Antihypertensive medication use and risk of cognitive impairment. The Honolulu-Asia Aging Study. Neurology 2013; 81: 888-95.
  31. Hajjar I, Catoe H, Sixta S, et al. Cross-sectional and longitudinal association between antihypertensive medications and cognitive impairment in an elderly population. J Gerontol A Biol Sci Med Sci 2005; 60 (1): 67-73.
  32. DeLoach T and Beall j. Diuretics: A possible keystone in upholding cognitive health. Ment Health Clin [Internet] 2018; 8 (1): 33-40.
  33. Tully PJ, Hanon O, Cosh S, et al. Diuretic antihypertensive drugs and incident dementia risk: a systematic review, meta-analysis and meta-regression of prospective studies J Hypertension 2016, 34: 1027-35.
  34. Sabbatini M, Tomassoni D, Amenta F. Hypertensive brain damage: comparative evaluation of protective effect of treatment with dihydropyridine derivatives in spontaneously hypertensive rats. Mech Ageing Dev 2001; 122: 2085-105.
  35. van Middelaar T, van Vught LA, Moll van Charante EP, et al. Lower dementia risk with different classes of antihypertensive medication in older patients. J Hypertens 2017; 35: 2095-2101.
  36. Peters R. No clear relationship between antihypertensive class and cognitive function over 12 months in a cohort study of community-dwelling adults aged 80 and over. Ther Adv Chronic Dis 2019; Jan 31; doi:10:2040622318820849.
  37. Rouch L, Cestac P, Hanon O, et al. Antihypertensive drugs, prevention of cognitive decline and dementia: a systematic review of observational studies, randomized controlled trials and meta-analyses, with discussion of potential mechanisms. CNS Drugs 2015; 29: 113-30.
  38. Gironacci MM, Vicario A, Cerezo GH, et al. The depressor axis of the renin–angiotensin system and brain disorders: a translational approach Clinical Science 2018; 132: 1021-38.
  39. Braszko JJ, Karwowska-Polecka W, Halicka D, et al. Captopril and enalapril improve cognition and depressed mood in hypertensive patients. J Basic Clin Physiol Pharmacol. 2003; 14: 323-43.
  40. Anderson C, Teo K, Gao P, et al. Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies. Lancet Neurol 2011; 10: 43-53.
  41. Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003; 21: 875-86.
  42. Skoog I, Lithell H, Hansson L, et al. SCOPE Study Group. Effect of baseline cognitive function and antihypertensive treatment on cognitive and cardiovascular outcomes: Study on Cognition and Prognosis in the Elderly (SCOPE). Am J Hypertens 2005; 18: 1052-59.
  43. Hajjar I, Hart M, Milberg W, et al. The rationale and design of the antihypertensives and vascular, endothelial, and cognitive function (AVEC) trial in elderly hypertensives with early cognitive impairment: Role of the renin angiotensin system inhibition BMC Geriatrics 2009, 9:48-58.
  44. Hajjar I, Hart M, Chen YL, et al. Effect of antihypertensive therapy on cognitive function in early executive cognitive impairment: a double-blind randomized clinical trial.Arch. Intern. Med 2012; 172: 442-44.
  45. Vicario A, Martinez CD, Barreto D, et al. Hypertension and cognitive decline: Impact on executive function. J Clin Hypertens 2005; 7: 598-604.
  46. Vicario A, del Sueldo M, Zilberman J, et al. Cognitive evolution in hypertensive patients: a six-years follow-up. Vasc Health Risk Manag 2011; 7: 1-5.
  47. Vicario A, Cerezo GH, del Sueldo M, et al. On behalf of the Heart-Brain Research Group in Argentina with the support of the Argentine Federation of Cardiology (FAC). Neurocognitive disorder in hypertensive patients. Heart-Brain Study. Hipertens Riesgo Vasc 2018; 35: 169-76.
  48. Li NC, Lee A, Whitmer RA, et al. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. Br Med J 2010; 340: b5465.
  49. Wharton W, Goldstein FC, Tansey MG, et al. Rationale and design of the mechanistic potential of antihypertensives in preclinical Alzheimer’s (HEART) trial. J Alzheimers Dis 2018; 61: 815-24.
  50. Ohrui T, Tomita N, Sato-Nakagawa T, et al. Effects of brain-penetrating ACE inhibitors on Alzheimer disease rogression. Neurology 2004; 63: 1324-25.
  51. Ho JK, Nation DA, Alzheimer’s Disease Neuroimaging Initiative. Memory is preserved in older adults taking AT1 receptor blockers. Alzheimers Res Ther 2017; 9 (1): 33.
  52. Rygiel K. Can angiotensin-converting enzyme inhibitors impact cognitive decline in early stages of Alzheimer’s disease? An overview of research evidence in the elderly patient population. J Postgrad Med 2016; 62: 242-48.
  53. Sink KM, Leng X, Williamson J, et al. Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the Cardiovascular Health Study. Arch. Intern. Med 2009; 169: 1195-1202.
  54. Gao Y, O’Caoimh R, Healy L, et al. Effects of centrally acting ACE inhibitors on the rate of cognitive decline in dementia. BMJ Open 2013; 3: 1-8.
  55. Stuhec M, Keuschler J, Serra-Mestres J, et al. Isetta M. Effects of different antihypertensive medication groups on cognitive function in older patients: A systematic review. Eur Psychiatry 2017; 46: 1-15.
  56. Levi Marpillat N, Macquin-Mavier I, Tropeano AI, et al. Antihypertensive classes, cognitive declineand incidence of dementia: a network meta-analysis. J Hypertens 2013; 31: 1073-82.
  57. Birns J, Morris R, Donaldson N, et al. The effects of blood pressure reduction on cognitive function: a review of effects based on pooled data from clinical trials. J Hypertens 2006; 24: 1907-14.
  58. Chang-Quan H, Hui W, Chao-Min W et al. The association of antihypertensive medications use with risk of cognitive decline and dementia: a meta-analysis of longitudinal studies. In J Clin Pract 2011; 65: 1295-305.
  59. Guangli Xu, Feng Bai, Xin Lin, et al. Association between Antihypertensive Drug Use and the Incidence of Cognitive decline and Dementia: A Meta-Analysis of Prospective Cohort Studies. BioMed Research International 2017, Article ID 4368474.

Publication: September 2019



BUSQUEDAS

Revista de FAC

gogbut


Contenidos Científicos
y Académicos

gogbut