- Email: [email protected]
Comparison of losartan and hydrochlorothiazide on cognitive function and quality of life in hypertensive patients
AJH
BRIEF COMMUNICATIONS
1999;12:1130 –1134
Comparison of Losartan and Hydrochlorothiazide on Cognitive Function and Quality of Life in Hypertensive Patients Michele Adolfo Tedesco, Gennaro Ratti, Salvatore Mennella, Gianluca Manzo, Michela Grieco, Anna Carmela Rainone, Diana Iarussi, and Aldo Iacono
We examined long-term changes in cognitive function and quality of life (QL) in hypertensive patients by comparing the antihypertensive effect of hydrochlorothiazide (HCTZ) and losartan. We studied 69 patients (age range, 30 to 73 years) with mild-to-moderate hypertension. All patients, in a double-blind study, were randomly allocated to either treatment with 50 mg losartan once daily or 25 mg HCTZ once daily. The sample in each treatment group was divided by age (younger than 60 years or 60 years or older). At baseline and after 26 months, a QL questionnaire appropriate for the hypertensive patients was given. Cognitive function was evaluated, at baseline and after 26 months, by psychometric tests consisting of items from the Mini-Mental State Examination (MMSE) and the Sandoz Clinical Assessment Geriatric (SCAG). A score of less than 24 on the MMSE and more than 40 on the SCAG was predictive of cognitive impairment. The losartan group had a significant improvement in SCAG (P < .001) and MMSE (P < .001). No significant changes were observed in the HCTZ group (SCAG, P ⴝ .1; MMSE, P ⴝ .2). Sixty-five percent of the elderly
L
ong-standing hypertension is one of the major risk factors for cerebral vascular disease1,2 and is associated with reduced cerebral blood flow, metabolism, and function.3,4 The relationship between blood pressure and cogni-
Received January 15, 1999. Accepted March 22, 1999. From the Medical Surgical Institute of Cardiology, Second University of Naples, Naples, Italy. Address correspondence and reprint requests to Dr. Michele A. Tedesco, Salita Due Porte 14, 80136 Naples, Italy; e-mail: tedesco@ napoli.pandora.it
© 1999 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
had a MMSE score less than 24 and 70% had a SCAG score greater than 40, v 35% and 48%, respectively, in younger patients. The health state index of QL improved significantly in both groups (losartan group, P < .01; HCTZ group, P < .02); the improvement in QL scores in patients using HCTZ was significant only in subjects aged 60 years and older (P < .04). These results suggest that losartan can have a positive effect not only on blood pressure but also on impaired cognitive function, reversing even minimal cognitive deficits induced by hypertension. The elderly patients in our sample had worse scores and cognitive performance was lower than in younger patients, even if in the losartan group the score improvement was the same at all ages. The same could not be said for HCTZ. Am J Hypertens 1999;12:1130 –1134 © 1999 American Journal of Hypertension, Ltd.
KEY WORDS:
Essential hypertension, cognitive function, quality of life, losartan, hydrochlorothiazide.
tive impairment has been found in animals and humans,5–7 particularly in hypertensive subjects older than 65 years, in whom high diastolic blood pressure was predictive of cognitive impairment.8,9 It is less clear whether this impairment could be reversible with antihypertensive treatment.10,11 Of all the drugs available, findings show that angiotensin converting enzyme (ACE) inhibitors can reverse impaired cognitive performance.12 Losartan, the first example of an angiotensin II receptor antagonist, showed a good effect on blood pressure and left ventricular mass,13,14 and seemed to improve cognitive function in hyperten0895-7061/99/$20.00 PII S0895-7061(99)00156-9
AJH–NOVEMBER 1999 –VOL. 12, NO. 11, PART 1
COGNITION, QUALITY OF LIFE WITH LOSARTAN
1131
TABLE 1. CHARACTERISTICS OF THE POPULATION DIVIDED BY AGE Losartan
Patients Age range (years) Gender (M/F) Body mass index (kg/m2) Duration of hypertension (years) Education (years) Smokers (%) Previous treatment (%) Continuously Discontinuously Not at all
< 60 Years
> 60 Years
23 30–59 11/12 27 ⫾ 3 4⫾1 9.5 ⫾ 3.6 35
19 60–73 11/8 25 ⫾ 4 6 ⫾ 2* 8.8 ⫾ 4 32
57 13 30
68 21 11
Hydrochlorothiazide All Patients
42 30–73 22/20 26.7 ⫾ 4 5 ⫾ 1.6 9.2 ⫾ 4 35 61 17 22
> 60 Years
< 60 Years
13 32–59 7/6 26.7 ⫾ 4 3.8 ⫾ 1 9.2 ⫾ 3.8 30
14 61–70 6/8 25 ⫾ 5 6 ⫾ 2.5† 8.7 ⫾ 4 29
54 8 38
64 15 21
All Patients
27 32–70 14/13 26 ⫾ 3 4.8 ⫾ 1.8 8.9 ⫾ 4 30 59 11 30
Values are expressed as mean ⫾ SD. * P ⬍ .001; † P ⬍ .01.
sive patients.13 The aim of this study was to examine long-term changes in cognitive function and quality of life (QL), comparing the antihypertensive effect during treatment with hydrochlorothiazide (HCTZ) and losartan. MATERIALS AND METHODS We studied 69 patients (36 men and 33 women; age range, 30 to 73 years), with uncomplicated mild-tomoderate essential hypertension. After 2 weeks of nonpharmacologic therapy, all patients had a diastolic blood pressure between 90 and 114 mm Hg. During this period, each patient underwent a biweekly physical examination in the outpatient clinic with three supine blood pressure measurements using a mercury sphygmomanometer. Patients with recent myocardial infarction or stroke, renal failure, chronic severe liver disease, and congestive heart failure were excluded. All patients were in sinus rhythm, homogeneous for body mass index, and had at least 5 years of education. Informed consent was provided before entering the study. After 2 weeks, in a double-blind study, the subjects were randomly allocated to either treatment with 50 mg losartan once a day (42 patients; 22 men and 20 women; mean age, 55 ⫾ 11 years) or 25 mg HCTZ once a day (27 patients; 14 men and 13 women; mean age, 54 ⫾ 10 years) administered in the early morning. Because the incidence of cognitive impairment could be age-related, the sample in each treatment group, was divided by age (⬍60 and ⱖ60). The entire study lasted 26 months. Routine blood tests and a noninvasive ambulatory blood pressure monitoring were performed at baseline and after 26 months. A QL questionnaire, with 46 items and appropriate for the hypertensive patients, covered symptomatic physical well-being, psychologic well-being, activity, and per-
ception of the effects of antihypertensive treatment on lifestyle, such as social participation, performance, and satisfaction at work. The questionnaire scored disability as a Health Index on a continuum from 0 (death) to 1 (perfect health).15 Cognitive function was evaluated by psychometric tests consisting of items from the Mini-Mental State Examination (MMSE)16 and the Sandoz Clinical Assessment Geriatric (SCAG).17 The MMSE and the SCAG are composed of 30 items and for each item the ratings run from a score of 1 (SCAG) or 5 (MMSE), indicating absence of the symptom or normal status, to a score of 7 (SCAG) or 0 (MMSE), indicating the most severe manifestations. These rating forms are valid instruments for assessing cognitive dysfunction, interpersonal relationships, apathy, affect, and somatic dysfunction. A score of less than 24 on the MMSE and more than 40 on the SCAG was predictive of cognitive impairment. All patients were questioned at baseline and after 26 months by a trained investigator blinded to clinical and active treatment findings. Statistical analysis was performed within-group with Student’s t test for paired data. Ninety-five percent confidence intervals (CI) for within-group changes from baseline were calculated. Differences between groups were compared by ANOVA with Bonferroni correction; P ⬍ .05 was considered statistically significant. The data are expressed as mean ⫾ SD. RESULTS All patients completed the study. There were no significant differences in patient characteristics at baseline. The duration of hypertension was statistically different when patients were divided by age (Table 1). Patients were matched for gender, education, and
1132
AJH–NOVEMBER 1999 –VOL. 12, NO. 11, PART 1
TEDESCO ET AL
TABLE 2. PSYCHOMETRIC TEST SCORES AND 24-H BLOOD PRESSURE BEFORE AND AFTER 26-MONTH TREATMENT IN THE LOSARTAN GROUP (N ⴝ 42) > 60 Years
< 60 Years Basal
SCAG MMSE QL 24-h SBP (mm Hg) 24-h DBP (mm Hg)
26 Months
44 ⫾ 10.8 36 ⫾ 8 25 ⫾ 2 28 ⫾ 2 0.91 ⫾ 0.09 0.97 ⫾ 0.06 148 ⫾ 10 129 ⫾ 11 92 ⫾ 7 80 ⫾ 6
P
Basal
26 Months
⬍.01 47 ⫾ 8.2 39 ⫾ 9 ⬍.001 22 ⫾ 3 26 ⫾ 3 ⬍.003 0.88 ⫾ 0.06 0.95 ⫾ 0.07 ⬍.001 153 ⫾ 7 132 ⫾ 8 ⬍.001 95 ⫾ 4 83 ⫾ 3
All Patients P
Basal
26 Months
⬍.01 45 ⫾ 9.8 37 ⫾ 8.4 ⬍.001 23 ⫾ 3 27 ⫾ 3 ⬍.02 0.90 ⫾ 0.08 0.96 ⫾ 0.06 ⬍.001 151 ⫾ 9 130 ⫾ 10 ⬍.001 94 ⫾ 5 82 ⫾ 4
P
⬍.001 ⬍.001 ⬍.01 ⬍.001 ⬍.001
Values are expressed as mean ⫾ SD. SCAG, Sandoz Clinical Assessment Geriatric; MMSE, Mini-Mental State Examination; QL, quality of life; 24-h SBP, 24-hour systolic blood pressure; 24-h DBP, 24-hour diastolic blood pressure.
body mass index. Moreover, the oldest patients in both groups had a higher rate of prior continuous treatment. Both drugs significantly lowered blood pressure, although losartan was more effective than HCTZ after a 26-month treatment (P ⬍ .001 v P ⬍ .02) (Tables 2, 3). The losartan group had a significant improvement in SCAG (P ⬍ .001; 95% CI, 3.8 –11.7) and MMSE (P ⬍ .001; 95% CI, ⫺4.8 to ⫺2.4) (Table 2); in the HCTZ group the mean changes were not statistically significant in SCAG (P ⫽ .1) and MMSE (P ⫽ .2) (Table 3). The MMSE score in elderly patients was less than 24 in 65% and SCAG score more than 40 in 70%; in younger patients, it was 35% and 48%, respectively. Despite these age-linked differences, patients using losartan in both age ranges had a greatly improved score at the end of the study. Educational level had no influence in either young or older patients. The health state index of QL improved in both groups, as illustrated in Tables 2 and 3, with statistical significance after 26 months (losartan group, P ⬍ .01; 95% CI, ⫺0.08 to ⫺0.02; HCTZ group, P ⬍ .02; 95% CI, ⫺0.09 to ⫺0.01). The improvement in QL scores in patients using HCTZ was significantly observed only in subjects aged 60 years and older (Table 3, P ⬍ .04; 95% CI, ⫺0.13 to ⫺0.01).
No complications in sexual performance were recorded. In the losartan group, 80% of patients were satisfied with their therapy and chose to continue (50% in the HCTZ group). Analysis of variance for different parameters (blood pressure [BP], MMSE, SCAG, QL) showed a significant difference between patients treated with losartan and patients treated with HCTZ (P ⬍ .001). No patients had cough or adverse laboratory events due to the two therapies. DISCUSSION A target for antihypertensive therapy should combine efficacy with good quality of life. Despite the effectiveness of different antihypertensive medications, there are still many patients with elevated blood pressure who give up because of poor compliance. Our results showed that both therapies lowered blood pressure and improved some aspects of QL, such as social life, work, quality of sleep, and free-time activities. In the HCTZ group these improvements were statistically significant compared with basal values only in elderly patients. Such improvements are difficult to attribute either to treatment or to close interpersonal relationship with the investigator during the study. Especially
TABLE 3. PSYCHOMETRIC TEST SCORES AND 24-H BLOOD PRESSURE BEFORE AND AFTER 26-MONTH TREATMENT IN THE HYDROCHLOROTHIAZIDE (HCTZ) GROUP (N ⴝ 27) > 60 Years
< 60 Years
SCAG MMSE QL 24-h SBP (mm Hg) 24-h DBP (mm Hg)
All Patients
Basal
26 Months
P
Basal
26 Months
P
Basal
26 Months
P
43 ⫾ 8 26 ⫾ 2.6 0.90 ⫾ 0.07 149 ⫾ 10 91 ⫾ 7
40 ⫾ 9 27 ⫾ 3 0.93 ⫾ 0.08 139 ⫾ 10 84 ⫾ 7
NS NS NS ⬍.02 ⬍.02
48 ⫾ 7 22 ⫾ 3.6 0.87 ⫾ 0.08 153 ⫾ 12 94 ⫾ 6
45 ⫾ 7 23 ⫾ 2.6 0.95 ⫾ 0.08 144 ⫾ 13 89 ⫾ 10
NS NS ⬍.05 NS NS
46 ⫾ 7.2 24 ⫾ 3 0.89 ⫾ 0.07 150 ⫾ 11 93 ⫾ 6
43 ⫾ 8.6 25 ⫾ 2.7 0.94 ⫾ 0.08 142 ⫾ 12 87 ⫾ 9
NS NS ⬍.02 ⬍.02 ⬍.01
Values are expressed as mean ⫾ SD. SCAG, Sandoz Clinical Assessment Geriatric; MMSE, Mini-Mental State Examination; QL, quality of life; 24-h SBP, 24-hour systolic blood pressure; 24-h DBP, 24-hour diastolic blood pressure.
1133
AJH–NOVEMBER 1999 –VOL. 12, NO. 11, PART 1
COGNITION, QUALITY OF LIFE WITH LOSARTAN
in elderly patients, this close relationship can give a feeling of general well-being. In contrast, patients treated with losartan showed major improvements in their QL, especially in job satisfaction and relationships within and away from their families in all patients regardless of age. As for cognitive function, we found significant improvements in the losartan group after 26 months of treatment; this was particularly true in scales evaluating memory, such as attention/concentration, comprehension, anxiety/depression, and interpersonal relationships. These results suggest that losartan can have a positive effect not only on blood pressure but also on impaired cognitive function, reversing even minimal cognitive deficits induced by hypertension. The relationship between hypertension and cognitive performance has been examined in several studies, particularly in the elderly, in whom high blood pressure has been correlated with poor performance on psychometric tests, with lower scores especially on attention/ concentration and depression items.8,9 The elderly patients in our sample had worse scores and cognitive performance was lower than in younger patients, even if in the losartan group the score improvement was the same at all ages. In the HCTZ group, these improvements were poor and not statistically significant compared with basal values, in all patients. As shown by previous evidence, long-standing hypertension is associated with white matter lesions, demyelination, arteriosclerosis, and a decline in brain metabolism. These morphologic and metabolic findings may explain poor performance on memory tests, attention, and depression (more frequent in elderly patients).3 A good long-term antihypertensive treatment ought to improve cognitive performance. Unfortunately, not all drugs are equally effective in reversing cognitive impairment, and only drugs that interfere with the renin-angiotensin-aldosterone system seem to be effective. In fact, ACE inhibitors positively influence mental function, this effect being due to their affinity to inhibit brain ACE activity and to remove the angiotensin-II–induced inhibition upon brain cholinergic-mediated function.18,19 Probably also the angiotensin-I metabolism is activated via alternative pathways, with increased synthesis of angiotensin-IV (angiotensin 3-8), which has been shown to possess vasodilating and cognitive-enhancing properties.20 In this regard, Mondadori and Etienne21 reported that orally administered captopril and enalapril reduce electroshock-elicited amnesia in rats. Barnes et al also demonstrated that a selective nonpeptide angiotensin-II receptor antagonist (losartan) has an anxiolytic-like effect without reducing alertness while enhancing cognitive performance in mice.22 Moreover, another nonpeptide AT1 receptor antagonist (EXP 3312) is able to attenuate the declining pas-
sive avoidance response to renin given intracerebroventricularly to rats.23 These findings may be due to the ability of losartan to cross the blood-brain barrier24 and to the AT2 receptor unmasking after AT1 receptor blockade by losartan, so that an increase in cerebral blood flow is produced and brain metabolism is ameliorated25; these agents are vasodilators and widely distributed in the cerebral blood vessels. In agreement with these findings, we here found that losartan reduced even minimal cognitive deficits from high blood pressure and it improved cognitive function. The same could not be said for HCTZ. ACKNOWLEDGMENTS We thank Professor Raffaello Buoninconti for his help in revising the manuscript, and acknowledge the nursing support of Gennaro Riccio.
REFERENCES 1.
Petty LA, Parker JR, Parker JC Jr: Hypertension and vascular dementia. Ann Clin Lab Sci 1992;22:34 –39.
2.
Dyken ML, Wolf PA, Bernett HJM, Bergan JJ, Hass WK, Kannel WB, et al: Risk factors in stroke: a statement for physicians by the subcommittee on risk factors and stroke of the Stroke Council. Stroke 1984;15:1105–1113.
3.
Fujishima M, Ibayashi S, Fujii K, Mori S: Cerebral blood flow and brain function in hypertension. Hypertens Res 1995;18:111–117.
4.
Wei L, Lin SZ, Tajima A, Nakata H, Acuff V, Patlak C, et al: Cerebral glucose utilization and blood flow in adult spontaneously hypertensive rats. Hypertension 1992;20:501–510.
5.
Wyss JM, Fisk G, Van Groen T: Impaired learning and memory in mature spontaneously hypertensive rats. Brain Res 1992;592:135–140.
6.
Franceschi M, Tancredi O, Smirne S, Mercinelli A, Canal N: Cognitive processes in hypertension. Hypertension 1982;4:226 –229.
7.
Elias MF, Wolf PA, D’Agostino RB, Cobb J, White LR: Untreated blood pressure level is inversely related to cognitive functioning: the Framingham study. Am J Epidemiol 1993;138:353–364.
8.
Gale CR, Martyn CN, Cooper C: Cognitive impairment and mortality in a cohort of elderly people. Br Med J 1996;312:608 – 611.
9.
Cacciatore F, Abete P, Ferrara N, Paolisso G, Amato L, Canonico S, et al: The role of blood pressure in cognitive impairment in an elderly population. J Hypertens 1997;15:135–142.
10.
Solomon S, Hotchkiss E, Saravay SM, Bayer C, Ramsey P, Blum RS: Impairment of memory function by antihypertensive medication. Arch Gen Psychiatry 1983;40: 1109 –1112.
11.
Farmer ME, Kittner SJ, Abbott RD, Wolz MM, Wolf PA, White LR: Longitudinally measured blood pressure, antihypertensive medication use and cognitive performance: The Framingham Study. J Clin Epidemiol 1990; 43:475– 480.
12.
Starr JM, Whalley LJ, Deary IJ: The effects of antihy-
1134
pertensive treatment on cognitive function: results from the HOPE Study. J Am Geriatr Soc 1996;44:411– 415. 13.
14.
Tedesco MA, Ratti G, Aquino D, Caccavale A, Acitorio M, Rocereto A, et al: Efficacia e tollerabilita` del losartan ed effetto sulla massa ventricolare sinistra in pazienti con ipertensione essenziale. Cardiologia 1998;43:53–59. Tedesco MA, Ratti G, Aquino D, Limongelli G, Di Salvo G, Mennella S, et al: Effects of losartan on hypertension and left ventricular mass: a long-term study. J Hum Hypertens 1998;12:505–510.
15.
Bulpitt CJ, Fletcher AE: The measurement of quality of life in hypertensive patients: a practical approach. Br J Clin Pharmacol 1990;30:353–364.
16.
Folstein MF, Folstein SE, McHugh PR: ‘Mini-Mental state’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12: 189 –198.
17.
Shader RI, Harmatz JS, Salzman C: A new scale for clinical assessment in geriatric populations: Sandoz Clinical Assessment-Geriatric (SCAG). J Am Geriat Soc 1974;22:107–113.
18.
AJH–NOVEMBER 1999 –VOL. 12, NO. 11, PART 1
TEDESCO ET AL
Barnes NM, Costall B, Egli P, Horovitz ZP, Ironside JW, Naylor RJ, et al: The ACE inhibitor [3H]SQ29,852 identifies a high affinity recognition site located in the human temporal cortex. Brain Res Bull 1990;25:183–185.
19.
Barnes JM, Barnes NM, Costall B, Coughlan J, Horovitz ZP, Kelly ME, et al: ACE inhibition and cognition, in MacGregor GA, Sever PS (eds): Current advances in ACE inhibition. Churchill Livingstone, London, 1989, pp 159 –171.
20.
Wright JW, Harding JW: Brain angiotensin receptor subtypes AT1, AT2, AT4 and their functions. Regul Pept 1995;59:269 –295.
21.
Mondadori C, Etienne P: Nootropic effect of ACE inhibition in mice. Psychopharmacology 1990;100:301–307.
22.
Barnes NM, Champaneria S, Costall B, Kelly ME, Murphy DA, Naylor RJ: Cognitive enhancing actions of DuP 753 detected in a mouse habituation paradigm. Neuroreport 1990;1:239 –242.
23.
DeNoble VJ, DeNoble KF, Spencer KR, Chiu AT, Wong PC, Timmermans BMWM: Non peptide receptor antagonist and angiotensin converting enzyme inhibitor: effect on a renin-induced deficit of a passive avoidance response in rats. Brain Res 1991;561:230 –235.
24.
Li Z, Bains JS, Ferguson AV: Functional evidence that the angiotensin antagonist losartan crosses the bloodbrain barrier in the rat. Brain Res Bull 1993;30:33–39.
25.
Stromberg C, Naveri L, Saavedra JM: Angiotensin AT2 receptors regulate cerebral blood flow in rats. Neuroreport 1992;3:703–704.
BRIEF COMMUNICATIONS
1999;12:1130 –1134
Comparison of Losartan and Hydrochlorothiazide on Cognitive Function and Quality of Life in Hypertensive Patients Michele Adolfo Tedesco, Gennaro Ratti, Salvatore Mennella, Gianluca Manzo, Michela Grieco, Anna Carmela Rainone, Diana Iarussi, and Aldo Iacono
We examined long-term changes in cognitive function and quality of life (QL) in hypertensive patients by comparing the antihypertensive effect of hydrochlorothiazide (HCTZ) and losartan. We studied 69 patients (age range, 30 to 73 years) with mild-to-moderate hypertension. All patients, in a double-blind study, were randomly allocated to either treatment with 50 mg losartan once daily or 25 mg HCTZ once daily. The sample in each treatment group was divided by age (younger than 60 years or 60 years or older). At baseline and after 26 months, a QL questionnaire appropriate for the hypertensive patients was given. Cognitive function was evaluated, at baseline and after 26 months, by psychometric tests consisting of items from the Mini-Mental State Examination (MMSE) and the Sandoz Clinical Assessment Geriatric (SCAG). A score of less than 24 on the MMSE and more than 40 on the SCAG was predictive of cognitive impairment. The losartan group had a significant improvement in SCAG (P < .001) and MMSE (P < .001). No significant changes were observed in the HCTZ group (SCAG, P ⴝ .1; MMSE, P ⴝ .2). Sixty-five percent of the elderly
L
ong-standing hypertension is one of the major risk factors for cerebral vascular disease1,2 and is associated with reduced cerebral blood flow, metabolism, and function.3,4 The relationship between blood pressure and cogni-
Received January 15, 1999. Accepted March 22, 1999. From the Medical Surgical Institute of Cardiology, Second University of Naples, Naples, Italy. Address correspondence and reprint requests to Dr. Michele A. Tedesco, Salita Due Porte 14, 80136 Naples, Italy; e-mail: tedesco@ napoli.pandora.it
© 1999 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
had a MMSE score less than 24 and 70% had a SCAG score greater than 40, v 35% and 48%, respectively, in younger patients. The health state index of QL improved significantly in both groups (losartan group, P < .01; HCTZ group, P < .02); the improvement in QL scores in patients using HCTZ was significant only in subjects aged 60 years and older (P < .04). These results suggest that losartan can have a positive effect not only on blood pressure but also on impaired cognitive function, reversing even minimal cognitive deficits induced by hypertension. The elderly patients in our sample had worse scores and cognitive performance was lower than in younger patients, even if in the losartan group the score improvement was the same at all ages. The same could not be said for HCTZ. Am J Hypertens 1999;12:1130 –1134 © 1999 American Journal of Hypertension, Ltd.
KEY WORDS:
Essential hypertension, cognitive function, quality of life, losartan, hydrochlorothiazide.
tive impairment has been found in animals and humans,5–7 particularly in hypertensive subjects older than 65 years, in whom high diastolic blood pressure was predictive of cognitive impairment.8,9 It is less clear whether this impairment could be reversible with antihypertensive treatment.10,11 Of all the drugs available, findings show that angiotensin converting enzyme (ACE) inhibitors can reverse impaired cognitive performance.12 Losartan, the first example of an angiotensin II receptor antagonist, showed a good effect on blood pressure and left ventricular mass,13,14 and seemed to improve cognitive function in hyperten0895-7061/99/$20.00 PII S0895-7061(99)00156-9
AJH–NOVEMBER 1999 –VOL. 12, NO. 11, PART 1
COGNITION, QUALITY OF LIFE WITH LOSARTAN
1131
TABLE 1. CHARACTERISTICS OF THE POPULATION DIVIDED BY AGE Losartan
Patients Age range (years) Gender (M/F) Body mass index (kg/m2) Duration of hypertension (years) Education (years) Smokers (%) Previous treatment (%) Continuously Discontinuously Not at all
< 60 Years
> 60 Years
23 30–59 11/12 27 ⫾ 3 4⫾1 9.5 ⫾ 3.6 35
19 60–73 11/8 25 ⫾ 4 6 ⫾ 2* 8.8 ⫾ 4 32
57 13 30
68 21 11
Hydrochlorothiazide All Patients
42 30–73 22/20 26.7 ⫾ 4 5 ⫾ 1.6 9.2 ⫾ 4 35 61 17 22
> 60 Years
< 60 Years
13 32–59 7/6 26.7 ⫾ 4 3.8 ⫾ 1 9.2 ⫾ 3.8 30
14 61–70 6/8 25 ⫾ 5 6 ⫾ 2.5† 8.7 ⫾ 4 29
54 8 38
64 15 21
All Patients
27 32–70 14/13 26 ⫾ 3 4.8 ⫾ 1.8 8.9 ⫾ 4 30 59 11 30
Values are expressed as mean ⫾ SD. * P ⬍ .001; † P ⬍ .01.
sive patients.13 The aim of this study was to examine long-term changes in cognitive function and quality of life (QL), comparing the antihypertensive effect during treatment with hydrochlorothiazide (HCTZ) and losartan. MATERIALS AND METHODS We studied 69 patients (36 men and 33 women; age range, 30 to 73 years), with uncomplicated mild-tomoderate essential hypertension. After 2 weeks of nonpharmacologic therapy, all patients had a diastolic blood pressure between 90 and 114 mm Hg. During this period, each patient underwent a biweekly physical examination in the outpatient clinic with three supine blood pressure measurements using a mercury sphygmomanometer. Patients with recent myocardial infarction or stroke, renal failure, chronic severe liver disease, and congestive heart failure were excluded. All patients were in sinus rhythm, homogeneous for body mass index, and had at least 5 years of education. Informed consent was provided before entering the study. After 2 weeks, in a double-blind study, the subjects were randomly allocated to either treatment with 50 mg losartan once a day (42 patients; 22 men and 20 women; mean age, 55 ⫾ 11 years) or 25 mg HCTZ once a day (27 patients; 14 men and 13 women; mean age, 54 ⫾ 10 years) administered in the early morning. Because the incidence of cognitive impairment could be age-related, the sample in each treatment group, was divided by age (⬍60 and ⱖ60). The entire study lasted 26 months. Routine blood tests and a noninvasive ambulatory blood pressure monitoring were performed at baseline and after 26 months. A QL questionnaire, with 46 items and appropriate for the hypertensive patients, covered symptomatic physical well-being, psychologic well-being, activity, and per-
ception of the effects of antihypertensive treatment on lifestyle, such as social participation, performance, and satisfaction at work. The questionnaire scored disability as a Health Index on a continuum from 0 (death) to 1 (perfect health).15 Cognitive function was evaluated by psychometric tests consisting of items from the Mini-Mental State Examination (MMSE)16 and the Sandoz Clinical Assessment Geriatric (SCAG).17 The MMSE and the SCAG are composed of 30 items and for each item the ratings run from a score of 1 (SCAG) or 5 (MMSE), indicating absence of the symptom or normal status, to a score of 7 (SCAG) or 0 (MMSE), indicating the most severe manifestations. These rating forms are valid instruments for assessing cognitive dysfunction, interpersonal relationships, apathy, affect, and somatic dysfunction. A score of less than 24 on the MMSE and more than 40 on the SCAG was predictive of cognitive impairment. All patients were questioned at baseline and after 26 months by a trained investigator blinded to clinical and active treatment findings. Statistical analysis was performed within-group with Student’s t test for paired data. Ninety-five percent confidence intervals (CI) for within-group changes from baseline were calculated. Differences between groups were compared by ANOVA with Bonferroni correction; P ⬍ .05 was considered statistically significant. The data are expressed as mean ⫾ SD. RESULTS All patients completed the study. There were no significant differences in patient characteristics at baseline. The duration of hypertension was statistically different when patients were divided by age (Table 1). Patients were matched for gender, education, and
1132
AJH–NOVEMBER 1999 –VOL. 12, NO. 11, PART 1
TEDESCO ET AL
TABLE 2. PSYCHOMETRIC TEST SCORES AND 24-H BLOOD PRESSURE BEFORE AND AFTER 26-MONTH TREATMENT IN THE LOSARTAN GROUP (N ⴝ 42) > 60 Years
< 60 Years Basal
SCAG MMSE QL 24-h SBP (mm Hg) 24-h DBP (mm Hg)
26 Months
44 ⫾ 10.8 36 ⫾ 8 25 ⫾ 2 28 ⫾ 2 0.91 ⫾ 0.09 0.97 ⫾ 0.06 148 ⫾ 10 129 ⫾ 11 92 ⫾ 7 80 ⫾ 6
P
Basal
26 Months
⬍.01 47 ⫾ 8.2 39 ⫾ 9 ⬍.001 22 ⫾ 3 26 ⫾ 3 ⬍.003 0.88 ⫾ 0.06 0.95 ⫾ 0.07 ⬍.001 153 ⫾ 7 132 ⫾ 8 ⬍.001 95 ⫾ 4 83 ⫾ 3
All Patients P
Basal
26 Months
⬍.01 45 ⫾ 9.8 37 ⫾ 8.4 ⬍.001 23 ⫾ 3 27 ⫾ 3 ⬍.02 0.90 ⫾ 0.08 0.96 ⫾ 0.06 ⬍.001 151 ⫾ 9 130 ⫾ 10 ⬍.001 94 ⫾ 5 82 ⫾ 4
P
⬍.001 ⬍.001 ⬍.01 ⬍.001 ⬍.001
Values are expressed as mean ⫾ SD. SCAG, Sandoz Clinical Assessment Geriatric; MMSE, Mini-Mental State Examination; QL, quality of life; 24-h SBP, 24-hour systolic blood pressure; 24-h DBP, 24-hour diastolic blood pressure.
body mass index. Moreover, the oldest patients in both groups had a higher rate of prior continuous treatment. Both drugs significantly lowered blood pressure, although losartan was more effective than HCTZ after a 26-month treatment (P ⬍ .001 v P ⬍ .02) (Tables 2, 3). The losartan group had a significant improvement in SCAG (P ⬍ .001; 95% CI, 3.8 –11.7) and MMSE (P ⬍ .001; 95% CI, ⫺4.8 to ⫺2.4) (Table 2); in the HCTZ group the mean changes were not statistically significant in SCAG (P ⫽ .1) and MMSE (P ⫽ .2) (Table 3). The MMSE score in elderly patients was less than 24 in 65% and SCAG score more than 40 in 70%; in younger patients, it was 35% and 48%, respectively. Despite these age-linked differences, patients using losartan in both age ranges had a greatly improved score at the end of the study. Educational level had no influence in either young or older patients. The health state index of QL improved in both groups, as illustrated in Tables 2 and 3, with statistical significance after 26 months (losartan group, P ⬍ .01; 95% CI, ⫺0.08 to ⫺0.02; HCTZ group, P ⬍ .02; 95% CI, ⫺0.09 to ⫺0.01). The improvement in QL scores in patients using HCTZ was significantly observed only in subjects aged 60 years and older (Table 3, P ⬍ .04; 95% CI, ⫺0.13 to ⫺0.01).
No complications in sexual performance were recorded. In the losartan group, 80% of patients were satisfied with their therapy and chose to continue (50% in the HCTZ group). Analysis of variance for different parameters (blood pressure [BP], MMSE, SCAG, QL) showed a significant difference between patients treated with losartan and patients treated with HCTZ (P ⬍ .001). No patients had cough or adverse laboratory events due to the two therapies. DISCUSSION A target for antihypertensive therapy should combine efficacy with good quality of life. Despite the effectiveness of different antihypertensive medications, there are still many patients with elevated blood pressure who give up because of poor compliance. Our results showed that both therapies lowered blood pressure and improved some aspects of QL, such as social life, work, quality of sleep, and free-time activities. In the HCTZ group these improvements were statistically significant compared with basal values only in elderly patients. Such improvements are difficult to attribute either to treatment or to close interpersonal relationship with the investigator during the study. Especially
TABLE 3. PSYCHOMETRIC TEST SCORES AND 24-H BLOOD PRESSURE BEFORE AND AFTER 26-MONTH TREATMENT IN THE HYDROCHLOROTHIAZIDE (HCTZ) GROUP (N ⴝ 27) > 60 Years
< 60 Years
SCAG MMSE QL 24-h SBP (mm Hg) 24-h DBP (mm Hg)
All Patients
Basal
26 Months
P
Basal
26 Months
P
Basal
26 Months
P
43 ⫾ 8 26 ⫾ 2.6 0.90 ⫾ 0.07 149 ⫾ 10 91 ⫾ 7
40 ⫾ 9 27 ⫾ 3 0.93 ⫾ 0.08 139 ⫾ 10 84 ⫾ 7
NS NS NS ⬍.02 ⬍.02
48 ⫾ 7 22 ⫾ 3.6 0.87 ⫾ 0.08 153 ⫾ 12 94 ⫾ 6
45 ⫾ 7 23 ⫾ 2.6 0.95 ⫾ 0.08 144 ⫾ 13 89 ⫾ 10
NS NS ⬍.05 NS NS
46 ⫾ 7.2 24 ⫾ 3 0.89 ⫾ 0.07 150 ⫾ 11 93 ⫾ 6
43 ⫾ 8.6 25 ⫾ 2.7 0.94 ⫾ 0.08 142 ⫾ 12 87 ⫾ 9
NS NS ⬍.02 ⬍.02 ⬍.01
Values are expressed as mean ⫾ SD. SCAG, Sandoz Clinical Assessment Geriatric; MMSE, Mini-Mental State Examination; QL, quality of life; 24-h SBP, 24-hour systolic blood pressure; 24-h DBP, 24-hour diastolic blood pressure.
1133
AJH–NOVEMBER 1999 –VOL. 12, NO. 11, PART 1
COGNITION, QUALITY OF LIFE WITH LOSARTAN
in elderly patients, this close relationship can give a feeling of general well-being. In contrast, patients treated with losartan showed major improvements in their QL, especially in job satisfaction and relationships within and away from their families in all patients regardless of age. As for cognitive function, we found significant improvements in the losartan group after 26 months of treatment; this was particularly true in scales evaluating memory, such as attention/concentration, comprehension, anxiety/depression, and interpersonal relationships. These results suggest that losartan can have a positive effect not only on blood pressure but also on impaired cognitive function, reversing even minimal cognitive deficits induced by hypertension. The relationship between hypertension and cognitive performance has been examined in several studies, particularly in the elderly, in whom high blood pressure has been correlated with poor performance on psychometric tests, with lower scores especially on attention/ concentration and depression items.8,9 The elderly patients in our sample had worse scores and cognitive performance was lower than in younger patients, even if in the losartan group the score improvement was the same at all ages. In the HCTZ group, these improvements were poor and not statistically significant compared with basal values, in all patients. As shown by previous evidence, long-standing hypertension is associated with white matter lesions, demyelination, arteriosclerosis, and a decline in brain metabolism. These morphologic and metabolic findings may explain poor performance on memory tests, attention, and depression (more frequent in elderly patients).3 A good long-term antihypertensive treatment ought to improve cognitive performance. Unfortunately, not all drugs are equally effective in reversing cognitive impairment, and only drugs that interfere with the renin-angiotensin-aldosterone system seem to be effective. In fact, ACE inhibitors positively influence mental function, this effect being due to their affinity to inhibit brain ACE activity and to remove the angiotensin-II–induced inhibition upon brain cholinergic-mediated function.18,19 Probably also the angiotensin-I metabolism is activated via alternative pathways, with increased synthesis of angiotensin-IV (angiotensin 3-8), which has been shown to possess vasodilating and cognitive-enhancing properties.20 In this regard, Mondadori and Etienne21 reported that orally administered captopril and enalapril reduce electroshock-elicited amnesia in rats. Barnes et al also demonstrated that a selective nonpeptide angiotensin-II receptor antagonist (losartan) has an anxiolytic-like effect without reducing alertness while enhancing cognitive performance in mice.22 Moreover, another nonpeptide AT1 receptor antagonist (EXP 3312) is able to attenuate the declining pas-
sive avoidance response to renin given intracerebroventricularly to rats.23 These findings may be due to the ability of losartan to cross the blood-brain barrier24 and to the AT2 receptor unmasking after AT1 receptor blockade by losartan, so that an increase in cerebral blood flow is produced and brain metabolism is ameliorated25; these agents are vasodilators and widely distributed in the cerebral blood vessels. In agreement with these findings, we here found that losartan reduced even minimal cognitive deficits from high blood pressure and it improved cognitive function. The same could not be said for HCTZ. ACKNOWLEDGMENTS We thank Professor Raffaello Buoninconti for his help in revising the manuscript, and acknowledge the nursing support of Gennaro Riccio.
REFERENCES 1.
Petty LA, Parker JR, Parker JC Jr: Hypertension and vascular dementia. Ann Clin Lab Sci 1992;22:34 –39.
2.
Dyken ML, Wolf PA, Bernett HJM, Bergan JJ, Hass WK, Kannel WB, et al: Risk factors in stroke: a statement for physicians by the subcommittee on risk factors and stroke of the Stroke Council. Stroke 1984;15:1105–1113.
3.
Fujishima M, Ibayashi S, Fujii K, Mori S: Cerebral blood flow and brain function in hypertension. Hypertens Res 1995;18:111–117.
4.
Wei L, Lin SZ, Tajima A, Nakata H, Acuff V, Patlak C, et al: Cerebral glucose utilization and blood flow in adult spontaneously hypertensive rats. Hypertension 1992;20:501–510.
5.
Wyss JM, Fisk G, Van Groen T: Impaired learning and memory in mature spontaneously hypertensive rats. Brain Res 1992;592:135–140.
6.
Franceschi M, Tancredi O, Smirne S, Mercinelli A, Canal N: Cognitive processes in hypertension. Hypertension 1982;4:226 –229.
7.
Elias MF, Wolf PA, D’Agostino RB, Cobb J, White LR: Untreated blood pressure level is inversely related to cognitive functioning: the Framingham study. Am J Epidemiol 1993;138:353–364.
8.
Gale CR, Martyn CN, Cooper C: Cognitive impairment and mortality in a cohort of elderly people. Br Med J 1996;312:608 – 611.
9.
Cacciatore F, Abete P, Ferrara N, Paolisso G, Amato L, Canonico S, et al: The role of blood pressure in cognitive impairment in an elderly population. J Hypertens 1997;15:135–142.
10.
Solomon S, Hotchkiss E, Saravay SM, Bayer C, Ramsey P, Blum RS: Impairment of memory function by antihypertensive medication. Arch Gen Psychiatry 1983;40: 1109 –1112.
11.
Farmer ME, Kittner SJ, Abbott RD, Wolz MM, Wolf PA, White LR: Longitudinally measured blood pressure, antihypertensive medication use and cognitive performance: The Framingham Study. J Clin Epidemiol 1990; 43:475– 480.
12.
Starr JM, Whalley LJ, Deary IJ: The effects of antihy-
1134
pertensive treatment on cognitive function: results from the HOPE Study. J Am Geriatr Soc 1996;44:411– 415. 13.
14.
Tedesco MA, Ratti G, Aquino D, Caccavale A, Acitorio M, Rocereto A, et al: Efficacia e tollerabilita` del losartan ed effetto sulla massa ventricolare sinistra in pazienti con ipertensione essenziale. Cardiologia 1998;43:53–59. Tedesco MA, Ratti G, Aquino D, Limongelli G, Di Salvo G, Mennella S, et al: Effects of losartan on hypertension and left ventricular mass: a long-term study. J Hum Hypertens 1998;12:505–510.
15.
Bulpitt CJ, Fletcher AE: The measurement of quality of life in hypertensive patients: a practical approach. Br J Clin Pharmacol 1990;30:353–364.
16.
Folstein MF, Folstein SE, McHugh PR: ‘Mini-Mental state’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12: 189 –198.
17.
Shader RI, Harmatz JS, Salzman C: A new scale for clinical assessment in geriatric populations: Sandoz Clinical Assessment-Geriatric (SCAG). J Am Geriat Soc 1974;22:107–113.
18.
AJH–NOVEMBER 1999 –VOL. 12, NO. 11, PART 1
TEDESCO ET AL
Barnes NM, Costall B, Egli P, Horovitz ZP, Ironside JW, Naylor RJ, et al: The ACE inhibitor [3H]SQ29,852 identifies a high affinity recognition site located in the human temporal cortex. Brain Res Bull 1990;25:183–185.
19.
Barnes JM, Barnes NM, Costall B, Coughlan J, Horovitz ZP, Kelly ME, et al: ACE inhibition and cognition, in MacGregor GA, Sever PS (eds): Current advances in ACE inhibition. Churchill Livingstone, London, 1989, pp 159 –171.
20.
Wright JW, Harding JW: Brain angiotensin receptor subtypes AT1, AT2, AT4 and their functions. Regul Pept 1995;59:269 –295.
21.
Mondadori C, Etienne P: Nootropic effect of ACE inhibition in mice. Psychopharmacology 1990;100:301–307.
22.
Barnes NM, Champaneria S, Costall B, Kelly ME, Murphy DA, Naylor RJ: Cognitive enhancing actions of DuP 753 detected in a mouse habituation paradigm. Neuroreport 1990;1:239 –242.
23.
DeNoble VJ, DeNoble KF, Spencer KR, Chiu AT, Wong PC, Timmermans BMWM: Non peptide receptor antagonist and angiotensin converting enzyme inhibitor: effect on a renin-induced deficit of a passive avoidance response in rats. Brain Res 1991;561:230 –235.
24.
Li Z, Bains JS, Ferguson AV: Functional evidence that the angiotensin antagonist losartan crosses the bloodbrain barrier in the rat. Brain Res Bull 1993;30:33–39.
25.
Stromberg C, Naveri L, Saavedra JM: Angiotensin AT2 receptors regulate cerebral blood flow in rats. Neuroreport 1992;3:703–704.