The ONTARGET Study

Researchers are expecting that combined drug therapies will help reduce heart disease-associated mortality. The ONTARGET trial looked at an angiotensin receptor blocker and ACE inhibitor (telmisartan and ramipril), traditionally anti-hypertensive drugs, in the treatment of cardiovascular disease in the absence of heart failure. The ONTARGET study findings were published in the April 10, 2008 issue of the New England Journal of Medicine.

 

The key molecule in the renin-angiotensin system (RAS) is angiotensin II. Angiotensin II exerts its actions via its receptor and is formed by the actions of angiotensin converting enzyme (ACE). Angiotensin receptor blockers (ARBs) and ACE inhibitors are pharmaceuticals currently used to treat hypertension. An ongoing study called ONTARGET (ONgoing Telmisartan Alone in combination with Ramipril Gobal Endpoint Trial) is finding that these medications may benefit patients with cardiovascular disease or diabetes, but not those with heart failure. Investigators are surprised, though, by results showing that combination therapy is not any more beneficial.

Angiotensin Receptor Blockers

The sartans are a family of compounds that block the binding of angiotensin II to its type 1 receptor (AT1R), 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, of which hypertension is but one manifestation.

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.

ACE Inhibitors

The ACE inhibitors prevent the enzyme from cleaving angiotensin I 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 by allowing blood vessels to relax, 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.

ARB and ACE Inhibitor Combination Therapy

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 conjunction 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, investigators found no additional benefit for combined therapy with telmisartan and ramipril.

Researchers have 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.