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PRIORITY PRESS - Annual Scientific Meeting of the Canadian Society of Internal Medicine

Montreal, Quebec / October 15-18, 2008

Among men and women with coronary, cerebral or peripheral arterial disease or end-organ damage related to diabetes, the expected rate of clinical events such as cardiovascular (CV) death, myocardial infarction (MI) and stroke is about 3% per year. These patients require both intensive lifestyle modification and pharmacological therapies proven to reduce CV risk, emphasized Dr. Gilles Dagenais, Professor Emeritus, Université Laval, Quebec.

“In high-risk patients the renin-angiotensin-aldosterone system (RAAS) is activated and angiotensin II is increased in the tissues, where it generates vasoconstriction, increases oxidative stress, and stimulates the proliferation of smooth muscle... all things that promote atherosclerosis,” Dr. Dagenais reminded the audience. Attenuation of the negative effects of angiotensin II can be achieved with five classes of medications, he stated. Beta blockade, which he described as “the old-fashioned way”, offers some RAAS inhibition. Current clinical practice is to employ angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), supplemented by aldosterone blockade in some individuals. Direct renin inhibitors are now being investigated.

A recent meta-analysis determined that in high-risk patients without heart failure or left ventricular (LV) systolic dysfunction, ACE inhibitors significantly reduce all-cause and CV mortality, non-fatal MI, stroke, heart failure, and coronary artery bypass surgery (Dagenais et al, Lancet 2006;368:581-8). Another meta-analysis comparing antihypertensive regimens based on ARBs or ACE inhibitors suggested the two classes have similar positive effects leading to a reduced risk of stroke, coronary heart disease and heart failure (Blood Pressure Lowering Treatment Triallists’ Collaboration, J Hypertens 2007;25(5):951-8). Still, Dr. Dagenais remarked, the evidence on the efficacy of ARBs against coronary heart disease was incomplete. “For example, in the CHARM trial, the ARB reduced the incidence of MI. On the other hand, several meta-analyses showed that ARBs do not reduce MI. There also were no data regarding the high-risk patient without heart failure or LV systolic dysfunction [treated with an ARB].”

Filling the Evidence Gap

The primary objective of the ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) was to determine whether in a population of high-risk patients the ARB telmisartan would be noninferior to ramipril in reducing the incidence of a composite of first clinical CV events ( CV death, nonfatal MI, stroke, or hospitalization for heart failure). Secondly, the trial was designed to establish whether the two agents used in combination would be more effective than ramipril alone in reducing the composite endpoint. The trial population was similar to that of the HOPE (Heart Outcomes Prevention Evaluation) trial, which was the first to establish the preventive benefit of ramipril 10 mg/day in patients at high risk.

ONTARGET was the largest study to date using an ARB. Study investigators randomly allocated 26,620 high-risk individuals aged at least 55 years (average 66.5) to ramipril 10 mg/day, telmisartan 80 mg/day, or both. The telmisartan, ramipril and combination therapy arms of the study each included more than 8500 subjects matched for age, sex, blood pressure (BP), proportions with coronary artery and cerebrovascular disease, diabetes, and the use of medications. Most subjects were receiving additional preventive therapies including diuretics (> 30%), beta blockers (> 50%), statins (>60%) and antiplatelet agents (>80%). This aggressive approach indicates the numerous advancements in pharmacological prevention in the years since the HOPE trial was envisioned and initiated, Dr. Dagenais remarked.

The results for the primary composite outcome in patients receiving telmisartan or ramipril over the 56-month study period were “superimposable” when depicted on a graph, Dr. Dagenais stated. A total of 16.5% of the ACE-inhibitor-treated patients (n=1412) and 16.7% of the ARB-treated individuals (n=1423) experienced a first CV event (Relative risk (RR) 1.01, CI 0.94-1.09, P=0.8). “There was no difference regarding cv mortality, MI, stroke, heart failure hospitalization or all death,” he confirmed. Moreover, the results were consistent across patient subgroups including patients of both genders and those with/without diabetes or hypertension. Dr. Dagenais explained that the margin of noninferiority was set at RR 1.13 to mirror the impact of ramipril versus placebo in the HOPE trial. “The 95% upper limit of the confidence interval is 1.09, which is well within the 1.13. So telmisartan was clearly noninferior to ramipril and, according to the design of the study, this is highly significant.”

Patients in the study who received both telmisartan and ramipril did not experience a reduction in clinical events compared with those receiving ramipril alone. This group also had a higher incidence of adverse events leading to discontinuation of treatment, including hypotension (RR 2.75, P<0.001), syncope (2.95 P=0.03), renal impairment (1.58, P<0.001) and diarrhea (3.28, P<0.001).

The data from ONTARGET provide compelling evidence that telmisartan is equivalent to and a good alternative to ramipril for CV risk reduction, Dr. Dagenais remarked. Although the combination of telmisartan and ramipril did not lead to additional CV risk reduction in ONTARGET, and therefore dual RAAS inhibition is not recommended for routine use, “certain patients with heart failure might benefit from the combination; [however,] in such cases, blood pressure and renal function should be well monitored,” he added.

The results of ONTARGET cannot be extrapolated to other ARBs and ACE inhibitors, because there is inadequate proof of dose equivalence among the various agents in the two classes. Clinical decisions should be based on existing evidence, Dr. Dagenais emphasized, although they may be influenced by practical considerations such as the physician’s familiarity with a certain medication, adverse effects, and costs.

Tolerability Advantages

Tolerability is an important factor for physicians choosing between an ACE inhibitor or ARB for their high-risk patients, as adverse events may well lead to discontinuation of therapy, noted Dr. Dagenais. In ONTARGET, the rate of cough among patients receiving telmisartan was significantly lower than that for ramipril (1.1% vs. 4.2%, P<0.0001). Angioedema was also rarer (0.1% vs. 0.3%, P=0.01). Hypotension occurred more frequently with the ARB (2.6% vs. 1.7%, P<001), although syncope occurred in similar numbers of patients (2.0% in both groups).

Dr. Dagenais commented that the rate of cough in ONTARGET patients taking ramipril was lower than is typically reported. The investigators had screened out patients with intolerance before the trial and halved the dose or even temporarily stopped therapy for patients who experienced cough on trial. “This was in a non inferiority trial where we needed good adherence. But in practice we know that at least 15% of patients – and probably it’s a higher number in women – are intolerant [of ACE inhibitors] and may stop taking the medication. It’s important [for long-term adherence] that the patient can tolerate the medication.”

TRANSCEND Findings

While ONTARGET demonstrated that telmisartan is equivalent to ramipril in patients who tolerated ACE inhibitors, the TRANSCEND (Telmisartan Randomised Assessment Study in ACE-intolerant Subjects with Cardiovascular Disease) trial, which was conducted at the same time and with the same end points, confirmed that telmisartan is effective in patients who do not tolerate ACE inhibitors. In this placebo-controlled study, which randomized 5926 patients with similar characteristics as those in ONTARGET, telmisartan was associated with a significantly lower incidence of CV death/MI/stroke at the end of a median 56 months of follow-up (13% vs. 14.8, P=0.048).

Although the relative reduction in risk with telmisartan in TRANSCEND was not as great as that achieved with ramipril in HOPE, this is almost certainly the result of more aggressive background therapy in TRANSCEND. Most conspicuously, about twice as many people were on statins in TRANSCEND than HOPE, and there were also differences in use of antiplatelet treatments and beta blockers. “We are treating our patients better than we used to do, 10 years ago,” Dr. Dagenais explained.

TRANSCEND confirms the findings of ONTARGET in that telmisartan did exert significant protection against events (as good as ramipril when compared head-to-head) but with a high degree of tolerability that makes this therapy potentially easier to use for long-term adherence.

RAAS Inhibition in Preventive Regimens

In the absence of contraindications, high-risk patients fitting the ONTARGET profile should receive an antiplatelet agent, a statin, an ACE inhibitor or ARB and antidiabetic therapy as needed; beta blockade is appropriate in those who have heart failure or have experienced an MI, Dr. Dagenais summarized. ONTARGET confirmed that telmisartan 80 mg/day is as effective as ramipril 10 mg/day for decreasing the risk of a first clinical event in this population. Lifestyle modification is also a key component of risk attenuation, he stressed.