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ABSTRACT: Cognitive deterioration and its sequelae of vascular or Alzheimer's dementia is rapidly increasing all over the world. This is primarily caused by the worldwide increase of the ageing population. Additional causes may be sought in factors such as genetics and a habitually unhealthy life style. The significance of high blood pressure in the process leading to cognitive deterioration is relatively unknown. However, timely detection and treatment of hypertension seems to contribute to the preservation of cognition. Experience has shown that this applies in particular to dihydropyridine calcium antagonists. Medical care tends to make insufficient use of the existing possibilities for treating hypertension.
Nederlands tijdschrift voor geneeskunde 12/2007; 151(44):2435-9.
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ABSTRACT: Hypertension has proven to be a major predisposing factor for the development of both vascular and degenerative (Alzheimer's) dementias, either following stroke or gradually through more insidious microcerebrovascular processes. In the latter case the interval between the respective manifestations of hypertension and dementia may vary between a few years and several decades. The temporal relationships may become complicated by the finding that blood pressure tends to fall shortly before the onset of overt Alzheimers' disease. Whether or not timely antihypertensive regimens may delay or even prevent the development of dementias later in life is still an ''educated'' guess, as long there has been no comprehensive trial comparing the potential of the different antihypertensive drug classes in this regard. Until then, the class of dihydropyridine calcium antagonists (exemplified by nitrendipine in the Syst-Eur trial) is the only category having statistically been proven to be of substantial value for prevention of Alzheimer's disease.
Panminerva medica 01/2005; 46(4):227-37. · 1.11 Impact Factor
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ABSTRACT: We recently found that femoral intima media thickness, as well as the incidence of hypertension, is influenced by genes encoding the angiotensin-converting enzyme (ACE; insertion/deletion [I/D]) polymorphism, alpha-adducin (Gly460Trp), and aldosterone synthase (-344C/T). By interfering with blood pressure or sodium homeostasis, these genetic polymorphisms also may change renal function. We therefore investigated serum creatinine level, calculated and measured creatinine clearances, and 24-hour urinary protein excretion in subjects previously genotyped for these three polymorphisms. The 1,454 participants drawn at random from the population (64.3% of those invited) were aged 43.4 years and included 744 women (51.2%). Blood pressure, measured by study nurses at subjects' homes, averaged 123/76 mm Hg. Mean values were 90 micromol/L for serum creatinine; 84 and 88 mL/min/1.73 m(2) for calculated and measured (n = 855) creatinine clearances, respectively; and 90 mg/d of protein for proteinuria (n = 556). The prevalence of mild renal dysfunction (creatinine clearance </= 60 mL/min/1.73 m(2)) was nearly 11%. In single-gene analyses with adjustment for significant covariables, the risk for mild renal dysfunction was positively associated with the ACE D allele. However, multiple-gene analyses showed that these associations were restricted to carriers of the mutated alpha-adducin Trp allele (40.1% of all subjects). Findings remained similar after hypertensive patients and women on hormonal therapy were excluded. In this phenotypically more homogeneous subgroup, serum creatinine level was 3.6 micromol/L (P = 0.02) and relative risks for mild renal dysfunction and proteinuria were 1.7-fold (P < 0.001) and 26% (P = 0.02) greater in ACE D subjects than ACE II homozygotes, respectively. The aldosterone synthase T allele did not strengthen genetic associations with the ACE D allele considered alone or in combination with the alpha-adducin Trp allele. Thus, in the present cross-sectional analysis, renal function was slightly but consistently impaired when both the ACE D and alpha-adducin Trp alleles were present. These findings, together with experimental studies and our previous reports on femoral intima media thickness and the incidence of hypertension, constitute a growing body of evidence delineating a clinical entity genetically determined by the risk-carrying ACE D and alpha-adducin Trp alleles.
American Journal of Kidney Diseases 12/2001; 38(6):1158-68. · 5.43 Impact Factor
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ABSTRACT: To assess the relationship between chronic intake of nonsteroidal anti-inflammatory drugs (NSAID) and outcome, in particular (gastrointestinal) bleeding and to investigate whether the effect of chronic NSAID intake was similar in untreated and treated elderly hypertensives.
Eligible patients (> or = 60 years, with systolic blood pressure 160-219 mm Hg and diastolic blood pressure < 95 mm Hg) were randomised to active treatment or placebo. Active treatment consisted of nitrendipine, with the possible addition of enalapril, hydrochlorothiazide, or both, titrated or combined to reduce the sitting systolic blood pressure by at least 20 mm Hg to below 150 mm Hg. Patients never taking NSAIDs (n = 2882) were compared with patients on chronic NSAID intake (n = 861), defined as reporting NSAID intake on at least 50% of the patient forms.
There was a tendency towards lower mortality (relative hazard rate (95% confidence interval (CI), 0.77 (0.56-1.06)) and higher incidence of bleeding (1.13 (0.63-2.05) with chronic NSAID intake. Although there was no significant interaction between calcium-channel blocker (CCB)-based treatment and chronic NSAID intake for any of the end points, chronic NSAID intake tended to be associated with a lower incidence of bleeding on active treatment as compared to placebo (P-value of the interaction term = 0.07).
The effect of chronic NSAID intake on outcome was similar in patients on active treatment based on a dihydropyridine CCB or on placebo. However, chronic NSAID intake might have a less deleterious effect on bleeding on active treatment as compared to placebo.
Journal of Human Hypertension 10/2001; 15(9):613-8. · 2.80 Impact Factor
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ABSTRACT: The genes encoding angiotensin converting enzyme (ACE, I/D), alpha-adducin (ADD, Gly460Trp) and aldosterone synthase (AS, -344C/T) share the potential of influencing blood pressure (BP) via sodium homeostasis. However, most studies in humans focused on single-gene effects and disregarded epistasis, the suppression or potentiation of a gene by other non-allelic genes.
We studied the singular and combined effects of the aforementioned candidate genes: (1) in relation to BP, plasma renin activity (PRA) and urinary aldosterone in 1461 subjects randomly selected from a Caucasian population; and (2) in relation to the incidence of hypertension in a subgroup of 678 initially normotensive subjects followed up for 9.1 years (median).
In cross-sectional analyses, AS/CC homozygosity was associated with slightly lower systolic BP (-1.32 mmHg; P = 0.08). AS/TT homozygotes showed both lower PRA and higher urinary aldosterone excretion (P < or = 0.05). In multiple-gene analyses, compared with the whole study population, ADD/Trp subjects had a higher relative risk of hypertension in the presence of the AS/T allele (1.29; P = 0.05), whereas in combination with AS/CC homozygosity ADD/Trp subjects had the smallest relative risk (0.48; P = 0.003). Hypertension developed in 229 subjects (36.6 cases per 1000 person-years). ACE/DD homozygosity, in comparison with the other ACE genotypes, was associated with increases in the incidence of hypertension, which amounted to 31% (P = 0.005) in single-gene analyses, to 59% (P = 0.004) in carriers of the ADD/Trp allele and to 122% (P = 0.0007) in AS/CC subjects. Among subjects who had both the ADD/Trp allele and the AS/CC genotype, ACE/DD homozygotes manifested a 252% (P = 0.001) higher incidence of hypertension.
Epistatic interactions between the ACE, ADD and AS genes contribute to the prevalence and incidence of hypertension in Caucasians. The clinical relevance of the risk-conferring haplotypes identified in our prospective study was underscored by their positive predictive values, which under the assumption of a 20% life-time risk of hypertension, ranged from 29.8-40.1%.
Journal of Hypertension 08/2001; 19(8):1349-58. · 4.02 Impact Factor
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ABSTRACT: We examined the relation of serum creatinine and uric acid to mortality and cardiovascular disease in older (aged >/=60 years) Chinese patients with isolated systolic hypertension (systolic/diastolic blood pressure >/=160/<95 mm Hg). We used Cox regression to correlate outcome with baseline serum creatinine and uric acid measured in 1880 and 1873, respectively, of the 2394 patients enrolled in the placebo-controlled Systolic Hypertension in China (Syst-China) TRIAL: Median follow-up was 3 years. In multiple Cox regression analysis with adjustment for gender, age, active treatment, and other significant covariates, serum creatinine was significantly associated with a worse prognosis. The relative hazard rates (95% CIs) associated with a 20-micromol/L increase in serum creatinine for all-cause, cardiovascular, and stroke mortality were 1.16 (1.05 to 1.27, P=0.003), 1.15 (1.01 to 1.31, P=0.03), and 1.37 (1.13 to 1.65, P=0.001), respectively. In a similar analysis, which also accounted for serum creatinine, serum uric acid was also significantly and independently associated with excess mortality of cardiovascular disease and stroke. The relative hazard rates associated with a 50-micromol/L increase of serum uric acid were 1.14 (1.02 to 1.27, P=0.02) for cardiovascular mortality and 1.34 (1.14 to 1.57, P<0.001) for fatal stroke. In conclusion, in older Chinese patients with isolated systolic hypertension, serum creatinine and serum uric acid were predictors of mortality.
Hypertension 04/2001; 37(4):1069-74. · 6.21 Impact Factor
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The Lancet 04/2001; 357(9259):880; author reply 880-1. · 38.28 Impact Factor
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S M Voyaki,
J A Staessen,
L Thijs,
J G Wang,
A D Efstratopoulos, W H Birkenhäger,
P W de Leeuw,
G Leonetti,
C Nachev,
J L Rodicio,
J Tuomilehto,
R Fagard
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ABSTRACT: In the outcome trials that provided information on renal function in older hypertensive patients, diuretics and beta-blockers were mostly used as first-line drugs. The long-term renal effects of calcium-channel blockers remain unclear.
To compare the changes in renal function in 2,258 treated and 2,148 untreated patients with isolated systolic hypertension, of whom 455 had diabetes mellitus and 390 had proteinuria.
We performed a post-hoc analysis of the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial. Active treatment was initiated with nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), or both, titrated or combined to reduce the sitting systolic blood pressure by at least 20 mmHg, to less than 150 mmHg. The main outcome measures were serum creatinine concentration and creatinine clearance calculated by the formula of Cockroft and Gault.
Serum creatinine concentration at the time when participants were randomly allocated to study groups was less than 176.8 micromol/l (2.0 mg/dl), averaging 88 micromol/l. At the time of the last serum creatinine measurement, the blood pressure difference (P< 0.001) between the two groups was 11.6/4.1 mmHg. In the intention-to-treat analysis (11,427 patient-years), serum creatinine and the calculated creatinine clearance were not influenced by active treatment. However, in the patients assigned randomly to receive active treatment, the incidence of mild renal dysfunction (serum creatinine at least 176.8 mmol/l) decreased by 64% (P= 0.04) and that of proteinuria by 33% (P= 0.03). Active treatment reduced the risk of proteinuria more in diabetic than in non-diabetic patients: by 71%, compared with 20% (P= 0.04). In non-proteinuric patients, active treatment did not influence serum creatinine, whereas in patients with proteinuria at entry to the study, serum creatinine decreased on active treatment (P< 0.001). Furthermore, in on-randomized treatment comparison stratified for risk at baseline, serum creatinine concentration did not change (P= 0.98) in patients continuing to receive monotherapy with nitrendipine, whereas it increased by 6.73 mmol/l (P < 0.001) in patients who received hydrochlorothiazide alone or in combination with other study medication (P < 0.001 for difference in trends).
In older patients with isolated systolic hypertension, antihypertensive treatment starting with the dihydropyridine calcium-channel blocker, nitrendipine, did not decrease blood pressure at the expense of renal function and prevented the development of proteinuria, especially in diabetic patients.
Journal of Hypertension 03/2001; 19(3):511-9. · 4.02 Impact Factor
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ABSTRACT: In this review the hypertensive status in older subjects is briefly examined from a diversity of angles: epidemiological/semiotic; pathophysiological (including haemodynamic/vascular, renal and neurohormonal features); components of blood pressure as separate cardiovascular risk factors in their own right, results of randomized trials comparing active with placebo treatment and comparing different active regimens (including diabetics as a subgroup with excessive risk); and, finally, modalities of treatment with a view on quality of life.
Blood Pressure 02/2001; 10(5-6):299-310. · 1.43 Impact Factor
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ABSTRACT: The prevalence and incidence of degenerative and vascular dementias increase exponentially with age, from 70 years onward. In view of the increasing longevity of humans, both varieties are bound to evolve into a major problem worldwide. According to several longitudinal studies, hypertension appears to predispose individuals to the development of cognitive impairment and ensuing dementia, after a period varying from a few years to several decades. Antihypertensive drug treatment, according to preliminary evidence, may serve to reduce the rates of such events. Such findings await to be confirmed by formal therapeutic trials against a backdrop of "historical" observational sources.
Archives of Internal Medicine 02/2001; 161(2):152-6. · 11.46 Impact Factor
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ABSTRACT: The prevalence and incidence of both degenerative (Alzheimer) and vascular dementias rise exponentially with aging. In both forms of dementia hypertension is a predisposing factor. The interval between the onset of hypertension and the manifestation of dementia amounts to 12-15 years. A complicating factor is the observation that initial dementia may be accompanied by secondary decrease in blood pressure. A preventive effect of current antihypertensive treatment is likely, according to preliminary evidence (particularly with regard to the use of the calcium antagonist nitrendipine), but the hopeful perspective of protection against dementias through antihypertensive treatment remains to be confirmed by further prospective comparative trials.
Nederlands tijdschrift voor geneeskunde 08/2000; 144(31):1469-74.
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ABSTRACT: In this review we attempt to determine the role of calcium channel blockers in preventing cardiovascular sequelae in patients with both hypertension and diabetes mellitus. The data have been collected from three sources: post-hoc analyses of subgroups of diabetic patients in placebo-controlled hypertension trials (SHEP, Syst-Eur, Syst-China); stepped-care blood pressure-oriented trials (HOT); and comparative trials focusing primarily on metabolic aspects and intermediate endpoints (ABCD, FACET). On balance, the data seem to indicate that long-acting calcium channel blockers score remarkably well in preventing cardiovascular complications in diabetic hypertensive patients.
Cardiovascular Drugs and Therapy 03/2000; 14(1):49-53. · 3.13 Impact Factor
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European Heart Journal 01/2000; 21(1):2-7. · 10.48 Impact Factor
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ABSTRACT: Angiotensin II (Ang II) acts at the cellular level on two receptor subtypes: the AT1 receptor which can be blocked by losartan and its analogues (the 'sartan family'), and the AT2 receptor that does not react with the above antagonists but which can be blocked by different compounds, such as PD123319. AT1 receptor blockade has proven to be a highly effective means of interference with the renin-angiotensin system (RAS) and hence of reducing high blood pressure. As a result of the terminal blockade of the RAS cascade, circulating Ang II levels tend to rise two- to threefold. The free access of such enhanced levels to uninhibited AT2 receptors may be clinically relevant, as argued in the present review. The most extensive experimental and clinical experience with AT1 receptor blockade so far has been obtained with the pioneer drug losartan, although major contributions have also been made on candesartan cilexetil, irbesartan and valsartan. All of these four drugs have been instrumental in substantial clinical trials, serving as sources of information in the clinically oriented part of this review. AT1 receptor blocking drugs generally provide a relatively gradual decrease in blood pressure, which is comparable to that obtained with conventional anti-hypertensive drugs. Clinical trials reveal an astounding lack of drug-related adverse effects, scoring even better than placebo in terms of frequencies and sometimes patterns. The trough/peak ratio on single dosages seems to have been mastered, particularly with the second generation of AT1 receptor blockers, as is evident from 24 h ambulatory blood pressure monitoring. Combination with low-dose thiazide regimens is well established. Intermediate endpoints (micro-albuminuria and left ventricular hypertrophy) appear to be controllable. Morbid cardiovascular sequelae are currently under study in comparison with beta- and calcium channel blockade.
Journal of Hypertension 08/1999; 17(7):873-81. · 4.02 Impact Factor
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Hypertension 07/1999; 33(6):1476-7. · 6.21 Impact Factor
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ABSTRACT: This review attempts to highlight the potential of calcium-channel blockers in the prevention of sequelae of diabetes mellitus and hypertension in patients who have both disorders. Evidence-based medicine is driven by the results of randomized, clinical trials. Major contributions were therefore derived from post hoc analyses of the diabetic patients enrolled in placebo-controlled trials, such as Systolic Hypertension in the Elderly Program (SHEP), Systolic Hypertension in Europe (Syst-Eur), and Systolic Hypertension in China (Syst-China), and stepped-care blood-pressure-oriented trials, such as the Hypertension Optimal Treatment (HOT) and United Kingdom Prospective Diabetes Study (UKPDS). Several studies, such as the Fosiniprl; versus Amlodipine Cardiovascular Events Trial (FACET) and Appropriate Blood Pressure Control in Diabetes (ABCD) Trial, have compared the relative merits of angiotensin-converting enzyme and calcium-channel blockers in preserving renal function and metabolic balance in diabetic patients with hypertension, but their publications focused on cardiovascular disorders, which were only secondary end points. On balance, the articles reviewed prove that dihydropyridine calcium-channel blockers score particularly well in the prevention of cardiovascular complications in diabetic patients with hypertension.
Current Hypertension Reports 07/1999; 1(3):225-31. · 2.50 Impact Factor
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J Gasowski,
J A Staessen,
H Celis,
R H Fagard,
L Thijs, W H Birkenhäger,
C J Bulpitt,
A E Fletcher,
G G Arabidze,
P de Leeuw, [......],
K Kawecka-Jaszcz,
G Leonetti,
C Nachev,
M Safar,
J L Rodico,
J Rosenfeld,
M L Seux,
J Tuomilehto,
J Webster,
Y Yodfat
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ABSTRACT: The Systolic Hypertension in Europe (Syst-Eur) trial proved that blood pressure (BP) lowering therapy starting with nitrendipine reduces the risk of cardiovascular complications in older (> or = 60 years) patients with isolated systolic hypertension (systolic BP > or = 160 mm Hg and diastolic BP < 95 mm Hg). After the completion of the Syst-Eur trial on 14 February 1997, 3506 consenting patients (93.0% of those eligible) were enrolled in phase 2 of the Syst-Eur trial. This open follow-up study aims to confirm the safety of long-term antihypertensive therapy based on a dihydropyridine. To lower the sitting systolic BP below 150 mm Hg (target BP), the first-line agent nitrendipine (10-40 mg/day) may be associated with enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), both add-on study drugs, or if required any other antihypertensive agent. On 1 November 1998, 3248 patients were still being followed, 86 patients had proceeded to non-supervised follow-up, and 43 had died. The median follow-up in Syst-Eur 2 was 14.3 months. At the last available visit, systolic/diastolic BP in the patients formerly randomised to placebo (n = 1682) or active treatment (n = 1824), had decreased by 13.2/5.2 mm Hg and by 4.6/1.6 mm Hg, respectively, so that the between-group BP difference was 1.7 mm Hg systolic (95% Ci: 0.8 to 2.6 mm Hg; P < 0.001) and 0.9 mm Hg diastolic (95% Cl: 0.4 to 1.5 mm mm Hg; P < 0.001). At the beginning of Syst-Eur 2, the goal BP was reached by 25.4% and 50.6% of the former placebo and active-treatment groups; at the last visit these proportions were 55.9% and 63.1%, respectively. At that moment, 45.9% of the patients were on monotherapy with nitrendipine, 29.3% took nitrendipine in combination with other study drugs. Until the end of 2001, BP control of the Syst-Eur 2 patients will be further improved. Cardiovascular complications and adverse events, such as cancer or gastro-intestinal bleeding, will be monitored and validated by blinded experts.
Journal of Human Hypertension 03/1999; 13(2):135-45. · 2.80 Impact Factor
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J Tuomilehto,
D Rastenyte, W H Birkenhäger,
L Thijs,
R Antikainen,
C J Bulpitt,
A E Fletcher,
F Forette,
A Goldhaber,
P Palatini,
C Sarti,
R Fagard
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ABSTRACT: Recent reports suggest that calcium-channel blockers may be harmful in patients with diabetes and hypertension. We previously reported that antihypertensive treatment with the calcium-channel blocker nitrendipine reduced the risk of cardiovascular events. In this post hoc analysis, we compared the outcome of treatment with nitrendipine in diabetic and nondiabetic patients.
After stratification according to center, sex, and presence or absence of previous cardiovascular complications, 4695 patients (age, > or =60 years) with systolic blood pressure of 160 to 219 mm Hg and diastolic pressure below 95 mm Hg were randomly assigned to receive active treatment or placebo. Active treatment consisted of nitrendipine (10 to 40 mg per day) with the possible addition or substitution of enalapril (5 to 20 mg per day) or hydrochlorothiazide (12.5 to 25 mg per day) or both, titrated to reduce the systolic blood pressure by at least 20 mm Hg and to less than 150 mm Hg. In the control group, matching placebo tablets were administered similarly.
At randomization, 492 patients (10.5 percent) had diabetes. After a median follow-up of two years, the systolic and diastolic blood pressures in the placebo and active-treatment groups differed by 8.6 and 3.9 mm Hg, respectively, among the diabetic patients. Among the 4203 patients without diabetes, systolic and diastolic pressures differed by 10.3 and 4.5 mm Hg, respectively, in the two groups. After adjustment for possible confounders, active treatment was found to have reduced overall mortality by 55 percent (from 45.1 deaths per 1000 patients to 26.4 deaths per 1000 patients), mortality from cardiovascular disease by 76 percent, all cardiovascular events combined by 69 percent, fatal and nonfatal strokes by 73 percent, and all cardiac events combined by 63 percent in the group of patients with diabetes. Among the nondiabetic patients, active treatment decreased all cardiovascular events combined by 26 percent and fatal and nonfatal strokes by 38 percent. In the group of patients receiving active treatment, reductions in overall mortality, mortality from cardiovascular disease, and all cardiovascular events were significantly larger among the diabetic patients than among the nondiabetic patients (P=0.04, P=0.02, and P=0.01, respectively).
Nitrendipine-based antihypertensive therapy is particularly beneficial in older patients with diabetes and isolated systolic hypertension. Thus, our findings do not support the hypothesis that the use of long-acting calcium-channel blockers may be harmful in diabetic patients.
New England Journal of Medicine 03/1999; 340(9):677-84. · 53.30 Impact Factor
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European Heart Journal 02/1999; 20(1):11-24. · 10.48 Impact Factor
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F Forette,
M L Seux,
J A Staessen,
L Thijs, W H Birkenhäger,
M R Babarskiene,
S Babeanu,
A Bossini,
B Gil-Extremera,
X Girerd,
T Laks,
E Lilov,
V Moisseyev,
J Tuomilehto,
H Vanhanen,
J Webster,
Y Yodfat,
R Fagard
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ABSTRACT: Systolic hypertension increases the risk of dementia in elderly people. The vascular dementia project, set up in the framework of the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial, investigated whether antihypertensive drug treatment could reduce the incidence of dementia.
Eligible patients had no dementia, were at least 60 years old, and had a blood pressure when seated of 160-219 mm Hg systolic and below 95 mm Hg diastolic. Active treatment consisted of nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), or both drugs, titrated or combined to reduce the systolic blood pressure by at least 20 mm Hg to reach a value below 150 mm Hg. Cognitive function was assessed by the mini mental state examination (MMSE). If the MMSE score was 23 or less, diagnostic tests for dementia were done (DSM-III-R criteria). The cause of dementia was established by the modified ischaemic score with brain imaging or the Hachinski score.
Median follow-up by intention to treat was 2.0 years. Compared with placebo (n=1180), active treatment (n=1238) reduced the incidence of dementia by 50% from 7.7 to 3.8 cases per 1000 patient-years (21 vs 11 patients, p=0.05). The median MMSE score at randomisation was 29 in both treatment groups. At the last available assessment, systolic and diastolic blood pressure were, respectively, 8.3 mm Hg and 3.8 mm Hg lower (p<0.001) in the active-treatment group, but on average the MMSE scores did not change in either group. In the control patients, however, the MMSE decreased (p=0.04) with decreasing diastolic blood pressure, whereas in the active-treatment group MMSE scores improved slightly (p=0.01) with greater reduction in diastolic blood pressure (p=0.002 for between-group difference).
In elderly people with isolated systolic hypertension, antihypertensive treatment was associated with a lower incidence of dementia. If 1000 hypertensive patients were treated with antihypertensive drugs for 5 years 19 cases of dementia might be prevented.
The Lancet 10/1998; 352(9137):1347-51. · 38.28 Impact Factor
