Effect of telmisartan/hydrochlorothiazide vs lisinopril ... - Nature

Journal of Human Hypertension (2006) 20, 177–185 & 2006 Nature Publishing Group All rights reserved 0950-9240/06 $30.00 www.nature.com/jhh

ORIGINAL ARTICLE

Effect of telmisartan/hydrochlorothiazide vs lisinopril/hydrochlorothiazide combination on ambulatory blood pressure and cognitive function in elderly hypertensive patients R Fogari, A Mugellini, A Zoppi, P Lazzari, M Destro, A Rinaldi and P Preti Department of Internal Medicine and Therapeutics, Clinica Medica II, IRCCS Policlinico S. Matteo, University of Pavia, Pavia, Italy

The aim of this study was to compare the effects of telmisartan/hydrochlorothiazide (HCTZ) vs lisinopril/ HCTZ combination on ambulatory blood pressure and cognitive function in elderly hypertensive patients. A total of 160 patients, 76 men and 84 women, aged 61–75 years, with sitting diastolic blood pressure (DBP) 490 mmHg and o110 mmHg and systolic blood pressure (SBP) 4140 mmHg were randomized to receive temisartan 80 mg/HCTZ 12.5 mg o.d. or lisinopril 20 mg/HCTZ 12.5 mg o.d. for 24 weeks, according to a prospective, open-label, blinded end point, parallelgroup design. At the end of a 2-week wash-out period and after 12 and 24 weeks of active treatment, 24-h noninvasive ambulatory BP monitoring (ABPM) was performed and cognitive function was evaluated through six different tests (verbal fluency, Boston naming test, word-list memory, word-list recall, wordlist recognition and Trails B). Both treatments signifi-

cantly reduced ambulatory BP. However, the telmisartan/HCTZ combination produced a greater reduction in 24-h, day-time and night time ABPM values. Lisinopril/ HCTZ did not induce significant changes in any of the cognitive function test scores at any time of the study, whereas at both 12 and 24 weeks telmisartan/HCTZ significantly improved the word-list memory score ( þ 17.1 and þ 15.7%, respectively, Po0.05 vs baseline), the word-list recall score ( þ 13.5 and þ 16.9%, Po0.05) and the Trails B score (33 and 30.5%, Po0.05). These results suggest that in elderly hypertensive patients treatment with telmisartan/HCTZ produces a slightly greater reduction in ambulatory BP than lisinopril/HCTZ combination and, unlike this latter, improves some of the components of cognitive function, particularly episodic memory and visuospatial abilities. Journal of Human Hypertension (2006) 20, 177–185. doi:10.1038/sj.jhh.1001964; published online 24 November 2005

Keywords: telmisartan/HCTZ; lisinopril/HCTZ; hypertensive elderly; cognitive functions

Introduction Longitudinal and epidemiological studies have shown a relationship between high blood pressure (BP) and cognitive impairment later in life.1–3 This suggests that, in addition to being a powerful risk factor for cardiovascular disease, hypertension in elderly patients increases the risk of decline in cognitive function. Active lowering of BP should prevent or reduce cognitive impairment, although not all antihypertensive agents seem to be equally effective in this regard.4–8

Correspondence: Dr R Fogari, Department of Internal Medicine and Therapeutics, Clinica Medica II, IRCCS Policlinico S. Matteo, University of Pavia, Piazzale Golgi 19, 27100 Pavia, Italy. E-mail: [email protected] Received 21 July 2005; revised 27 September 2005; accepted 1 October 2005; published online 24 November 2005

Growing evidence has suggested that the renin– angiotensin system (RAS) in the central nervous system participates in the processing of sensory information, learning and memory.9,10 Brain angiotensin II (Ang II) and its fragments Ang IV and Ang III have been shown to influence performance in learning and memory paradigms directly or by modulating the activity of other neurotransmitters, like acetylcholine, catecholamines, serotonin and other peptides.11–13 Beyond being implicated in neuronal functions regulation, these neurotransmitters also regulate local vasomotility and endothelium-dependent relaxation, which is of relevance for maintaining the physiological self-regulation of brain flow, that is presumed to be necessary to correct performance of cerebral functions.14 Owing to the role of the RAS in modulating cognitive processes, drugs that interfere with the RAS like angiotensin-converting enzyme inhibitors (ACE-I)

Antihypertensive treatment and cognitive functions in the elderly R Fogari et al 178

and Ang II AT1 receptor blockers (ARB) possess the potential of preventing cognitive decline and even improving cognitive function in hypertensive patients. Indeed experimental and clinical studies have shown that these drugs may influence cognitive performance positively, improving learning and memory.15–22 Both ACE-I and ARB are used in the treatment of hypertension in the elderly, due to their good efficacy/tolerability profile. However, in order to achieve the newly recommended BP goals, the use of combination therapy has been advocated on the grounds that its individual components may exert additive if not synergistic effect on BP.23,24 In this regard, since the pharmacological effects of hydrochlorothiazide (HCTZ) include the activation of the RAS, its association with an ACE-I or an ARB is a rational and useful approach, affording effective BP control while minimizing possible side effects.25,26 To date, at our knowledge, no data have been reported about the influence of this type of combination therapy on cognitive performance. With this background, the present study was undertaken to compare the effects of the fixed combination of the ARB telmisartan27 and HCTZ with those of the fixed combination of the ACE-I lisinopril28 and HCTZ on ambulatory BP and cognitive function of elderly hypertensive patients, who are likely to be the most susceptible to the effects of antihypertensive drugs on cognitive function.29

Patients and methods This was a prospective, randomized, open-label, blinded end point (PROBE),30 parallel group study with two treatment arms. A total of 160 outpatients aged 61–75 years entered a 2-week wash-out period, after which they were considered eligible for enrolment if they had a sitting diastolic BP (DBP)X95 and o110 mmHg and a sitting systolic BP (SBP)4140 mmHg. Exclusion criteria included: secondary hypertension, myocardial infarction or cerebrovascular accident within the preceding 6 months, clinically significant valvular heart disease, heart failure, renal or hepatic insufficiency and known hypersensitivity to the drugs used in the study. The study was performed in accordance with the Declaration of Helsinki; the protocol was approved by the local Ethical Committee and all of the patients gave their informed consent before enrolment. At the end of an initial 2-week wash-out period, during which any eventual antihypertensive drug was discontinued, patients fulfilling the inclusion criteria were randomized to the telmisartan (80 mg)/HCTZ (12.5 mg) combination or to the lisinopril (20 mg)/HCTZ (12.5 mg) combination, both given once daily at the same hour in the morning (approximately at 0800) for 24 weeks. Journal of Human Hypertension

Patients were checked at the end of the wash-out period and after 12 and 24 weeks of active treatment. At each visit, 24-h ambulatory BP monitoring (ABPM) was performed, using a portable, noninvasive, fully automatic BP recorder (ICR 90207; Spacelabs Inc., Bellevue, CA, USA), validated against intra-arterial BP measurements.31 The recorder was set to take readings at 15-min intervals throughout the 24-h period. Recordings were always started at the same hour in the morning and were performed throughout the 24-h period, during which patients were allowed to follow their normal daily routine after they left the laboratory. Recordings were excluded from the analysis when more than 10% of all readings or more than one reading per hour were missing or incorrect. For each patient, the following data relating to SBP, DBP and heart rate (HR) were provided by the analysis of the recordings: 24-h mean values, daytime (0700–2300) mean values, night time (2300– 0700) mean values and hourly mean values. Furthermore, for each patient the percentage of 24-h, day time and night time SBP and DBP readings 4140 and 490 mmHg, respectively, was provided by the system. Following the recommendations of US Food and Drug Administration (FDA),32 the trough-to-peak (T/P) ratio, defined as the ratio between the effect of an antihypertensive agent at the end of the interval between doses (trough) and at the time of its maximum effect (peak), was evaluated in each treatment group. For each ABPM recording, trough SBP and DBP levels were calculated as the average of the BP readings taken 22–24 h after the dose, whereas the peak values were calculated as the average of the hour that showed the maximal average decrease in BP between 2 and 8 h after the dose plus the preceding or the following hour depending on which showed the greater decreae in BP.33 Data were averaged for all patients. To quantify the homogeneity of the antihypertensive effect over the 24 h, the smoothness index (SI) was also computed by dividing the average of the 24 hourly change after treatment by the corresponding (s.d.).34 This measurement has been shown to reflect whether treatment smoothly reduces BP throughout a 24-h period and seems to provide a better assessment of homogeneity of antihypertensive treatment than T/P ratio.34 Cognitive function was assessed at the end of the wash-out period and after 12 and 24 weeks of active treatment by means of the following six tests. Verbal fluency

The subjects were asked to name as many animals as possible in 1 min and the score was the total number of different animals named. Higher scores indicated less cognitive impairment. This verbal fluency test35 measures impairments in verbal production, semantic memory and language and is particularly sensi-


tive to early mental decline in older people. It is also a sensitive indicator of damage to the lateral frontal lobe.36 Modified Boston naming test

The subjects were asked to name 15 objects presented as line drawings, with a maximum of 10 s being allowed for each. The modified Boston naming test37 was scored on the basis of the number of correct answers (maximum score: 15). Word-list memory test

A total of 10 printed words were presented at the rate of one every 2 s, and the subjects were then asked to recall as many as possible within a period of 90 s (maximum score: 10). This word-list memory test38 assesses the ability to remember newly learned information. Word-list recall test

This delayed memory test38 assesses the ability to remember the same 10 printed words after a delay of 10 min. A maximum of 90 s is allowed (maximum score: 10). Word-list recognition

The 10 words from the word-list memory test are presented with 10 distractors. The subject’s score in this recognition test is the number of correctly recognized words.39 For the word-list tests, two different word lists were used at baseline and after 12 and 24 weeks of treatment in order to avoid that the patients have already learned the list once. Trails B test

This is a test of speeded mental operations, attention, visual scanning, visual sequential abilities and executive function.40 Scores are measured in seconds, with higher scores indicating slower or poorer performance; an upper cutoff score of 181 s was used when time to complete the text exceeded 180 s. The cognitive function tests were performed on each visit by the same investigator blinded to clinical and active treatment findings. Persons who administered the tests attended a 2-day training session conducted by neuropsychologists who were experts in cognitive function measurements. The tests used in the study were chosen because they have been shown to be reproducible and are valid measures of cognitive function.38 Also, in our experience the test–retest reliability has been found to be high (r ¼ 0.78 for verbal fluency test; r ¼ 0.71 for Boston naming test; r ¼ 0.70 for word-list memory test; r ¼ 0.81 for word-list recall test; r ¼ 0.77 for word-list recognition test; r ¼ 0.79 for Trails B test).

Adverse events spontaneously reported or elicited by indirect questioning by investigators blinded to patients’ treatment were recorded. Treatment compliance was assessed by counting the tablets remaining at each visit. Statistical analysis

All analyses were conducted using the SAS system, version 6.12 (SAS Institute Inc., Cary, NC, USA). Analysis of covariance (ANCOVA) was used to compare the changes in clinical variables. In addition 95% confidence intervals for pairwise differences between treatment means were calculated. Differences in T/P ratios between treatments were evaluated by nonparametric test (signed rank test Proc Univariate), whereas the paired Student’s t-test was used to assess the differences in SI. Correlation analysis was performed using Pearson’s correlation test. A P-value of o0.05 was set as the level of clinical significance. All of the results are given as mean values7s.d.

Results A total of 160 patients, 76 men and 84 women, with a mean age of 67.674.5 years were randomized to receive telmisartan 80 mg/HCTZ 12.5 mg (n ¼ 80) or lisinopril 20 mg/HCTZ 12.5 mg (n ¼ 80). Their demographic and clinic characteristics at baseline are shown in Table 1. No statistically significant differences between groups were found in any of the baseline characteristics. In all, 13 patients withdrew after randomization, six for adverse events (two in the telmisartan/HCTZ group for headache, dizziness and nausea, four in the lisinopril/HCTZ group: three for cough and one for hypotension), four for inadequate therapeutic response (DBP reduction o10 mmHg) and three did not return for clinic visit. A total pf 147 patients completed the study, 75 in the telmisartan/HCTZ group and 72 in the lisinopril/HCTZ group. Results of 24-h ABPM, daytime and night time SBP and DBP obtained during treatment with telmisartan/HCTZ and lisinopril/HCTZ combination are shown in Table 2. Both treatments signifiTable 1 Main baseline demographic and clinic characteristics of the patients of the two treatment groups

Number of patients Age (years) Gender (male/female) Body weight (kg) Duration of hypertension (years) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats/min)

Telmisartan/ HCTZ

Lisinopril/ HCTZ

80 67.8975.4 35/45 71.8712.3 8.276.5 163.877.9 101.774.0 75.976.1

80 68.375.6 39/41 72.1712.2 8.576.6 164.277.7 101.374.1 76.275.8

Journal of Human Hypertension


cantly decreased ambulatory SBP and DBP values as compared to baseline (Po0.01 vs baseline for both SBP and DBP with both drugs). However, analysis for adjusted means showed that the mean decreases in 24-h, daytime and night time SBP and DBP obtained with the telmisartan/HCTZ combination were significantly greater than those obtained with the lisinopril/HCTZ combination, particularly at 24 weeks (Po0.05 for 24-h and daytime SBP and DBP and for night time SBP; Po0.01 for night time DBP) (Figure 1). Calculation of hourly average SBP and DBP (Figure 2) showed that both telmisartan/HCTZ and lisinopril/HCTZ combination maintained their antihypertensive efficacy throughout the 24 h, including the hours farthest from the last drug intake, without

altering the normal circadian BP pattern. Both combinations significantly decreased the percentages of SBP readings 4140 mmHg as well as the percentages of DBP readings 490 mmHg in all ABPM periods. However, telmisartan/HCTZ combination was significantly superior to lisinopril/HCTZ in reducing the percentages of SBP readings 4140 mmHg in the 24-h and daytime ABPM periods at both 12 and 24 weeks as well as the percentages of DBP readings 490 mmHg in the 24-h and daytime ABPM periods at 12 weeks (Table 3). For both treatments, the T/P ratios for SBP and DBP were greater than 0.5, with no significant differences between telmisartan/HCTZ and lisinopril/HCTZ combination. Also the average SI of SBP and DBP was similar for the two treatments (Table 4).

Table 2 Mean values (7s.d.) of ambulatory BP during treatment with telmisartan/HCTZ and lisinopril/HCTZ Variable

24 h Baseline

12 weeks

SBP (mmHg) Telm/HCTZ 151.579.9 132.175.0 Lisin/HCTZ 151.3710.2 133.675.5 DBP (mmHg) Telm/HCTZ Lisin/HCTZ

90.273.8 90.174.2

77.075.6* 78.776.4

Daytime 24 weeks

Baseline

12 weeks

Night time 24 weeks

Baseline

12 weeks

24 weeks

129.375.2* 155.879.9 136.075.0* 133.175.3* 138.7711.5 120.476.8 117.476.8* 131.775.4 155.5710.2 137.575.5 135.475.4 138.7711.6 121.877.4 119.877.2 75.076.6* 76.975.5

93.573.9 93.474.1

79.775.7 81.476.6

78.176.8* 79.877.0

79.975.7 80.375.9

68.476.5 69.877.0

66.277.1** 68.676.3

* ¼ Po0.05 vs lisinopril/HCTZ. ** ¼ Po0.01 vs lisinopril/HCTZ.

Figure 1 Mean7s.d. decreases from baseline in 24-h ambulatory blood pressure monitoring and daytime and nigth time systolic blood pressure (SBP) and diastolic blood pressure (DBP) obtained after 12 and 24 weeks of treatment with telmisartan/HCTZ and lisinopril/ HCTZ. Differences (and 95% confidence intervals) between treatments are shown at the bottom of each pair of histograms. Journal of Human Hypertension


Ambulatory HR was not affected by treatment with both telmisartan/HCTZ and lisinopril/HCTZ combination.

The average cognitive test scores at baseline and after 12 and 24 h of active treatment are shown in Table 5. Lisinopril/HCTZ combination did not lead to any significant changes in any test score at any time of the study, whereas telmisartan/HCTZ combination significantly increased the scores of the word-list memory ( þ 17.1% at 12 weeks, Po0.05 vs baseline and vs lisinopril/HCTZ; þ 15.7% at 24 weeks, Po0.05 vs baseline), the word-list recall ( þ 13.5% at 12 weeks, Po0.05 vs baseline; þ 16.9% at 24 weeks, Po0.05 vs baseline and vs lisinopril/ HCTZ) and the Trails B (33% at 12 weeks, Po0.05 vs baseline; 30.5% at 24 weeks, Po0.05 vs baseline). The scores of the Boston naming, wordlist recognition and verbal fluency tests were not significantly changed by telmisartan/HCTZ (Figure 3). There was no significant correlation between the changes in cognitive test scores and the decrease in BP after 12 and 24 weeks of treatment with either drug. Based on counting the remaining tablets at each visit, 94% of the prescribed tablets were taken during telmisartan/HCTZ therapy and 92% during lisinopril/HCTZ therapy, indicating good treatment compliance. Both treatments were generally well tolerated. Six patients reported one or more adverse events: two

Figure 2 Systolic blood pressure (SBP) and diastolic blood pressure (DBP) (24 h) at baseline and after receiving telmisartan/ HCTZ for 12 and 24 weeks.

Table 3 Mean percentages of ambulatory BP readings exceeding 140 mmHg for systolic BP (SBP) and 90 mmHg for diastolic BP (DBP) during treatment with telmisartan/HCTZ and lisinopril/HCTZ Variable

24 h

Daytime

Night time

Baseline

12 weeks

24 weeks

Baseline

12 weeks

24 weeks

Baseline

12 weeks

24 weeks

SBP4140 (mmHg) Telm/HCTZ Lisin/HCTZ

77.0 75.9

24.0*** 29.7

15.4*** 20.8

89.1 87.9

31.4*** 38.7

20.2*** 26.9

40.8 39.8

1.7* 5.7

1.1 2.7

DBP490 (mmHg) Telm/HCTZ Lisin/HCTZ

52.7 53.9

6.2** 10.2

67.7 68.0

8.0*** 13.2

9.7 11.8

0.8 1.1

0.2 0.6

5.0 6.5

6.6 8.4

* ¼ Po0.05 vs lisinopril/HCTZ. ** ¼ Po0.01 vs lisinopril/HCTZ. *** ¼ Po0.001 vs lisinopril/HCTZ.

Table 4 Trough/peak ratio and smoothness index (mean values7s.d.) for systolic BP (SBP) and diastolic BP (DBP) during treatment with telmisartan/HCTZ and lisinopril/HCTZ Variable

Trough/peak ratio

Smoothness index

12 weeks

24 weeks

12 weeks

24 weeks

SBP (mmHg) Telmisartan/HCTZ Lisinopril/HCTZ

0.6370.35 0.5770.44

0.6370.30 0.5870.37

2.3271.55 2.0671.35

2.6971.81 2.4471.53

DPB (mmHg) Telmisartan/HCTZ Lisinopril/HCTZ

0.6470.36 0.5670.37

0.6270.30 0.5670.26

1.9670.91 1.8770.91

2.3271.13 2.0870.94



Table 5 Mean scores of verbal fluency, word-list memory, word-list recall, word-list recognition, Boston naming test and Trails B at the end of the wash-out period and after 12 and 24 weeks of treatment with telmisartan/HCTZ and lisinopril/HCTZ

Verbal fluency (no. words) Word-list memory (no. words) Word-list recall (no. words) Word-list recognition (n.c.a.) Boston naming test (n.c.a.) Trails B (s)

Verbal fluency (no. words) Word-list memory (no. words) Word-list recall (no. words) Word-list recognition (n.c.a.) Boston naming test (n.c.a.) Trails B (s)

Baseline

Telmisartan/HCTZ 3 months

Telmisartan/HCTZ 6 months

14.676.4 7.072.7 5.972.6 7.171.5 13.971.2 158.7774.4

14.876.5 8.272.1*,** 6.772.2* 7.971.4 14.271.3 106.3739.2*

14.475.9 8.172.2* 6.972.1*,** 7.871.3 14.171.4 110.2744.1*

Baseline

Lisinopril/HCTZ 3 months

Lisinopril/HCTZ 6 months

14.176.8 6.972.6 5.872.3 7.271.4 14.171.3 176.5770.7

14.576.7 6.772.7 5.772.4 7.171.3 14.271.4 143.4771.2

14.676.9 6.872.8 5.972.5 7.371.4 13.971.2 145.7771.4

n.c.a.: number of correct answer. * ¼ Po0.05 vs baseline. ** ¼ Po0.05 vs lisinopril/HCTZ.

Figure 3 Systolic blood pressure (SBP) and diastolic blood pressure (DBP) (24 h) at baseline and after receiving lisinopril/ HCTZ for 12 and 24 weeks.

(2.6%) treated with telmisartan/HCTZ (one headache, one dizziness) and four (5.5%) treated with lisinopril/HCTZ (two patients cough, one dizziness and one gastric discomfort). There were no serious adverse experiences considered to be possibly or probably related to the trial medications.

Discussion The results of this study indicate that in elderly hypertensive patients treatment with both telmisartan/HCTZ and lisinopril/HCTZ combination, both Journal of Human Hypertension

administered once daily, produced a clinically relevant reduction in ambulatory BP values, without affecting the normal BP circadian profile. However, the telmisartan/HCTZ combination produced a slightly, but significantly greater decrease in 24-h mean values of SBP and DBP as well as in daytime and night time BP levels. Also the BP load, defined as the percentage of BP readings recorded by the ABPM tecnique that are abnormal in a 24-h period, was more decreased by treatment with the telmisartan/HCTZ combination than with lisinopril/HCTZ. This observation is important since BP load is considered a better determinant of cardiac and vascular damages than either clinic or mean 24-h ABPM values.41 When evaluating the duration and the homogeneity of the hypotensive action over the 24 h, the T/P ratios for SBP and DBP obtained with the telmisartan/HCTZ and the lisinopril/HCTZ combination fulfilled the FDA guidelines (T/P ratio 450%), with no significant difference between the two treatments. This indicates that the antihypertensive action of both treatments was sustained throughout the 24 h, which renders them suitable for once daily administration. Whereas the T/P ratio is exclusively an index of the duration of the antihypertensive effect, the SI is a measure of homogeneity of the hypotensive action.34 In the present study, the SI of SBP and DBP was similar with the two treatments, which indicates that both telmisartan/HCTZ and lisinopril/HCTZ combination smoothly reduced BP values throughout the 24 h, without difference between the two regimens. There was no significant alteration in ambulatory HR values. The most original findings of this study, however, regard the effects of the trial medications on cognitive function. Telmisartan/HCTZ combination


significantly improved the scores of the word-list memory, the word list recall and the Trails B tests. These findings are in agreement with the results obtained by ourselves in previous studies of ARBs21,22 and suggest that the cognitive effects of these drugs may be selective. In particular, there were favourable effects on episodic memory and visuospatial skills, but not on semantic memory and verbal skills. Since episodic memory and visuospatial skills reflect the operation of networks that are widely distributed in the brain, their biological complexity makes them more sensitive to numerous conditions affecting brain function.42–44 Unlike episodic memory, memory span is relatively well preserved in many conditions affecting cognitive function,45 so that it might be difficult to detect any treatment effect on memory span in otherwise healthy hypertensive patients, at least over a relatively short period. The positive effects of telmisartan/HCTZ on memory might be explained by the interactions between Ang II and acethylcoline.46 Ang II inhibits the in vitro release of acethylcholine from the entorhinal cortex associated with cognitive performance and this action is reversed by ARBs.15,47 Besides, experimental studies have shown that endogenous Ang II, which is released in response to AT1 receptor blockade, interacts with AT2 receptors, which may lead to memory-enhancing effects, possibly through the modulation of dopaminergic and noradrenergic transmission.48 Blockade of Ang II at AT1 receptor level may also result in increased synthesis of Ang IV, that selectively binds to AT4 receptors; activation of AT4 receptors is involved in memory acquisition and recall, perhaps by modulating neurotransmitter release and/or remodelling the cholinergic and glutamatergic pathways in the hyppocampus.49,50 Unlike telmisartan/HCTZ combination, lisinopril/ HCTZ combination did not significantly affect any of the cognitive function test scores at any time of the study. These findings confirm that the use of this ACE-I/HCTZ combination did not deteriorate cognitive performance over a period of 24 weeks, which is reassuring when treating elderly hypertensive patients, but did not afford any improving effect. Mechanisms other than the simple ACE-induced inhibition of Ang II synthesis, including the involvement of other fragments of brain Ang II and of brain AT2 and AT4 receptors, might perhaps explain the different effects of telmisartan and lisinopril on cognitive function tests. Correlation analysis showed no relationship between the changes in the cognitive test scores and the decrease in BP after 12 and 24 weeks of treatment with either drug, which suggests that the better outcome of telmisartan/HCTZ combination cannot be ascribed to its greater lowering effect on ambulatory BP levels. It is interesting to note that in the present study using HCTZ in combination with an ARB or an ACEI did not yeld to a deterioration in cognitive

performance of elderly hypertensive or even improved it, whereas contrasting data have been reported in the literature about the cognitive effects of thiazide diuretic monotherapy.5,51,52

Conclusions In conclusion, the results of this study indicate that 24 weeks of treatment with both telmisartan 80 mg/HCTZ 12.5 mg and lisinopril 20 mg/HCTZ 12.5 combination were effective in reducing BP in elderly hypertensive patients. Telmisartan/HCTZ combination, however, produced a greater reduction in ambulatory BP levels and, unlike lisinopril/ HCTZ, improved some cognitive functions, particularly episodic memory and visuospatial abilities. Conflict of interests: None

What is known about this topic: K There is a relationship between high BP and cognitive impairment in later life3 K The brain renin–angiotensin system participates in the processing of attention, learning and memory10 K Angiotensin II AT1 receptors blocker monotherapy seems to improve learning and memory in hypertensive elderly patients22 What this study adds: K An angiotensin II AT1 receptors blockers also in combination with hydrochlorothiazide improves cognitive functions, particularly episodic memory and visual-spatial abilities K An ACE inhibitor, given in combination with hydrochlorothiazide, has no effects on cognitive functions K The changes in cognitive functions are unrelated with the changes in BP

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