After a 3-week run-in period to eliminate those who were unable to tolerate either medication or were nonadherent, a total of 25,620 patients remained. They were randomly assigned to take ramipril 10 mg/d, telmisartan 80 mg/d, or both the ACE inhibitor and the ARB. The researchers followed the patients for a median of 56 months.
The primary composite outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure;1 the main renal outcome was a composite of first dialysis, doubling of serum creatinine, or death.6
The percentage of patients with the primary outcome was the same in all 3 groups (~16.5%). This finding was somewhat surprising because the blood pressure of patients in the combination therapy group was 2 to 3 mm Hg lower overall (both systolic and diastolic) than the blood pressure of patients on monotherapy—a difference that in other studies has been associated with an estimated 4% to 5% reduction in risk.1,2 Patients in the combination group had more hypotensive symptoms compared with those in the ramipril group (4.8% vs 1.7%, number needed to harm [NNH]=32, P<.001).
Renal dysfunction was highest in dual therapy group
Patients in the combination therapy group had higher rates of renal dysfunction than either the ramipril group (13.5% vs 10.2%, NNH=30, P<.001) or the telmisartan group (10.6%), despite a decrease in proteinuria among those on dual therapy. Patients taking the 2-drug combination also had higher rates of hyperkalemia.
While telmisartan proved to be equal to ramipril in reducing vascular events in high-risk patients, patients taking the ACE inhibitor experienced more cough (NNH=32, P<.001) and angioedema (NNH=500, P=.01). In both monotherapy groups, the rates of adverse drug reactions were probably lower than what we typically see in clinical practice because after the run-in period, only patients who were better able to tolerate both medications remained.
WHAT’S NEW: Combination causes renal impairment
This study established that telmisartan, an ARB, is not inferior to ramipril, an ACE inhibitor, in reducing cardiovascular and renal events in patients without heart failure. In addition, as the largest RCT to explore the effects of a dual blockade of the renin-angiotensin system with an ACE inhibitor and an ARB, it casts fresh doubt on the assumption that proteinuria is an accurate surrogate marker for progressive renal dysfunction. The reduction in proteinuria seen in patients in the combination therapy group came at a cost of increased renal impairment.
CAVEATS: Findings do not apply to heart failure patients
More than 11% of potential subjects were excluded from this study during the run-in period. This suggests that physicians in practice are likely to find a significant number of patients who are unable to tolerate (or fail to adhere to) monotherapy with ACE inhibitors or ARBs.
At baseline, only a small subgroup—13%—had overt diabetic nephropathy, the hallmark for a substantial continuous decline of GFR. However, 38% of the study group had diabetes, and almost 30% of these diabetes patients had microalbuminuria. Subgroup analysis found results consistent with the overall group, and the large sample size reduces the likelihood that these findings were due to low power. The overall rate of dialysis and doubling of serum creatinine was low, but still statistically significant, due to the large size of this study.
In determining treatment for high-risk patients with vascular disease or diabetes, it is important to keep the study population in mind. Studies of patients with poorly controlled congestive heart failure (CHF) have shown potential benefits from an ACE inhibitor–ARB combination.7 The ONTARGET trial specifically excluded individuals with CHF, and its findings—and recommendations to avoid combination therapy—should not be applied to heart failure patients.
CHALLENGES TO IMPLEMENTATION: Best microalbuminuria Tx remains elusive
Although albuminuria has been considered an early sign of the onset of diabetic nephropathy, the ONTARGET study demonstrated that combination therapy may cause further reduction in albuminuria but still adversely affect renal function. Thus, this study raises important questions about the best treatment for patients with diabetes who have microalbuminuria and are already on either an ACE inhibitor or an ARB. We wonder, too, whether we should continue to test for microalbuminuria in patients who are taking one of these agents, given the lack of guidance regarding further treatment.
Acknowledgements
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.