Results from ONTARGET are not a class effect

A trial comparing two medications, telmisartan (an angiotensin receptor blocker or AIIA) and ramipril (an angiotensin converting enzyme inhibitor or ACEi), has shown that both drugs are equally effective in reducing the risk of cardiovascular events in high cardiovascular risk patients,1 however telmisartan was better tolerated than ramipril. The results of the study have raised questions whether the results of ONTARGET are a class effect.

The ONTARGET study

The ONTARGET (the ongoing telmisartan alone and in combination with ramipril global endpoint trial) study involved over 25 thousand participants in 40 countries (including Australia). The trial aimed to establish whether both hypertensive and normotensive patients who are at high risk from heart attack, heart failure, stroke or death could benefit from using the AIIA, telmisartan (Micardis).¹

Participants were assigned to one of three groups. The first group was administered 80mg of telmisartan per day. The second group was administered 10mg of ramipril (Ramace) per day. Ramipril has been favoured for its ability to both reduce hypertension, and prevent cardiovascular events. The final group was administered telmisartan and ramipril in combination. Participants were followed for 3.5 to 5.5 years and health outcomes were monitored.¹

The results suggested that telmisartan was as effective as ramipril in reducing cardiovascular events. In both groups, around 16% of patients experienced a primary outcome (cardiovascular death, non-fatal myocardial infarction or stroke, or hospitalisation for congestive heart failure). No advantage was found when taking both medications in combination. Higher compliance with the treatment protocol was found in the telmisartan group, probably due to the side effects associated with ramipril (e.g., increased rates of cough and angioneurotic edema).¹ 

Can these results be applied to all AIIA’s?

The term ‘class-effect’ has been used to describe the phenomenon whereby the results of trials with one particular drug are extrapolated to other drugs within the same class. If a class effect is assumed, then further clinical trials to establish the mortality and morbidity profiles of newer drugs could be avoided.² If costly clinical trials are avoided, then this can potentially reduce the cost of drugs to the consumer. However, several observers have cautioned against assuming a class effect for any type of drug, arguing that risks to the welfare of patients far outweigh any potential economical benefit.^2-4

The results of ONTARGET demonstrate that telmisartan is as effective preventing cardiovascular events high CV risk patients. Based on the results of this trial, can we extrapolate the results of telmisartan to other AIIAs in the class? The simple answer is no.

"Every drug should be treated on its own merits and the results of telmisartan in ONTARGET therefore shouldn’t be applied to other drugs" said Professor Krum, Director of NHMRC Centre of Clinical Research Excellence in Therapeutics.

A central problem is that the idea of a ‘class of drugs’ is not well defined. A class is usually a group of drugs with a common mechanism of action. However, many drugs within a class will have multiple and often different mechanisms of action, in addition to any common mechanism of action. These additional mechanisms may lead to different benefits or detriments (e.g., side effects or drug-drug interactions) to the patient’s health outcome, as compared to other drugs in the same class.^2,4)

The problem in assuming a class effect is shown in a recent study of beta-blockers.⁵ The study followed the progress of over 30 thousand patients who were prescribed beta-blockers in order to lower mortality rates following myocardial infarction. Patients were prescribed one of three different beta-blockers (metoprolol, atenolol or acebutolol). Despite all three drugs belonging to the same class, mortality rates were significantly higher for patients prescribed metoprolol, as compared to the other two beta-blockers.⁵ Telmisartan has been shown to have a pharmacological profile which differs from other AIIAs in the class. It has a longer plasma half life, a larger volume of distribution and a higher affinity for AT₁ receptors than other AIIAs, which seems to have clinical relevance because telmisartan has provided better and longer-lasting blood pressure control than other AIIAs.⁶ As the results of ONTARGET are independent of blood pressure reductions, and telmisartan has a different pharmacological profile, one can not assume the benefits would be provided by other AIIAs.

The results of ONTARGET show that the AIIA telmisartan is effective as ramipril in providing cardiovascular protection to high cardiovascular risk patients however, this cannot be extrapolated to other AIIA’s for treating the same condition.

In the interests of evidence based practice, it is recommended that health professionals prescribe medications that have been properly tested in randomised controlled trials, at the dosages that have shown clinical benefits in the trial. There is no guarantee that benefits found with one drug will be equivalent for other drugs in the same class.¹

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. Furberg CD, Psaty BM. Should evidence-based proof of drug efficacy be extrapolated to a “class of agents”? Circulation. 2003; 108: 2608–2610.
3. Antman EM, Furguson JJ. Should evidence-based proof of efficacy as defined for a specific therapeutic agent be extrapolated to encompass a therapeutic class of agents? Circulation 2003; 108: 2604-2607.
4. Kereiakes DJ, Willerson JT. Therapeutic substitution: Guilty until proven innocent. Circulation. 2003; 108: 2611-2612. 
5. Rinfret S, Abrahamowicz M, Tu J,  Huries K, Eisenberg MJ, Richard H et al. A population-based analysis of the class effect of beta-blockers after myocardial infarction. American Heart Journal. 2006; 153: 224-230.
6. Costa VF. Telmisartan: Standing out in a crowded contest. High blood press cardiovasc prev. 2006; 13(3): 85-94.