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JOURNAL CLUB Based on the ONTARGET trial published in: N Engl J Med 2008 Apr 10;358(15):1547-59 and Presentations during the 57th Annual Scientific Sessions of the American College of Cardiology

Chicago, Illinois / March 29-April 1, 2008

BASED ON INTERVIEWS WITH:

Ellen D. Burgess, MD, FACP, FRCPC Professor, Department of Medicine Director, Hypertension Research Clinic University of Calgary Foothills Hospital Calgary, Alberta

Pierre Larochelle, MD, PhD, FRCPC Director, Clinical Research Institut de recherches cliniques de Montréal Université de Montréal Montreal, Quebec

Jonathan G. Howlett, MD, FACC, FRCPC Associate Professor of Medicine Dalhousie University Queen Elizabeth II Health Sciences Centre Halifax, Nova Scotia

ONTARGET Overview: Similarity of Efficacy and Safety

ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) demonstrated that an angiotensin receptor blocker (ARB) is as effective as an ACE inhibitor for the composite outcome of death from cardiovascular (CV) causes, myocardial infarction, stroke or hospitalization for heart failure. In the study, patients were randomized to an ARB, an ACE inhibitor or a combination of the two. After a median follow-up of 56 months, the event rates were nearly identical in all three study arms (16.7%, 16.5% and 16.3% for the ARB, ACE inhibitor and combination, respectively); however, the rate of adverse events was different. Although the combination was associated with more adverse events than either treatment alone, the ARB was better tolerated than the ACE inhibitor, including significantly lower rates of cough and angioedema.

ONTARGET, the largest comparison of an ARB and an ACE inhibitor yet conducted, randomized 25,620 patients aged =55 (average 66.5 years) with coronary, peripheral or cerebral vascular disease, or diabetes with end-organ damage to one of three treatment arms. At randomization, more than 80% had CV disease, almost 70% had hypertension and almost 40% had diabetes. The assigned treatment was added to optimal medical management, which included antiplatelet therapy in more than 80% of patients, statins in more than 60% and beta blockers in more than 50%. The study ARB was telmisartan and the ACE inhibitor was ramipril.

Although a run-in period excluded patients intolerant to the ACE inhibitor, tolerability remained significantly better in the group receiving an ARB. Consistent with previous studies that have associated ARBs with a side-effect profile comparable to placebo, the ARB, relative to the ACE inhibitor, produced lower rates of cough (1.1% vs. 4.2%; P<0.001) and angioedema (0.1% vs. 0.3%; P=0.01). Hypotensive symptoms did occur more commonly with the ARB than the ACE inhibitor (2.6% vs. 1.7%; P<0.001), but the combination group achieved slightly lower blood pressure (BP) levels (2.4/1.4 mm Hg greater reduction). Significant hypotensive side effects were uncommon in both groups and the rate of syncope (2.0%) was the same in both groups.

ONTARGET was intentionally designed to evaluate an ARB in the same population as HOPE (Heart Outcomes Protection Evaluation), which is credited for establishing BP-independent benefits for ACE inhibitors. According to ONTARGET senior investigator Dr. Salim Yusuf, Population Health Research Institute, McMaster University, Hamilton, Ontario, the study results confirm that an ARB may be used in place of an ACE inhibitor in first-line therapy for reducing CV risk in patients with vascular disease or diabetes.

Contrary to a second study hypothesis, however, dual renin-angiotensin system (RAS) inhibition with an ARB and an ACE inhibitor is not more efficacious than either alone for reducing the risk of CV events. Rather, without providing any added clinical protection despite a slightly greater BP reduction, the combination, relative to the ACE inhibitor, was associated with increased rates of hypotensive symptoms (4.8% vs. 1.7%; P<0.001), syncope (0.3% vs. 0.2%; P=0.03) and renal dysfunction (13.5% vs. 10.2%; P<0.001). However, substudy analysis yet to be completed may reveal an advantage for dual RAS inhibition for selected populations, such as those with left ventricular dysfunction or nephropathy.

The ONTARGET findings are important because current guidelines identify ARBs as an acceptable substitute for ACE inhibitors for those who are ACE inhibitor-intolerant, and confirm that ARBs can be considered first-line in CV risk management. Although senior investigator Dr. Yusuf was not ready to concede that results could be applied to all agents in the treatment classes studied, other experts maintained that these results could be applied to all well-studied ARBs relevant to all proven ACE inhibitors.

Protecting the Kidney to Prevent Cardiovascular Events: Current Strategies in the Context of ONTARGET

Viewpoint:

Ellen D. Burgess, MD, FACP, FRCPC

In patients with chronic kidney disease (CKD), the goals of antihypertensive treatment are to lower blood pressure, reduce the risk of cardiovascular (CV) disease and slow progression of kidney disease. While vascular events such as myocardial infarction and stroke are the cause of death in 40% of CKD patients, end-stage renal disease is the estimated cause of 15% to 19% of deaths associated with CKD. Moreover, deaths due to stopping dialysis or suicide are also common in this patient group. Angiotensin receptor blockers (ARBs) are already the preferred antihypertensive therapy for patients with type 2 diabetes and CKD on the basis of controlled trials showing renoprotection, but the new information from ONTARGET is that ARBs, which are better tolerated than ACE inhibitors, can be used first-line for the goal of reducing the risk of CV events in high-risk patients.

Results of the ONTARGET (Ongoing Telmisartan Alone and In Combination with Ramipril Global Endpoint Trial) were not unexpected. Although this was the largest direct comparison of an angiotensin receptor blocker (ARB) and an ACE inhibitor yet conducted, other published data have also indicated comparable protection against cardiovascular (CV) events. In data that became available in the summer of 2007, the UMPIRE study reported outcomes in patients over the age of 65 who received an ARB or an ACE inhibitor in a large Canadian database (Verma et al. J Am Soc Hypertens 2007;1:286-94). In this study, the largest population-based comparative evaluation of ARBs and ACE inhibitors, the odds ratio (OR) of hospitalization for an acute coronary syndrome (ACS) was lower but not significantly different among those receiving an ARB than those receiving an ACE inhibitor (OR 0.89; 95% CI 0.76-1.04). In a previous comparison of an ARB and an ACE inhibitor conducted in an acute myocardial infarction (MI) population, ARBs also achieved comparable protection against CV events relative to an ACE inhibitor (Pfeffer et al. N Engl J Med 2003;349(20):1893-906).

Renin-angiotensin system (RAS) inhibitors are indicated in chronic kidney disease (CKD) whether or not the patient has diabetes and whether or not the patient has hypertension. RAS inhibition slows CKD progression. On an evidence basis, current guidelines identify ACE inhibitors as the first-line choice for patients with type 1 diabetes and ARBs as the first-line choice for patients with type 2 diabetes, yet these recommendations are not based on comparisons but on single-agent trials demonstrating efficacy. Guidelines typically accept either type of RAS inhibitor as a substitute for another when tolerability or other issues make one choice more appropriate than the other.

The landmark trial with an ACE inhibitor showing protection against end-stage renal disease (ESRD) in patients with type 1 diabetes was conducted with captopril and published in 1993. Similar protection was observed in those with type 2 diabetes in a series of studies with ARBs. In RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan), one of the studies establishing ARBs as first-line therapies in diabetic nephropathy, the 28% reduction in ESRD (P=0.002) relative to placebo was substantially greater than that predicted by the modest differences in end-of-study blood pressure (BP) (140/74 mm Hg vs. 142/74 mm Hg). Similarly favourable BP-independent protection against diabetic nephropathy was observed in IDNT (Irbesartan in Diabetic Nephropathy Trial) and in IRMA II (Irbesartan Microalbuminuria Type 2 Diabetes in Hypertensive Patients), which evaluated an ARB for nephropathy prevention.

For protection against either CKD or CV disease, BP control should be considered the first priority in selection of an antihypertensive treatment strategy, but the expectation of BP-independent benefits has attracted particular interest in RAS inhibitors. The first and still one of the most compelling examples of BPindependent protection from CV events was the LIFE (Losartan Intervention For Endpoint Reduction) study, which compared the ARB losartan to the beta blocker atenolol for clinical event reduction in patients with left ventricular hypertrophy (LVH). Although BP reductions were comparable in the two groups, losartan was associated with a 13% greater reduction in the composite end point of death, MI or stroke. Losartan was also associated with a 25% (P=0.001) relative reduction in new-onset diabetes. In the placebocontrolled HOPE (Heart Outcomes Protection Evaluation), the 22% (P<0.001) reduction in the primary end point of MI, stroke or death from a CV cause for the ACE inhibitor ramipril was achieved despite the modest mean 3/2 mm Hg difference in end-of-study BP. Although the modest 4/3 mm Hg difference among patients with diabetes in the HOT (Hypertension Optimal Treatment) study resulted in a 50% reduction in CV events, MI and CV mortality, and demonstrated that even modest BP reductions may be important, it has been argued that at least some benefit in HOPE was BP-independent.

ONTARGET was largely designed to determine whether an ARB could provide the same benefit achieved with ramipril in HOPE. A third arm, testing the combination of an ARB and an ACE inhibitor, was added. In a population with vascular disease or high-risk diabetes, the ARB was found to provide comparable CV protection. For the primary composite end point of death from CV causes, MI, stroke or hospitalization for heart failure, there was no significant difference between any of the three study arms, but as expected, the study ARB telmisartan was better tolerated than the ACE inhibitor. The combination provided no additional benefit over either therapy alone but did increase the risk of adverse events relative to both.

From the perspective of a high-risk patient, these results indicate that an ARB is as effective as an ACE inhibitor for protection from CV events, but we do not yet have a breakdown for protection in patients with renal impairment. Results are awaited from substudies comparing strategies for protection from progressive nephropathy. The question of whether dual mechanisms of RAS inhibition, despite failing to show an advantage in the CV system, are better than monotherapeutic strategies for preventing or controlling proteinuria is of particular interest. Preliminary data from a Japanese study suggesting an additive benefit from dual RAS inhibition in slowing progression of nephropathy in patients without diabetes has led to empiric use of this combination by some clinicians. The soon-to-bereleased data from ONTARGET regarding relative protection against surrogate measures of progressive nephropathy, such as proteinuria, should help clarify this issue, but it is important to recognize that ONTARGET is a CV study. The relative effect of the treatment strategies on renal function was not a primary end point and cannot, therefore, be a definitive indication of relative benefits. From the perspective of preventing CKD, the companion TRANSCEND (Telmisartan Randomized Assessment Study in Ace Intolerant Subjects with Cardiovascular Disease) will be potentially more revealing for assessing renoprotection from an ARB, because proteinuria was an exclusion criterion in this study, allowing protection against initiation of nephropathy to be measured.

Large prospective trials such as ONTARGET permit objective comparisons useful for verifying or refuting hypotheses generated by retrospective data analyses. For example, ONTARGET provides a convincing rejection of the controversial assertion that ARBs may be associated with a relative increase in the risk of MI. This hypothesis, published in a peerreviewed journal, was highly criticized and subsequently dismissed because the authors chose to selectively evaluate data, but ONTARGET provides further supportive data. Conversely, the design of ONTARGET is likely to have blunted the safety advantage of the ARB relative to the ACE inhibitor. Due to a run-in period that excluded patients who did not tolerate ramipril, the relative differences in such side effects as cough and angioedema favouring the ARB were almost certainly lower than they would be in a real-world comparison.

In CKD, the benefit of RAS inhibitors is already established even in non-hypertensive individuals. In those with hypertension, reaching guideline BP targets should be achieved with a treatment strategy that includes a RAS inhibitor. However, it is essential to consider the treatment of CKD in the context of CV risk management. For preventing CV events, including MI and stroke, ONTARGET has now confirmed that an ARB offers BP-independent benefits in high-risk patients comparable to those previously established with ACE inhibitors. This is an important and reassuring finding and we now await outcome data in patients stratified by renal function.

Summary

ONTARGET provides evidence that ARBs are just as effective as ACE inhibitors in reducing the risk of vascular events in high-risk patients. Data from subpopulations with renal dysfunction are eagerly awaited. Although RAS inhibitors are first-line therapy to control CKD in both those with or without diabetes, control of nephropathy must be considered in the context of preventing CV events, an important cause of death in CKD patients. A direct comparison establishing comparable efficacy between an ARB and an ACE inhibitor for CV protection permits clinicians who prescribe an ARB in patients with type 2 diabetes and nephropathy to draw confidence that this choice is appropriate for renal and CV outcomes.

Blood Pressure-independent Effects in High-risk Patients: Relevance of ARB vs. ACE Inhibitor Comparison to Routine Hypertension Management

Viewpoint:

Pierre Larochelle, MD, PhD, FRCPC

In patients with essential hypertension, reaching target blood pressure (BP) is the fundamental goal. Although there is now evidence for greater risk reductions at the same BP control with different treatment strategies in high-risk patients, comparable data may never become available in low-risk patients due to a low rate of clinical events that makes a blinded prospective trial impractical. In the recently completed ONTARGET, which was conducted in patients who already have vascular disease, angiotensin receptor blockers (ARBs) were found to be as effective as ACE inhibitors for reducing a composite end point of death from cardiovascular causes, myocardial infarction, stroke or hospitalization from heart failure, but the combination of the ACE inhibitor and the ARB was no more effective and less well tolerated. The ability of renin-angiotensin system inhibitors to protect target organs, including the heart and the kidney, are reassuring when using these agents for BP control in low-risk patients. However, relative protection against events in latestage disease should not overshadow the primary goal of BP control in essential hypertension management.

Blood pressure (BP)-independent benefits from renin-angiotensin system (RAS) inhibitors were first established with ACE inhibitors and then largely reproduced by angiotensin receptor blockers (ARBs) in several specific settings, including acute myocardial infarction (MI), heart failure and diabetic end-stage renal disease. In HOPE (Heart Outcomes Protection Evaluation), which set the stage for ONTARGET (Ongoing Telmisartan Alone and In Combination with Ramipril Global Endpoint Trial), an ACE inhibitor was associated with a 22% reduction (P<0.001) in the composite end point of MI, stroke or death from cardiovascular (CV) causes relative to placebo despite only a modest additional reduction in BP. In the new ONTARGET comparison, which, like HOPE, was largely a secondary prevention trial, an ARB was compared to an ACE inhibitor for the same end point. The ARB was found to be as effective as the ACE inhibitor. Disappointingly, a third arm with a combination of an ARB and ACE inhibitor was no more effective but was less well tolerated.

Even though the ACE inhibitor in HOPE was not compared against an active control, the small difference in end-of-study BP in the two arms led to the conclusion by the investigators that a substantial proportion of the clinical benefits observed in that study were BP-independent. In the new comparison of the ACE inhibitor to the ARB, a similar degree of benefit was achieved in a comparable high-risk population with an ARB. The ability of RAS inhibitors to provide some BP-independent benefit is consistent with evidence that upregulated RAS is one of the mediators of vascular and cardiac hypertrophy, cardiac remodelling and renal insufficiency. While BP control is of major importance as a benefit of RAS inhibitors, the additional effects of RAS inhibitors are likely to contribute to the event rate reductions associated with ACE inhibitors and ARBs in heart failure, acute MI and renal impairment.

In low-risk patients, BP-independent protection of target organs is more difficult to demonstrate. In addition to the considerable expense of a study large enough and of sufficient duration to demonstrate a difference in clinical events among antihypertensive drugs with different mechanisms of action, there is the added challenge of controlling for other modifiable risk factors, such as hyperlipidemia or insulin resistance over the period of study. However, relative differences between strategies achieving the same BP control have been demonstrated in patients with mainly primary prevention, most notably in the LIFE (Losartan Intervention for Endpoint Reduction) trial. In contrast to the HOPE and ONTARGET study populations, of which about one-third did not have hypertension at entry, LIFE randomized patients with essential hypertension to the ARB losartan or the beta blocker atenolol. Although LIFE patients were at high risk due to an inclusion criterion of left ventricular hypertrophy (LVH), this was mainly a primary prevention study even though 30% of patients had a prior history of CV disease. In the study, patients were randomized to either a beta blocker-based strategy, which was considered a first-line antihypertensive agent at the time, or to an ARB-based strategy. At the end of the study, those randomized to the ARB-based strategy had a 13% reduction (P=0.021) in the composite end point of death, MI or stroke relative to those in the beta blocker-based arm.

Other primary prevention studies have also suggested BP-independent differences in clinical benefit between antihypertensive strategies. In the BP-lowering arm of ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), patients randomized to the amlodipine-based regimen had had a 33% reduction (P=0.0003) in fatal and non-fatal stroke relative to those randomized to the atenolol-based regimen. Although the 10% reduction (P=0.1) in the primary end point of non-fatal MI and fatal coronary heart disease did not reach statistical significance, the data safety monitoring committee stopped the trial prematurely due to concern about an excess benefit in the arm randomized to the calcium channel blocker (CCB) strategy.

Regarding practical application of these findings, it is important to remember that all clinical end point studies, including LIFE, are best characterized as comparisons of treatment strategies than of single agents. In LIFE, the initial randomization was to losartan or a beta blocker, but the majority of patients in both arms received a second antihypertensive agent, usually a diuretic, to reach BP targets. In ASCOTBPLA, the initial randomization was to a CCB or a beta blocker, but a second agent was prespecified for both arms. In the amlodipine arm, this second agent was the ACE inhibitor perindopril and in the atenolol arm, the second agent was a diuretic. Again, most participants in ASCOT-BPLA received at least two agents and a third agent was allowed if needed to attain BP control in both LIFE and ASCOT-BPLA.

The importance of BP control as an essential starting point in comparing treatment strategies was possibly illustrated by VALUE (Valsartan Antihypertensive Long-term Use Evaluation), which was also designed to compare BP-lowering strategies for relative CV protection in high-risk patients. Contrary to the study hypothesis, this study did not show any greater protection against cardiac morbidity and mortality for an ARB-based strategy relative to a CCBbased strategy, but the study also failed to produce comparable BP lowering in the study arms. Due to the titration scheme, BP was consistently lower on the CCB-based strategy. The difference was particularly marked during the first six months of the study. While VALUE produced a negative result for the study hypothesis, it is perhaps notable that the ARB-based arm achieved similar protection for the primary composite cardiac end point against events despite the potential disadvantage of less effective BP lowering. There were some differences in the predetermined secondary end points.

In Canadian hypertension guidelines, the acceptable first-line single-agent therapies for uncomplicated hypertension are a beta blocker in patients <60 years, an ACE inhibitor, a long-acting CCB, a diuretic or an ARB. The addition of an ARB to first-line management was largely based on results of the LIFE study associating a losartan-based therapy with benefit in primary prevention. However, the guidelines also state that most patients will require a combination treatment to reach treatment goals. RAS inhibitors are an attractive part of a combination in low-risk patients because they are effective for BP control. Although it is difficult to demonstrate BP-independent benefits in uncomplicated essential hypertension, it is reasonable to speculate that target organs in these individuals undergo or will undergo the same disease progression characteristic of advanced pathology. Evidence of target organ protection from RAS inhibitors is found in such surrogates as protection against left ventricular hypertrophy, but proof of a reduction in clinical events relative to other options may never be obtained from a prospective study.

In low-risk patients with essential hypertension, this comparison of an ARB and an ACE inhibitor in ONTARGET will not directly alter therapeutic choices, but the evidence that ARBs are as effective as ACE inhibitors in preventing CV disease in late-stage disease is reassuring. ARBs have already been identified as an acceptable first-line therapy in Canadian guidelines for essential hypertension, and the evidence that they are as effective as ACE inhibitors in late-stage disease is an important new piece of information. Relative to ACE inhibitors, ARBs are better tolerated in some patients because of less cough, which can be a significant advantage for a chronic therapy to which compliance is essential for clinical benefit.

Summary

The relevance of the recent ARB-vs.-ACE inhibitor comparison to the management of essential hypertension is indirect. Despite the large body of evidence that RAS inhibitors offer target organ protection independent of BP control, including those with established vascular disease, the priority in the treatment of uncomplicated hypertension is BP control. Of first-line therapies, a RAS inhibitor is an attractive choice, alone or in combination, in order to achieve target BP reductions.

ONTARGET in Context: Evaluating ARBs and ACE Inhibitors for Preventing Cardiovascular Events

Viewpoint:

Jonathan G. Howlett, MD, FACC, FRCPC

In high-risk patients, a newly completed trial has demonstrated that angiotensin receptor blockers (ARBs) and ACE inhibitors are equivalent for preventing cardiovascular events. Although the most recent study is not the first to show comparable efficacy between the two available types of inhibitors of the renin angiotensin system, it is the largest trial yet conducted. The recent study enrolled patients with vascular disease or high-risk diabetes (but no heart failure). A previous large multicentre trial published four years ago demonstrated similar results in patients treated after an acute myocardial infarction. In both studies, the ARB was as effective as the ACE inhibitor, which was the standard. In both studies, the combination of an ARB and an ACE inhibitor did not further reduce risk but did increase the risk of adverse events when compared to either agent alone. Until now, ARBs have been identified in many guidelines as acceptable substitutes for ACE inhibitors in high-risk patients. These data indicate that both ACE inhibitors and ARBs may now be considered as first-line treatment.

In ONTARGET (Ongoing Telmisartan Alone and In Combination with Ramipril Global Endpoint Trial), the largest and most recent study to compare angiotensin receptor blockers (ARBs) to ACE inhibitors, the agents were equivalent for the primary composite outcome of death from cardiovascular (CV) causes, myocardial infarction (MI), stroke or hospitalization for heart failure. For preventing major CV events in high-risk patients, ONTARGET establishes that ARBs and ACE inhibitors can be considered equally effective. However, there was a difference between the drugs for adverse events. The ARB telmisartan was associated with a lower risk of cough and angioedema than the ACE inhibitor ramipril. Overall, the data suggest that both compounds are excellent choices for risk management in patients who have vascular disease or high-risk diabetes.

A Long History of Evidence in CV Protection

The study of renin-angiotensin system (RAS) inhibitors for blood pressure (BP)-independent benefits began with a series of ACE inhibitor studies in patients with a low ejection fraction, such as those in heart failure, or with acute MI. In patients with left ventricular ejection fraction (LVEF) <35%, the landmark studies were CONSENSUS (Cooperative New Scandinavian Enalapril Survival Study) and SOLVD (Study of Left Ventricular Dysfunction), both of which associated an ACE inhibitor with prevention of clinical events. A subsequent group of studies, led by SAVE (Survival and Ventricular Events), associated ACE inhibitor therapy with protection from clinical events in patients with acute MI and depressed LVEF. In SAVE, the ACE inhibitor captopril was associated with a 19% (P=0.019) reduction in total mortality, a 25% reduction in recurrent MI (P=0.015) and a 37% reduction in the risk of progressive heart failure (P<0.001) relative to placebo. Similar results using different ACE inhibitors were generated by AIRE (Acute Infarction Ramipril Efficacy) and TRACE (Trandolapril Cardiac Evaluation). ACE inhibitors were then evaluated in acute MI patients without regard to the presence of heart failure or a low LVEF. Again, in such studies as GISSI-3 (the third Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico) and ISIS-4 (the fourth International Study of Infarct Survival), ACE inhibitors reduced the risk of clinical events relative to placebo despite modest or no differences in BP.

The reductions in recurrent MI and other vascular events in the heart failure and acute MI populations led to HOPE (Heart Outcomes Protection Evaluation), a large vascular prevention study in high-risk patients without heart failure or recent MI. HOPE was the first multicentre, placebo-controlled study to examine the effects of a RAS inhibitor, ramipril, compared to placebo in a non-acute MI high-risk population. In this 9000- patient study, ramipril use was associated with a 26% reduction (P<0.001) in death from CV causes, a 20% reduction in MI (P<0.001), a 32% reduction in stroke (P<0.001) and a 14% reduction in death from any cause (P=0.005). The reduction in events was achieved despite a modest reduction in BP, leading many to speculate that a portion of the benefits may be attributable to BP-independent effects of ACE inhibitors. Until ONTARGET, it was not known whether ARBs or ACE inhibitors would have comparative effects in this highrisk vascular population. Another important aspect of these trials was that patients were not required to be hypertensive at study entry. Although almost 70% of the ONTARGET participants did have a history of hypertension, the average systolic BP at study entry was very close to 140 mm Hg.

ACE Inhibitors and ARBs: Exploring Equivalency and Combination Strategies

The first evidence that ARBs were comparable to ACE inhibitors for CV risk reduction was generated by VALIANT (Valsartan In Acute Myocardial Infarction Trial), which compared high-dose valsartan to the same captopril regimen used in the SAVE study. In addition, the combination of both medications was compared with captopril in a third arm, in order to determine if further benefits would be seen. The 15,000-patient VALIANT trial was conducted in patients with either LVEF <40% or clinical heart failure immediately following acute MI. The results showed valsartan to be non-inferior to captopril; it was the first large study to show this. The combination was not more effective than either drug alone, but it did increase the risk of adverse events.

However, even prior to VALIANT, the landmark LIFE (Losartan Intervention for Endpoint Reduction) trial was the first to show one antihypertensive agent to be more efficacious than another for CV risk protection at the same BP control. In LIFE, the ARB losartan provided a 13% reduction (P=0.021) in the composite end point of death, MI or stroke relative to atenolol in a group of hypertensive patients with left ventricular hypertrophy. In addition to the composite primary end point, those randomized to losartan also had a 25% reduction (P=0.001) in risk of stroke as well as a significant reduction in the risk of new-onset diabetes. While the LIFE study was the first to demonstrate the improved efficacy of RAS-containing BP control regimens, others now exist. The most prominent published study is ASCOT-BPLA (Anglo-Scandinavian Cardiovascular Outcomes Trial – Blood Pressure Lowering Arm). Again, the arm containing a RAS inhibitor, in this case an ACE inhibitor, was more efficacious for reducing the risk of CV events when compared to the arm without a RAS inhibitor.

To date, there appears to be only two clinical situations where combination ACE inhibitor and ARB therapy provide potential benefit. These are heart failure and chronic kidney disease (CKD), although a clear reduction in CV clinical end points has not yet been proven for either indication. In heart failure, which was an exclusion criterion for ONTARGET, perhaps the strongest evidence of benefit from dual RAS inhibition was generated by CHARM-Added (the addition of candesartan for patients already receiving an ACE inhibitor in the Candesartan in Heart failure: Assessment of Reduction in Mortality program). In CHARM-Added, an ARB and ACE inhibitor were associated with a 15% further reduction (P=0.01) in the composite end point of CV death or hospital admission for heart failure over an ACE inhibitor alone. In CKD, several studies have demonstrated that the combination is more antiproteinuric than either monotherapy. The clinical data for both indications suggest that a certain minimum risk must be present before two mechanisms of RAS inhibition leads to further end point reduction. ONTARGET, which includes a substudy evaluating relative effects of the three tested strategies on renal function, is expected to generate data with which to further consider this issue.

Current and Future Implications of ONTARGET Findings

In practical terms, the evidence that an ARB is as effective as an ACE inhibitor is an important finding. ARBs are better tolerated than ACE inhibitors, facilitating compliance. Ultimately, effective medicines are ineffective if not taken on the schedule associated with benefit, and ARBs have a tolerability profile that has been comparable to placebo. Outside of a clinical trial for a therapy that is to be taken indefinitely, a relative tolerability advantage should not be underestimated.

The aggregate of data support the concept that RAS inhibition is achieved to a comparable degree and with a comparable clinical benefit whether generated by ARBs or ACE inhibitors. Despite the differences in the mechanisms by which they inhibit the RAS, which have led to a number of theories regarding the potential for differences in effect, there are no strong data yet to suggest differences within and between these classes. It is appropriate for clinicians to prescribe specific agents with which they are familiar, but the expectation is that either ARBs or ACE inhibitors can be used first-line in several settings, including acute MI and in high-risk patients. Although HOPE and ONTARGET are largely secondary prevention trials, whereas LIFE randomized patients without a prior CV event, there are now clinical end point data across a broad spectrum of at-risk populations.

The data available to date do not answer all questions regarding the relative utility of ARBs and ACE inhibitors in preventing clinical events. In this summary, several issues were identified, such as the potential differences between single and dual RAS inhibition in specific risk groups, which have not yet been satisfactorily resolved. In addition, further data from ONTARGET may be revealing or at least hypothesis-generating about the relative role of these agents for very specific end points, such as relative protection from stroke, diabetes or proteinuria, particularly in context of any differences in BP control. However, the conclusion that both ACE inhibitors and ARBs can be considered first-line therapy for CV risk reduction is of immediate clinical relevance.

Summary

The ONTARGET study has expanded the evidence that ARBs can be considered a first-line option for providing protection against CV events in high-risk patients. The study has added more than 25,000 patients to an already sizeable data pool demonstrating that ARBs are as effective as ACE inhibitors in providing CV risk reductions independent of BP lowering. Despite unique mechanisms of action, ARBs and ACE inhibitors do not appear to have additive benefit in the high-risk population evaluated in ONTARGET. While previous landmark ARB studies, such as LIFE, have suggested that CV risk protection is not the same for antihypertensive agents at the same BP control, ONTARGET confirms that both ACE inhibitors and ARBs can be used first-line in high-risk patients. -