PREVEND IT: Prevention of Renal and Vascular Endstage Disease Intervention Trial

Luis Gruberg, MD, FACC

Disclosures

December 30, 2003

Editorial Collaboration

Medscape &

Presenters: Folkert Asselbergs, MD, and WH van Gilst, MD, University of Groningen (Groningen, The Netherlands)

Microalbuminuria has been associated with increased morbidity and mortality in patients at high cardiovascular risk. Angiotensin-converting enzyme (ACE) inhibitors and statins have been shown to reduce microalbuminuria and cardiovascular risk in this patient population. The true impact of ACE inhibitor therapy and/or statins in reducing microalbuminuria and clinical events has not been previously studied in a lower-risk population.

Aim

The Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) was designed to assess the effects of the ACE inhibitor, fosinopril and pravastatin, on cardiovascular morbidity and mortality in microalbuminuric subjects without hypertension or hypercholesterolemia.

Primary Endpoint

The primary endpoint of the study was cardiovascular mortality, hospitalization for cardiovascular morbidity, and end-stage renal disease.

Study Design

Inhabitants of the city of Gromingen (The Netherlands), aged 28-75 years, were asked to provide a morning urine sample for the microalbuminuria analysis (> 10 mg/L). A total of > 40,000 inhabitants responded and sent back a sample.

After performing the analysis for microalbuminuria, 8592 inhabitants were screened at the outpatient clinic and 1439 patients were subsequently considered eligible for enrollment in the PREVEND IT study.

Only 864 patients were randomized into the study, and data were available for analysis in 854 of them. The study was performed in a 2 x 2 factorial design, where patients were randomized to either one of the study drugs plus placebo for 4 years:

  • Fosinopril 20 mg (n = 425) vs placebo (n = 429)

  • Pravastatin 40 mg (n = 427) vs placebo (n = 427)

Inclusion Criteria
  • Urinary albumin excretion rate 15-300 mg/24 hours

  • Blood pressure < 160/100

  • No antihypertensive treatment

  • Total cholesterol < 308 mg/dL or < 193 mg/dL in patients with previous myocardial infarction

  • No use of lipid-lowering medication

Results

Baseline clinical characteristics were similar between all 4 groups (Table).

Table. PREVEND IT: Baseline Clinical Characteristics
Characteristic Placebo vs Fosinopril Placebo vs Pravastatin
Placebo
(n = 429)
Fosinopril
(n = 425)
Placebo
(n = 427)
Pravastatin
(n = 427)
Age (yrs) 52 51 50 52
Male (%) 64 66 63 67
Smoking (%) 65 70 72 73
Diabetes (%) 2.8 2.1 2.3 2.6
Albuminuria (mg/24 hours) 22 24 24 22

Over the course of a mean follow-up period of 46 months, a reduction in systolic and diastolic blood pressure was noted in patients assigned to fosinopril (5.1 and 4.3 mm Hg, respectively) and a reduction in total cholesterol and LDL cholesterol was observed in patients assigned to pravastatin (43.2 mg/dL and 45.6 mg/dL, respectively), neither of which was observed in patients assigned to the placebo arm of the study.

At 3 months, albuminuria levels were significantly reduced in patients assigned to fosinopril, and the reduced levels were sustained at 4-year follow-up. The use of pravastatin, however, was not associated with any reductions in albuminuria (Figure 1).

Figure 1. PREVEND IT: changes in albuminuria levels -- fosinopril vs pravastatin.

The primary endpoint occurred in 42 (4.9%) patients. Overall, the incidence of the primary endpoint was reduced by 44% in patients treated with fosinopril and by 25% in patients treated with pravastatin; however, neither reduction reached statistical significance compared with placebo. However, after adjusting the analysis to include only patients whose baseline microalbuminuria was > 50 mg/24 hrs, investigators achieved a statistically significant reduction in the primary endpoint in patients treated with fosinopril (P = .048).

Compared with placebo, use of fosinopril was associated with a significant reduction in the rate of stroke (P = .028), but had no effect on the incidence of cardiovascular mortality or myocardial ischemia. By contrast, pravastatin significantly reduced the incidence of myocardial ischemia (attributed to its effects of cholesterol reduction; P = .03), but had no effect on the incidence of mortality or stroke compared with placebo (Figure 2).

Figure 2. PREVEND IT: primary endpoint components – placebo vs fosinopril and placebo vs pravastatin.
Conclusions

On the basis of their results, investigators concluded that:

  • Cardiovascular events were lower than expected in this microalbuminuric population without hypertension or hypercholesterolemia

  • The anticipated event rate was observed only in subjects whose baseline microalbuminuria was > 50 mg/24 hrs

  • Pravastatin significantly reduced cholesterol but had no effect on microalbuminuria or the incidence of the primary endpoint

  • Fosinopril significantly reduced blood pressure and microalbuminuria, and this reduction was associated with a trend toward a reduction in the incidence of the primary endpoint

  • Fosinopril normalized the increased risk for cardiovascular events in subjects with microalbuminuria > 50 mg/24 hrs

  • The results of PREVEND IT favor further studies in microalbuminuric patients without indication for primary prevention. Interventions directed at the renin-angiotensin system appear to be the therapy of first choice in such studies

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