The angiotensin receptor blocker (ARB) telmisartan (Micardis, Boehringer Ingelheim) was “noninferior” to the angiotensin-converting enzyme (ACE) inhibitor ramipril in patients with vascular disease or high-risk diabetes in the landmark Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) [1]. However, the combination of the two drugs was associated with more adverse events without an increase in benefit.
The results of the trial were presented at the American College of Cardiology 57th Annual Scientific Session and published simultaneously online in the New England Journal of Medicine.
Lead investigator of the trial, Dr Salim Yusuf (McMaster University, Hamilton, ON), commented: “This study is of clinical importance because it demonstrates that telmisartan is an effective and safe alternative to ramipril. This means both patients and physicians have choices and can use telmisartan where appropriate with a high degree of confidence.”
In the paper, Yusuf and his coauthors explain that previous studies such as Heart Outcomes Prevention Evaluation (HOPE) have shown that ACE inhibitors reduce cardiovascular morbidity and mortality in patients with vascular disease or high-risk diabetes. They note that ACE inhibitors do not block the production of all angiotensin II and have the additional action of enhancing bradykinin, which leads to the side effects of cough and angioedema. They therefore conducted the current study to test whether an ARB (which blocks the effects of angiotensin II without enhancing bradykinin) was similarly effective to an ACE inhibitor and whether the combination of an ACE inhibitor and an ARB may be superior.
The ONTARGET trial enrolled 25,620 patients with coronary heart disease or diabetes plus additional risk factors who were over the age of 55 years of age but did not have evidence of heart failure. Patients were randomized to receive ramipril 10 mg per day, telmisartan 18 mg a day, or the combination of the two. The mean duration of follow-up of the study was 55 months.
Results showed that mean blood pressure [BP] was lower in the telmisartan (a 0.9/0.6-mm-Hg-greater reduction) and the combination-therapy group (a 2.4/1.4-mm-Hg-greater reduction) than in the ramipril group. At the end of the study, the primary end point (a composite of cardiovascular death, myocardial infarction [MI], stroke, or hospitalization for heart failure) had occurred in a similar number of patients in all three groups of patients. Compared with the ramipril group, telmisartan patients had lower rates of cough and angioedema and a higher rate of hypotensive symptoms, and patients given the combination treatment had higher rates of hypotensive symptoms, syncope, renal dysfunction, and hyperkalemia, with a trend toward an increased risk of renal function requiring dialysis.
ONTARGET: Key results
| Outcome | Ramipril, n=8576 (%) | Telmisartan, n=8542 (%) | Combination, n=8502 (%) | Risk ratio (95% CI), telmisartan vs ramipril | Risk ratio (95% CI), combination therapy vs ramipril |
|---|---|---|---|---|---|
| CV death/MI/stroke/ CHF hospitalizationa | 16.5 | 16.7 | 16.3 | 1.01 (0.94–1.09) | 0.99 (0.92–1.07) |
| CV death/MI/strokeb | 14.1 | 13.9 | 14.1 | 0.99 (0.91–1.07) | 1.00 (0.93–1.09) |
| MI | 4.8 | 5.2 | 5.2 | 1.07 (0.94–1.22) | 1.08 (0.94–1.23) |
| Stroke | 4.7 | 4.3 | 4.4 | 0.91 (0.79–1.05) | 0.93 (0.81–1.07) |
| CHF hospitalization | 4.1 | 4.6 | 3.9 | 1.12 (0.97–1.29) | 0.95 (0.82–1.10) |
| CV death | 7.0 | 7.0 | 7.3 | 1.00 (0.89–1.12) | 1.04 (0.93–1.17) |
| Any death | 11.8 | 11.6 | 12.5 | 0.98 (0.90–1.07) | 1.07 (0.98–1.16) |
| Renal impairment | 10.2 | 10.6 | 13.5 | 1.04 (0.96–1.14) | 1.33 (1.22–1.44) |
aPrimary end point
bPrimary end point in the HOPE trial
ONTARGET: Reasons for permanent discontinuations
| Outcome | Ramipril (%) | Telmisartan (%) | Combination (%) | p, telmisartan vs ramipril | p, combination therapy vs ramipril |
|---|---|---|---|---|---|
| Hypotensive symptoms | 1.7 | 2.7 | 4.8 | <0.001 | <0.001 |
| Syncope | 0.2 | 0.2 | 0.3 | 0.49 | 0.03 |
| Cough | 4.2 | 1.1 | 4.6 | <0.001 | 0.19 |
| Diarrhea | 0.1 | 0.2 | 0.5 | 0.20 | <0.001 |
| Angioedema | 0.3 | 0.1 | 0.2 | 0.01 | 0.30 |
| Renal impairment | 0.7 | 0.8 | 1.1 | 0.46 | <0.001 |
Yusuf et al conclude: “Our data show that, in patients who have vascular disease or high-risk diabetes but do not have heart failure, telmisartan is an equally effective alternative to ramipril,” and “the choice between the two agents will depend on the preferences of patients and physicians and the individual patient’s susceptibility to specific adverse events.”
They add: “There is no additional advantage (and there is some harm) from the combination of telmisartan and ramipril used in full doses in this population, as compared with ramipril alone,” and they say the lack of additional benefit of the combination despite a substantial lowering of blood pressure is “puzzling.”
Confirmation that ARBs are no better
In an accompanying editorial [2], Dr John McMurray (University of Glasgow, Scotland) comments: “As the fourth and largest comparative trial, the ONTARGET study confirms, beyond doubt, that angiotensin receptor blockers are not better than ACE inhibitors at reducing fatal and nonfatal cardiovascular events.” But he says the ONTARGET trial was a “high-quality noninferiority trial” and shows that telmisartan provides a similar benefit to that of a proven ACE inhibitor, a result that was also found with valsartan (Diovan, Novartis) vs captopril in the Valsartan in Acute Myocardial Infarction Trial (VALIANT) in MI patients.
He adds: “However, because ARBs are more costly than ACE inhibitors and are not better tolerated overall, their primary value is as an alternative for patients who cannot tolerate ACE inhibitors because of cough.”
McMurray further points out that, like ONTARGET, the VALIANT study also showed no added benefit (but additional adverse effects) with the combination of an ARB and an ACE inhibitor. This contrasts with observations from two heart-failure trials (The Valsartan Heart Failure Trial [Val-HeFT] and Candesartan in Heart Failure–Assessment of Mortality and Morbidity [CHARM]) in which valsartan and candesartan (Atacand, Taketa Pharmaceuticals/AstraZeneca) both showed additional benefits when added to ACE-inhibitor therapy. But he notes that these two heart-failure studies did not use a full dose of ACE inhibitor in all patients, and thus it cannot be known for sure whether the benefits of combination therapy seen in these studies was due to the condition studied (heart failure) or the type or regimen of ACE inhibition used.
The ONTARGET study was sponsored by Boehringer Ingelheim. Yusuf and several other members of the writing committee report have disclosed receiving consulting/lecture fees and research support from Boehringer Ingelheim and several other drug companies in the field. One member of the writing committee is an employee of Boehringer Ingelheim. McMurray has disclosed receiving lecture fees from AstraZeneca and Takeda.
Sources
- Yusuf S, Teo KK, Pogue J, et al for the ONTARGET investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008: 358:1547-1559.
- McMurray, JJV. ACE inhibitors in cardiovascular disease–unbeatable? N Engl J Med 2008: 358:1515-1516.
