Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Based on presentations from the 57th Scientific Session of the American College of Cardiology

Chicago, Illinois / March 29-April 1, 2008

Editorial Overview:

J. Malcolm O. Arnold, MD, FRCP, FRCPC, FACC

Cardiology Division London Health Sciences Centre, London, Ontario

Professor of Medicine Division of Cardiology/ Physiology and Pharmacology University of Western Ontario, London, Ontario

ONTARGET Study Design

The ONTARGET study was designed to test the hypothesis that the angiotensin-receptor blocker (ARB) telmisartan is as effective as the ACE inhibitor ramipril for preventing cardiovascular (CV) events in high-risk patients. The study was also designed to evaluate whether the combination of the two agents was more effective than ramipril alone. The primary composite outcome was death from CV causes, myocardial infarction (MI), stroke, or hospitalization for heart failure. The eligibility criteria included an age of 55 years or older and coronary, peripheral, or cerebral vascular disease or diabetes with end-organ damage. After a single blind run-in period, patients were randomized to standard doses of telmisartan (80 mg o.d.), ramipril (10 mg o.d.) or the combination of these agents (at the same doses). The randomized treatments were evaluated on top of therapy the patients were already receiving, which included antiplatelet therapy in about 80% of patients, statins in about 60%, beta blockers in about 55%, and a calcium channel blocker (CCB) in about 30%.

At the end of a median follow-up of 56 months, a primary event had occurred in 16.7% of the 8542 patients randomized to 80 mg of the ARB, 16.5% of the 8576 patients randomized to 10 mg the ACE and 16.3% in the 8502 patients randomized to the combination. There were no significant differences or trends for differences between these proportions. There were small differences in mean blood pressures (BP). Relative to ramipril, the combination provided a mean 2.4/1.4 mm Hg greater reduction in BP and telmisartan provided a mean 0.9/0.6 mm Hg greater reduction. However, the event reductions remained comparable after adjusting for the potential effects of these differences in BP.

The rate of adverse effects (AEs) provided the greatest differentiation between the treatment arms. While the combination was the least well tolerated, producing a higher rate of AEs overall, including a higher rate of discontinuations relative to ramipril (29.3% vs. 24.5%; P<0.001), there was also a tolerability advantage for telmisartan relative to ramipril. This included a lower rate of cough (1.1% vs. 4.2%; P<0.001) and angioedema (0.1% vs. 0.3%; P=0.01). Although hypotensive symptoms were more common on telmisartan (2.7% vs. 1.7%; P<0.001), serious AEs of any kind were rare in all groups.

ONTARGET builds on the experience of the landmark HOPE (Heart Outcomes Prevention Evaluation) trial, which associated ramipril with a 22% reduction (P<0.001) in the composite end point of death from CV causes, MI, or stroke relative to placebo (N Engl J Med 2000;342;142-3). The benefit of ramipril, which lowered BP by a mean of 3/3 mm Hg at the end of the HOPE study relative to baseline and by 3/1 mm Hg relative to end-of-treatment levels on placebo, was attributed largely to the inhibition of the renin-angiotensin-aldosterone system (RAAS), which is upregulated in patients with CV disease and drives several pathogenic processes in vascular and cardiac tissue. ONTARGET was designed to determine whether an ARB, which also blocks the effects of an upregulated RAAS, provides comparable benefit to the proven ACE inhibitor from the HOPE trial (Figure 1).

Figure 1. End Points: ONTARGET vs. HOPE *

Other Studies in Cardiovascular Disease

The ONTARGET trial is the largest clinical trial ever conducted with an ARB. Its relevance is best understood in the context of other landmark studies documenting BP independent protection against specific target-organ pathology with RAAS inhibitors. The CV protection in acute MI that was first demonstrated with ACE inhibitors in such trials as SAVE (Survival and Ventricular Enlargement), which associated the ACE inhibitor with a 19% reduction (P=0.019) in total mortality relative to placebo, and AIRE (Acute Infarction Ramipril Efficacy), which associated the ACE inhibitor with a 27% reduction (P=0.002) in total mortality, relative to placebo. When an ARB was compared to an ACE inhibitor in VALIANT (Valsartan in Acute Myocardial Infarction Trial) the relative protection against events did not differ. In heart failure treatment, SOLVD (Studies of Left Ventricular Dysfunction) associated an ACE inhibitor with a 16% reduction (P=0.0036) in total mortality relative to placebo. In V-HeFT II (Vasodilator-Heart Failure Trial), there was 25% reduction (P=0.016) in total mortality for the ACE inhibitor relative to hydralazine plus isosorbide dinitrate. When ARBs were compared to ACE inhibitors for heart failure in such studies as Val-HeFT (Valsartan Heart Failure Trial) and CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity), the relative protection against cardiovascular events or other outcomes did not differ significantly. With ONTARGET, the protection observed with an ACE inhibitor in the high-risk patients recruited for HOPE has now been reproduced with telmisartan.

In ONTARGET, the initial design was to prove non-inferiority employing pre-defined statistical analyses that would provide a sufficient margin of confidence to conclude that the 80-mg dose of telmisartan could be considered as effective as the proven 10-mg dose of ramipril. When evaluated across an array of patient characteristics such as baseline BP, age, presence of absence of diabetes, gender, or HOPE risk score, the protection of telmisartan relative to ramipril remained well within the confidence intervals for comparable effect (Figure 2).

The lack of an additional benefit from dual inhibition of RAAS is disappointing. Although both ACE inhibitors and ARBs inhibit the effects of upregulated RAAS, their mechanisms are unique, providing a basis for exploring whether a combination might provide additive benefit. While ACE inhibitors block one of the pathways responsible for synthesis of angiotensin, the RAAS-mediated hormone most closely associated with hypertension, vascular hypertrophy, and cardiac remodelling, ARBs block angiotensin at its receptor. In addition, each type of molecule may exert benefit through other pathways, including stimulation of factors that promote vasodilation. In an ONTARGET population of high-risk individuals, there was no evidence that dual inhibition of both sets of mechanisms provided any additional protection relative to one alone. However, there remains a strong potential for dual RAAS inhibition to provide additional benefit in some specific subgroups, such as those with heart failure or diabetic nephropathy. ONTARGET Substudies may provide insight about the role of dual RAAS inhibition for these indications.

-inferiority Margins

<img1805|center>

Class Effect and Evidence-based Medicine

The issue of class effect in the assessment of the ONTARGET results remains difficult to resolve. While the most rigorous approach to evidence-based medicine is to use the same medications in the same doses as those that demonstrated efficacy in controlled trials, trials with different members of each class of RAAS inhibitors have demonstrated the same types of benefits across a variety of indications. However, there are potentially important differences in both the pharmacokinetics and the actions of these agents. One of the most notable features of telmisartan is a half life of approximately 24 hours, which is about twice as long as irbesartan and up to four fold longer than valsartan or losartan.

For once-daily, morning dosing, the duration of the half-life may be particularly relevant for protection against the early morning surge in BP and risk of clinical events. In a previous comparative trial called PRISMA (Prospective Randomized Investigation of the Safety and Efficacy of Micardis vs. Ramipril Using Ambulatory BP Monitoring), differences in BP control between telmisartan and ramipril were especially pronounced in the morning (Lacourciere et al. Am J Hypertens 2006;19:104-12). In PRISMA, 812 adults with mild-to-moderate hypertension (mean baseline BP (148/93 mm Hg) were randomized to telmisartan 80 mg or ramipril 10 mg and followed for 14 weeks. The ARB produced significantly greater reductions in BP than the ACE overall (mean systolic BP reductions of 14.1 mm Hg compared to 11.0 mm Hg (P<0.0001) and mean diastolic BP reductions of 9.6 mm Hg compared to 7.2 mm Hg (P<0.0001) respectively), but the magnitude of the early morning BP surge was reduced by 4.9 mm Hg more with telmisartan than ramipril in the group of patients with the highest early morning BP surge (SBP reductions of 12.7 mm Hg compared to 7.8 mm Hg, (P=0.0004).

Direct comparisons between ARBs for clinically important outcomes remain limited, although the differences in addition to half-life include relative affinity for the AT1 receptor and effects outside of the RAAS system, such as actions on nuclear receptors (Benson et al. Hypertension 2004; 43:1-10). The importance of these differences to target organ protection, if any, would require controlled comparisons to evaluate.

Tolerability Profile

In ONTARGET, it is important to emphasize that the tolerability advantage of telmisartan was achieved despite a design that would have been expected to minimize the differences. After eligibility for ONTARGET was confirmed, patients entered into a three-week, single-blind run-in period to test tolerability to the study medications, thereby screening those who were ACE inhibitor-intolerant. Despite this aspect of the study design, telmisartan was associated with fewer withdrawals (P=0.02) and slighlty better tolerability. This is a clinically relevant finding because of the importance of long-term compliance to the benefits of therapy. At the end of two years, the proportion of patients on full doses of their assigned medication was 81.7% in the ramipril group and 88.6% in the telmisartan group. Outside of a clinical trial that includes periodic follow-up, the adherence rates would be expected to be lower in both groups, but with a greater likelihood of reduced compliance in those experiencing AEs. For those already on a well-tolerated ACE inhibitor, ONTARGET does not provide any incentive to switch. For those initiating therapy, the choice between telmisartan and ramipril should be guided by tolerability and cost.

The size of the ONTARGET study has permitted and will continue to permit comparisons to be made between telmisartan and ramipril for a broad array of end points and for specific relative benefits in important subgroups. For example, the results appear to definitively resolve the controversial assertion that ARBs may increase the risk of MI. When any of the end points included in the composite primary outcome were evaluated separately, including MI, the relative protection offered by telmisartan did not differ from the ACE inhibitor. Relative protection from the initial list of secondary outcomes, such as revascularization, worsening or new angina, new diagnosis of diabetes, heart failure, new atrial fibrillation, or renal impairment, also showed no significant differences in relative effect of the ARB and ACE inhibitor. Like other large trials, a stream of data is expected to flow from ONTARGET over the next several years. These may yet reveal clinically meaningful differences between the ARB, the ACE inhibitor, or the combination.

One Class Does Not Fit All

The contribution made by ONTARGET to the concept of BP- independent benefits may be meaningful to the initial stages of disease. While the RAAS inhibitor trials have largely been conducted in secondary prevention, there is a growing array of evidence that drugs with similar antihypertension potency are not similarly protective against clinical risks. In LIFE (Losartan Intervention For Endpoint reduction), an ARB was found to offer greater protection against CV events than a beta blocker in a population with left ventricular hypertrophy (LVH) with no previous history of MI. In ASCOT (Anglo-Scandinavian Clinical Outcomes Trial), a strategy that included a CCB and an ACE inhibitor was also superior for primary prevention of events relative to a beta blocker and a diuretic. While major guidelines have been adjusted to recognize that antihypertensive agents with similar BP-lowering potency may not be interchangeable in specific populations at risk, the importance of RAAS inhibition in preventing progression of late-stage disease may be relevant for inhibiting the same mechanisms driving vascular pathology in early disease.

For specific target organ protection, however, dose as a variable independent of pharmacokinetics may be critical determinant of benefit. While the relative importance of systemic upregulation and tissue-specific upregulation of RAAS remains controversial, it is reasonable to speculate that cardiac remodelling, vascular hypertrophy, proteinuria, and other signs of tissue organ damage are at least partially mediated by upregulated RAAS at the tissue level. It has been speculated that the failure of losartan to show non-inferiority to captopril in the ELITE II (the second Evaluation of Losartan in the Elderly) trial was due to selection of an inadequate dose of the ARB, which might have been inadequate to inhibit RAAS at target organs. It is significant that the comparable effect of telmisartan and ramipril in ONTARGET was achieved with conventional and approved doses of each agent.

Summary

The ONTARGET study fills an important gap in information regarding the relative effect of RAAS inhibitors. It has demonstrated that either the ARB telmisartan or the ACE inhibitor ramipril are appropriate first-line therapies for reducing the risk of clinical events in high-risk patients. It also confirms that dual RAAS inhibition cannot be recommended as a routine risk reduction strategy. While all three study arms provided comparable protection against clinical events, the ARB was the best tolerated. Although other considerations in drug selection may be important, including cost, tolerability is a critical issue for therapies that must be taken indefinitely. This vast study has immediate relevance to drug selection.