Michael B. Murphy

Statins do more than just lower cholesterol

Clinical trials have demonstrated that inhibitors of 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins) greatly reduce cardiovascular-related morbidity and mortality in patients with and without coronary artery disease. 1,2 These drugs were designed to inhibit the rate-limiting enzyme of cholesterol synthesis in the liver, thereby decreasing hepatic production of lowdensity lipoprotein (LDL), and upregulating expression of hepatic LDL receptors, thus lowering concentrations of circulating LDL. With lower plasma LDL concentrations, plaque development should be retarded or should regress because of lipid loss, which would render the plaque less occlusive and less likely to disrupt or cause thrombosis. The use of simvastatin in the Scandinavian (4S) secondary intervention study 1 and the use of pravastatin in the West of Scotland Coronary Prevention Study (WOSCOPS) primary intervention trial 2 supported the hypothesis that drugs that lower plasma cholesterol concentration are of benefit to patients with coronary artery disease. However, the clinical benefit of the drugs used in these studies is manifest early in the course of lipidlowering therapy before plaque regression could occur. Quantitative angiographic assessments of the impact of statin therapy on coronary atherosclerosis have demonstrated that improvement in arterial topographical morphology occurs slowly and only to a small extent. 3 In the Multicentre Anti-Atheroma Study (MAAS), 3

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.

Glucose intolerance in hypertensive patients treated with diuretics; a fourteen-year follow-up.

Abstract Glucose tolerance was studied prospectively in thirty-four hypertensive patients treated with oral thiazide diuretics without interruption for 14 years. Standard oral glucose tolerance tests were carried out before treatment and after 1, 6, and 14 years. Mean fasting blood glucose increased from 4·7±0·6 to 6·0±2·3 mmol/l and the 2 h value rose from 5·5+1·9 to 8·0±4·7 mmol/l after 14 years. Withdrawal of thiazide therapy for 7 months in ten of the patients resulted in mean reductions of 10% in fasting blood glucose and 25% in the 2 h value.

Renal and hemodynamic effects of intravenous fenoldopam versus nitroprusside in severe hypertension.

The renal and hemodynamic effects of intravenously administered fenoldopam mesylate, a novel dopamine-1 receptor agonist, were compared with those of sodium nitroprusside in 28 patients (18 male; 26 black, two white; average age, 49 +/- 3 years) with an average blood pressure of 219/137 mm Hg, most of whom presented with acute target organ damage. Fenoldopam and nitroprusside lowered blood pressure safely to an average pressure of 176/105 mm Hg; highly significant dose-response relations were found for the 13 patients receiving fenoldopam and the 15 receiving nitroprusside. Volume and sodium, potassium, and creatinine concentrations were measured in freely voided urine specimens both before and during intravenous therapy. In the fenoldopam-treated patients, there were significant increases in urinary flow (92 +/- 21 to 168 +/- 37 ml/hr, p less than 0.003), sodium excretion (227 +/- 73 to 335 +/- 90 mu eq/min, p less than 0.001), and creatinine clearance (70 +/- 11 to 93 +/- 13 ml/hr, p less than 0.003). In the nitroprusside-treated group, however, all these parameters decreased, but not significantly. For direct comparison of the two agents, the increments in urinary flow rate (+76 +/- 20 vs. -16 +/- 15 ml/hr, fenoldopam vs. nitroprusside), sodium excretion (+109 +/- 28 vs. -39 +/- 28 mu eq/min), and creatinine clearance (+23 +/- 6 vs. -11 +/- 7 ml/min) were significantly greater (p less than 0.001 for each) in the fenoldopam-treated group. Significant differences were also obtained when these parameters were calculated as percentage increase over baseline. Fenoldopam and nitroprusside are effective therapies for severe, accelerated, or malignant hypertension, but fenoldopam had additional salutary renal effects in these patients.

Augmentation of renal blood flow and sodium excretion in hypertensive patients during blood pressure reduction by intravenous administration of the dopamine1 agonist fenoldopam.

Activation of dopamine1 (DA1) receptors relaxes vascular smooth muscle, especially in the renal vascular bed. Fenoldopam, the first selective DA1-receptor agonist that can be administered to man, was infused intravenously in 17 patients with essential hypertension (mean blood pressure 152/101 mm Hg). It reduced blood pressure in a dose-dependent fashion at doses between 0.025 and 0.5 microgram/kg/min and the antihypertensive effect was sustained during 2 hr infusions. In 10 patients studied during free-water diuresis, fenoldopam increased renal plasma flow by 42%, glomerular filtration rate by 6%, and sodium excretion by 202%, while lowering mean arterial pressure by 12% (all p less than .05). Similar promotion of sodium excretion was observed during blood pressure reduction in six additional patients studied without water loading. Pronounced enhancement of renal function in spite of blood pressure reduction suggests that fenoldopam might have a special role in the treatment of patients with hypertension and renal impairment.

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.

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.

Role of nifedipine in treatment of hypertension.

The efficacy of nifedipine in the treatment of hypertension was assessed in 15 patients whose hypertension continued while being treated with atenolol 100 mg and bendrofluazide 5 mg daily. Nifedipine was added in doses of 10, 20, and 30 mg three times daily in a placebo controlled, double blind trial. One patient was withdrawn from the trial because of severe postural hypotension with the highest dose. Erect and supine blood pressure in the remaining 14 patients were significantly reduced by all doses of nifedipine. The drug was well tolerated but plasma potassium fell by 0.3 mmol(mEq)/1 during treatment (p less than 0.05). Nifedipine is thus effective in the treatment of hypertension but should probably be used in combination with a potassium sparing diuretic.