AN ANGIOTENSIN RECEPTOR BLOCKER PROVIDES SIMILAR CARDIOVASCULAR BENEFITS AS AN ANGIOTENSIN‐CONVERTING ENZYME INHIBITOR IN HIGH‐RISK PATIENTS, BUT BOTH AGENTS TOGETHER DID NOT PROVIDE AN Y ADDITIONAL BENEFIT—;THE ONGOING TELMISARTAN ALONE AND IN COMBINATION WITH RAMIPRIL GLOBAL ENDPOINT TRIAL
In the Heart Outcomes Prevention Evaluation (HOPE), the use of the angiotensin‐converting enzyme (ACE) inhibitor ramipril in addition to other medications was found to prevent significantly more cardiovascular (CV) events than a regimen that did not include an ACE inhibitor in high‐risk patients with established vascular disease or diabetes plus one additional risk factor. It remained unknown whether treatment with an angiotensin receptor blocker (ARB) would provide similar benefit in preventing CV events and whether the combination of full‐dose ACE inhibitor and full‐dose ARB therapy would offer additional clinical benefit when compared with full‐dose ACE inhibitor therapy alone. The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) was designed to answer these clinical questions.
ONTARGET was an industry‐sponsored, prospective, international, double‐blind, randomized clinical outcomes trial. Inclusion criteria included a history of one of the following: coronary artery disease, peripheral artery disease, cerebrovascular disease, or diabetes mellitus with evidence of end‐organ damage. History of heart failure, significant renal dysfunction, or previous intolerance to ACE inhibitor or ARB therapy were among the exclusion criteria. Eligible patients (N=29,019) from 733 centers in 40 countries were enrolled in a 3‐week single‐blind run‐in phase to establish medication tolerability while they received increasing doses of a combination of low‐dose ramipril and telmisartan. Intolerance to active medication during this run‐in phase from poor compliance (3.9%), symptomatic hypotension (1.7%), elevated serum potassium (0.8%) or creatinine (0.2%), death (0.1%), or other reasons (3.0%) led to exclusion from the randomized phase of the study (about 1100 patients were excluded). A total of 25,620 patients were then randomized to either ramipril (n=8576), telmisartan (n=8542), or a combination of both medications (n=8502) plus other medications. Ramipril was initiated at a dosage of 5 mg once daily for 2 weeks, followed by an increase to 10 mg once daily for the remainder of the study. Telmisartan was administered at the full dosage of 80 mg once daily throughout the randomized study period. Combination therapy was initiated with telmisartan 80 mg + ramipril 5 mg for the first 2 weeks, then 80 mg + 10 mg for the remainder of the study. Follow‐up visits occurred at 6 weeks, 6 months, and every 6 months thereafter until study termination. The prespecified primary end point was a composite of CV death, myocardial infarction, stroke, or hospitalization for heart failure. Additional primary end points included CV death, myocardial infarction, or stroke (the primary end point of HOPE) and all of its individual components. Secondary end points included the need for revascularization, hospitalization for angina, new or worsening angina, new onset of diabetes mellitus, heart failure, new atrial fibrillation, renal impairment, renal failure requiring dialysis, and dementia. The study was designed and powered to determine (1) whether the ARB was noninferior to the ACE inhibitor for the primary end point (if noninferiority was demonstrated, further statistical analysis for evidence of superiority of the ARB would be done) and (2) whether the combination of ramipril and telmisartan was superior to ramipril alone for the primary end point. All end points were adjudicated by a central committee blinded to treatment allocation. The primary analysis used a time‐to‐event approach, counting the first component of the composite primary end point and including all randomized patients in accordance with intention‐to‐treat principles.
Patient characteristics were similar in all 3 study groups, with a mean age of 66 years; 27% of the participants were women, 85% had a history of established CV disease, 69% had hypertension, and 38% had diabetes. Thus, this was not specifically a hypertension study. On entry, 62% were taking statins, 81% aspirin, 57%β‐blockers, and 27% diuretics. Baseline blood pressure was 142/82 mm Hg in all 3 groups. Over the course of the trial, the study drug was discontinued in 23.7%of patients in the ramipril group and 21.0% in the telmisartan group; in the combination group, 29.4% discontinued one or both study medications. Among patients in the ACE inhibitor group, 3.3% were being treated with an ARB at the end of the study; among patients in the ARB group, 6.4%were on an ACE inhibitor at the end of the study; and among patients in the combination therapy group, 6.0% were on only an ACE inhibitor and 6.4% received only an ARB at the end of the study. Six weeks after randomization, blood pressure had decreased by 6.4/4.3 mm Hg in the ramipril group, 7.4/5.0 mm Hg in the telmisartan group, and 9.8/6.3 mm Hg in the combination group. As compared with the ACE inhibitor group, patients in the ARB group had slightly lower blood pressure throughout the study (average difference, 0.9/0.6 mm Hg), as did patients in the combination group (average difference, 2.4/1.4 mm Hg).
After a mean follow‐up of 56 months, with 99.8% of patients followed until a primary event occurred or until the end of the study, the incidence of the primary end point was virtually identical in the 2 groups (16.5% vs 16.7%; relative risk [RR], 1.01; 95% confidence interval [CI], 0.94–1.09). There were no significant differences in any of the secondary or additional end points and no significant difference in any prespecified subgroup, including those patients with and without a history of hypertension or diabetes. While telmisartan was not inferior to ramipril (lower boundary for noninferiority, 1.09 vs 1.13; P=.004), this medication was not superior either (lower boundary for superiority, 0.94 vs 1.09). As compared with the ACE inhibitor group, the ARB group had a lower incidence of cough (1.1% vs 4.2%; P<.001) and angioedema (0.1% vs 0.3%; P=.01) and a slightly higher incidence of hypotension (2.6% vs 1.7%;P<.001), but not syncope. In the combination therapy group, the primary end point occurred in 16.3% of patients (RR, 0.99; 95% CI, 0.92–1.07, as compared with the ACE inhibitor alone group). Once again, no between‐group differences were seen in any secondary end points or in any particular subgroup. As compared with the ramipril group, the combination group had a higher incidence of hypotensive symptoms (4.8% vs 1.7%; P<.001), syncope (0.3% vs 0.2%; P=.03), and renal dysfunction (13.5% vs 10.2%; P<.001).
This well‐designed clinical trial found that the addition of the ARB telmisartan to other medications was not inferior to the ACE inhibitor ramipril in reducing CV events among high risk patients with underlying vascular disease or high‐risk diabetes; the use of the 2 medications together was associated with a higher incidence of adverse events without an increase in benefit.—ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril or both in patients at high risk for vascular events. New Engl J Med. 2008;358:1547–1559.
COMMENT
Based on the results of available clinical data, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) noted that there is a “compelling indication” to use ACE inhibitor therapy in patients at “high risk for vascular events,” including those with established vascular disease or high‐risk diabetes. The present study, with its high rates of adherence to both drug regimens, found that the addition of telmisartan to other agents was not inferior to ramipril plus other drugs for both the prespecified primary outcome of death from CV causes, myocardial infarction, stroke, or hospitalization for heart failure and/or death from CV causes, myocardial infarction, or stroke. Based on the boundary of the CIs for noninferiority, telmisartan appears to be clinically equivalent to ramipril. If the Telmisartan Randomized Assessment Study in ACE‐Intolerant Subjects with Cardiovascular Disease (TRANSCEND) finds a benefit of telmisartan therapy compared with placebo, future guidelines should extend the benefit JNC 7 afforded ACE inhibitor use to ARB therapy as well.
In treating this patient population, choosing between an ACE inhibitor and an ARB can be difficult. ACE inhibitor therapy is available generically and is always less expensive than treatment with an ARB, where no generic currently exists. Accordingly, most experts would suggest starting with an ACE inhibitor in this patient population. As demonstrated in ONTARGET, however, ARB use, specifically with telmisartan 80 mg has a better tolerability profile than the ACE inhibitor ramipril 10 mg; side effects, including angioedema but more often cough, remain a barrier to patient adherence with ACE inhibitors (even when patients received ramipril treatment during the run‐in period). For those patients in whom the side effect profile is the major concern, it may be reasonable to start with an ARB. In other patients, with whom cost is an important factor, ACE inhibitor therapy remains an appropriate first choice, and use of an ARB can be reserved for those individuals who do not tolerate an ACE inhibitor.
It is important for clinicians to recognize that the results from both HOPE and ONTARGET are not particularly relevant if patients only have hypertension. Neither of these studies was truly a hypertension study. In fact, (1) hypertension was not a requirement for entry, (2) patients were followed less frequently than clinically required with hypertension, and (3) no standardized training for BP measurement occurred for the investigators. Overall, 30% of the ONTARGET cohort had no history of hypertension, and baseline blood pressure on entry was 142/82 mm Hg. On the other hand, the study is germane to many patients at high risk for vascular disease. Clinicians should consider the use of ACE inhibitor or ARB therapy in patients with established vascular disease or diabetes in addition to other medication regardless of their blood pressure. While it seems most likely that the vascular protection offered by these agents is a class effect, as with the HOPE study, there will continue to be some debate as to whether the specific use of ramipril or telmisartan at the specific doses used is required to obtain these results.
ONTARGET convincingly demonstrates that in patients at high risk for vascular events but without heart failure or clinical proteinuria, there is no advantage to using an ACE inhibitor/ARB combination. In fact, with combination therapy, there was a higher incidence of adverse events including symptomatic hypotension, renal dysfunction, and syncope. These findings are similar to those of the Valsartan in Acute Myocardial Infarction (VALIANT) study: in patients with a history of myocardial infarction, the combined use of the ARB valsartan and the ACE inhibitor captopril (in reduced dose) provided no additional benefit compared with either medication alone (at full dose). There is some evidence that combining an ACE inhibitor and an ARB may improve outcome in patients with symptomatic heart failure or proteinuria; however, some of the data in these patients are not convincing. While the Combination Treatment of Angiotensin‐II Receptor Blocker and Angiotensin‐Converting‐Enzyme Inhibitor in Non‐Diabetic Renal Disease (COOPERATE) study first seemed to show an advantage in reduction of proteinuria with combined use of an ACE inhibitor and an ARB, there are some methodological issues with the study design that have subsequently led observers to question this finding. Furthermore, while use of combined ACE inhibitor and ARB treatment in both the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)‐Added and Valsartan Heart Failure Trial (Val‐HeFT) studies led to a reduction in heart failure hospitalization, the incremental benefit was relatively modest and there was no effect on cardiovascular mortality in these individuals. Further studies are clearly needed to better understand the clinical role of dual renin‐angiotensin‐aldosterone system blockade (and the potential role of direct renin inhibitors) in patients with significant symptomatic heart failure or nephropathy.
The ONTARGET investigators should be commended for designing and executing a well‐powered, large‐scale clinical trial that has allowed for a better understanding of when to use ARB therapy in patients at high risk for vascular events. For now, the choice between an ACE inhibitor and an ARB will depend on patient and physician preference (including cost). In addition, the combination of both drugs does not appear to offer any advantages, with some increase in adverse effects.