Practice changer
Avoid prescribing an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) for patients at high risk of vascular events or renal dysfunction. The combination does not reduce poor outcomes, and leads to more adverse drug-related events than an ACE inhibitor or ARB alone.1
Strength of recommendation
B: 1 large, high-quality randomized controlled trial (RCT).
The ONTARGET investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547-1559.
ILLUSTRATIVE CASE
A 56-year-old patient with well-controlled type 2 diabetes and hypertension comes to see you for routine follow up. His blood pressure is controlled with lisinopril 40 mg/d. But his albumin-to-creatinine ratio is 75 mg/g, and your records reveal that his albuminuria is getting progressively worse.
You’re aware of the potential benefits of a dual angiotensin blockade, and are considering adding an angiotensin receptor blocker (ARB) to your patient’s medication regimen. You wonder whether the combination of an angiotensin-converting enzyme (ACE) inhibitor and an ARB will slow the decline of renal function. You also wonder whether the combination will reduce your patient’s cardiovascular risk.
ACE inhibitors are known to reduce cardiovascular morbidity and mortality, as well as proteinuria in patients with vascular disease or diabetes, whether or not they have heart failure.2 But few studies have compared the effects of ACE inhibitors and ARBs in high-risk patients without heart failure. Nor has there been a definitive study of the effects of an ACE inhibitor–ARB combination on proteinuria and cardiovascular risk.
Are 2 drugs better than 1?
In a recent meta-analysis, researchers reported that combination therapy had a beneficial effect on proteinuria.3 But that observation was based on a small number of patients (N=309 from 10 studies), short follow up, and a lack of data on key clinical end points such as decline of the glomerular filtration rate (GFR) and the onset of dialysis.
Other evidence comes from a study of 199 patients with diabetes and microalbuminuria, in which the ACE inhibitor-ARB combination reduced proteinuria more than either agent alone.4 And in a study of 336 patients with nondiabetic nephropathy, the 2-drug combination slowed the decline in renal function more than monotherapy.5
Small studies raise hopes. These preliminary findings, along with the theoretical benefits of dual angiotensin blockade, suggested that the benefits of taking both agents together could be significant. A large, well-done randomized controlled trial (RCT) was needed to determine the following: (1) whether an ARB is as effective as an ACE inhibitor in reducing morbidity and mortality in high-risk patients who don’t have heart failure, and (2) whether the ACE inhibitor–ARB combination is better than monotherapy for patients at high risk.
Key findings
The ONTARGET study:
- established that telmisartan, an ARB, is not inferior to ramipril, an ACE inhibitor, in reducing cardiovascular and renal events in high-risk patients without heart failure.
- found that either drug alone is more effective than combination therapy for this patient population.
- cast fresh doubt on the assumption that proteinuria is an accurate surrogate marker for progressive renal dysfunction.
STUDY SUMMARY: Vascular outcomes same for ACE inhibitors, ARBs
The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), a multi-year study of thousands of patients, addressed both of those questions. The researchers compared the effects of both telmisartan (Micardis, an ARB) alone and a telmisartan + ramipril (Altace, an ACE inhibitor) combination with the effects of the ACE inhibitor alone in patients ≥55 years of age with established atherosclerotic vascular disease or diabetes with end-organ damage.1 Exclusion criteria included major renal artery stenosis, uncorrected volume or sodium depletion, a serum creatinine concentration of ≥3 mg/dL, and uncontrolled hypertension (>160 mm Hg systolic or >100 mm Hg diastolic).