The Ontarget Study Explained

The renin-angiotensin system’s involvement in cardiovascular regulation makes it a key target for drugs fighting heart disease. The ONTARGET (ONgoing Telmisartan Alone in combination with Ramipril Gobal Endpoint Trial) study findings were published in the April 10, 2008 issue of the New England Journal of Medicine. ONTARGET is an ongoing study of angiotensin receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors in patients with cardiovascular disease or diabetes, but not those with heart failure.

The key molecule in the renin-angiotensin system (RAS) is angiotensin II. Angiotensin II exerts its actions via receptors on the cell surface of target tissues and is formed by the actions of ACE. ARBs and ACE inhibitors are currently used to treat hypertension. Investigators have been surprised, though, by results showing that combination therapy is not any more beneficial than single therapy for some conditions.

The sartans are a family of compounds that block the binding of angiotensin II to its type 1 receptor, the receptor associated with natural increases in blood pressure. The receptor is also part of systems controlling the growth and differentiation of smooth muscle and cardiac cells, the induction of inflammatory mediators, and genetic pathways via transcription factor activation. The ARBs are likely candidates for broader applications and the prevention of other cardiovascular disorders. Telmisartan is one the ARBs used for anti-hypertensive therapy; it is marketed under the names Micardis, Pritor, Kinzal, Telmar, Telday, and Teleact D, depending on the manufacturer. The most common dosage is 40 mg daily, though some patients receive a benefit when receiving only 20 mg, according to FDA recommendations. The highest maximum dosage tested, and allowed, is 80 mg daily.

The ACE inhibitors prevent the enzyme ACE from cleaving a precursor protein into angiotensin II, thus keeping the protein deactivated and preventing increases in the level of angiotensin II. Lower angiotensin II levels result in decreased blood pressure via relaxed blood vessels, a byproduct of decreased RAS activity. Ramipril is an ACE inhibitor marketed as Tritace, Tamace, or Altace to treat hypertension and congestive heart failure in prescriptions of 1.25 mg to 10 mg daily. However, the drug is not recommended for use in patients with renal failure, making alternative treatments attractive. It is also, according to FDA recommendations, to be avoided by anyone who is pregnant.

Telmisartan at 80 mg once daily was shown in the HOPE trial (Heart Outcomes Prevention Evaluation) to be equivalent to 10 mg ramipril daily when administered separately, meaning that both the ARB and ACE inhibitor were capable of preventing morbidity and mortality from cardiovascular disease at the same rate. When used in combination with one another to treat hypertension, blood pressure is further decreased, leading researchers to expect an added risk reduction for cardiovascular morbidity by combination therapy. However, ONTARGET investigators found no additional benefit for patients receiving combined therapy with telmisartan and ramipril.

In the ONTARGET study, researchers concluded that the main benefit of ARBs for treating cardiovascular disease in the absence of heart failure is as an alternative to ACE inhibitors in patients who do not tolerate the medication.