Long-awaited ONTARGET cardiovascular trial results released

The eagerly awaited results of the largest cardiovascular study of its type, the ONTARGET trial were presented overnight at the American College of Cardiology Congress in Chicago and published today in the New England Journal of Medicine (NEJM). The study has shown that the drug telmisartan (Micardis), normally used to lower blood pressure, can provide protection for generally healthy, high risk individuals with normal or controlled blood pressure from heart attack, heart failure, stroke and even death.1 Importantly, it was found to be equally as effective in reducing cardiovascular risk as ramipril, an angiotensin converting enzyme (ACE) inhibitor widely used to reduce the risk of cardiovascular events in patients.1

Click here to watch a video on results from ONTARGET.

The ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) study has been ongoing for five and a half years. It is the largest of its kind, with over 25,000 participants from 40 countries, including 1300 from Australia. The aim of the trial was to investigate whether telmisartan, an AT₁ receptor blocker (ARB), was as effective as the ACE inhibitor ramipril in reducing the risk of vascular and heart failure endpoints. In addition, the trial examined whether using the two drugs in combination would produce a superior effect compared to using either drug alone.²

Telmisartan was also shown to be significantly better tolerated than ramipril, with respect to typical ACE-inhibitor side-effects.¹ 359 patients in the ramipril treatment arm stopped their treatment because they experienced cough versus only 93 patients in the telmisartan arm. Given that ACE-inhibitor intolerant patients were removed from ONTARGET and placed in the TRANSEND trial, this shows the superior tolerability of telmisartan even in this pre-selected patient group. 

25 patients stopped their treatment in the ramipril arm because of angioneurotic edema, versus only 10 in the telmisartan arm.¹

The ONTARGET data also show that telmisartan is associated with a higher treatment compliance.¹ Besides efficacy, tolerability and compliance are also important factors to consider as they are crucial for effective long-term treatment for the prevention of serious cardiovascular events.

Prior to the release of the ONTARGET results, only ramipril had been shown to reduce heart attacks, stroke and cardiovascular deaths in high-risk patients with normal or well controlled blood pressure by approximately 20% compared with placebo.³ The same effect can now be attributed to telmisartan. This study is clinically important as the findings provide patients and doctors with a new treatment option to reduce cardiovascular events among high-risk patients, which is effective and better tolerated."

Speaking from Chicago, Australian coordinator for the ONTARGET study, Professor Garry Jennings from the Baker Heart Research Institute, claimed the results of the landmark trial were significant and would help curb the epidemic of cardiovascular disease in Australia.

"While telmisartan is currently used to treat high blood pressure, the levels of cardiovascular protection recorded in the trial are beyond what could be achieved solely through reductions in blood pressure."

"The ONTARGET study provides evidence that when used by high-risk patients both telmisartan and ramipril can prevent premature deaths, heart attacks, strokes and hospitalisation due to heart failure. The challenge now is to better identify the so-called ‘healthy but high-risk’ patient and ensure they receive appropriate treatment."

ONTARGET researchers found that patients treated with telmisartan received a higher level of cardiovascular protection as well as reduced side effects and complications compared to the other two treatment groups alone and that there was no additional advantage in combining the telmisartan with ramipril.¹

The ONTARGET study is a randomized, double-blind, multi-centre international outcome trial. Patients enrolled in the study were aged over 55 years and while they had normal or well controlled blood pressure and few signs of poor health, they had a history of heart attack, stroke, transient ischaemic attack, peripheral arterial disease or diabetes with kidney disease.⁴

Participants were randomised to receive a daily dose of either 10 mg ramipril, 80 mg telmisartan or a combination of both drugs. The primary composite outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure and the mean duration of follow-up of the study was 55 months.¹

Telmisartan was shown be equally as effective as ramipril in terms of the primary outcome, with 16.7% of patients on telmisartan experiencing a primary composite endpoint and 16.5% of the ramipril group. The most unexpected result was that patients receiving a two drug therapy regime did not achieve any additional benefit in terms of the primary endpoint which occurred in 16.3% of patients. This occurred despite the reduction in blood pressure seen in the combination group which would have given an expected 4-5% reduction in risk.¹

The rate of statin use increased from 60% to 70% over the course of the study demonstrating the very high standard of care patients were receiving. This high standard makes the results of the trial even more meaningful in terms of clinical implications.

The telmisartan group also reported lower rates of cough (1.1% vs. 4.2%; p < 0.001) and angioedema (0.1% vs. 0.3%; p = 0.01) than the ramipril group but a higher rate of hypotensive symptoms (2.6% vs. 1.7%; p < 0.001). While patients receiving combination therapy had increased the risk of hypotension, hyperkalemia, syncope and renal dysfunction.¹

Additionally, more patients adhered to treatment with telmisartan alone than patients receiving ramipril either as a monotherapy or in combination due to cough and angioedema. Compared with the ramipril group the combination therapy group saw higher levels of cessation of therapy because of hypotensive symptoms, renal impairment, diarrhoea or syncope.¹

The findings of the ONTARGET study have demonstrated the effectiveness and superior tolerability and compliance of telmisartan over ramipril, which means that it could potentially become the preferred treatment for patients with vascular disease or high risk diabetes. However, professionals should discuss treatment options with their patients to determine which therapy would be best suited to them.

Professor Garry Jennings said, "This study confirms that telmisartan not only saves lives and prevents heart attacks, strokes and heart failure in high-risk patients – regardless of their blood pressure levels – but that it is well tolerated and promotes long-term compliance to therapy."

References

1. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med  2008; 358(15): 1547-59.
2. American College of Cardiology Annual Scientific Session 2008. March 29 – April 1. Chicago, Illinois. Results of the ONTARGET Study Comparing Ramipril With Telmisartan, and its Combination in High-Risk Individuals Without Heart Failure. Presenter: Salim Yusuf. Author: Rick McGuire. Available from URL: http://www.cardiosource.com/rapidnewssummaries/index.asp?eid=31&DoW=Mon&SumID=299
3. Fitchett D. Clinical trial update: focus on the ONTARGET study. Vascular Health and Risk Management. 2007; 3(6): 1-8.
4. US National Institutes of Health. Effectiveness of Telmisartan and Ramipril Alone and in Combination in CHF Patients [online] 2008 [cited 18 Feb 2008] Available from URL: http://www.clinicaltrials.gov/ct2/show/NCT00153101?term=ontarget&rank=1