Microalbuminuria and tubular proteinuria as risk predictors of cardiovascular morbidity and mortality in essential hypertension: final results of a prospective long-term study (MARPLE Study)*.

OBJECTIVE: To evaluate the impact of microalbuminuria (MAU) or tubular proteinuria (TPU) on cardiovascular and cerebrovascular events and all-cause mortality, and to assess whether a normalization of MAU and/or TPU induced by angiotensin-converting enzyme-inhibitor-based antihypertensive treatment with ramipril improves cerebrovascular prognosis in essential hypertensive patients without diabetes mellitus. METHOD: A prospective, controlled, multicenter study was performed involving 3529 hypertensive participants (average follow-up 42.5 months). Ramipril was the basic antihypertensive medication. Proteinuria analysis (albumin, alpha 1-microglobulin, SDS electrophoresis) was performed by quantitative measurement every year. Ambulatory blood pressure monitoring was performed once yearly. The main outcome determined was cardiovascular and cerebrovascular events and all-cause mortality. RESULTS: In patients with TPU and/or MAU, the risk for endpoints increased significantly compared with normal (TPU, 30.0%; MAU, 54.7%; MAU + TPU, 64.0%; macroproteinuria, 74.4%). A change of protein excretion either from pathologic to normal or from normal to pathologic showed a clear trend to correlate with cerebrovascular endpoints (P = 0.056 and P = 0.055). Normal protein excretion at baseline and during follow-up indicated a significantly better prognosis than pathologic proteinuria at baseline and during follow-up. (P < 0.0001). TPU normalized in 31.9%, MAU in 30.6%, MAU + TPU in 29.3%, and macroproteinuria in 10.2% of patients. A total of 445 (25.4%) patients with normal protein excretion developed pathologic proteinuria during follow-up. CONCLUSIONS: In non-diabetic hypertensive patients, MAU as well as TPU increases the incidence of cardiovascular events. Normalization of MAU, TPU or macroproteinuria during angiotensin-converting enzyme-inhibitor-based treatment correlates with a reduction of cardiovascular events. Beyond blood pressure control, normalization of MAU and TPU should be considered as a further therapeutic goal. There is a need for further studies to optimize treatment if proteinuria is unresponsive to angiotensin-converting enzyme inhibitors.

Cost effectiveness of ramipril in patients at high risk for cardiovascular events : economic evaluation of the HOPE (Heart Outcomes Prevention Evaluation) study for Germany from the Statutory Health Insurance perspective.

BACKGROUND: In the HOPE (Heart Outcomes Prevention Evaluation) trial, ramipril (compared with placebo) significantly reduced cardiovascular death and all-cause mortality as well as the incidence of costly cardiovascular events, such as myocardial infarction, revascularisation, stroke, cardiac arrest, hospitalisation due to heart failure and worsening angina pectoris, new-onset diabetes mellitus and microvascular diabetic complications. OBJECTIVE: Data from the HOPE study were used in a cost-effectiveness analysis to determine the additional cost per life-year gained (LYG) when the ACE inhibitor ramipril was added to the current medication of patients at high risk for cardiovascular events. The aim was to establish the incremental cost-effectiveness ratio (ICER) of ramipril versus placebo from the perspective of the Statutory Health Insurance (SHI) provider in Germany, for both the study population as a whole and for the subgroup of patients with diabetes. DESIGN: A modelling approach was used, based on secondary analysis of published data and retrospective application of costs. In the base-case analysis, average case-related expenses of the SHI were applied and LYG were quantified using the average of the difference between the survival rates in the ramipril and placebo groups during the HOPE trial. LYG beyond the trial duration were estimated by the method of declining exponential approximation of life expectancy. RESULTS: After a treatment period of 4.5 years, the ICER of ramipril versus placebo was Euros 4074/LYG and Euros 2486/LYG (discounted at 5% per annum and in 1998-2002 values; Euro 1 approximately USD 0.88; first quarter 2002 values) for the HOPE study population as a whole and the subgroup of patients with diabetes, respectively. To test the model's robustness, the influence of the model variables on the results was quantified using a deterministic model, and a best-case/worst-case scenario analysis. The effect of random variables was investigated in a Monte Carlo simulation. The acquisition cost for ramipril had the greatest impact on the ICER of ramipril (2.2-fold greater than the impact of the number of LYG). In 95% of the 10,000 simulation steps, the ICER of ramipril after 4.5 years of treatment was between Euros 1290 and Euros 9005 per LYG for the entire HOPE study population and between Euros 290 and Euros 6115 per LYG in the diabetic subgroup. CONCLUSIONS: Results of this evaluation suggest that ramipril is likely to be cost effective in secondary prevention of cardiovascular events from the perspective of the SHI (third-party payer) in Germany. The estimated ICER of ramipril compares well with other ICERs of widely accepted treatments used for the management of cardiovascular diseases, such as HMG-CoA reductase inhibitors.

High-dose furosemide for established ARF: a prospective, randomized, double-blind, placebo-controlled, multicenter trial.

BACKGROUND: The effect of furosemide on the survival and renal recovery of patients presenting with acute renal failure (ARF) is still debated. METHODS: Three hundred thirty-eight patients with ARF requiring dialysis therapy were randomly assigned to the administration of either furosemide (25 mg/kg/d intravenously or 35 mg/kg/d orally) or matched placebo, with stratification according to severity at presentation. The primary end point was survival. The secondary end point was number of dialysis sessions. Tertiary end points included time on dialysis therapy, time to achieve a serum creatinine level less than 2.26 mg/dL (<200 micromol/L), and time to reach a 2-L/d diuresis. RESULTS: There were no differences in survival and renal recovery rates between the 2 groups. Time to achieve a 2-L/d diuresis was shorter with furosemide (5.7 +/- 5.8 days) than placebo (7.8 +/- 6.8 days; P = 0.004). Overall, 148 patients achieved a urine output of at least 2 L/d during the study period (94 of 166 patients; 57%) with furosemide versus 54 of 164 patients (33%) with placebo ( P < 0.001). However, there were no significant differences in number of dialysis sessions and time on dialysis therapy between the furosemide and placebo groups, even in the subgroup of patients reaching a 2-L/d diuresis. CONCLUSION: High-dose furosemide helps maintain urinary output, but does not have an impact on the survival and renal recovery rate of patients with established ARF.

Use of ramipril in preventing stroke: double blind randomised trial.

OBJECTIVE: To determine the effect of the angiotensin converting enzyme inhibitor ramipril on the secondary prevention of stroke. DESIGN: Randomised controlled trial with 2x2 factorial design. SETTING: 267 hospitals in 19 countries. PARTICIPANTS: 9297 patients with vascular disease or diabetes plus an additional risk factor, followed for 4.5 years as part of the HOPE study. OUTCOME MEASURES: Stroke (confirmed by computed tomography or magnetic resonance imaging when available), transient ischaemic attack, and cognitive function. Blood pressure was recorded at entry to the study, after 2 years, and at the end of the study. RESULTS: Reduction in blood pressure was modest (3.8 mm Hg systolic and 2.8 mm Hg diastolic). The relative risk of any stroke was reduced by 32% (156 v 226) in the ramipril group compared with the placebo group, and the relative risk of fatal stroke was reduced by 61% (17 v 44). Benefits were consistent across baseline blood pressures, drugs used, and subgroups defined by the presence or absence of previous stroke, coronary artery disease, peripheral arterial disease, diabetes, or hypertension. Significantly fewer patients on ramipril had cognitive or functional impairment. CONCLUSION: Ramipril reduces the incidence of stroke in patients at high risk, despite a modest reduction in blood pressure.