Combination Therapy With the Angiotensin-Converting Enzyme Inhibitor Ramipril and the Angiotensin Receptor Blocker Telmisartan Fails to Reduce Renal Events in Patients at High Risk for Coronary Heart Disease: The ONTARGET Study
Clinical practice guidelines recommend that initial treatment of hypertension in those with chronic kidney disease (CKD) includes either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB). Both classes of antihypertensive agents have demonstrated favorable reductions in proteinuria and improved other renal outcomes in patients with hypertension and CKD. In the absence of data from long-term outcome studies, the most suitable add-on antihypertensive medication for a patient with hypertension and CKD who is already receiving either an ACE inhibitor or an ARB but whose blood pressure (BP) remains above the recommended goal of 130/80 mm Hg remains unknown. Possibilities include a second drug that blocks the renin-angiotensin system (RAS) or a drug that works through a different mechanism. The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoints Trial (ONTARGET) provided an opportunity to investigate the renal effects of the ACE inhibitor ramipril, the ARB telmisartan, and their combination in patients at high risk for coronary heart disease (CHD) events.
To be eligible for participation in ONTARGET, individuals had to be at least 55 years of age and have a history of established atherosclerotic disease or diabetes with end-organ damage. Major exclusion criteria included known renal artery stenosis, uncorrected volume or sodium repletion, serum creatinine level >265 μmol/L, and uncontrolled hypertension (baseline systolic BP >160 mm Hg or baseline diastolic BP >100 mm Hg). After a 3-week single-blind run-in phase with eligible participants receiving increasing doses of both ramipril and telmisartan, participants were randomized in a double-blind fashion to therapy with either telmisartan 80 mg/d, ramipril 10 mg/d, or the combination of the two. The primary end point of ONTARGET was a composite of cardiovascular events (cardiovascular death, stroke, myocardial infarction, or hospitalization for heart failure). Prior to the unblinding of the study, the steering committee developed a statistical analysis plan to evaluate renal outcomes. The primary composite renal outcome was the first occurrence of any dialysis, renal transplant, doubling of serum creatinine value, or death. No cases of renal transplant were reported during the trial. The secondary renal outcomes included the composite of any dialysis and doubling of serum creatinine value; individual components of the primary renal end point; changes in estimated glomerular filtration rate (eGFR); progression of proteinuria (defined as newly developed microalbuminuria or macroalbuminuria); and any renal impairment leading to discontinuation of study medication (as defined by the treating investigator). The eGFR was defined using the Modification of Diet in Renal Disease (MDRD) formula. The primary analysis used a time-to-event approach and included all randomized participants in accordance with intention-to-treat analysis.
Overall, 25,620 participant (mean age, 66; baseline BP, 142/82 mm Hg; 64% previously on ACE inhibitor or ARB therapy) were randomized and included in the renal analysis. They were seen at 6 weeks and every 6 months thereafter until study completion. Serum creatinine was measured locally at the study sites without standardization before run-in, 6 weeks after randomization, after 2 years, and at study completion. Mean serum creatinine value at baseline was 93.7 μmol/L and mean eGFR was 73.6 mL/min/1.73 m2. Stage 3 or 4 CKD (eGFR <60 mL/min/1.73 m2) was noted in 6157 patients (24.0%), but only 263 (1.0%) participants had a baseline eGFR <30 mL/min/1.73 m2. The urinary albumin:creatinine ratio was measured centrally before run-in, at 2 years, and at the final visit. Standard definitions were used to define microalbuminuria and macroalbuminuria. On entry, microalbuminuria was present in 13.1% of all participants, including 29.7% with diabetes and 9.2% without known diabetes. Macroalbuminuria was seen in 4% of all participants, including 12.2% with diabetes and 1.4% without known diabetes. Information about dialysis was requested at each visit, and a questionnaire was sent to each site at which dialysis occurred after the trial about the duration of dialysis and primary reasons for any acute dialysis. Acute dialysis was defined as a duration of renal replacement therapy of ≤2 months, with chronic dialysis being renal replacement therapy lasting >2 months.
During a mean 56 months of follow-up, the frequency of the composite primary renal outcome (dialysis, doubling of serum creatinine level, or death) was similar with telmisartan (1147, 13.4%) and ramipril (1150, 13.5%) but increased with combination therapy (1233, 14.5%; hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.01–1.18; P=.037). The secondary renal end point of doubling of serum creatinine level or dialysis was similar with telmisartan (189, 2.21%) and ramipril (174, 2.03%) but also increased with combination therapy (212, 2.49%; HR, 1.24; 95% CI, 1.01–1.51; P=.038). In the entire study, there were only 162 cases of dialysis (0.06%); the incidence of acute dialysis (n=61) was greater in the combination than in the monotherapy groups, but the incidence of chronic dialysis was similar in all 3 groups. The eGFR decreased more with telmisartan and with combination therapy than with ramipril alone, but the differences, although statistically significant, were small. Urinary albumin excretion increased at 2 years and at study end to a lesser extent with telmisartan than with ramipril or combination therapy, and once again the differences, though statistically significant, were small. The risk of new microalbuminuria, macroalbuminuria, or both was similar between telmisartan (949, 11.1%) and ramipril (1018, 11.7%) but was lower with combination therapy (888, 10.4%; HR, 0.88; 95% CI, 0.81–0.96; P=.003). In all of the subgroups analyzed, including those with and without diabetes, diabetic retinopathy, presence of microalbuminuria or macroalbuminuria, or decreased eGFR, there were no significant differences between telmisartan or ramipril in the incidence of the primary renal end point. Combination therapy demonstrated no clear benefit in reducing the primary renal end point in patients who were at the highest risk for renal disease—including those with hypertension, diabetes, diabetic nephropathy, or baseline decreased eGFR—but was associated with worse renal outcomes among patients at lower risk (those without hypertension, diabetes, microalbuminuria, or macroalbuminuria).
Among participants at high vascular risk, telmisartan’s effects on major renal outcomes were no different than ramipril’s. The combination of telmisartan and ramipril reduces eGFR and proteinuria to a greater extent than either monotherapy but led to a higher incidence of major renal outcomes.—Mann JF, Schmieder RE, McQueen M, et al; ONTARGET Investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372:547–553.