Ruth Peters

Treatment of Hypertension in Patients 80 Years of Age or Older

BACKGROUND Whether the treatment of patients with hypertension who are 80 years of age or older is beneficial is unclear. It has been suggested that antihypertensive therapy may reduce the risk of stroke, despite possibly increasing the risk of death. METHODS We randomly assigned 3845 patients from Europe, China, Australasia, and Tunisia who were 80 years of age or older and had a sustained systolic blood pressure of 160 mm Hg or more to receive either the diuretic indapamide (sustained release, 1.5 mg) or matching placebo. The angiotensin-converting-enzyme inhibitor perindopril (2 or 4 mg), or matching placebo, was added if necessary to achieve the target blood pressure of 150/80 mm Hg. The primary end point was fatal or nonfatal stroke. RESULTS The active-treatment group (1933 patients) and the placebo group (1912 patients) were well matched (mean age, 83.6 years; mean blood pressure while sitting, 173.0/90.8 mm Hg); 11.8% had a history of cardiovascular disease. Median follow-up was 1.8 years. At 2 years, the mean blood pressure while sitting was 15.0/6.1 mm Hg lower in the active-treatment group than in the placebo group. In an intention-to-treat analysis, active treatment was associated with a 30% reduction in the rate of fatal or nonfatal stroke (95% confidence interval [CI], -1 to 51; P=0.06), a 39% reduction in the rate of death from stroke (95% CI, 1 to 62; P=0.05), a 21% reduction in the rate of death from any cause (95% CI, 4 to 35; P=0.02), a 23% reduction in the rate of death from cardiovascular causes (95% CI, -1 to 40; P=0.06), and a 64% reduction in the rate of heart failure (95% CI, 42 to 78; P<0.001). Fewer serious adverse events were reported in the active-treatment group (358, vs. 448 in the placebo group; P=0.001). CONCLUSIONS The results provide evidence that antihypertensive treatment with indapamide (sustained release), with or without perindopril, in persons 80 years of age or older is beneficial. (ClinicalTrials.gov number, NCT00122811 [ClinicalTrials.gov].).

Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial

BACKGROUND Observational epidemiological studies have shown a positive association between hypertension and risk of incident dementia; however, the effects of antihypertensive therapy on cognitive function in controlled trials have been conflicting, and meta-analyses of the trials have not provided clear evidence of whether antihypertensive treatment reduces dementia incidence. The Hypertension in the Very Elderly trial (HYVET) was designed to assess the risks and benefits of treatment of hypertension in elderly patients and included an assessment of cognitive function. METHODS Patients with hypertension (systolic pressure 160-200 mm Hg; diastolic pressure <110 mm Hg) who were aged 80 years or older were enrolled in this double-blind, placebo-controlled trial. Participants were randomly assigned to receive 1.5 mg slow release indapamide, with the option of 2-4 mg perindopril, or placebo. The target systolic blood pressure was 150 mm Hg; the target diastolic blood pressure was 80 mm Hg. Participants had no clinical diagnosis of dementia at baseline, and cognitive function was assessed at baseline and annually with the mini-mental state examination (MMSE). Possible cases of incident dementia (a fall in the MMSE score to <24 points or a drop of three points in 1 year) were assessed by standard diagnostic criteria and expert review. The trial was stopped in 2007 at the second interim analysis after treatment resulted in a reduction in stroke and total mortality. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00122811. FINDINGS 3336 HYVET participants had at least one follow-up assessment (mean 2.2 years) and were included: 1687 participants were randomly assigned to the treatment group and 1649 to the placebo group. Only five reports of adverse effects were attributed to the medication: three in the placebo group and two in the treatment group. The mean decrease in systolic blood pressure between the treatment and placebo groups at 2 years was systolic -15 mm Hg, p<0.0001; and diastolic -5.9 mm Hg, p<0.0001. There were 263 incident cases of dementia. The rates of incident dementia were 38 per 1000 patient-years in the placebo group and 33 per 1000 patient-years in the treatment group. There was no significant difference between treatment and placebo groups (hazard ratio [HR] 0.86, 95% CI 0.67-1.09); however, when these data were combined in a meta-analysis with other placebo-controlled trials of antihypertensive treatment, the combined risk ratio favoured treatment (HR 0.87, 0.76-1.00, p=0.045). INTERPRETATION Antihypertensive treatment in elderly patients does not statistically reduce incidence of dementia. This negative finding might have been due to the short follow-up, owing to the early termination of the trial, or the modest effect of treatment. Nevertheless, the HYVET findings, when included in a meta-analysis, might support antihypertensive treatment to reduce incident dementia.

Diet and colon cancer in Los Angeles County, California

The diets of 746 colon cancer cases in Los Angeles County, California (USA) were compared with those of 746 controls matched on age, sex, race, and neighborhood. In both genders, total energy intake was associated with significantly increased risk, and calcium intake was associated with significantly decreased risk. These effects were reduced only slightly after adjustment for the nondietary risk factors (weight, physical activity, family history, and, if female, pregnancy history). In men, total fat and alcohol intakes were responsible for the calorie effect; in women, no individual source of calories was associated independently with risk. Neither saturated fat nor fat from animal sources was responsible for the fat effect. There were no additional independent significant effects for sucrose, fiber, cruciferous vegetables, β-carotene, other vitamins, or any other nutrient or micronutrient. In univariate analyses, meats, poultry, breads, and sweets were associated with excess risk, and yogurt was protective. After adjustment for sources of calories, no individual food was associated with excess risk, but yogurt remained significantly protective. Total calories were associated with excess risk throughout the colon while the effects of calcium, fat, and alcohol appeared somewhat stronger in the distal colon. After adjustment, crude fiber was significantly protective in the ascending colon but not even weakly protective in the distal colon.

Alcohol, dementia and cognitive decline in the elderly: a systematic review

BACKGROUND dementia and cognitive decline have been linked to cardiovascular risk. Alcohol has known negative effects in large quantities but may be protective for the cardiovascular system in smaller amounts. Effect of alcohol intake may be greater in the elderly and may impact on cognition. METHODS to evaluate the evidence for any relationship between incident cognitive decline or dementia in the elderly and alcohol consumption, a systematic review and meta-analyses were carried out. Criteria for inclusion were longitudinal studies of subjects aged >or=65, with primary outcomes of incident dementia/cognitive decline. RESULTS 23 studies were identified (20 epidemiological cohort, three retrospective matched case-control nested in a cohort). Meta-analyses suggest that small amounts of alcohol may be protective against dementia (random effects model, risk ratio [RR] 0.63; 95% CI 0.53-0.75) and Alzheimers disease (RR 0.57; 0.44-0.74) but not for vascular dementia (RR 0.82; 0.50-1.35) or cognitive decline (RR 0.89; 0.67-1.17) However, studies varied, with differing lengths of follow up, measurement of alcohol intake, inclusion of true abstainers and assessment of potential confounders. CONCLUSIONS because of the heterogeneity in the data these findings should be interpreted with caution. However, there is some evidence to suggest that limited alcohol intake in earlier adult life may be protective against incident dementia later.

Smoking, dementia and cognitive decline in the elderly, a systematic review

BackgroundNicotine may aid reaction time, learning and memory, but smoking increases cardiovascular risk. Cardiovascular risk factors have been linked to increased risk of dementia. A previous meta-analysis found that current smokers were at higher risk of subsequent dementia, Alzheimers disease, vascular dementia and cognitive decline.MethodsIn order to update and examine this further a systematic review and meta-analysis was carried out using different search and inclusion criteria, database selection and more recent publications. Both reviews were restricted to those aged 65 and over.ResultsThe review reported here found a significantly increased risk of Alzheimers disease with current smoking and a likely but not significantly increased risk of vascular dementia, dementia unspecified and cognitive decline. Neither review found clear relationships with former smoking.ConclusionCurrent smoking increases risk of Alzheimers disease and may increase risk of other dementias. This reinforces need for smoking cessation, particularly aged 65 and over. Nicotine alone needs further investigation.

Literature Review of the Clock Drawing Test as a Tool for Cognitive Screening

Background/Aims: The Clock Drawing Test (CDT) is used in clinical practice for the screening of cognitive disorders. This systematic review aims to present and discuss the CDT scoring methods available in the literature, in order to find differences in administration and utility of the CDT. Methods: A literature search was carried out in Medline (1966 to June 2008), Psychinfo (1967 to June 2008) and EMBASE (1980 to June 2008). Results: All studies showed good interrater and test-retest reliabilities. The correlation with other standard screening tests was statistically significant in most studies, but the results were influenced by age, education and language. In studies that included patients with mild or questionable dementia, the CDT had a low sensitivity and variable specificity. Conclusion: The CDT has the characteristics of a good screening method for moderate and severe dementia. However, the scoring method used and potential confounders need to be taken into consideration.

Effect of Troglitazone on Insulin Sensitivity and Pancreatic β-Cell Function in Women at High Risk for NIDDM

We conducted a randomized placebo-controlled study to determine the effects of the thiazolidinedione compound troglitazone on whole-body insulin sensitivity (SI), pancreatic β-cell function, and glucose tolerance in 42 Latino women with impaired glucose tolerance (IGT) and a history of gestational diabetes mellitus (GDM), characteristics that carry an 80% risk of developing NIDDM within 5 years. After baseline oral (OGTT) and intravenous (IVGTT) glucose tolerance testing, subjects were assigned to take placebo or 200 or 400 mg troglitazone daily for 12 weeks (14 subjects per treatment group). An OGTT and IVGTT were repeated during the 12th week of treatment. Five subjects failed to complete the trial for personal reasons, and medication compliance averaged 90% in the remaining subjects, none of whom experienced a serious adverse event. SI, calculated by minimal model analysis of IVGTT results, changed by only 4 ± 14% during 12 weeks of placebo administration, but increased 40 ± 22 and 88 ± 22% above basal during treatment with 200 and 400 mg troglitazone, respectively (P = 0.01 among groups). Troglitazone administration was also associated with a dose-dependent reduction in the total insulin area during IVGTTs, which was highly significant (P < 0.001), and with a reduction during OGTTs, which approached statistical significance (P = 0.09). Glucose tolerance improved slightly in all groups, but the magnitude of change did not differ significantly among groups, whether it was assessed as the number of subjects who continued to manifest IGT at 12 weeks (P = 0.64 among groups), the change in total glucose area during OGTTs (P = 0.58), or the change in fractional glucose disappearance rates during IVGTTs (P = 0.28). Among the women who received troglitazone, the greatest improvement in SI occurred in the women who had the highest diastolic blood pressures and the best IVGTT insulin responses during baseline testing. Our findings indicate that troglitazone improved whole-body insulin sensitivity and lowered circulating insulin concentrations in women with prior GDM who are at very high risk for NIDDM. The lack of improvement in glucose tolerance despite improved insulin sensitivity may be a manifestation of the β-cell defect that predisposes the women to NIDDM. The overall pattern of response to troglitazone in our high-risk patients indicates that the drug is an ideal agent with which to test whether the amelioration of insulin resistance can delay or prevent diabetes in women with limited β-cell reserve.

Immediate and late benefits of treating very elderly people with hypertension: results from active treatment extension to Hypertension in the Very Elderly randomised controlled trial

Objective To assess if very elderly people with hypertension obtain early benefit from antihypertensive treatment. Design One year open label active treatment extension of randomised controlled trial (Hypertension in the Very Elderly Trial (HYVET)). Setting Hospital and general practice based centres mainly in eastern and western Europe, China, and Tunisia. Participants People on double blind treatment at the end of HYVET were eligible to enter the extension. Interventions Participants on active blood pressure lowering treatment continued taking active drug; those on placebo were given active blood pressure lowering treatment. The treatment regimen was as used in the main trial—indapamide SR 1.5 mg (plus perindopril 2-4 mg if required)—with the same target blood pressure of less than 150/80 mm Hg. Main outcome measures The primary outcome was all stroke; other outcomes included total mortality, cardiovascular mortality, and cardiovascular events. Results Of 1882 people eligible for entry to the extension, 1712 (91%) agreed to participate. During the extension period, 1682 patient years were accrued. By six months, the difference in blood pressure between the two groups was 1.2/0.7 mm Hg. Comparing people previously treated with active drug and those previously on placebo, no significant differences were seen for stroke (n=13; hazard ratio 1.92, 95% confidence interval 0.59 to 6.22) or cardiovascular events (n=25; 0.78, 0.36 to 1.72). Differences were seen for total mortality (47 deaths; hazard ratio 0.48, 0.26 to 0.87; P=0.02) and cardiovascular mortality (11 deaths; 0.19, 0.04 to 0.87; P=0.03). Conclusion Very elderly patients with hypertension may gain immediate benefit from treatment. Sustained differences in reductions of total mortality and cardiovascular mortality reinforce the benefits and support the need for early and long term treatment. Trial registration Clinical trials NCT00122811.

Type 2 Diabetes as a Risk Factor for Dementia in Women Compared With Men: A Pooled Analysis of 2.3 Million People Comprising More Than 100,000 Cases of Dementia

OBJECTIVE Type 2 diabetes confers a greater excess risk of cardiovascular disease in women than in men. Diabetes is also a risk factor for dementia, but whether the association is similar in women and men remains unknown. We performed a meta-analysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia. RESEARCH DESIGN AND METHODS A systematic search identified studies published prior to November 2014 that had reported on the prospective association between diabetes and dementia. Study authors contributed unpublished sex-specific relative risks (RRs) and 95% CIs on the association between diabetes and all dementia and its subtypes. Sex-specific RRs and the women-to-men ratio of RRs (RRRs) were pooled using random-effects meta-analyses. RESULTS Study-level data from 14 studies, 2,310,330 individuals, and 102,174 dementia case patients were included. In multiple-adjusted analyses, diabetes was associated with a 60% increased risk of any dementia in both sexes (women: pooled RR 1.62 [95% CI 1.45–1.80]; men: pooled RR 1.58 [95% CI 1.38–1.81]). The diabetes-associated RRs for vascular dementia were 2.34 (95% CI 1.86–2.94) in women and 1.73 (95% CI 1.61–1.85) in men, and for nonvascular dementia, the RRs were 1.53 (95% CI 1.35–1.73) in women and 1.49 (95% CI 1.31–1.69) in men. Overall, women with diabetes had a 19% greater risk for the development of vascular dementia than men (multiple-adjusted RRR 1.19 [95% CI 1.08–1.30]; P < 0.001). CONCLUSIONS Individuals with type 2 diabetes are at ∼60% greater risk for the development of dementia compared with those without diabetes. For vascular dementia, but not for nonvascular dementia, the additional risk is greater in women.

The effect of treatment based on a diuretic (indapamide) ± ACE inhibitor (perindopril) on fractures in the Hypertension in the Very Elderly Trial (HYVET)

BACKGROUND fractures may have serious implications in an elderly individual, and fracture prevention may include a careful choice of medications. DESIGN the Hypertension in the Very Elderly Trial (HYVET) was a double-blind placebo-controlled trial of a thiazide-like diuretic (indapamide 1.5 mg SR) with the optional addition of the angiotensin-converting enzyme (ACE) inhibitor (perindopril 2-4 mg). Fracture was a secondary end point of the trial. SETTING HYVET recruited participants from Eastern and Western Europe, China, Australasia, and Tunisia. SUBJECTS all participants were > or =80 years of age and hypertensive. METHODS participants were randomised to receive a thiazide-like diuretic (indapamide 1.5 mg SR) +/- ACE inhibitor (perindopril 2-4 mg) or matching placebos. Incident fractures were validated and analysed based on time to first fracture. RESULTS there were 3,845 participants in HYVET and a total 102 reported fractures (42 in the active and 60 in the placebo group). When taking only validated first fractures, 90 were included in the analyses (38 in the active and 52 in the placebo group). Cox proportional hazard regression, adjusted for key baseline risk factors, resulted in a point estimate of 0.58 (95% CI 0.33-1.00, P = 0.0498). CONCLUSIONS despite the lowering of blood pressure, treatment with a thiazide-like diuretic and an ACE inhibitor does not increase and may decrease fracture rate.