OUP user menu

Vascular protection: telmisartan in the ONTARGET Trial Programme

Gilles R. Dagenais
DOI: http://dx.doi.org/10.1093/eurheartj/sup025 F47-F53 First published online: 17 November 2009


The ONTARGET Trial Programme includes the ONTARGET and TRANSCEND studies. In both studies, participants were at high cardiovascular risk because they had vascular disease without heart failure, or diabetes with end-organ damage. Participants also received proven therapies for cardiovascular risk reduction. In ONTARGET, telmisartan 80 mg was compared with ramipril 10 mg, and the combination of telmisartan and ramipril was compared with ramipril alone. Telmisartan was as effective as ramipril on the primary outcome and other cardiovascular events and was better tolerated, with fewer treatment discontinuations. In TRANSCEND, telmisartan and placebo, both added to background therapy, were compared in high-risk patients intolerant to angiotensin-converting enzyme-inhibitors. There was a lower incidence of cardiovascular events than assumed in power calculations probably due to higher use of background therapy than expected based upon the HOPE trial. This may explain why the reduction in the primary outcome associated with telmisartan was not statistically significant. Nevertheless, the results of TRANSCEND were consistent with the outcome of the HOPE trial, and the secondary endpoint in TRANSCEND, which was equal to the HOPE primary endpoint (cardiovascular death, myocardial infarction, and stroke), was indeed significant. Telmisartan plus ramipril did not reduce the primary outcome compared with ramipril alone and was associated with a greater likelihood of adverse events. The combination is not recommended for the prevention of cardiovascular events in this patient population. In summary, telmisartan was as effective as ramipril on major vascular events in high-risk patients in ONTARGET but showed a non-significant benefit in TRANSCEND. In both studies, the lower rate of treatment discontinuations with telmisartan is important life-long adherence to therapy.

  • Angiotensin-converting enzyme-inhibitors
  • Angiotensin II receptor blocker
  • Cardiovascular events
  • Ramipril
  • Randomized controlled trial
  • Telmisartan


Effective management of individuals at high cardiovascular risk is essential to improve outcomes and reduce premature death. The selection of treatment should be guided by evidence-based medicine.1 The renin–angiotensin system (RAS) plays a pivotal role in the regulation of cardiovascular function, with angiotensin II being involved in haemodynamic and non-haemodynamic mechanisms in the pathophysiology of cardiovascular disease.2 There is extensive clinical evidence that pharmacological modulation of the RAS using either an angiotensin-converting enzyme (ACE)-inhibitor or an angiotensin II receptor blocker (ARB) confers cardiovascular protection.3

Numerous outcome studies have demonstrated that ACE-inhibitors reduce cardiovascular morbidity and mortality in patients at high risk. Examples include the randomized placebo-controlled studies, Heart Outcomes Prevention Evaluation (HOPE)4 and EURopean trial On Reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA).5 The HOPE study done in 9297 patients with stable cardiovascular disease or diabetes plus an additional risk factor but without heart failure or left ventricular systolic dysfunction showed that ramipril 10 mg compared with placebo reduced the relative risk of the primary outcome, the composite of cardiovascular death, non-fatal myocardial infarction, or stroke by 22%, and each component by 26, 20, and 32%, respectively.4 The EUROPA study done in 12 218 patients with stable coronary heart disease without heart failure or left ventricular systolic dysfunction showed that perindopril 8 mg compared with placebo reduced the composite of cardiovascular mortality, non-fatal myocardial infarction, or resuscitated cardiac arrest by 20% and non-fatal myocardial infarction by 22% and not achieving statistical significant reduction in the two other components.5

In the case of ARBs, the evidence base shows that they reduce mortality in patients with heart failure and stroke or in patients with hypertension and left ventricular hypertrophy. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study showed the superiority of a losartan-based therapy over atenolol-based therapy in reducing the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke among 9193 patients with severe hypertension and electrocardiographic signs of left ventricular hypertrophy.6 The overall results of the Candesartan Heart failure Assessment of Reduction in mortality and Morbidity (CHARM)7 study found that the ARB reduced the composite of cardiovascular mortality or hospitalization for heart failure when used in addition to other proven therapies. The VALsartan In Acute myocardial iNfarction Trial (VALIANT),8 which was conducted in patients with recent myocardial infarction with heart failure and/or left ventricular systolic dysfunction, found that valsartan was as effective as captopril in reducing the primary outcome, death from any cause, and other adverse cardiovascular outcomes.

The potential benefit of more complete blockade of the RAS using a combination of an ACE-inhibitor and an ARB has also been examined. In the VALIANT study, combining the ACE-inhibitor, captopril, with the ARB, valsartan, increased the rate of adverse events without reducing the primary outcome, all-cause deaths, and other pre-specified cardiovascular outcomes,8 although in a post hoc analysis a reduction in the risk of hospitalization for heart failure was documented.9 In CHARM-Added, the addition of candesartan in patients with chronic heart failure and reduced left ventricular ejection fraction taking ACE-inhibitors reduced the risk of the composite outcome of hospitalization for heart failure or cardiovascular mortality.10

Until the recent completion of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) Programme,11 there were no data on the effects of ARBs either given alone or in combination with an ACE-inhibitor on cardiovascular morbidity and mortality in patients at high cardiovascular risk or with diabetes and end-organ damage, but without heart failure. Within the ONTARGET Programme, there were two studies: ONTARGET and Telmisartan Randomized AssessmeNt Study in aCE-iNtolerant subjects with cardiovascular Disease (TRANSCEND). This article relates the general findings of ONTARGET and TRANSCEND.

ONTARGET Programme

The ONTARGET programme includes the ONTARGET and TRANSCEND studies. The ONTARGET study had two arms. The objective of the first arm was to determine whether telmisartan 80 mg once daily was as effective as ramipril 10 mg once daily in reducing the first event of the primary outcome, the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure.11 This study had a non-inferiority design using the HOPE trial as a comparator trial, which showed the superiority of ramipril 10 mg daily over placebo in the treatment of high-risk patients.4 In addition of using ramipril 10 mg, similar patients and the same outcome as in the HOPE trial, the study fulfilled the other criteria of non-inferiority design in selecting a large cohort and having a good adherence of both medication, ramipril and telmisartan. The objective of the second arm of the ONTARGET study was to determine whether the combination of telmisartan plus ramipril was superior to ramipril alone in reducing the same outcomes as in the first arm study.11 The patients were defined as being at high risk because of a history of coronary artery disease, peripheral artery disease, cerebrovascular disease, or diabetes mellitus with end-organ damage. Patients with heart failure, uncontrolled high blood pressure, and elevated serum creatinine were specifically excluded. Patients who were intolerant to ACE-inhibitors were randomized to TRANSCEND.

ONTARGET trial: telmisartan vs. ramipril

Baseline characteristics

Men and women at high risk of cardiovascular events were randomized to either ramipril (n = 8576) or telmisartan (n = 8542).12 Approximately one-quarter of subjects were women. Reflecting the inclusion criterion of a minimum age of 55 years, patients, on average, were 66.4 years old. Other baseline characteristics were also comparable in the ramipril and telmisartan arms. The most common reasons for classifying the patients as being high risk were coronary artery disease (75%), previous myocardial infarction (49%), stable angina pectoris (35%), previous stroke or transient ischaemic attack (21%), and diabetes (38%). Hypertension was present in 69% of patients. At baseline, a high proportion of patients were being treated with statins (62%), anti-platelet therapy (81%), aspirin (76%), clopidogrel or ticlopidine (11%), beta-blockers (57%), calcium channel blockers (33%), and diuretics (28%). Because of the multinational nature of ONTARGET, which was conducted at 733 centres in 40 countries, there was a diverse ethnicity that included Africans, Arabs, Asians, and Europeans, but it was consistent across the two treatment groups.

Adherence to telmisartan and ramipril

In ONTARGET, every effort was made by the investigators to ensure good adherence. During the median follow-up period of 56 months, more patients assigned to ramipril (2029 patients) permanently stopped study drug treatment than those receiving telmisartan (1796 patients).12 The most common reason for permanent discontinuation was cough (Table 1).12 A dry, persistent cough is a common side effect of ACE-inhibitors, occurring in up to ∼20% of patients.13 Many patients find the cough so troublesome that they discontinue ACE-inhibitor therapy; in HOPE, 7.3% of patients were withdrawn during the course of the study because of cough compared with 1.8% in the patients allocated to the placebo group.4 In ONTARGET, discontinuations due to cough were relatively lower (4.2%) in patients randomized to ramipril compared with in patients randomized to telmisartan (1.1%). The impact of the greater tolerability of telmisartan in ONTARGET, because of the efforts of the investigators to encourage patients to remain on the full dose of drug and the lower rate of discontinuations than in HOPE, could be attributed to a better exclusion of patients at screening who were known to be intolerant of ACE-inhibitors or who developed a cough during the run-in stage of the study when in receipt of ramipril. The timing of the onset of ACE-inhibitor-induced cough can be very variable, ranging from a matter of hours after the first dose to several months after starting therapy.14 This may explain why cough necessitating permanent discontinuation from ONTARGET still occurred in some patients randomized to ramipril during the course of the study. Finally, telmisartan was associated with a greater rate of hypotension compared with ramipril (2.7 vs. 1.7%) but a lower rate of angio-oedema (0.1 vs. 0.3%) (Table 1).

View this table:
Table 1

Reasons for permanent discontinuation of ramipril or telmisartan treatment12

ReasonRamipril (n = 8567)Telmisartan (n = 8542)Telmisartan vs. ramipril
Relative riskP-value
Hypotension149 (1.7%)229 (2.7%)1.540.001
Syncope15 (0.2%)19 (0.2%)1.270.49
Cough360 (4.2%)93 (1.1%)0.26<0.001
Diarrhoea12 (0.1%)19 (0.2%)1.590.20
Angio-oedema25 (0.3%)10 (0.1%)0.400.01
Renal impairment60 (0.7%)68 (0.8%)1.140.46

Impact of telmisartan and ramipril on blood pressure and outcomes

At baseline, mean systolic blood pressure (SBP) and mean diastolic blood pressure (DBP) were 141.8/82.1 and 141.7/82.1 mmHg, respectively, in the ramipril and telmisartan groups. During the trial, SBP was reduced by 6.4 and 7.4 mmHg, with ramipril and telmisartan respectively, and DBP by 4.3 and 5.0 mmHg, respectively.12

ONTARGET demonstrated the non-inferiority of telmisartan in comparison with ramipril on the primary outcome, the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure (Figure 1).12 In total, 1419 (16.5%) patients receiving ramipril as opposed to 1423 (16.7%) patients receiving telmisartan experienced the primary outcome during the median follow-up of 56 months. As can be seen from Figure 1, the upper boundary of the 95% confidence interval (CI) was significantly lower (P = 0.0033) than the pre-defined non-inferiority margin.12 Similarly, for the HOPE composite outcome (the secondary outcome in ONTARGET), which did not include hospitalization for heart failure,4 telmisartan was non-inferior to ramipril, and the non-inferiority was highly significant (P= 0.0008). When the individual components of the ONTARGET composite primary outcome were examined, telmisartan was consistently non-inferior to ramipril.

Figure 1

The non-inferiority of telmisartan compared with ramipril in the ONTARGET study.12 CV, cardiovascular; MI, myocardial infarction; RR, relative risk; CI, confidence interval.

The other outcomes evaluated in ONTARGET comprised death from any cause, revascularization, hospitalization for angina, worsening or new angina, new diagnosis of diabetes, any heart failure, new atrial fibrillation, renal impairment, and renal failure requiring dialysis. For all these outcomes, there were no significant differences in the incidences between the two treatment groups, with relative risks for telmisartan vs. ramipril varying between 0.95 (95% CI 0.84–1.07) for worsening or new angina and 1.09 (95% CI 0.74–1.61) for renal failure requiring dialysis. The most common outcome was revascularization, which occurred in 15.1% of telmisartan-treated patients and in 14.8% of ramipril-treated patients. Renal failure requiring dialysis, which was the most infrequent outcome, occurred in only 0.7% of patients receiving telmisartan or ramipril.

In summary, ONTARGET demonstrated that telmisartan is non-inferior to ramipril, with the two agents showing consistent results among a wide spectrum of outcomes studied. Telmisartan was shown to have a slightly better tolerability and fewer treatment discontinuations than ramipril.

TRANSCEND trial: telmisartan vs. placebo

TRANSCEND11 addressed the issue that some patients cannot be treated with an ACE-inhibitor because of intolerance, which is apparent as cough or the less frequently occurring side effect of angio-oedema.15 Angio-oedema of the lips and the tongue with pharyngeal and laryngeal involvement may cause narrowing of the airways that can be life-threatening.16 Cough and angio-oedema/anaphylaxis were the reasons for 88.2 and 1.3%, respectively, of patients being included in TRANSCEND.17

Baseline characteristics

Participants in TRANSCEND were randomized to receive either telmisartan (n = 2954) or placebo (n = 2972). Their additional cardiovascular therapies included antiplatelet therapy (79%), beta-blockers (58%), diuretics (33%), calcium channel blockers (40%), and statins (55%). The baseline characteristics of patients in TRANSCEND were similar to those of the patients in ONTARGET, with the exception of there being more females (43% compared with 27%), a higher proportion of Asians (21% compared with 14%), and a higher incidence of hypertension (76% compared with 69%) in TRANSCEND than in ONTARGET. The higher proportion of women and Asians recruited to TRANSCEND is consistent with the previous observations that these patients are more susceptible to ACE-inhibitor cough.18,19

Impact of telmisartan on blood pressure and outcomes

Similar to those of patient in the telmisartan and ramipril arms of ONTARGET, the baseline SBP/DBP was 140.7/81.8 mmHg in the telmisartan group and 141.3/82.0 mmHg in the placebo group.17 At the end of the study, SBP and DBP were lowered more in the telmisartan than in the placebo group, the differences in SBP/DBP between groups being 3.2/1.3 mmHg.17 The primary outcome (i.e. the same composite as in ONTARGET of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure) was documented in 15.4% of the patients randomized to telmisartan and in 17.0% of those randomized to placebo; the hazard ratio was 0.92 (95% CI 0.81–1.05).17 However, this 8% difference was not statistically significant (P = 0.2158). For the secondary outcome, the HOPE primary endpoint, there was a significant 13% difference between treatments in favour of telmisartan (hazard ratio 0.87; 95% CI 0.76–1.00; P = 0.048). For the primary composite endpoint, the incidences of events started to diverge after about 2.5 years and continued to do so for the duration of the trial (Figure 2A), whereas for the HOPE outcome this divergence started to become apparent after about 18 months (Figure 2B).17

Figure 2

Time to (A) the primary outcome of a composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure and (B) the secondary outcome of a composite of cardiovascular death, myocardial infarction, stroke in the TRANSCEND study.17 HR, hazard ratio; CI, confidence interval. Reproduced with permission from the TRANSCEND Investigators.17

During the design of TRANSCEND, an assumption was made that the annual rate of cardiovascular events would be 5.1% in the placebo group, which would confer a 94% power to detect a hazard ratio of 0.81 for telmisartan compared with placebo for primary outcome in 6000 patients.11 The assumption was based on the HOPE data, which was conducted in 9297 patients followed for 54 months.4 In reality, the overall incidence of the primary endpoint during the mean follow-up of 56 months was 17.0, representing an annual rate of 3.6% instead of the assumed 5.1%. With the exception of hospitalization for heart failure, the incidences of the components of the primary outcome of TRANSCEND17 in the placebo group were consistently lower compared with those of the placebo group of HOPE.4 Most notably, the incidence of myocardial infarction in the placebo group was only 5.0% in TRANSCEND vs. 12.3% in HOPE. In retrospect, therefore, TRANSCEND was underpowered to detect a difference between telmisartan and placebo. The lower event rate in TRANSCEND than was assumed in the power calculations is most probably due to the high use of concomitant therapy.

A common feature of cardiovascular outcome trials is that patients receive other drugs, such as anti-platelet agents, anti-hypertensive agents, and statins, to treat cardiovascular risk factors; most of these medications are known to improve the prognosis of high-risk patients. In recent years, there has been a more aggressive approach to the pharmacological management of cardiovascular risk. This is illustrated by comparing the results of HOPE with those of TRANSCEND. Beta-blockers were given to only 39.5% of patients in HOPE4 as opposed to 58.3% in TRANSCEND,17 and the use of diuretics increased from 15.3 to 33.5% and of lipid-lowering agents from 28.6 to 55.2%. Even within TRANSCEND, there were differences in the use of these medications between telmisartan and placebo groups: more non-study anti-hypertensive agents were used during the study in the placebo group. Although there was little change in their use at the end-study compared with baseline in the telmisartan arm, treatment with concomitant anti-hypertensive agents had increased at the end of the study in the placebo arm. The differences in the prescribing of anti-hypertensive medications were statistically significant for diuretics (telmisartan 33.7% vs. placebo 40.0%; P < 0.0001) and calcium channel blockers (telmisartan 38.0% vs. placebo 45.9%; P < 0.0001). This helps to explain the unexpectedly low rate of events in patients receiving placebo. Furthermore, prior to the trial, ∼30% of patients randomized to the telmisartan and placebo groups were receiving an ARB; the effect of this therapy may have been carried forward into the trial, possibly attenuating the event rates in both arms.

Despite TRANSCEND being underpowered and there being a low rate of cardiovascular events, there is still consistency with the findings of HOPE.4 In TRANSCEND, the hazard ratio for the secondary composite outcome, the primary HOPE outcome, was 0.87 (95% CI 0.76–1.00; P = 0.0475) compared with 0.78 (0.70–0.86; P < 0.001) in the HOPE study. The benefit of telmisartan over placebo is likely to have become more apparent if there were more patient-years of treatment. Moreover, telmisartan was well tolerated compared with placebo in addition to the current standard of care.

ONTARGET trial: telmisartan plus ramipril vs. ramipril

In addition to the direct comparison of ramipril 10 mg and telmisartan 80 mg, the second treatment arm of ONTARGET was designed to determine whether or not a combination of telmisartan 80 mg plus ramipril 10 mg was more effective than ramipril 10 mg alone.11 The rationale was that using two different agents that target the RAS by different mechanisms would result in more complete blockade of the pathophysiological effects of angiotensin II and confer additional cardiovascular benefit.

Baseline characteristics

The baseline characteristics of the 8502 patients in the telmisartan plus ramipril treatment arm of ONTARGET were very similar to those in the ramipril treatment arm of ONTARGET.12 Baseline SBP/DBP was 141.9/82.1 mmHg in both arms, and similar proportions of patients randomized to the combination or mono-therapy were receiving concomitant lipid-lowering, anti-platelet, and anti-hypertensive medications.

Adherence to telmisartan plus ramipril vs. ramipril

A major finding of ONTARGET was that the use of the combination of telmisartan plus ramipril was accompanied by a relatively high incidence of side effects that resulted in treatment discontinuation.12 The combination was permanently discontinued by 22.7% of the patients randomized to telmisartan plus ramipril, and an additional 6.7% discontinued one of the two medications. There was a significantly higher incidence of hypotension that necessitated discontinuation of the combination: 4.8% with telmisartan plus ramipril as opposed to 1.7% with ramipril (P < 0.001). In association with the hypotension, there was significantly higher incidence of syncope in the combination arm (0.3% with telmisartan plus ramipril vs. 0.2% with ramipril; P = 0.03). There was also a higher incidence of diarrhoea (0.5 vs. 0.1%; P < 0.001) and of renal impairment (1.1 vs. 0.7%; P < 0.001). As would be anticipated, the incidence of cough was similar in the patients receiving telmisartan plus ramipril to that in those receiving ramipril.

Impact of telmisartan plus ramipril vs. ramipril

It would be expected that targeting the RAS by two different mechanisms would result in greater blockade of the haemodynamic effects of angiotensin II. This was the case, with telmisartan plus ramipril, resulting in a 2.4 mmHg greater reduction in SBP and a 1.4 mmHg greater reduction in DBP compared with ramipril alone.12 A blood pressure reduction of this magnitude may be associated with an incidence of cardiovascular events in the combination treatment group being lower by the order of 4–5%.20 However, this was not observed.12

The primary outcome occurred in 16.3% (1386/8576) of the patients receiving telmisartan plus ramipril, and this incidence was similar to the 16.5% (1412/8576) observed in ramipril-treated patients (relative risk 0.99; 95% CI 0.92–1.07). This finding was not driven by any single component of the composite primary outcome; relative risk ratios were similar for cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure (Figure 3).12 Therefore, although the combination does not provide greater cardiovascular protection than ramipril alone, it is associated with higher rates of adverse events and treatment discontinuations.

Figure 3

Comparison of the effect on telmisartan plus ramipril vs. ramipril on the primary composite endpoint of cardiovascular (CV) death, myocardial infarction (MI), stroke, and hospitalization for heart failure (CHF Hosp) in the ONTARGET study.12 RR, relative risk; CI, confidence interval.


In the HOPE trial, ramipril reduced major cardiovascular outcomes and total mortality in high-risk patients without known heart failure. The results of the ONTARGET study have demonstrated that the ARB, telmisartan, is as effective as the ACE-inhibitor, ramipril, in high-risk patients with similar features as those participating in HOPE study. Telmisartan is better tolerated than ramipril, with patients being less likely to discontinue treatment because of side effects. For the primary endpoint in TRANSCEND, which was conducted in patients who were intolerant of ACE-inhibitors, giving telmisartan in addition to other drugs that have been shown to be effective in cardiovascular risk resulted in a non-significant decrease in the primary outcome. However, the results of TRANSCEND are consistent with those of HOPE. Telmisartan, therefore, may be used to treat patients with established vascular disease in the absence of heart failure or those with diabetes and end-organ damage who are intolerant to ACE-inhibitors. The combination of telmisartan plus ramipril is not recommended for the prevention of cardiovascular morbidity and mortality in high-risk patients without heart failure. Nevertheless, the use of an ACE-inhibitor and an ARB may be appropriate in patients with heart failure or left ventricular systolic dysfunction, with the proviso that blood pressure and renal function be well monitored. The good tolerability of telmisartan exhibited in both ONTARGET and TRANSCEND is likely to be important for an agent that will have to be taken by the patient for the long term.


The ONTARGET Program was supported by a grant from Boehringer Ingelheim.

Conflict of interest: G.R.D. has received funds for research projects, and honoraria for lectures and advisory board participation from Sanofi-aventis, as well as honoraria for lectures and advisory board participation from Boehringer Ingelheim.


View Abstract