PROGRESS beyond HOPE and LIFE: The ONTARGET Trial ...

European Heart Journal Supplements (2003) 5 (Supplement F), F40—F47

PROGRESS beyond HOPE and LIFE: The ONTARGET Trial Programme P. Sleight John Radcliffe Hospital, Oxford, U.K.

KEYWORDS Angiotensin-converting enzyme inhibitors Angiotensin II receptor blockers; Blood pressure; Cardiovascular risk; Clinical trials; Ramipril Telmisartan

Large-scale cardiovascular trials traditionally have targeted clinical hypertension, diabetes or survivors of myocardial infarction, but the recent trend in such trials has been to consider the treatment of high-risk individuals rather than specific diseases. This allows the use of a much broader screening process to enrol patients. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) act directly on the renin—angiotensin system to effect blood pressure control. The Heart Outcomes Prevention Evaluation (HOPE) and the Perindopril pROtection against REcurrent Stroke Study (PROGRESS) showed that angiotensinconverting enzyme inhibitors (ramipril and perindopril plus the diuretic indapamide), significantly decreased the risk for stroke and other adverse cardiovascular outcomes. Both studies showed benefits in patients with conventionally normal blood pressure. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial showed that losartan, an ARB, could also significantly decrease the risk of stroke to an extent greater than that predicted by the decrease in blood pressure. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) Trial Programme is currently underway to study the effect of ramipril and the ARB telmisartan, and a combination of the two agents in patients at high risk of cardiovascular disease. © 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved

Introduction Despite important advances in treatment, cardiovascular disease remains the leading cause of death in the Western world.1 Multiple risk factors, both genetic and environmental, make cardiovascular disease a significant challenge for epidemiology and prevention.2,3 Recently, the trend in cardiovascular clinical trials has been to target high-risk individuals rather than specific Correspondence: Peter Sleight, MD, FRCP, FACC, Professor Emeritus of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, U.K.

diseases, as exemplified by the Heart Outcomes Prevention Evaluation (HOPE)4 and the Heart Protection Study.5 The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) Trial Programme is currently underway to study the effect of telmisartan and ramipril, and a combination of the two agents in patients (similar to HOPE) at high risk of cardiovascular disease. Compared with previous trials that specifically targeted hypertension,6,7 diabetes8 or survivors of myocardial infarction (MI),9 these recent and ongoing trials can use a much broader screening process to enrol patients and can be relevant to normal clinical practice.

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RAAS blockade and cardiovascular reduction

High-risk patients High-risk patients can readily be identified as possessing several of the following risk factors: older age, male sex, smoking, diabetes, known vascular disease (MI, revascularization, stroke, transient ischaemic attack, peripheral vascular disease), hypertension, adverse family history, left ventricular hypertrophy or heart failure.10 Statistics show that approximately 25% of men and 38% of women will die within 1 year after having an initial recognized MI.11 About one-third of heart disease deaths occur within minutes of a MI, and meta-analysis revealed that 23% of patients experiencing a first MI died before reaching hospital and a further 13% died during hospital admission.12 If the patient survives the first MI, then cardiovasacular mortality is about 10% in the first year. After a subsequent MI, 33% of patients died before reaching the hospital and 20% died in hospital.12 The second event is most likely to involve an independent plaque,13 suggesting that once a threshold for events has been reached the morbidity may be accelerated. As the population ages, the burden of cardiovascular disease is becoming greater.14 However, effective interventions, with the appropriate use of drug therapy, can reduce this burden.15

The renin—angiotensin—aldosterone system The renin—angiotensin—aldosterone system (RAAS) maintains volume homeostasis and regulates blood pressure via the angiotensin II type 1 (AT1) receptor.16 Stimulation of the AT1 receptor results in several pathophysiological changes, including vasoconstriction, release of vasopressin and aldosterone, sodium retention by the renal tubules and changes in renal perfusion. Activation of the AT1 receptor also promotes vascular growth and proliferation and endothelial dysfunction, which contribute to chronic disease pathology.17—20 Agents designed to act directly on the RAAS, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), can suppress its effects as a result of attenuating the activity of angiotensin II.16 The ACE inhibitors act by preventing the conversion of angiotensin I to angiotensin II;16 they also prevent the catabolism of bradykinin.21 The ARBs selectively block the AT1 receptors, which mediate most of the negative cardiovascular effects of the RAAS, but they do not block the AT2 receptors, which are responsible for some of the beneficial effects.22

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ACE inhibitors were once thought to lower blood pressure solely by limiting the formation of angiotensin II.23 However, it is evident that during chronic ACE inhibitor treatment plasma angiotensin II levels may rise, with the effects of an ACE inhibitor being attenuated after administration for about 1 year.24 Prevention of the degradation of bradykinin and other vasodilatory peptides by ACE inhibitors may contribute to the beneficial cardiovascular effects, including blood pressure lowering.25 When ARBs are administered, angiotensin II levels rise, although the AT1 receptors are no longer stimulated. The circulating angiotensin II is still available to bind to the active sites of the AT2 receptors. The consequent stimulation of the AT2 receptors in the brain, for example, increases blood flow to ischaemic cerebral tissue in a manner that is independent of AT1 receptors and blood pressure.26,27 The use of a synthetic AT2 agonist, namely PD-123319, has been shown to improve survival in a gerbil model of stroke due to restoration of blood flow rather than the lowering of blood pressure.26 Lowering of angiotensin II levels may not be a treatment goal for stroke patients, and unpublished data suggest that drugs that increase available angiotensin II, such as calcium channel blockers, diuretics and ARBs, may protect against stroke in hypertension trials.

Cardiovascular protective effects of angiotensin-converting enzyme inhibitors The HOPE study4 is an example of a large-scale outcomes study conducted to establish the effect of an ACE inhibitor in patients at high risk for cardiovascular disease. The study was performed in high-risk patients, all of whom were older than 55 years.28 Study participants had clinical evidence of vascular disease or diabetes, and at least one other cardiovascular risk factor had to be present (hypertension, elevated levels of total cholesterol, low levels of high-density lipoprotein cholesterol, cigarette smoking or microalbuminuria). Patients with hypertension were only included if their blood pressure was already controlled. A total of 9257 patients were randomly assigned to receive either placebo or the ACE inhibitor ramipril at a dose of 10 mg orally once daily; the mean duration of treatment was 4.5 years. Compared with placebo, ramipril was associated with a 22% average risk reduction (P90 mmHg, mean SBP/DBP at baseline 159/94 mmHg) and normotensive (mean SBP/DBP at baseline 136/79 mmHg) subgroups of patients. This finding provides further support for the proposal that, in high-risk patients, the threshold for blood pressure lowering should be lowered. The benefit gained by the addition of a diuretic in the PROGRESS trial could conceivably be explained by chance, because the diuretic was not randomized.31 Alternatively, the larger blood pressure reduction achieved with combination therapy compared with monotherapy may have been responsible for the difference in efficacy. On the other hand, in the HOPE study, the observed benefits of ACE inhibition were independent of diuretic use.4 Pahor et al.33 reported a review and metaanalysis of four trials in which patients with type 2 diabetes and hypertension were randomly

assigned to an ACE inhibitor or an alternative drug. The following studies were included: the Appropriate Blood pressure Control in Diabetes (ABCD) trial,34 which compared the ACE inhibitor enalapril with the calcium channel blocker nisoldipine; the CAPtopril Prevention Project (CAPPP),35 which compared the ACE inhibitor captopril with diuretics or beta-blockers; the Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET),36 which compared the ACE inhibitor fosinopril with the calcium channel blocker amlodipine; and the UK Prospective Diabetes Study (UKPDS),37 which compared captopril with the beta-blocker atenolol. Although not observed in the UKPDS, the cumulative results of the first three trials showed that ACE inhibitors conferred a significant benefit in terms of reducing cardiovascular outcomes. However, the ACE inhibitors were not found to be superior in the reduction of stroke. Once again, none of the findings could be attributed to differences in blood pressure control.

Cardiovascular protective effects of angiotensin II receptor blockers The Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial38 compared the ARB losartan at a starting dose of 50 mg/day with the beta-blocker atenolol, which was given at an initial dose of 50 mg/day. A total of 9193 older patients with previously treated or untreated hypertension and ECG evidence of left ventricular hypertrophy (LVH) were enrolled in the study. After 2 months, hydrochlorothiazide 12.5 mg/day

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P. Sleight

(a)

(b)

Fig. 3 The effect of losartan and atenolol based therapy (a) in fatal/non-fatal stroke and (b) fatal/non-fatal myocardial infarction in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial.38 Reprinted with permission from Elsevier (Lancet 2002;359:995—1003).

was added to each treatment, and drug doses were up-titrated in order to achieve a target SBP/DBP below 140/90 mmHg. Losartan-based therapy was superior to atenolol in reducing the frequency of the primary composite end-point of cardiovascular death, stroke and MI.38 Losartan was superior (by approximately 25%; P=0.001) to atenolol in reducing the incidence of stroke (but not MI), despite the fact that the SBP/DBP reductions achieved with the two drugs were virtually identical: 30.2/16.6 mmHg for losartan compared with 29.1/16.8 mmHg for atenolol (Fig. 3).

Losartan was also superior to atenolol in reducing LVH, and although the reduction in blood pressure did not fully explain the regression of LVH, neither did the improvement in LVH fully explain the lowered stroke incidence. An analysis of the 1195 patients with diabetes in the LIFE study showed that, although both losartan and atenolol again decreased blood pressure to an almost identical degree, losartan was associated with a 37% greater decrease in cardiovascular death.39 The implication of the LIFE study, that losartan — an ARB — could have a significant effect on stroke over and above blood pressure reduction, extends


RAAS blockade and cardiovascular reduction

Fig. 4 Design of the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease (TRANSCEND), forming The ONTARGET Trial Programme.

the results of the HOPE study, which suggested the same for ACE inhibitors.4 The hypertensive patients enrolled in the LIFE trial40 were very different from the HOPE patient population. The baseline average SBP/DBP in HOPE was 139/79 mmHg,4 as compared with 174/98 mmHg in the LIFE study.40 It is also possible that the lack of difference between losartan and atenolol for MI reduction could be due to the fact that the betablocker also reduces sudden death and reinfarction (i.e. also by mechanisms unrelated to blood pressure reduction).41 The OPtimal Trial In Myocardial infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL)42 compared losartan 50 mg given once daily with the ACE inhibitor captopril 50 mg given three times daily. A non-significant decrease in total mortality in favour of captopril was detected in patients with evidence of heart failure or left ventricular dysfunction after acute MI. Although losartan was used at a dose of 50 mg in that study, higher doses (up to 150 mg) have been tested in patients with heart failure and shown to result in progressively increased plasma renin and angiotensin II as a result of negative feedback.42 Use of losartan in OPTIMAAL was better tolerated than captopril and was associated with significantly fewer discontinuations.

The ONTARGET Trial Programme The ONTARGET Trial Programme is designed to compare the efficacy of ramipril and the ARB telmisartan given as monotherapy or in combination in a large cohort of patients at high risk of developing cardiovascular disease (it is

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envisaged, for example, that approximately 35% will have diabetes).43 A projected target of over 23 000 patients were recruited globally from 40 countries and were randomized to once-daily treatment with ramipril 10 mg, telmisartan 80 mg or a combination of the two drugs (Fig. 4). A dry, persistent cough as a side-effect of ACE inhibitors may make their use in some patients unacceptable, but earlier studies have shown telmisartan to be associated with a significantly lower incidence of treatment-related cough than were the ACE inhibitors enalapril and lisinopril.44,45 A parallel study, Telmisartan Randomized AssessmeNt Study in aCE-iNtolerant subjects with cardiovascular Disease (TRANSCEND), will compare telmisartan 80 mg with placebo in 6000 patients who cannot tolerate ACE inhibitors (Fig. 4). Both ACE inhibitors and ARBs show comparable blood pressure lowering and clinical outcome profiles. Telmisartan, which is approved worldwide for treatment of hypertension, has been shown to have efficacy similar to that of enalapril46—48 or lisinopril45 in lowering trough blood pressure in patients with mild-to-moderate essential hypertension. Telmisartan is likely to be as effective as ramipril and better tolerated. The combination of an ACE inhibitor and an ARB is expected to result in higher plasma angiotensin II levels; ACE-independent pathways may be responsible for formation of angiotensin II.50 The rationale behind the combination approach in the ONTARGET study is threefold. The use of telmisartan to provide AT1 receptor blockade should overcome the negative consequences of ACE escape associated with ramipril monotherapy. Furthermore, the selectivity of telmisartan for the AT1 receptors will ensure that any excess angiotensin II acts to stimulate the AT2 receptors, which appear to be associated with more beneficial effects in stroke patients. An additional potential advantage is that ramipril will bring about increased plasma levels of bradykinin, and this may result in further tissue protection as a result of vasodilatation. The primary end-points of both ONTARGET and TRANSCEND are cardiovascular death, MI, stroke and hospitalization for congestive heart failure. The premise of the studies is that angiotensin II affects vascular disease also by blood pressureindependent mechanisms. Although reduction of SBP/DBP to below 130/80 mmHg is a primary goal, high-risk patients require multiple therapies, including aspirin, lipid-lowering agents, betablockers post-MI, ACE inhibitors (or ARBs in the case of intolerance to ACE inhibitors) or calcium channel blockers.


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Conclusion Accumulated data from outcome studies have convincingly shown that, for individuals with hypertension or who are at high risk for cardiovascular disease, it is important to treat the overall risk and not just the isolated symptoms. The importance of lowering blood pressure and controlling serum lipid levels is now well accepted as making an important contribution to the management of cardiovascular morbidity and mortality. Guidelines have defined the goals to be achieved. Such aims, however, may instil a degree of complacency in high-risk individuals, especially the elderly. In patients at high risk, it may be beneficial to lower what may be considered ‘normal’ levels of low-density lipoprotein cholesterol and what in lower-risk subjects may be regarded as acceptable levels of blood pressures.

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