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Recent Advances in Cardiovascular Risk Reduction: Implications of ONTARGET ROBERT GUTHRIE, MD Professor of Emergency Medicine, Internal Medicine, and Pharmacology The Ohio State University Columbus, Ohio

Renin–angiotensin–aldosterone system (RAAS) overactivity is associated with increased cardiovascular risk, a finding that may be explained by the key role of the RAAS in stimulating vascular and cardiac remodeling. Inhibition of RAAS activity with the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) has been shown to reduce cardiovascular mortality in patients with heart failure. ACE inhibitors have also been shown to reduce the incidence of stroke, myocardial infarction (MI), and heart failure in high-risk patients without heart failure. These findings led to the evaluation of the ARB telmisartan versus the ACE inhibitor ramipril in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), a cardioprotection trial conducted in high-risk patients without left ventricular dysfunction or heart failure. The results of this trial showed that the ACE inhibitor ramipril and the ARB telmisartan are equally effective in reducing the incidence of cardiovascular death, MI, stroke, and hospitalization for heart failure in patients without heart failure or left ventricular dysfunction but at high risk for cardiovascular disease (CVD). These results confirm that RAAS inhibition, using ACE inhibitors or ARBs, is an effective approach to reducing cardiovascular mortality and morbidity in patients without heart failure who are at high risk for CVD. (Clinical Cornerstone. 2009;9[Suppl 3]:S18–S26) © 2009 Elsevier. Angiotensin II, the primary effector peptide of the renin– angiotensin–aldosterone system (RAAS), stimulates vascular and cardiac remodeling through hemodynamic and nonhemodynamic pathways.1 Blockade of angiotensin II is therefore a plausible method to inhibit vascular and cardiac remodeling and potentially to reduce cardiovascular risk, particularly in patients with increased RAAS activity. In several large randomized clinical trials,2−8 angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce overall mortality and death from cardiovascular causes in patients with and without left ventricular dysfunction or heart failure. In addition, ACE inhibitors have been proven to reduce the incidence of myocardial infarction (MI), heart failure, and stroke in high-risk populations without heart failure.7,8 However, ACE inhibitor therapy is associated with a bothersome dry cough, which can lead to discontinuation in a significant proportion of patients.1 Angioedema is also seen in a minority of patients.1 The positive results obtained with ACE inhibitors in these cardioprotection trials and the finding that

cough and angioedema can lead to reduced compliance and discontinuation have prompted the evaluation of alternative methods of angiotensin II inhibition. Angiotensin II receptor antagonists, or angiotensin II receptor blockers (ARBs), have been shown to reduce cardiovascular mortality in patients with heart failure.9−11 More recently, the ARB telmisartan was compared with the ACE inhibitor ramipril in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET),12 a cardioprotection trial conducted in high-risk patients without left ventricular dysfunction or heart failure. This paper reviews the rationale for ONTARGET, the primary trial results, and the implications of these results for the care of patients at high risk for cardiovascular disease (CVD). EFFECTS OF RENIN-ANGIOTENSIN ACTIVITY ON THE CARDIOVASCULAR SYSTEM The RAAS plays a primary role in the short-term and long-term regulation of arterial blood pressure (BP). In S18

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this cascade, the enzyme renin is released in response to various conditions that can decrease arterial BP (eg, acute blood volume loss, congestive heart failure, liver cirrhosis). Renin cleaves its substrate angiotensinogen to yield the decapeptide angiotensin I. ACE then catalyzes the cleavage of angiotensin I to the octapeptide angiotensin II, a potent vasoconstrictor that acts via multiple mechanisms to increase total peripheral resistance, alter renal function, and, over the long term, modify cardiovascular structure through nonhemodynamic and hemodynamic mechanisms (Figure 1).13 Angiotensin II has been shown to promote the migration, proliferation, and hypertrophy of vascular smooth muscle cells and increase the synthesis of extracellular matrix proteins by increasing the expression of specific proto-oncogenes and growth factors.1 In addition, the hemodynamic effects of angiotensin II result in increased cardiac preload and afterload, as well as increased vascular wall tension.1 Overall, these effects result in vascular and cardiac hypertrophy and remodeling, implicating angiotensin II and the RAAS in general in the development of CVD. Therefore, blockade of the RAAS with the use of ACE inhibitors and ARBs has become a major focus of cardiovascular risk-reduction studies.

KEY POINT Angiotensin II has been shown to promote the migration, proliferation, and hypertrophy of vascular smooth muscle cells and increase the synthesis of extracellular matrix proteins by increasing the expression of specific proto-oncogenes and growth factors.

ACE INHIBITORS AND CARDIOVASCULAR RISK REDUCTION ACE inhibitors form the cornerstone of therapy for hypertension, particularly in patients with additional cardiovascular risk factors such as coronary heart disease, stroke, MI, heart failure, diabetes, or chronic kidney disease.14 However, ACE inhibitors have also been shown to reduce cardiovascular and overall mortality in patients at high risk for CVD, both due to and independent of their BP-lowering effects (Table I).2−8 The antiatherosclerotic effects of ACE inhibitors may be due to their ability to decrease coronary

Angiotensinogen

Kininogen Kallikrein

Renin Angiotensin I

Increased prostaglandin synthesis

Bradykinin Converting enzyme (kininase II)

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Angiotensin II

1 Inactive

2 Vasodilatation Vasoconstriction

Aldosterone secretion

Increased peripheral vascular resistance

Increased sodium and water retention

Decreased peripheral vascular resistance

Increased blood pressure

Decreased blood pressure

Figure 1. Sites of action of (1) angiotensin-converting enzyme inhibitors and (2) angiotensin II receptor blockers. Reprinted with permission from Benowitz NL. Antihypertensive agents. In: Katzung BG, ed. Basic & Clinical Pharmacology, Sixth Edition. Norwalk, Conn: Appleton & Lange; 1995. © 1995 The McGraw-Hill Companies, Inc. S19

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TABLE I. EVIDENCE FOR EFFICACY OF ACE INHIBITORS IN CARDIOVASCULAR RISK REDUCTION. Study

Drugs Evaluated

Patient Population

Primary End Point

Results

CONSENSUS, 19872

Enalapril 2.5–40 mg/d vs placebo

Severe CHF

6-Mo mortality

40% Reduction in mortality

SOLVD, 19913

Enalapril 2.5–20 mg/d

Reduced LVEF and CHF

Overall mortality

16% Reduction in mortality; 26% reduction in hospitalization for worsening HF

Val-HeFT, 19914

Enalapril 20 mg/d vs hydralazine 300 mg/d + isosorbide dinitrate 160 mg/d

Chronic CHF

2-Y mortality

28% Reduction in 2-y mortality

SAVE, 19925

Captopril vs placebo

LV dysfunction after MI

All-cause mortality

19% Reduction in all-cause mortality; 21% reduction in death from cardiovascular causes; 37% reduction in development of severe HF; 22% reduction in CHF requiring hospitalization; 25% reduction in recurrent MI

AIRE, 19936

Ramipril vs placebo

Evidence of HF after MI

All-cause mortality

27% Reduction in all-cause mortality; 19% reduction in death, severe/resistant HF, MI, or stroke

HOPE, 20007

Ramipril 10 mg/d vs placebo Perindopril 8 mg/d vs placebo

MI, stroke, or death from cardiovascular causes Cardiovascular death, MI, or cardiac arrest

22% Reduction in primary end point

EUROPA, 20038

High risk for CVD but no HF or LV dysfunction Stable CAD without HF

20% Risk reduction in primary end point

ACE = angiotensin-converting enzyme; CONSENSUS = Cooperative North Scandinavian Enalapril Survival Study; CHF = congestive heart failure; SOLVD = Studies of Left Ventricular Dysfunction; LVEF = left ventricular ejection fraction; HF = heart failure; Val-HeFT = Valsartan Heart Failure Trial; SAVE = Survival and Ventricular Enlargement; LV = left ventricular; MI = myocardial infarction; AIRE = Acute Infarction Ramipril Efficacy; HOPE = Heart Outcomes Prevention Evaluation; CVD = cardiovascular disease; EUROPA = EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease; CAD = coronary artery disease.

remodeling or counteract endothelial dysfunction in patients with cardiovascular risk factors.15,16 Several large, randomized, prospective studies2−6 of patients with varying degrees of left ventricular systolic dysfunction have shown that ACE inhibitors prevent or delay the progression of heart failure, decrease overall mortality, reduce the incidence of MI, and decrease the rate of hospitalization. In later studies, similar benefits of ACE inhibitors were demonstrated for patients without left ventricular dysfunction or heart failure who were at high risk for CVD. In the Heart Outcomes Prevention Evaluation (HOPE) study,7 the ACE inhibitor ramipril was studied in 9297 high-risk patients who had a history of coronary heart disease, stroke, peripheral vascular disease, or diabetes and ≥1 other risk factor for CVD (eg, hypertension, hypercholesterolemia, smoking, documented microalbuminuria). The primary outcome was a composite of MI, death from cardiovascular causes, or stroke. After 5 years, patients treated

with ramipril had significantly lower rates of death from cardiovascular causes, death from any cause, MI, stroke, revascularization procedures, heart failure, and complications related to diabetes in patients with diabetes at baseline. The reduction in cardiovascular risk was evident after 1 year and became significant at 2 years.7 Similarly, the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA)8 demonstrated the cardiovascular riskreduction benefits of the ACE inhibitor perindopril in patients with stable coronary disease and no apparent heart failure. In this study, treatment with perindopril 8 mg/d resulted in a 20% relative risk (RR) reduction in terms of the primary end point (cardiovascular death, MI, or cardiac arrest). These benefits were observed in all patient subgroups, including those with renal impairment, previous revascularization, or diabetes. The observed treatment benefits were consistent among high-risk, intermediate-risk, and low-risk patients.17−20 S20

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The HOPE and EUROPA studies confirm the cardiovascular benefits of ACE inhibitors in patients without heart failure or left ventricular dysfunction who were at high risk for CVD.

Although ACE inhibitors have a favorable tolerability profile, cough and angioedema—both of which are related specifically to ACE inhibition—may lead to poor compliance and discontinuation of therapy.

KEY POINT

KEY POINT

ACE inhibitors have been shown to

ACE inhibitors have a favorable tol-

reduce cardiovascular and overall

erability profile, but cough and an-

mortality in patients with and with-

gioedema—both of which are relat-

out left ventricular dysfunction or

ed specifically to ACE inhibition—

heart failure.

may lead to poor compliance and discontinuation of therapy.

ADVERSE EFFECTS OF ACE INHIBITORS In general, ACE inhibitors are very well tolerated and have a favorable adverse-event profile, with positive effects on insulin sensitivity and cholesterol and lipoprotein levels in high-risk patients. Common side effects include hypotension, cough, and angioedema.1 Hypotension may occur more frequently in patients with congestive heart failure, those being treated with multiple antihypertensive agents, or those undergoing therapy with diuretics.1 In these patient populations, ACE inhibitor therapy should be initiated at very low doses, or salt intake should be increased and diuretics withdrawn before beginning therapy.1 A bothersome dry cough occurs in 5% to 20% of patients treated with ACE inhibitors.1 This side effect is not dose related, occurs more frequently in women, and develops between 1 week and 6 months after initiating therapy.1 ACE inhibitor–induced cough is thought to be a result of accumulation of bradykinin, substance P, and/or prostaglandins in the lungs.1 In addition to converting angiotensin I to angiotensin II, ACE catalyzes the degradation of bradykinin, a peptide that stimulates the production of nitric oxide (NO) and prostaglandin I2 (PGI2). Hence, ACE inhibition leads to increased levels of bradykinin, NO, and PGI2. Dry cough leads to discontinuation of therapy in a significant portion of patients. In the HOPE trial,7 7.3% of patients in the ramipril group discontinued therapy because of cough compared with 1.8% in the placebo group. Angioedema occurs in only 0.1% to 0.2% of patients treated with ACE inhibitors but may require discontinuation of therapy.1 Angioedema is also thought to be due to accumulation of bradykinin.

ARBS AS AN ALTERNATIVE TO ACE INHIBITORS FOR CARDIOVASCULAR RISK REDUCTION As discussed, the primary source of angiotensin II is the conversion of angiotensin I by ACE. However, angiotensin II may also be produced by chymases and other non–ACE-dependent mechanisms. Thus, physiologically active concentrations of angiotensin II may persist despite therapy with ACE inhibitors. ARBs selectively block the AT1 receptor subtypes that mediate the deleterious effects of angiotensin II, potentially providing more thorough blockade of RAAS activity. In addition, ARBs are associated with less cough or angioedema as they do not directly affect ACE or its substrates.1 Like ACE inhibitors, ARBs have been shown to reduce cardiovascular risk and outcomes in patients with essential hypertension and left ventricular hypertrophy (LVH) and in patients with chronic heart failure (Table II).9–11

KEY POINT ARBs have been shown to reduce cardiovascular risk and outcomes in patients with essential hypertension and LVH and in patients with chronic heart failure.

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TABLE II. EVIDENCE FOR EFFICACY OF ARBS IN CARDIOVASCULAR RISK REDUCTION. Study LIFE, 20029

Drugs Evaluated Losartan vs atenolol

Patient Population Hypertension and LVH

Primary End Point Rate of primary cardiovascular events

Results BP reductions: 30.2/16.6 vs 29.1/16.8 mm Hg RR for primary end point: 0.87 reduction in incidence of new-onset diabetes

CHARMOverall, 200310

Candesartan 32 mg/d vs placebo

CHF

All-cause mortality

Reduction in cardiovascular deaths and hospital admissions for CHF

Val-HeFT, 200111

Valsartan 160 mg BID vs placebo

CHF

Mortality; combined mortality and morbidity (incidence of cardiac arrest with resuscitation, hospitalization for HF, receipt of IV inotropic or vasodilator therapy for at least 4 hours)

13.2% Reduction in combined mortality and morbidity end point

ARBs = angiotensin II receptor blockers; LIFE = Losartan Intervention For Endpoint; LVH = left ventricular hypertrophy; BP = blood pressure; RR = relative risk; CHARM = Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity; CHF = congestive heart failure; Val-HeFT = Valsartan Heart Failure Trial; HF = heart failure.

In the Losartan Intervention For Endpoint (LIFE) reduction in hypertension study,9 patients 55 to 80 years of age with essential hypertension and electrocardiographic confirmed LVH were randomized to once-a-day losartanor atenolol-based antihypertensive therapy for 4 years. Although BP reductions were similar in the 2 arms, losartan-based treatment was associated with a significantly lower rate of primary cardiovascular events (death, MI, or stroke) compared with atenolol-based treatment. In the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) trial,10 candesartan was compared with placebo in 3 groups of patients: those with left ventricular ejection fraction (LVEF) ≤40% receiving an ACE inhibitor therapy, those with LVEF ≤40% not receiving an ACE inhibitor because of intolerance, and those with LVEF >40%. More than half of the patients were also receiving C-blockers. Candesartan significantly reduced cardiovascular deaths and hospitalizations for heart failure across all populations studied. Among heart failure patients with LVEF ≤40% receiving ACE inhibitor therapy, addition of the ARB resulted in a 15% risk reduction versus placebo in the primary end point (cardiovascular death or hospitalization for heart failure). Among patients who were intolerant of ACE inhibitors, 33% of those randomized to candesartan experienced cardiovascular death or hospitalization for heart failure versus 40% of those randomized to placebo (unadjusted hazard ratio, 0.77 [95% CI,

0.67−0.89], P = 0.0004; covariate adjusted, 0.70 [95% CI, 0.60−0.81], P < 0.0001).21 The ARB valsartan has also been studied as a cardioprotective agent in patients with chronic heart failure.11 A total of 5010 patients were randomized to receive valsartan 160 mg or placebo twice daily in addition to their current prescribed heart failure therapies (ACE inhibitors, C-blockers, and/or aldosterone antagonists). The primary outcomes were mortality and the combined end point of mortality and morbidity (incidence of cardiac arrest with resuscitation, hospitalization for heart failure, or receipt of intravenous inotropic or vasodilator therapy for ≥4 hours). At follow-up, overall mortality was not significantly different between groups; however, in the valsartan arm, the incidence of the combined mortality and morbidity end point was 13.2% lower versus placebo (RR, 0.87; 97.5% CI, 0.77−0.97; P = 0.009). The effect was primarily due to the lower rate of hospitalizations for heart failure in the valsartan arm (13.8% vs 18.2%; P < 0.001). Significant improvements versus placebo were also observed with respect to New York Heart Association class, ejection fraction, signs and symptoms of heart failure, and quality of life (all, P < 0.01). THE ONTARGET STUDY The CHARM-Added trial22 found that the addition of an ARB to ACE inhibitor therapy reduced cardiovascular events and mortality in patients with chronic heart failS22

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ure. The ARB candesartan also reduced cardiovascular mortality in patients with heart failure who were intolerant of ACE inhibitors.21 However, it was not known whether the cardiovascular risk-reduction benefit of an ARB alone or in combination with an ACE inhibitor would be observed in patients without heart failure who were at risk for CVD. In addition, no prior randomized trial had directly compared the effects of an ARB with those of an ACE inhibitor in a high-risk patient population without heart failure. ONTARGET was designed to address these issues.12

KEY POINT ONTARGET was the first study to directly compare the efficacy of an ARB with an ACE inhibitor in reducing cardiovascular morbidity and mortality in a high-risk patient population without heart failure.

ONTARGET12 enrolled a high-risk population of patients with coronary, peripheral, or cerebrovascular disease or with diabetes and end-organ damage. Patients entered a 3-week, single-blind, run-in period in which they received ramipril 2.5 mg/d for 3 days, telmisartan 40 mg/d plus ramipril 2.5 mg/d for 7 days, and ramipril 5 mg/d plus telmisartan 40 mg/d for 11 to 18 days to assess tolerability to both agents. Following the run-in period, patients were randomly assigned to treatment with telmisartan 80 mg/d (n = 8542), ramipril 10 mg/d (n = 8576), or a combination of the 2 drugs (n = 8502). For the first 2 weeks, the dosage of ramipril was 5 mg/d, after which it was increased to 10 mg/d. Follow-up occurred at 6 weeks, 6 months, and every 6 months thereafter. The primary objective of the trial was to compare the ARB telmisartan with the ACE inhibitor ramipril with respect to reducing the composite outcome of death from cardiovascular causes, MI, stroke, or hospitalization for heart failure. A second objective was to determine whether the combination of telmisartan and ramipril would be superior to ramipril alone with respect to reducing the composite outcome. Secondary and other outcomes included the composite of death from cardio-

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vascular causes, MI, or stroke (primary outcome in the HOPE trial); new heart failure; new-onset diabetes; atrial fibrillation; dementia or cognitive decline; nephropathy; revascularization procedures; death from any cause or noncardiovascular causes; angina; transient ischemic attack; development of LVH; microvascular complications of diabetes; BP changes; and new cancers. A total of 25,620 patients underwent randomization after the initial run-in period. At a mean follow-up of 56 months, the incidence of the primary end point was not significantly different between the ramipril and telmisartan groups (16.5% vs 16.7%; RR, 1.01; 95% CI, 0.94−1.09). In the combination therapy group, the primary outcome occurred in 16.3% of patients (RR, 0.99; 95% CI, 0.92−1.07) (Figure 2).12 The incidence of the primary outcome was not significant between groups despite differences in systolic/diastolic BP reduction: –6.4/4.3 mm Hg, –7.4/5.0 mm Hg, and –9.8/6.3 mm Hg in the ramipril, telmisartan, and combination therapy groups, respectively. The rates of cough and angioedema were significantly higher in the ramipril group compared with the telmisartan group (cough: 4.2% vs 1.1%, P < 0.001; angioedema: 0.3% vs 0.1%, P = 0.01). Hypotensive symptoms occurred at a significantly higher rate in the telmisartan group (2.6% vs 1.7%; P < 0.001), while syncope occurred at comparable rates in the ramipril and telmisartan groups. The incidences of hypotensive symptoms, syncope, and renal dysfunction were significantly higher in the combination therapy group compared with the ramipril group (4.8% vs 1.7%, P < 0.001; 0.3% vs 0.2%, P = 0.01; 13.5% vs 10.2%, P < 0.001; respectively). These adverse events were consistent with the pattern of discontinuations. More patients receiving ramipril, either as monotherapy or with telmisartan, discontinued ramipril due to cough or angioedema than discontinued telmisartan alone. The results from ONTARGET suggest that the ACE inhibitor ramipril and the ARB telmisartan are equally effective in reducing the incidence of cardiovascular death, MI, stroke, and hospitalization for heart failure in patients without heart failure or left ventricular dysfunction but at high risk for CVD. These results confirm the value of angiotensin II blockade as a method of reducing cardiovascular risk in high-risk patients, including those with and without heart failure. Based on these findings, telmisartan is an effective alternative to S23

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Telmisartan Ramipril Telmisartan + ramipril

Cumulative Hazard Ratio

0.20

0.15

0.10

0.05

0 0

1

2

3

4

5

Years of Follow-Up No. at Risk Telmisartan Ramipril Telmisartan + ramipril

8542 8576

8177 8214

7778 7832

7420 7472

7051 7093

1687 1703

8502

8133

7738

7375

7022

1718

Figure 2. Kaplan-Meier curves for the telmisartan, ramipril, and combination therapy groups of ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) with respect to the primary composite outcome (death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure). Reprinted with permission from Yusuf S, Teo KK, Pogue J, et al, for the ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547−1559. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

ACE inhibitors for cardioprotection in high-risk patients. The choice of agent should be based on individual patient characteristics, anticipated compliance, and tolerability. The ongoing Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND)23 evaluated the efficacy of telmisartan as a cardioprotective agent specifically in high-risk patients without heart failure who are intolerant of ACE inhibitor therapy. Investigators concluded that telmisartan had no significant effect on the primary outcome of the study, although it did modestly reduce the risk of the composite outcome of cardiovascular death, MI, or stroke. Telmisartan was, however, well tolerated in patients unable to tolerate ACE inhibitors. In ONTARGET,12 it was hypothesized that the use of dual complementary mechanisms to inhibit angiotensin II activity (ie, ACE inhibition and AT1 receptor blockade) would improve cardiovascular outcomes compared with

KEY POINT The results of ONTARGET confirmed that inhibition of RAAS activity, using either an ACE inhibitor or an ARB, is an effective approach to reducing cardiovascular morbidity and mortality in patients without heart failure but at high risk for CVD.

use of either approach alone. However, combination therapy with ramipril and telmisartan did not confer any significant clinical benefit versus monotherapy with either agent, despite greater systolic/diastolic BP reduction of 2.4/1.4 mm Hg that persisted throughout the study S24

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period. Moreover, combination therapy was associated with a greater incidence of hypotensive symptoms and renal dysfunction compared with ramipril monotherapy. These results are similar to those obtained in the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial,24 in which the combination of valsartan and full doses of captopril did not reduce all-cause mortality compared with valsartan alone in patients who had had an acute MI complicated by left ventricular systolic dysfunction, heart failure, or both. As in ONTARGET, combination therapy was associated with a greater incidence of adverse events than was monotherapy with either agent. A post hoc analysis of the Valsartan Heart Failure Trial,11 which compared valsartan with placebo in patients with chronic heart failure, sheds some light on the surprising results of ONTARGET. In this analysis of concomitant background therapy, it was found that in the subgroup of patients taking an ACE inhibitor or a C-blocker, valsartan therapy had a modest beneficial effect in terms of morbidity. However, in patients taking both an ACE inhibitor and a C-blocker, valsartan had an adverse effect with respect to mortality and morbidity. Interestingly, valsartan conferred the greatest benefit for patients who were not taking an ACE inhibitor or a C-blocker. In ONTARGET,12 ~56% of patients in each of the randomization groups were taking C-blockers. It is possible that the potential benefits of combination ramipril-telmisartan therapy were blunted by concomitant C-blocker therapy. Future subgroup analyses of the ONTARGET data may help clarify the reasons for the unexpected findings of the study.

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any significant clinical benefit compared with monotherapy, despite the greater reduction in BP achieved with the former. The findings of ONTARGET support that either telmisartan or ramipril can be used safely to reduce cardiovascular outcomes in high-risk patients without heart failure, thus providing clinicians a broader armamentarium with which to combat CVD. ACKNOWLEDGMENTS The author would like to thank Viji Anantharaman for her writing and research assistance in the preparation of this manuscript. This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. REFERENCES 1. Jackson EK, Garrison JC. Renin and angiotensin. In: Hardman JG, Limbird LE, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, Ninth Edition. New York, NY: McGraw-Hill; 1996. 2. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429− 1435. 3. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325: 293−302. 4. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325:303−310. 5. Pfeffer MA, Braunwald E, Moyé LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992;327:669−677. 6. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821−828. 7. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients [published corrections appear in N Engl J Med. 2000;342:1376; N Engl J Med. 2000;342:748]. N Engl J Med. 2000;342:145−153. 8. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362: 782−788. 9. Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention

CONCLUSIONS ACE inhibitors and ARBs have been independently shown to be effective as cardioprotective agents in patients with and without heart failure, reducing the risk of cardiovascular mortality, MI, and stroke in these high-risk populations. ONTARGET was the first study to directly compare an ARB and an ACE inhibitor as a cardioprotectant in patients without heart failure or left ventricular dysfunction. In addition, the study evaluated whether a combination of an ARB and ACE inhibitor (telmisartan and ramipril) would be superior to monotherapy with either agent. The study found that telmisartan and ramipril were equally effective in reducing the risk of cardiovascular mortality and morbidity; surprisingly, combination therapy did not confer S25

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10.

11.

12.

13.

14.

15.

16.

17.

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For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet. 2002;359: 995−1003. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme. Lancet. 2003;362:759−766. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667−1675. Yusuf S, Teo KK, Pogue J, et al, for the ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358: 1547−1559. Benowitz NL. Antihypertensive agents. In: Katzung BG, ed. Basic & Clinical Pharmacology, Sixth Edition. Norwalk, Conn: Appleton & Lange; 1995. National Heart, Lung, and Blood Institute. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Institutes of Health, US Dept of Health and Human Services; 2003. Rodriguez-Granillo GA, de Winter S, Bruining N, et al, for the EUROPA/PERSPECTIVE Investigators. Effect of perindopril on coronary remodelling: Insights from a multicentre, randomized study. Eur Heart J. 2007;28: 2326−2331. Ceconi C, Fox KM, Remme WJ, et al, for the EUROPA Investigators; PERTINENT Investigators and the Statistical Committee. ACE inhibition with perindopril and endothelial function. Results of a substudy of the EUROPA study: PERTINENT. Cardiovasc Res. 2007;73: 237−246. Brugts JJ, Boersma E, Choncol M, et al, for the EUROPA Investigators. The cardioprotective effects of the angiotensin-converting enzyme inhibitor perindopril in patients with stable coronary artery disease are not modified by mild to moderate renal insufficiency: Insights from the EUROPA trial. J Am Coll Cardiol. 2007;50:2148−2155.

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18. Fox KM, Bertrand ME, Remme WJ, et al, for the EUROPA Investigators. Efficacy of perindopril in reducing risk of cardiac events in patients with revascularized coronary artery disease. Am Heart J. 2007;153:629− 635. 19. Daly CA, Fox KM, Remme WJ, et al, for the EUROPA Investigators. The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: Results from the PERSUADE substudy. Eur Heart J. 2005;26:1369−1378. 20. Deckers JW, Goedhart DM, Boersma E, et al. Treatment benefit by perindopril in patients with stable coronary artery disease at different levels of risk. Eur Heart J. 2006;27:796−801. 21. Granger CB, McMurray JJ, Yusuf S, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced leftventricular systolic function intolerant to angiotensinconverting-enzyme inhibitors: The CHARM-Alternative trial. Lancet. 2003;362:772−776. 22. McMurray JJ, Ostergren J, Swedberg K, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensinconverting-enzyme inhibitors: The CHARM-Added trial. Lancet. 2003;362:767−771. 23. Yusuf S, Teo K, Anderson C, et al, for the Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: A randomised controlled trial [published correction appears in Lancet. 2008;372:1384]. Lancet. 2008;372:1174–1183. 24. Pfeffer MA, McMurray JJ, Velazquez EJ, et al, for the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both [published correction appears in N Engl J Med. 2004;350:203]. N Engl J Med. 2003;349:1893− 1906.

Address correspondence to: Robert Guthrie, MD, Department of Emergency Medicine, The Ohio State University, 1380 Edgehill Road, Columbus, OH 43212. E-mail: [email protected] S26