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The VA NEPHRON-D trial tackled an important question about the combination therapy of ACEi and ARBs. We know from the RENAAL trial that losartan has significant benefits in diabetic nephropathy. The authors of the VA NEPHRON-D tiral aimed to assess if the addition of an ACE inhibitor to ARB therapy prevent eGFR reduction, ESRD, or death in patients with T2DM, CKD stage 2-3, and elevated urine albumin: creatinine. The trial included a reasonable number of 1448 patients who were randomized to losartan + placebo group and combination group of losartan and lisinopril. The trial was ended earlier due to inconclusive results. The authors of VA NEPHRON-D trial concluded that combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. Source: NEJM
2000, Effect of ACE inhibitors, ramipril on cardiovascular morbidity and mortality, NEJM
HOPE Trial Summary
HOPE – “Effects of an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Cardiovascular Events in High-Risk Patients’ was a randomized, double-blinded, multi-national (267 centers), placebo-controlled, clinical trial (recruited patients between 1993 and 1995), which investigated the role of ACE inhibitor (ramipril 10mg oral daily) in patients >= 55 years of age with vascular disease (CAD, stroke, or PAD) or diabetes and one additional CV risk factor (HTN, elevated total cholesterol, low HDL, smoking, or microalbuminuria), but who did not have MI or stroke in the preceding 4 weeks, history of HF, LVEF <40%, uncontrolled HTN, overt nephropathy, and who were not already on ACE inhibitor.
After a run-in phase, 9541 patients were randomized. The study was terminated early because of the beneficial effect of ramipril. At 4 years, the primary outcome, which was the composite of MI, stroke and cardiovascular death, was significantly less with ramipril (14% vs 17.8%; RR: 0.78; 95% CI: 0.70-0.86; P<0.001). Of note, these beneficial effects became statistically significant at 2 years and continued to improve. Rates of individual components primary outcome were also statistically lower with ramipril.
Other outcomes- death from any cause, worsening angina and heart failure were less with ramipril as well. The benefit with ramipril, in terms of the primary outcome, was also observed in the predefined subgroups- above or below 65 years of age, male or female, with or without diabetes, with or without evidence of vascular disease, with or without history of HTN, with or with or without microalbuminuria.
Worth mentioning, the BP at baseline was similar in the two groups (139/79 mmHg) and very small reduction in systolic and diastolic BP (3 and 2 mmHg respectively) was noticed in the ramipril arm.
Authors of this trial (Yusuf S., et al) concluded: “treating 1000 patients with ramipril for four years prevents about 150 events in approximately 70 patients”.