Boehringer Ingelheim wish to announce that the European Commission has approved Micardis (telmisartan) for the reduction of cardiovascular morbidity in patients with:
I. manifest atherothrombotic cardiovascular disease (history of coronary heart disease, stroke, or peripheral arterial disease) or,
II. type 2 diabetes mellitus with documented target organ damage.
Telmisartan, a modern member of the Angiotensin II Receptor Blocker (ARB) class, is the first treatment in its class to be approved for this indication.
Approximately 10,000 people in Ireland die each year from cardiovascular disease making it the leading cause of death in Ireland, accounting for 36% of all deaths. Overactivity of the Renin-angiotensin-aldosterone system (RAAS) is associated with increased cardiovascular risk, likely due to its key role in stimulating vascular and cardiac remodelling. Inhibition of RAAS activity with the use of angiotensin-converting enzyme (ACE) inhibitors or ARBs has been shown to reduce cardiovascular mortality in patients with heart failure. However, in high risk patients without heart failure, whereas ACE inhibitors have been shown to reduce mortality and morbidity from cardiovascular causes, the role of ARBs was still unknown.
The approval is based upon a review of clinical trial results, including the ONTARGET trial (1). ONTARGET was the first study to directly compare the efficacy of an ARB with an ACE inhibitor in reducing cardiovascular morbidity and mortality in a high-risk patient population without heart failure.
Objective of ONTARGET
The primary objective of the trial was to compare the ARB telmisartan with the ACE inhibitor ramipril with respect to reducing the composite outcome of death from cardiovascular causes, MI, stroke, or hospitalisation for heart failure (primary composite outcome). A second objective was to determine whether the combination of telmisartan and ramipril would be superior to ramipril alone with respect to reducing the composite outcome.
Study Design
The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) was a cardioprotection trial conducted in 25,620 patients with vascular disease or high-risk diabetes without left ventricular dysfunction or heart failure. After a 3-week, single-blind run-in period, patients underwent double-blind randomisation to ramipril 10mg per day, telmisartan 80mg per day, or both (combination therapy).
ACE inhibitor ramipril and the ARB telmisartan equally effective in reducing the incidence of cardiovascular events
At a median follow-up of 56 months, the incidence of the primary end point was not significantly different between the ramipril and telmisartan groups: the primary outcome had occurred in 16.5% of the ramipril-treated patients, compared to 16.7% of the telmisartan-treated patients and 16.3% of patients receiving the combination.
This similarity in primary outcome was observed despite differences in systolic/diastolic BP reduction: −6.4/4.3mmHg in the ramipril group compared to −7.4/5.0mmHg in the telmisartan group, and −9.8/6.3mmHg in the combination therapy group.
Side-effect Profile
As compared with the ramipril group, the telmisartan group had lower rates of cough (1.1% vs. 4.2%, p<0.001) and angioedema (0.1% vs. 0.3%, p=0.01). Hypotensive symptoms occurred at a significantly higher rate in the telmisartan group (2.6% vs. 1.7%; p<0.001), while syncope occurred at comparable rates in the ramipril and telmisartan groups.
The incidences of hypotensive symptoms, syncope, and renal dysfunction were significantly higher in the combination therapy group compared with the ramipril group (4.8% vs. 1.7%, p<0.001; 0.3% vs. 0.2%, p=0.01; 13.5% vs. 10.2%, p<0.001; respectively). Fewer patients discontinued telmisartan compared with ramipril.
Conclusion
The results of ONTARGET showed that RAAS inhibition using either the ACE inhibitor ramipril or the ARB telmisartan are equally effective approaches to reducing cardiovascular mortality and morbidity in patients without heart failure but at high risk for CVD. The combination of the two drugs was associated with more adverse events without an increase in benefit.
Professor Giuseppe Mancia, Professor of Medicine and Chairman of the Department of Clinical Medicine of the University of Milan, Bicocca, Italy said: “This new indication of telmisartan is a significant development for physicians and their at-risk patients. Prevention of CV events is vital as these are the primary causes of pathological death in Europe, due to lack of proper control of treatable risk factors and disease. The approval of telmisartan offers patients a well-tolerated treatment option which also provides CV protection.”
Reference: 1- Yusuf S, Teo KK, Pogue J et al. and for the ONTARGET Investigators. N Engl J Med 358 (2008), pp. 1547–1559
Full prescribing information and references available from Boehringer Ingelheim Ireland Ltd. Telephone: (01)2959620.
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