Gerard J. Blauw

Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial

BACKGROUND Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals, their efficacy and safety in elderly people is not fully established. Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with, or at high risk of developing, cardiovascular disease and stroke. METHODS We did a randomised controlled trial in which we assigned 5804 men (n=2804) and women (n=3000) aged 70-82 years with a history of, or risk factors for, vascular disease to pravastatin (40 mg per day; n=2891) or placebo (n=2913). Baseline cholesterol concentrations ranged from 4.0 mmol/L to 9.0 mmol/L. Follow-up was 3.2 years on average and our primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. Analysis was by intention-to-treat. FINDINGS Pravastatin lowered LDL cholesterol concentrations by 34% and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo (hazard ratio 0.85, 95% CI 0.74-0.97, p=0.014). Coronary heart disease death and non-fatal myocardial infarction risk was also reduced (0.81, 0.69-0.94, p=0.006). Stroke risk was unaffected (1.03, 0.81-1.31, p=0.8), but the hazard ratio for transient ischaemic attack was 0.75 (0.55-1.00, p=0.051). New cancer diagnoses were more frequent on pravastatin than on placebo (1.25, 1.04-1.51, p=0.020). However, incorporation of this finding in a meta-analysis of all pravastatin and all statin trials showed no overall increase in risk. Mortality from coronary disease fell by 24% (p=0.043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. INTERPRETATION Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people.

Persistent epigenetic differences associated with prenatal exposure to famine in humans

Extensive epidemiologic studies have suggested that adult disease risk is associated with adverse environmental conditions early in development. Although the mechanisms behind these relationships are unclear, an involvement of epigenetic dysregulation has been hypothesized. Here we show that individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944–45 had, 6 decades later, less DNA methylation of the imprinted IGF2 gene compared with their unexposed, same-sex siblings. The association was specific for periconceptional exposure, reinforcing that very early mammalian development is a crucial period for establishing and maintaining epigenetic marks. These data are the first to contribute empirical support for the hypothesis that early-life environmental conditions can cause epigenetic changes in humans that persist throughout life.

The design of a prospective study of pravastatin in the elderly at risk (PROSPER)

The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomized, double-blind, placebo-controlled trial designed to test the hypothesis that treatment with pravastatin will diminish risk of subsequent major vascular events in a cohort of men and women (70 to 82 years old) with preexisting vascular disease or significant risk of developing this condition. Five thousand eight hundred four men and women in addition to receiving advice on diet and smoking, have been randomized equally to treatment with 40 mg pravastatin/day or matching placebo in 3 centers (Cork, Ireland, Glasgow, Scotland, and Leiden, The Netherlands). Following an average 3.5-year intervention period, a primary assessment will be made of the influence of this therapy on major vascular events (a combination of coronary heart disease, death, nonfatal myocardial infarction, and fatal and nonfatal stroke). A number of additional analyses will also be conducted on the individual components of the primary end point, on men, on women, and on subjects with and without previous evidence of vascular disease. Finally, an assessment will be made of the effects of treatment on cognitive function, disability, hospitalization or institutionalization, vascular mortality, and all-cause mortality.

Can metabolic syndrome usefully predict cardiovascular disease and diabetes? Outcome data from two prospective studies.

BACKGROUND Clinical use of criteria for metabolic syndrome to simultaneously predict risk of cardiovascular disease and diabetes remains uncertain. We investigated to what extent metabolic syndrome and its individual components were related to risk for these two diseases in elderly populations. METHODS We related metabolic syndrome (defined on the basis of criteria from the Third Report of the National Cholesterol Education Program) and its five individual components to the risk of events of incident cardiovascular disease and type 2 diabetes in 4812 non-diabetic individuals aged 70-82 years from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). We corroborated these data in a second prospective study (the British Regional Heart Study [BRHS]) of 2737 non-diabetic men aged 60-79 years. FINDINGS In PROSPER, 772 cases of incident cardiovascular disease and 287 of diabetes occurred over 3.2 years. Metabolic syndrome was not associated with increased risk of cardiovascular disease in those without baseline disease (hazard ratio 1.07 [95% CI 0.86-1.32]) but was associated with increased risk of diabetes (4.41 [3.33-5.84]) as was each of its components, particularly fasting glucose (18.4 [13.9-24.5]). Results were similar in participants with existing cardiovascular disease. In BRHS, 440 cases of incident cardiovascular disease and 105 of diabetes occurred over 7 years. Metabolic syndrome was modestly associated with incident cardiovascular disease (relative risk 1.27 [1.04-1.56]) despite strong association with diabetes (7.47 [4.90-11.46]). In both studies, body-mass index or waist circumference, triglyceride, and glucose cutoff points were not associated with risk of cardiovascular disease, but all five components were associated with risk of new-onset diabetes. INTERPRETATION Metabolic syndrome and its components are associated with type 2 diabetes but have weak or no association with vascular risk in elderly populations, suggesting that attempts to define criteria that simultaneously predict risk for both cardiovascular disease and diabetes are unhelpful. Clinical focus should remain on establishing optimum risk algorithms for each disease.

Total cholesterol and risk of mortality in the oldest old

BACKGROUND The impact of total serum cholesterol as a risk factor for cardiovascular disease decreases with age, which casts doubt on the necessity for cholesterol-lowering therapy in the elderly. We assessed the influence of total cholesterol concentrations on specific and all-cause mortality in people aged 85 years and over. METHODS In 724 participants (median age 89 years), total cholesterol concentrations were measured and mortality risks calculated over 10 years of follow-up. Three categories of total cholesterol concentrations were defined: < 5.0 mmol/L, 5.0-6.4 mmol/L, and > or = 6.5 mmol/L. In a subgroup of 137 participants, total cholesterol was measured again after 5 years of follow-up. Mortality risks for the three categories of total cholesterol concentrations were estimated with a Cox proportional-hazards model, adjusted for age, sex, and cardiovascular risk factors. The primary causes of death were coded according to the International Classification of Diseases (ICD-9). FINDINGS During 10 years of follow-up from Dec 1, 1986, to Oct 1, 1996, a total of 642 participants died. Each 1 mmol/L increase in total cholesterol corresponded to a 15% decrease in mortality (risk ratio 0.85 [95% CI 0.79-0.91]). This risk estimate was similar in the subgroup of participants who had stable cholesterol concentrations over a 5-year period. The main cause of death was cardiovascular disease with a similar mortality risk in the three total cholesterol categories. Mortality from cancer and infection was significantly lower among the participants in the highest total cholesterol category than in the other categories, which largely explained the lower all-cause mortality in this category. INTERPRETATION In people older than 85 years, high total cholesterol concentrations are associated with longevity owing to lower mortality from cancer and infection. The effects of cholesterol-lowering therapy have yet to be assessed.

Evidence of genetic enrichment for exceptional survival using a family approach : the Leiden Longevity study

We conducted a sib pair study in very old subjects for the purpose of mapping longevity loci. In the present analysis, we explore whether our recruitment strategy has resulted in a population enriched for a heritable component for exceptional longevity. Our study includes families with at least two long-living siblings (men aged 89 years or above; women aged 91 years or above). Data were collected on date of birth and, if applicable, date of death of parents, brothers and sisters, offspring, and spouses of the long-living participants. Standardised mortality ratios (SMRs) compared with the general Dutch population, were calculated. The SMR for all siblings of the long-living participants was 0.66 (95% CI 0.60–0.73). A similar survival benefit was also observed in the parents (SMR=0.76, 95% CI 0.66–0.87) and in the offspring of the long-living subjects (SMR=0.65, 95% CI 0.51–0.80). The SMR of the spouses of the long-living subjects was 0.95 (95% CI 0.82–1.12). The familial clustering of extended survival is unlikely to be caused by ascertainment bias, because in all analyses the long-living participants were excluded. Moreover, it is also unlikely to be caused by environmental factors, because the spouses of the long-living participants had a mortality risk comparable with the general Dutch population, whereas they share the same environment. We conclude that our sample is genetically enriched for extreme survival.

C-Reactive Protein Is a Strong but Nonspecific Risk Factor of Fatal Stroke in Elderly Persons

An elevated level of C-reactive protein is a strong predictor of cardiovascular events in elderly persons. Whether C-reactive protein has direct adverse vascular effects or is a marker of aspecific systemic inflammation remains to be determined. The aim of this study was to investigate the relation between C-reactive protein and the occurrence of fatal strokes in elderly persons. In the Leiden 85-Plus Study, a population-based prospective follow-up study, we studied the levels of C-reactive protein in 80 participants who died from stroke within the first 5 years of follow-up. Levels of C-reactive protein were determined in serum samples at baseline. Levels of C-reactive protein were also determined in 82 control subjects who survived for the first 5 years of follow-up and in 83 participants who died from noncardiovascular causes. Mortality risks were estimated with logistic regression and adjusted for differences in age, sex, smoking, medication, total cholesterol, history of diabetes or hypertension, and previous cardiovascular events. Levels of C-reactive protein at baseline were 2-fold higher in subjects who died from stroke than in control subjects (median 5.7 versus 2.7 mg/L, P<0.005). The levels of C-reactive protein in subjects who died from stroke or from noncardiovascular causes were similar (median 5.7 versus 4.9 mg/L, P=0.7). The risk of death from stroke as well as from noncardiovascular causes increased linearly up to 10-fold in subjects with the highest levels of C-reactive protein at baseline (P<0.001). The levels of C-reactive protein were lower when more time had elapsed between blood sampling and time of death during follow-up (P=0.01). C-reactive protein is a strong but nonspecific risk factor of fatal stroke in old persons. The data do not support the idea that C-reactive protein has direct vascular effects that underlie fatal cerebrovascular disease.

Association between high‐density lipoprotein and cognitive impairment in the oldest old

Low high‐density lipoprotein cholesterol is associated with an increased risk for cardiovascular disease and stroke. At the same time, cardiovascular disease and stroke are important risk factors for dementia. We assessed the association between total and fractionated cholesterol and cognitive impairment and explored whether observed associations were dependent on or independent of atherosclerotic disease. In a population‐based study, total cholesterol, triglycerides, low‐density lipoprotein cholesterol, and high‐density lipoprotein cholesterol were measured in 561 subjects 85 years old and grouped in three equal strata representing decreasing serum concentrations. History of cardiovascular disease and stroke was determined. All subjects completed the Mini‐Mental State Examination (MMSE), and the presence of dementia was determined. Median MMSE scores were significantly lower in subjects with low high‐density lipoprotein cholesterol (25 points vs 27 points, p < 0.001). No differences in MMSE scores were found for other lipids and lipoproteins. MMSE scores in subjects with and without cardiovascular disease were 26 and 27 points (p = 0.007), respectively, and in subjects with and without stroke were 21 and 26 points (p < 0.001), respectively. The associations between low MMSE scores and low high‐density lipoprotein cholesterol remained significant after subjects with cardiovascular disease or stroke were excluded. In a comparison of subjects with low high‐density lipoprotein cholesterol with subjects with high high‐density lipoprotein cholesterol, the odds ratio for dementia was 2.3 (95% confidence interval, 1.2–4.3), and in subjects without cardiovascular disease or stroke, it was 3.7 (95% confidence interval, 1.3–10.1). All odds ratios were unaffected by education, low‐density lipoprotein cholesterol, triglycerides, and survival. Low high‐density lipoprotein cholesterol is associated with cognitive impairment and dementia. At least part of the association between high‐density lipoprotein cholesterol and cognitive function is independent of atherosclerotic disease.

Reproducibility of total cerebral blood flow measurements using phase contrast magnetic resonance imaging

To evaluate reproducibility of total cerebral blood flow (CBF) measurements with phase contrast magnetic resonance imaging (pcMRI).

C-Reactive Protein and Prediction of Coronary Heart Disease and Global Vascular Events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)

Background— The role of C-reactive protein (CRP) in predicting vascular events and response to statin therapy remains uncertain. Additional large prospective studies are required. Methods and Results— Baseline CRP was related to risk over 3.2 years for primary a combined end point (definite or suspected death from coronary heart disease, nonfatal myocardial infarction, and fatal or nonfatal stroke; n=865 events) and secondary (coronary heart disease events or stroke alone) and tertiary (stroke plus transient ischemic attack) end points in the Prospective Study of Pravastatin in the Elderly at Risk (n=5804 men and women; age, 70 to 82 years). CRP levels were higher in subjects who had a subsequent primary end-point event compared with those who did not (geometric mean; 3.64 mg/L [SD, 3.08 mg/L] versus 3.01 mg/L [SD, 3.05 mg/L]; P<0.0001). CRP correlated positively with body mass index and smoking status and negatively with high-density lipoprotein cholesterol. The unadjusted hazard ratio for the primary end point was 1.48 (95% CI, 1.26 to 1.74) in a comparison of top and bottom thirds for CRP, falling to 1.36 (95% CI, 1.15 to 1.61) with adjustment for established predictors and body mass index. Similar results were obtained for other end points or when results were examined separately by history of vascular disease. However, baseline CRP added minimally to risk prediction beyond conventional predictors and did not relate to the magnitude of pravastatin benefit. Conclusions— Elevated CRP minimally enhances cardiovascular disease prediction beyond established vascular risk factors and does not predict response to statin therapy in elderly subjects at risk. These data suggest that CRP has limited clinical value in cardiovascular disease risk stratification or predicting response to statin therapy in elderly people.