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Clinical evidence from ONTARGET: proven cardio- and vascular protection

Koon K. Teo
DOI: http://dx.doi.org/10.1093/eurheartj/sup032 F9-F15 First published online: 17 November 2009

Abstract

ONTARGET compared the angiotensin II receptor blocker telmisartan with the angiotensin-converting enzyme (ACE) inhibitor ramipril, and the two agents in combination with ramipril alone, in a broad cross section of patients with vascular disease or high-risk diabetes without heart failure. Telmisartan was as effective as the gold standard ramipril in the prevention of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure [relative risk (RR) 1.01, 95% confidence interval (CI) for non-inferiority 0.94–1.09], however significantly more ramipril-treated patients withdrew because of cough or angio-oedema; hypotensive symptoms were more common with telmisartan. Tolerability as observed in ONTARGET should be seen in light of the fact that recruited patients had to be tolerant to ACE inhibitors [those being intolerant to ACE inhibitors were randomized into another trial (TRANSCEND)] and that vigorous attempts were made to restart patients back on study drug(s) when they discontinued them. There was no difference in the incidence of the primary composite outcome between the ramipril and combination therapy groups (RR 0.99, 95% CI 0.92–1.07), but hypotension, syncope, and diarrhoea were more common with combination therapy. Furthermore, the risk of the composite outcome of dialysis, doubling of serum creatinine, or death was higher with combination therapy than with ramipril (hazard ratio 1.09, 95% CI 1.01–1.18, P = 0.037). Hence, combination therapy with the two drugs is not recommended in this patient population.

  • Angiotensin-converting enzyme inhibitors
  • Angiotensin II receptor blockers
  • ONTARGET
  • Ramipril
  • Telmisartan

Introduction

Angiotensin-converting enzyme (ACE) inhibitors were first introduced for the treatment of hypertension, but subsequent landmark trials have shown that they are highly effective in reducing cardiovascular mortality and morbidity in patients with left ventricular dysfunction or heart failure,13 myocardial infarction,46 and vascular disease.7,8 As a result, these agents have attained a central place in the treatment of patients at high risk of vascular events. However, ACE inhibitors are subject to certain limitations. Angiotensin II can be produced by non-ACE pathways, such as chymase, that are not affected by ACE inhibitors,9,10 and hence in many patients angiotensin II concentrations may return to baseline levels (‘angiotensin escape’) despite continued ACE inhibitor therapy.11 Furthermore, ACE inhibitors block the degradation of bradykinin by kininase, resulting in bradykinin accumulation; although this may be advantageous because of the potentially beneficial vasodilator effects of bradykinin,12 it may also increase the risk of adverse events such as cough and angio-oedema. These concerns can be avoided by the use of angiotensin II receptor blockers (ARBs), which selectively block the deleterious AT1-receptor-mediated effects of angiotensin II, irrespective of the source of angiotensin II, while preserving potentially advantageous effects of AT2-receptor activation such as vasodilatation.13

Major outcome trials with ARBs have shown that these agents reduce mortality and morbidity associated with heart failure among patients with heart failure1416 and decrease the risk of stroke in hypertensive patients with left ventricular hypertrophy.17 In addition, the recent ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) study18 has shown that the benefits of therapy with the ARB telmisartan extend to high-risk patients with vascular disease or diabetes mellitus who do not have heart failure. The results of the ONTARGET study are reviewed in this paper.

Rationale and design of the ONTARGET study

Although the potential benefits of ACE inhibitors have been clearly demonstrated, up to 20% of patients are unable to tolerate these agents due to adverse events such as cough and, to a lesser extent, hypotensive symptoms, renal dysfunction, and angio-oedema.19,20 Previous studies have shown that ARBs are effective in preventing cardiovascular mortality and morbidity in heart failure patients who are unable to tolerate ACE inhibitors,14 and hence it is important to know whether the same is true for the far broader cross section of cardiovascular high-risk patients without heart failure. Furthermore, several studies have suggested that the combination of an ACE inhibitor and an ARB may offer additive benefits in heart-failure patients,15,16,21 and so it is appropriate to evaluate such combination therapy in patients without heart failure who are at risk of vascular events due to a previous event such as a myocardial infarction.

The ONTARGET study examined the effects of the ARB telmisartan, 80 mg daily, and the ACE inhibitor ramipril, 10 mg daily, and the two agents in combination, in patients with vascular disease (coronary artery, cerebrovascular, or peripheral arterial disease) or diabetes with end-organ damage, who did not have heart failure. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for congestive heart failure. The aims of the study were to establish whether telmisartan was more effective (i.e. non-inferior) than ramipril, and whether the combination of the two agents was as effective as ramipril alone, in this patient population. The efficacy of ramipril, 10 mg daily, in high-risk patients had previously been established in the Heart Outcomes Prevention Evaluation (HOPE) study.7

The principal inclusion and exclusion criteria of the ONTARGET study are summarized in Table 1.18,22 Patients who were found to be intolerant to ACE inhibitors were enrolled in a separate trial, the TRANSCEND (Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease) study.23

View this table:
Table 1

Principal inclusion and exclusion criteria of the ONTARGET study18,22

Inclusion criteriaExclusion criteria
Patients aged ≥55 years with one of the following:
  • Coronary artery disease:

    •  – previous (>2 days) uncomplicated myocardial infarction

    •  – stable or unstable angina (>30 days) with documented multivessel disease

    •  – previous (<3 months) revascularization

  • Peripheral arterial disease:

    •  – intermittent claudication

    •  – previous limb bypass surgery or angioplasty

    •  – previous limb or foot amputation

    •  – significant (>50%) documented peripheral artery stenosis

  • Cerebrovascular disease:

    •  – previous stroke

    •  – transient ischaemic attack >7 days or <1 year before inclusion

    •  – Diabetes mellitus with evidence of end-organ damage

  • Inability to discontinue ACE inhibitors or ARBs

  • Known intolerance or hypersensitivity to ACE inhibitors or ARBsa

  • Symptomatic congestive heart failure

  • Uncontrolled hypertension (>160/100 mmHg) on treatment

  • Haemorrhagic stroke

  • Significant renal artery disease

  • Serum creatinine >265 µmol/L

  • Hyperkalaemia

  • Hepatic dysfunction

  • aPatients found to be intolerant to ACE inhibitors were enrolled into the TRANSCEND study.23

In ONTARGET, patients entered a single-blind run-in phase, during which they received ramipril 2.5 mg daily for 3 days, followed by ramipril 2.5 mg daily, plus telmisartan 40 mg daily, for 7 days and ramipril 5 mg, plus telmisartan 80 mg daily, for 11–18 days. They were then randomized to receive ramipril 5 mg daily, telmisartan 80 mg daily, or the two agents in combination; the dose of ramipril was increased to 10 mg daily after 2 weeks. Throughout the trial, investigators were encouraged to keep patients on therapy. The median duration of follow-up was 56 months.

A total of 29 019 patients were enrolled, of whom 25 620 were randomized and 25 577 (99.8%) were followed until either the primary endpoint or the end of the study was reached. The principal reasons for exclusion during the run-in phase were poor compliance (3.9%), patient withdrawals (2.1%), and symptomatic hypotension (1.7%). Baseline characteristics of the randomized patients are summarized in Table 2. It should be noted that the patients were extensively co-medicated in this study: at baseline, ∼62% of patients were receiving a statin, 57% were receiving beta-blockers, and 81% were receiving antiplatelet therapy (Table 1). This high use of concomitant medication reflects the advances in the management of cardiovascular disease that have occurred during the last decade; in contrast, in the HOPE study7 only 29% were receiving lipid-lowering therapy and 39% were receiving beta-blockers. During the course of the ONTARGET study, the use of statins increased from 61.6 to 70.6%, and diuretic use increased from 28.0 to 32.5%; in contrast, the use of antiplatelet agents decreased slightly during the study, from 80.9 to 77.5%.

View this table:
Table 2

Baseline characteristics of randomized patients in the ONTARGET study18

Ramipril (n = 8576)Telmisartan (n = 8542)Ramipril + Telmisartan (n = 8502)
Age (years)a66.4 ± 7.266.4 ± 7.166.5 ± 7.3
Women2331 (27.2%)2250 (26.3%)2250 (26.5%)
Blood pressure (mmHg)a141.8 ± 17.4/82.1 ± 10.414.9 ± 17.6/82.1 ± 10.4141.7 ± 17.2/82.1 ± 10.4
Medical history
 Coronary artery disease6382 (74.4%)6367 (74.5%)6353 (74.7%)
 Stroke/transient ischaemic attack1805 (21.0%)1758 (20.6%)1779 (20.9%)
 Peripheral arterial disease1136 (12.7%)1161 (13.6%)1171 (13.8%)
 Diabetes3146 (36.7%)3246 (38.0%)3220 (37.9%)
Concomitant medications
 Statins5234 (61.0%)5294 (62.0%)5255 (61.8%)
 Beta-blockers4847 (56.5%)4860 (56.9%)4876 (57.4%)
 Aspirin6473 (75.5%)6469 (75.7%)6461 (76.0%)
 Clopidogrel/ticlopidine927 (10.8%)966 (11.3%)931 (11.0%)
 Antiplatelet agents6903 (80.5%)6926 (81.1%)6898 (81.1%)
 Diuretics2454 (28.6%)2359 (27.6%)2351 (27.7%)
 Calcium channel blockers2821 (32.9%)2787 (32.6%)2864 (33.7%)
  • aData are presented as mean ± SD.

Efficacy and tolerability of telmisartan vs. ramipril

Adherence to treatment was good during the ONTARGET study. At 1 year of follow up, 92.2% of patients assigned to ramipril were on an ACE inhibitor, with 86.1% on full dose treatment with assigned ramipril. In the telmisartan or placebo, 93.6% were on an ARB at 1 year, with 88.8% on full dose of the assigned temisartan. At the end of the study 84.7% remained on assigned ramipril, with 74.8% on full dose. The corresponding data for telmisartan were 85.6% and 76.0% respectively. The proportion of patients in the ramipril group who received a concomitant ARB increased during the study from 1 to 3.3%; conversely, 2.6% of patients in the telmisartan group were receiving a concomitant ACE inhibitor at 1 year, and this proportion increased to 6.4% by the end of the study. The number of permanent treatment discontinuations was significantly higher in the ramipril group than in the telmisartan group (24.5 vs. 23.0%, respectively; P = 0.02). Significantly more ramipril-treated patients discontinued treatment because of cough (4.2 vs. 1.1%, P < 0.0001) or angio-oedema (0.3 vs. 0.1%, P = 0.0115), whereas discontinuations because of hypotensive symptoms were more common among telmisartan-treated patients (2.7 vs. 1.7%, P = 0.0001).

The incidence of the primary outcome was 16.5% in the ramipril group and 16.7% in the telmisartan group, giving a hazard ratio (HR) of 1.01 [95% confidence interval (CI) 0.94–1.09]. The upper limit of the 95% confidence interval was significantly (P = 0.004) lower than the pre-defined non-inferiority boundary of 1.13 (Figure 1), indicating that telmisartan was not inferior in efficacy to ramipril. Similarly, when the effects of the two treatments on the composite endpoint used in the HOPE study (cardiovascular death, myocardial infarction, or stroke) were compared, telmisartan was again found to be non-inferior to ramipril (Figure 1). There were no significant differences between the two groups in the incidence of any component of the primary composite outcome, all-cause mortality, or various secondary outcomes (Table 3). Similarly, there were no significant differences between the groups in the incidence of the primary endpoint in any prespecified subgroup (Figure 2).

Figure 1

Non-inferiority comparison of telmisartan and ramipril in the ONTARGET study.18 The upper limit of the 95% confidence interval for the relative risk in the telmisartan group, compared with the ramipril group, was significantly lower than the pre-defined non-inferiority boundary of 1.13. This was true both for the primary endpoint [cardiovascular (CV) death, myocardial infarction (MI), stroke, or hospitalization for heart failure], and for the primary endpoint used in the HOPE study7 (CV death, MI, or stroke). Reproduced with permission from the ONTARGET Investigators.18

Figure 2

Relative incidence of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure in ramipril-treated and telmisartan-treated patients in pre-specified patient subgroups in the ONTARGET study. Reproduced with permission from the ONTARGET Investigators.18

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Table 3

Incidence of components of the primary composite outcome, all-cause mortality, and predefined secondary outcomes in patients receiving ramipril alone, telmisartan alone, and the two drugs in combination in the ONTARGET study18

Incidence in ramipril group (%)Incidence in telmisartan group (%)Relative risk, telmisartan vs. ramipril (95% CI)Incidence in combination therapy group (%)Relative risk, combination therapy vs. ramipril (95% CI)
Cardiovascular death7.07.01.00 (0.89–1.12)7.31.04 (0.93–1.17)
Myocardial infarction4.85.21.07 (0.94–1.22)5.21.08 (0.94–1.23)
Stroke4.74.30.91 (0.79–1.05)4.40.93 (0.81–1.07)
Hospitalization for heart failure4.14.61.12 (0.97–1.29)3.90.95 (0.82–1.10)
All-cause mortality11.811.60.98 (0.90–1.07)12.51.07 (0.98–1.16)
Revascularization14.815.11.03 (0.95–1.11)15.11.04 (0.97–1.13)
New diabetes mellitus6.77.51.12 (0.97–1.29)6.10.91 (0.78–1.06)
Any heart failure6.06.31.05 (0.93–1.19)5.60.94 (0.83–1.07)
Hospitalization for angina10.811.21.04 (0.95–1.14)11.21.04 (0.95–1.14)
New atrial fibrillation6.96.70.97 (0.86–1.09)6.50.96 (0.85–1.07)

In summary, the results of the ONTARGET study show that telmisartan alone is as effective as the gold standard ramipril alone in the prevention of cardiovascular events in high-risk patients without heart failure, and better tolerated. Comparison of these results with those of the HOPE trial suggests that at least 95% of the benefits of ramipril seen in the latter trial are preserved with telmisartan. Even in ONTARGET, where patients were selected for ACE inhibitor tolerance and investigators encouraging patients to remain on study medication, telmisartan offers superior tolerability to ramipril in this patient population, being associated with lower incidences of cough and angio-oedema. Although the incidence of mild hypotensive symptoms was higher with telmisartan than with ramipril, reflecting greater blood pressure reduction, there was no significant difference between the groups in the incidence of more severe symptoms such as syncope.

Efficacy and tolerability of combination therapy vs. ramipril alone

Adherence with combination therapy was 85.5% at 1 year, and decreased to 73.6% at the end of the study, when 75.3% of patients were receiving full-dose treatment. The proportion of patients in the combination therapy group who were receiving additional ACE inhibitors or ARBs increased from 2.8 and 3.5% at 1 year to 6.0 and 6.4%, respectively, at the end of the study. Significantly more patients discontinued treatment permanently in the combination therapy group (29.3%) than in the ramipril group (23%, P < 0.001), and the incidences of hypotension (4.8 vs. 1.7% for ramipril, P < 0.001), syncope (0.3 vs. 0.2% for ramipril, P = 0.032), diarrhoea (0.5 vs. 0.1% for ramipril, P = 0.001), and renal impairment (1.1 vs. 0.7% for ramipril, P = 0.001) were also significantly higher with combination therapy.

Combination therapy resulted in a greater reduction in blood pressure than ramipril alone: the mean treatment difference was 2.4/1.4 mmHg. However, this greater blood pressure decrease was not associated with a further reduction in the risk of cardiovascular events (HR 0.99, 95% CI 0.92–1.07). Similarly, there were no significant differences between the ramipril and combination therapy groups in the risk for individual components of the primary endpoint, all-cause mortality, and secondary outcomes (Table 3). Subgroup analyses showed no significant differences in the risks for the primary endpoint between the combination therapy and ramipril groups in any patient subgroup (Figure 3).

Figure 3

Relative incidence of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure in patients receiving ramipril alone or a combination of ramipril and telmisartan in pre-specified patient subgroups in the ONTARGET study. Reproduced with permission from the ONTARGET Investigators.18

Effects of combination therapy on renal function

Previous studies have shown that both ACE inhibitors and ARBs reduce proteinuria and prevent or delay the progression of renal impairment in patients with kidney disease.24 Furthermore, combination treatment with an ACE inhibitor and an ARB has been reported to improve renal function to a greater extent than either agent alone in patients with non-diabetic renal disease in the COOPERATE study,25 although concerns have been raised about the design of this trial.26 Hence, a pre-planned analysis in ONTARGET investigated the effects of combination therapy on renal function. The primary endpoint in this analysis was a composite of dialysis, doubling of serum creatinine, and death.27 The incidence of this composite outcome was significantly higher in patients receiving combination therapy than in those receiving ramipril alone (14.5 vs. 13.4%, respectively; HR 1.09, 95% CI 1.01–1.18, P = 0.037) (Figure 4). In addition, compared with ramipril alone, combination therapy resulted in an increased incidence of a composite of dialysis and doubling of serum creatinine (HR 1.24, 95% CI 1.01–1.51, P = 0.038) and of acute dialysis (HR 2.19, 95% CI 1.13–4.22, P = 0.02). Estimated glomerular filtration rate decreased during the study by a mean [±standard deviation (SD)] of −6.11 ± 17.9 mL/min/1.73 m2 in the combination therapy group compared with −2.82 ± 17.2 mL/min/1.73 m2 in the ramipril group (P < 0.0001). This represents an annual decline in renal function of ∼1 mL/min in patients receiving combination therapy. It should be noted, however, that this decrease is less than those seen in other studies with ARBs or ACE inhibitors in patients at a higher level of renal risk, in which decreases of 4–10 mL/min/year have been reported.2830 Overall, renal abnormalities occurred in 13.5% of patients receiving combination therapy, compared with 10.2% of those receiving ramipril alone and 10.6% of those receiving telmisartan alone [relative risk (RR) vs. ramipril 1.33, 95% CI 1.22–1.44, P < 0.0001]. Such abnormalities led to permanent discontinuation of treatment in 1.1% of patients in the combination therapy group, 0.7% of those in the ramipril group, and 0.8% of those in the telmisartan group (RR vs. ramipril 1.58, P < 0.005).

Figure 4

Kaplan–Meier curves showing the incidence of (A) dialysis, doubling of serum creatinine or death; (B) dialysis and doubling of serum creatinine; (C) dialysis in the ONTARGET study. Reproduced with permission from Mann et al.27

In summary, the ONTARGET study has shown that the combination of ramipril and telmisartan does not reduce the risk of vascular events to a greater extent than ramipril alone in high-risk patients without heart failure. Moreover, the combination is associated with an increased risk of adverse events, notably hypotension and renal dysfunction.

Conclusions: implications of ONTARGET for clinical practice

The HOPE study has previously shown that ACE inhibition with ramipril significantly reduces cardiovascular mortality and morbidity in high-risk patients with vascular disease.7 The ONTARGET study included a similar patient population, and the dose of ramipril was the same as that used in the HOPE trial; the results showed that telmisartan was as effective as ramipril in reducing cardiovascular events in this high-risk population. Furthermore, telmisartan was better tolerated than ramipril, with lower incidences of cough and angio-oedema, and was associated with lower rates of treatment discontinuation despite the positive selection for being ACE inhibitor tolerant and investigators encouraging patients to remain on study medication. Telmisartan can therefore be recommended for use in strategies to reduce cardiovascular risk in high-risk patients without heart failure.

In contrast to some previous trials with ARBs in heart-failure patients,15,16,21 combination therapy with ramipril and telmisartan in ONTARGET did not result in a further reduction in vascular events, compared with either therapy alone. Moreover, the combination was associated with adverse renal outcomes and an increased incidence of adverse events, notably hypotensive symptoms. Hence, the ONTARGET results suggest that combination therapy with these drugs is not recommended in high-risk patients with vascular disease or diabetes in the absence of heart failure.

Funding

The ONTARGET study was supported by Boehringer Ingelheim, Germany.

Conflict of interest: KKT received research grants, honoraria and consultation fees from Boehringer Ingelheim, Germany.

References

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