Michael E. Hyland

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.

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.

Derivation and Validation of a Composite Index of Severity in Chronic Obstructive Pulmonary Disease The DOSE Index

RATIONALE Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a multicomponent disease with systemic consequences and effects on quality of life. Single measures such as lung function provide a limited reflection of how the disease affects patients. Composite measures have the potential to account for many of the facets of COPD. OBJECTIVES To derive and validate a multicomponent assessment tool of COPD severity that is applicable to all patients and health care settings. METHODS The index was derived using data from 375 patients with COPD in primary care. Regression analysis led to a model explaining 48% of the variance in health status as measured by the Clinical COPD Questionnaire with four components: dyspnea (D), airflow obstruction (O), smoking status (S), and exacerbation frequency (E). The DOSE Index was validated in cross-sectional and longitudinal samples in various health care settings in Holland, Japan, and the United Kingdom. MEASUREMENTS AND MAIN RESULTS The DOSE Index correlated with health status in all data sets. A high DOSE Index score (> or = 4) was associated with a greater risk of hospital admission (odds ratio, 8.3 [4.1-17]) or respiratory failure (odds ratio, 7.8 [3.4-18.3]). The index predicted exacerbations in the subsequent year (P < or = 0.014). CONCLUSIONS The DOSE Index is a simple, valid tool for assessing the severity of COPD. The index is related to a range of clinically important outcomes such as health care consumption and predicts future events.

Diary keeping in asthma: comparison of written and electronic methods.

OBJECTIVE--To determine the extent to which symptom diaries of asthmatic patients are inaccurate or based on retrospective recall. DESIGN--Comparison of electronic and pencil and paper diaries. Both forms were completed twice daily at home for 14 days. SETTING--Outpatient clinic. SUBJECTS--24 asthmatic outpatients also tested for severity of asthma and for anxiety. RESULTS--More sessions were missed in the evening than in the morning for both types of diaries. Significantly more retrospective entries were made in the evening (26 entries, 14 patients) than in the morning (6 entries, 3 patients). Discrepant entries of peak expiratory flow accounted for 15% of those made on the appropriate day, and three quarters of patients made at least one discrepant entry. Variation in peak expiratory flow was significantly related to number of discrepancies and number of missing days, and anxiety score was significantly related to number of missing days. About a fifth of written entries may have errors. CONCLUSION--Poor diary completion may result from having unreasonable expectations of patients and giving incomplete instructions. Electronic, time coded diaries could ensure better quality of records.

A short outpatient pulmonary rehabilitation programme: immediate and longer-term effects on exercise performance and quality of life.

Pulmonary rehabilitation is widely available in North America and parts of Europe for patients with chronic obstructive pulmonary disease (COPD). Here, we describe the feasibility and benefits of providing a comprehensive but cost effective pulmonary rehabilitation programme in a U.K. district general hospital. Two hundred and sixty-seven patients with respiratory disability were referred for pulmonary rehabilitation. Patients were assessed and recruited onto a 7 week outpatient-based pulmonary rehabilitation programme including elements of exercise and education without longer term maintenance. Exercise performance was measured by the shuttle walking test and a treadmill endurance test, and quality of life as measured by two disease specific questionnaires, the Breathing Problems Questionnaire and the Chronic Respiratory Disease Questionnaire. Of 267 patients referred between 1993 and 1996, 132 (110 with COPD) have completed rehabilitation and could be evaluated. For all graduates, shuttle distance increased by 58 m (27%) and treadmill endurance time increased by 15.9 min (294%). The Breathing Problems Questionnaire proved sensitive to changes in quality of life in some domains. The Chronic Respiratory Disease Questionnaire showed significant improvements in all domains in a sub-set of 57 patients who completed it. Longer term follow-up of 49 patients at a mean of 10.3 months following pulmonary rehabilitation revealed that previous gains in exercise performance and quality of life were maintained with improvements in shuttle walking distance of 33 m (14% over baseline) and endurance time of 16 min (280% over baseline). The Breathing Problems Questionnaire showed no overall change but the Chronic Respiratory Disease Questionnaire showed continued improvement in a small number of patients. We therefore concluded that a short outpatient based pulmonary rehabilitation programme without a maintenance element has produced significant gains in exercise performance and quality of life for 132 patients at a district general hospital in the U.K.

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.

Attrition from self-directed interventions: investigating the relationship between psychological predictors, intervention content and dropout from a body dissatisfaction intervention

The aims of this study were to (a) identify the predictors of attrition from a fully self-directed intervention, and (b) to test whether an intervention to increase gratitude is an effective way to reduce body dissatisfaction. Participants (N=479, from the United Kingdom) aged 18-76 years took part in a self-help study via the Internet and were randomized to receive one of two interventions, gratitude diaries (n=130), or thought monitoring and restructuring (n=118) or a waitlist control (n=231) for a two week body dissatisfaction intervention. The gratitude intervention (n=40) was as effective as monitoring and restructuring (n=22) in reducing body dissatisfaction, and both interventions were significantly more effective than the control condition (n=120). Participants in the gratitude group were more than twice as likely to complete the intervention compared to those in the monitoring and restructuring group. Intervention content, baseline expectancy and internal locus of control significantly predicted attrition. This study shows that a gratitude intervention can be as effective as a technique commonly used in cognitive therapy and is superior in retaining participants. Prediction of attrition is possible from both intervention content and psychological variables.

Testing cognitive function in elderly populations: the PROSPER study

Objectives: For large scale follow up studies with non-demented patients in which cognition is an endpoint, there is a need for short, inexpensive, sensitive, and reliable neuropsychological tests that are suitable for repeated measurements. The commonly used Mini-Mental-State-Examination fulfils only the first two requirements. Methods: In the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), 5804 elderly subjects aged 70 to 82 years were examined using a learning test (memory), a coding test (general speed), and a short version of the Stroop test (attention). Data presented here were collected at dual baseline, before randomisation for active treatment. Results: The tests proved to be reliable (with test/retest reliabilities ranging from acceptable (r=0.63) to high (r=0.88) and sensitive to detect small differences in subjects from different age categories. All tests showed significant practice effects: performance increased from the first measurement to the first follow up after two weeks. Conclusion: Normative data are provided that can be used for one time neuropsychological testing as well as for assessing individual and group change. Methods for analysing cognitive change are proposed.

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.