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white matter hyperintensities in the elderly.

Heuvel, D.M.J. van den

Citation

Heuvel, D. M. J. van den. (2005, November 17). White matters : a longitudinal study on

causes and consequences of white matter hyperintensities in the elderly. Retrieved from

https://hdl.handle.net/1887/3729

Version:

Corrected Publisher’s Version

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Chapter

2

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The data of this thesis were collected within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), a randomised, double blind, placebo-controlled trial to test the hypothesis that treatment with pravastatin (40 mg/day) reduces the risk of vascular disease in elderly men and women with pre-existing vascular disease or with significant risk of developing this condition. Three European coor-dinating centers – Glasgow in Scotland, Cork in Ireland, and Leiden in the Netherlands – participated in the study. Moreover, in Leiden a MRI substudy was integrated within the PROSPER main study. This chapter gives a brief overview of the PROSPER study design, rationale and main results and introduces the PROS-PER MRI substudy. The protocol of the PROSPROS-PER study has been described in detail by Shepherd et al1, 2.

Rationale

Previous investigations have reported that the 3-hydroxy-3-methylglutaryl Coenzyme A reductase inhibitors (statins) have beneficial effects on both primary and secondary prevention of coronary and cerebrovascular disease in middle-aged men and women3-8. However, there has been debate whether the benefits of

statin-based cholesterol lowering drugs can be extrapolated to people older than 70 years. The efficacy of such treatment is not clear since, in contrast with mid-dle-aged subjects, raised plasma cholesterol in elderly subjects is no longer asso-ciated with increased risk of coronary or cerebrovascular disease. However, some investigations have reported benefits of statin therapy on stroke and on cognitive functioning9, 10. In light of the aforementioned findings, the PROSPER study was

primarily designed to investigate the efficacy of cholesterol lowering in elderly subjects. The aim of the PROSPER main study was to investigate whether treat-ment with pravastatin 40mg/day reduces the risk of cardiac events, stroke, cog-nitive decline and disability in those with existing (secondary prevention) and in those at high risk of developing vascular disease (primary prevention). Additionally, the primary objective of the nested PROSPER MRI substudy was to investigate the effect of treatment with pravastatin on the occurrence of incident cerebral ischemic lesions and on cerebral perfusion in the elderly at risk.

Study design

Participants Between the 15th of December 1997 and 7th of May 1999, elderly individuals from Scotland, Ireland and the Netherlands were enrolled and screened for the PROSPER study and followed for an average period of 3.2 years (range 2.8-4.0). Briefly, individuals were identified in either primary care settings or trial centers in close proximity to each of the coordinating centers. Men and women aged 70-82 years were recruited if they had either pre-existing vascular disease (coronary, cerebral or peripheral) or raised risk of such disease because of smoking, hypertension or diabetes. Specific inclusion and exclusion criteria for enrollment are outlined in table 1.

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In total 23,770 men and women were screened, and 5,804 were included in the PROSPER main study (2,520 from Scotland, 2,184 from Ireland, and 1,100 from the Netherlands). The characteristics of the PROSPER study sample have been described in detail elsewhere1.

A part of the eligible Dutch participants of the PROSPER main study were asked to also participate at the same time in the nested MRI substudy. In addition to the exclusion criteria of the PROSPER main study, subjects with cardiac pacemak-ers, hearing implants, intraorbital vascular clips, collagen disease, multiple scle-rosis, or claustrophobia were excluded from participation in the PROSPER MRI substudy. In total 646 Dutch participants consented for and were included in the PROSPER MRI substudy. Baseline characteristics of the participants of the PROS-PER MRI substudy are shown in table 2.

Methods At subsequent visits during the PROSPER study period data were col-lected regarding the demographic and health status of the participants. This data set included standard risk factors such as age, sex, blood pressure, heart rate, body mass index, history of hypertension, diabetes, smoking and vascular disease. Furthermore, fasting venous blood samples were drawn for biochemical and haematological checks and lipoprotein quantification. Also, 12 lead ECG readings were recorded. Cognitive functioning was evaluated with use of the Mini Mental State Examination (MMSE) and various psychometric tests (Picture-Word Learning Test, Stroop (Picture-Word Colour Test, Letter Digit Coding Test) measur-ing memory and executive functionmeasur-ing. As a measure of ‘activities of daily liv-ing’, questionnaires (modified Barthel and Instrumental Activities of Daily Living) were administered.

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Main results

The main finding of the PROSPER study was that treatment of elderly individuals for 3 years with pravastatin produced a 15% relative reduction (Hazard Ratio (95% CI); 0.85 (0.74-0.97)) in the risk of coronary and cerebrovascular events (i.e. primary endpoint). When the primary endpoint was separated into coronary and cerebrovascular components, a reduction of 19% (HR (95%CI); 0.81 (0.69-0.94) was noted in coronary events but no discernible effect on cerebrovascular events was found (HR (95% CI); 1.03 (0.81-1.31)). Thus, statin therapy (i.e. pravastatin), even in a period as short as 3 years, reduced the risk of coronary disease in elderly older than age 70 years. The PROSPER study therefore suggests that the strategy for vascular risk management in middle-aged people should also be applied to elderly individuals. However, there was a less clear effect of statins on the prevention of cerebrovascular disease. Although the apparent reduction in transient ischaemic attacks seen with pravastatin treatment was encouraging, a clear result on stroke is likely to require a longer period of treatment, if indeed statins are beneficial in this age range1.

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Table 1. Inclusion and exclusion criteria for the PROSPER main study

________________________________________________________________________ Inclusion criteria

. Men or women aged 70-82 yrs . Total cholesterol 4.0 – 9.0 mmol/L

. Physician diagnosed stable angina or intermittent claudication

. Stroke, transient ischemic attack, myocardial infarction, arterial surgery, or amputa-tion for vascular disease >6 months before study entry

. >1 of the following risk factors for vascular disease Current smoker

Hypertension, currently receiving drug treatment

Known diabetes mellitus or fasting blood glucose >7 mmol/L Exclusion criteria

. Recent stroke, transient ischemic attack, myocardial infarction, arterial surgery, or amputation for vascular disease ?6 months before study entry

. Any surgery requiring overnight hospitalization for a medical reason (including ang-ioplasty) ?6 months before study entry

. Poor cognitive function at baseline (Mini Mental Score Examination <24) . Physically or mentally unable to attend the clinic for the screening visit . Total cholesterol <4.0 mmol/L or total cholesterol >9.0 mmol/L . Total triglycerides >6.0 mmol/L

. History of malignancy within the past 5 years except localized basal cell carcinoma of the skin

. Congestive heart failure (New York Heart Association functional class III or IV) . Electrocardiographic evidence of atrial fibrilation or other significant arrhythmia, or

Wolff-Parkinson-White syndrome

. Implanted cardiac pacemakers with the capacity for ventricular pacing . Organ transplant recipient

. Current lipid-lowering drug treatment . Cyclosporin treatment

. Previous participation in a clinical trial using an HMG CoA reductase inhibitor . Inability to give informed consent

. Planned long-term travel or emigration within next 3 years . Current alcohol or drugs abuse

. Cohabitation with another trial participant

. <75% or >120% compliance with placebo lead-in medication

. Receipt of any investigational drugs (including placebo) within 30 days of enrollment . Inability to tolerate oral medication or a history of significant malabsorption . Any other medical condition that renders the patient unable to complete the stud y

or that would interfere with optimal participation in the study or produce significant risk to the patient

. Abnormal laboratory findings, including . Hemoglobin <11 g/dl and hematocrit <33%

. Thyroid stimulating hormone >20 U/L or >10 U/L with an abnormal free thyroxine Glucose >15 mmol/L

Platelet count <100,000/mm3

White blood cell count <3,500/mm3 or >15,000/ mm3 Serum creatinine >200 μmol/L

Aspartate aminotransferase or alinine aminotransferase >3,0 × upper limit of normal for the laboratory, Creatine kinase >3 × upper limit of normal for the laboratory

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Table 2: Baseline characteristics of the participants of the MRI substudy (n=646) ________________________________________________________________________ Demographic variables Age (years) 75.0 (3.2) Gender: Male 363 (56.8) Risk factors SBP (mmHg) 157.5 (21.9) DBP (mmHg) 86.1 (11.5) Total cholesterol (mmol/L) 5.75 (0.86) LDL cholesterol (mmol/L) 3.91 (0.75) HDL cholesterol (mmol/L) 1.23 (0.32) Smoking: Current 140 (21.9) Former 305 (47.7) Never 194 (30.4) History of Disease Diabetes 109 (17.1) Hypertension 402 (62.9) Angina 135 (21.1) Claudication 24 (3.8) MI 88 (13.8) Stroke 41 (6.4) TIA 66 (10.3) CABG 26 (4.1) PTCA 21 (3.3) PAD surgery 26 (4.1) Cognitive functioning MMSE 28.1 (1.5) ________________________________________________________________________ Data shown are mean (SD) for continuous variables and n (%) for categorical variables SBP; systolic blood pressure. DBP; diastolic blood pressure. LDL; low-density lipoprotein. HDL; high-density lipoprotein. BMI; body mass index. MI; myocard infarction. TIA; transient ischemic attack. CABG; coronary artery bypass graft. PTCA; percutaneous transluminal coronary angioplasty. PAD; peripheral arterial disease. MMSE; mini mental state examina-tion.

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Reference List

1. Shepherd J, Blauw GJ, Murphy MB et al. Pravastatin in elderly individuals at risk of vas-cular disease (PROSPER): a randomised controlled trial. Lancet2002 November 23; 360 (9346):1623-30.

2. Shepherd J, Blauw GJ, Murphy MB et al. The design of a prospective study of Pravastatin in the Elderly at Risk (PROSPER). PROSPER Study Group. PROspective Study of Pravastatin in the Elderly at Risk.Am J Cardiol 1999 November 15; 84(10):1192-7.

3. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994 November 19; 344(8934):1383-9.

4. Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravas-tatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995 November 16;333(20):1301-7.

5. Sacks FM, Pfeffer MA, Moye LA et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996 October 3;335(14):1001-9. 6. Downs JR, Clearfield M, Weis S et al. Primary prevention of acute coronary events with

lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998 May 27;279(20):1615-22.

7. Prevention of cardiovascular events and death with pravastatin in patients with coro-nary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998 November 5;339(19):1349-57.

8. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002 July 6; 360(9326):7-22.

9. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000 October;57(10):1439-43.

10. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of demen-tia. Lancet 2000 November 11;356(9242):1627-31.

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