Adriaan M. Kamper

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.

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.

Association Between Apolipoprotein E4 and Cognitive Decline in Elderly Adults

OBJECTIVE: To determine the influence of apolipoprotein E on cognitive decline in a cohort of elderly men and women.

Plasma lipoproteins and apolipoproteins as predictors of cardiovascular risk and treatment benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).

Background— Statins are important in vascular disease prevention in the elderly. However, the best method of selecting older patients for treatment is uncertain. We assessed the role of plasma lipoproteins as predictors of risk and of treatment benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Method and Results— The association of LDLc and HDLc with risk was examined in the 5804 70- to 82-year-old subjects of PROSPER. Baseline LDLc showed no relation to risk of the primary end point in the placebo group (P=0.27), nor did on-treatment LDLc in the pravastatin group (P=0.12). HDLc was inversely associated with risk in subjects on placebo (P=0.0019) but not in those on pravastatin (P=0.24). Risk reduction on pravastatin treatment was unrelated to baseline LDLc (P=0.38) but exhibited a significant interaction with HDLc (P=0.012). Subjects in the lowest 2 quintiles of HDLc (<1.15 mmol/L) had a risk reduction of 33% (hazard ratio, 0.67; 95% confidence limits, 0.55, 0.81; P<0.0001), whereas those with higher HDLc showed no benefit (RR, 1.06; 95% confidence limits, 0.88, 1.27; P=0.53). During follow-up, there was no relation between achieved level of LDLc or HDLc and risk. However, the change in the LDLc/HDLc ratio on statin treatment appeared to account for the effects of therapy. Conclusions— In people >70 years old, HDLc appears to be a key predictor of risk and of treatment benefit. Findings in PROSPER suggest that statin therapy could usefully be targeted to those with HDLc <1.15 mmol/L or an LDLc/HDLc ratio >3.3.

Association between apolipoprotein E4 and cognitive decline in elderly adults

OBJECTIVE: To determine the influence of apolipoprotein E on cognitive decline in a cohort of elderly men and women.

Serum Calcium and Cognitive Function in Old Age

OBJECTIVES: To determine whether serum calcium is associated with cognitive function in elderly individuals in the general population.

Lower blood pressure associated with higher mortality in elderly diabetic patients (ZODIAC-12)

OBJECTIVE to investigate the relationship between blood pressure over time and mortality in elderly patients with type 2 diabetes mellitus (T2DM). DESIGN prospective observational cohort study. SETTING primary care, Zwolle, The Netherlands. SUBJECTS patients with T2DM aged 60 years and older (n = 881). The cohort was divided into two age categories: 60-75 years and older than 75 years. METHODS updated means for systolic, diastolic and pulse pressures were calculated after a median follow-up time of 9.8 years. These values were used as time-dependent covariates in a Cox proportional hazard model. Main outcome measures were all-cause and cardiovascular mortality. RESULTS all of the blood pressure measures were inversely related to all-cause mortality in elderly diabetic patients (>75 years). Furthermore, these relationships were specifically found in elderly patients treated with antihypertensive medication at baseline. A decrease of 10 mm Hg in systolic blood pressure, diastolic blood pressure and pulse pressure led to a mortality increase of 22% [95% confidence interval (95% CI): 13-31%], 30% [95% CI: 13%-46%] and 22% [95% CI: 11%-33%], respectively. In the low age group (60-75 years), no relationship was found between blood pressure and mortality. CONCLUSIONS blood pressure is a marker for mortality in elderly T2DM patients; however, the relationship is inverse.

Prostaglandins are involved in acetylcholine- and 5-hydroxytryptamine-induced, nitric oxide-mediated vasodilatation in human forearm.

Both acetylcholine (ACh) and 5-hydroxytryptamine (5HT) are used to examine nitric oxide (NO)-mediated vasodilatation in humans. Animal data suggest that both substances can also induce the release of prostacyclin (PGI2). This study was designed to investigate the role of the prostaglandin pathway in Ach- and 5HT-induced vasodilation in humans. The experiments were done in three groups of healthy male volunteers. In group 1 (n = 6), ACh (100–1,000 ng/kg/min) and sodium-nitroprusside (10–100 ng/kg/min) were infused into the brachial artery alone, together with a continuous infusion of indomethacin (1.3 &mgr;g/kg/min) and during a combined infusion of indomethacin and the competitive NO synthase inhibitor NG-monomethyl-l-arginine (l-NMMA; 30 &mgr;g/kg/min). In group 2 (n = 5), 5HT (0.3–1.0 ng/kg/min) was infused alone and together with a continuous infusion of indomethacin and l-NMMA. In group 3 (n = 6), the synthetic prostaglandin analog iloprost (0.5–4.5 ng/kg/min) was infused together with a continuous infusion of saline, l-NMMA, and l-NMMA with indomethacin, respectively. The infusions of indomethacin and l-NMMA started 10 min before the infusion of ACh, 5HT, iloprost, and sodium nitroprusside. Forearm blood flow was measured using computerized venous occlusion plethysmography. Both the Ach- and 5HT-induced vasodilator responses were significantly attenuated by indomethacin (p < 0.05 for both), but not further influenced by a concomitant infusion of l-NMMA. The vasodilatation induced by iloprost was significantly inhibited by l-NMMA (p < 0.05) and not affected by indomethacin. The sodium nitroprusside–induced vasodilation was influenced by neither l-NMMA nor indomethacin. It is concluded that in the human forearm, the prostaglandin pathway is involved in both the Ach- and 5HT-induced NO-mediated vasodilatation.

Recognition of Delirium in Postoperative Elderly Patients : A Multicenter Study

To evaluate to what extent delirium experts agree on the diagnosis of delirium when independently assessing exactly the same information and to evaluate the sensitivity of delirium screening tools in routine daily practice of clinical nurses.

Assessment of orthostatic fluid shifts with strain gauge plethysmography

We evaluated the use of strain gauge plethysmography (SGP) for the assessment of orthostatic fluid shifts during head up tilt (HUT). Subjects wore a parachute harness fixed to the tilt table to avoid muscle tension in the lower limbs during HUT. 22 Healthy subjects (9 women) were tilted for 5 minutes. Calf volume changes as measured by SGP, surface EMG, heart rate and blood pressure were measured continuously. Ten subjects underwent a second tilt test during which circulation in one leg was occluded with a pressure cuff at 250 mmHg. During HUT with occlusion, calf volume increased in the non-occluded leg by 1.9+/-0.3% (mean +/- SEM) and 0.2+/-0.2% in the occluded leg (p<0.001). During HUT without occlusion a significant correlation (r = 0.9) was found between measurements of the left and right leg with a mean difference of 0.03+/-0.1%. HUT did not cause significant changes of surface EMG. An unexpected gender effect was found: calf volume increased significantly more in men than in women. Men were significantly taller, but the hemodynamic response to HUT did not differ between both sexes. The gender effect on orthostatic increases of calf volume remained significant after adjustment for heart-to-calf distance. SGP during HUT with a parachute harness is a new, promising method to assess orthostatic fluid shifts. The gender differences in orthostatic pooling in the calf may be explained by a higher calf compliance in men together with a greater hydrostatic pressure due to a greater height in men.