Combination ACE Inhibitor and Angiotensin Receptor Blocker Therapy—Future Considerations

Abstract

Angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers are regularly prescribed for the management of hypertension. Each of these drug classes has also been shown to provide survival benefits for patients with heart failure, proteinuric chronic kidney disease, and/or a high cardiac risk profile. The individual gains seen with each of these drug classes have led to speculation that their combination might offer additive if not synergistic outcome benefits. The foundation of this hypothesis, although biologically possible, has thus far not been sufficiently well proven to support the everyday use of these 2 drug classes in combination. Additional outcomes trials, which are currently proceeding to their conclusion, may provide the necessary proof to support an expanded use of these 2 drug classes in combination.

Inhibition of the renin‐angiotensin system (RAS) by administration of either an angiotensin‐converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) similarly reduces blood pressure (BP) in hypertensive patients. ¹ Both ACE inhibitors and ARBs also slow the progressive decline in renal function that marks renal injury, particularly in patients with diabetic nephropathy. ² , ³ , ⁴ The renoprotective effects of these drugs relate, in part, to their capacity to moderate protein excretion. ⁵ , ⁶ Both ACE inhibitor and ARB therapy also decrease the cardiovascular event rate in high‐risk cardiac patients. ⁷ , ⁸ , ⁹ , ¹⁰ Moreover, ACE inhibitors and ARBs are both of proven benefit in systolic forms of heart failure (HF). ¹¹ , ¹²

The unrelenting search for better combination therapies quickly settled on ACE inhibitors and ARBs as a particularly desirable combination since several lines of evidence had suggested that these agents are additive in their actions. Instinctively, the combination of an ACE inhibitor and an ARB seemed destined for considerable therapeutic success in light of the pervasive involvement of the RAS in disease initiation and progression. Of the available studies in hypertension, however, where an ACE inhibitor has been given with an ARB, the observed results have generally shown minimal additivity, with typically inconsistent and poorly generalizable findings. ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ Alternatively, the studies of combination ACE inhibitor and ARB therapy in proteinuric chronic kidney disease (CKD) have shown more consistent findings, particularly as relates to providing an incremental benefit in reducing protein excretion. ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ The same can be said for combination therapy in HF, where the addition of an ARB to an ACE inhibitor affords symptomatic benefit in addition to improving outcomes above and beyond what is seen with ACE inhibitor therapy alone. ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ , ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹

The present review summarizes the pathobiologic basis for combined use of ACE inhibitors and ARBs, describes the results of available clinical trials in this area, and addresses outcomes studies that may establish (or not) whether combination therapy offers cardiovascular benefits beyond what is seen with ACE inhibitor therapy alone.

BACKGROUND

Experimental Basis for Combining an ACE Inhibitor and an ARB

The pharmacologic actions of both ACE The pharmacologic actions of both ACE inhibitors and ARBs have been well characterized. BP reduction and/or tissue‐based protection, achieved through interruption of the RAS, relates specifically to the distinctive pharmacodynamic effects of either an ACE inhibitor or an ARB. ⁶² , ⁶³ Factors that have some bearing on the final response to either of these drug classes include drug half‐life, the phenomenon of angiotensin II (Ang‐II) escape, and/or interruption of the short feedback loop, which increases upstream components of the RAS—so‐called reactive hyperreninemia. ⁶³

At the outset of therapy with an ACE inhibitor, both circulating and tissue concentrations of Ang‐II fall. This drop in Ang‐II concentrations is not unexpected, given that ACE inhibition per se prevents the enzymatic conversion of Ang‐I to Ang‐II. On the other hand, with long‐term ACE inhibitor treatment there is a gradual return of circulating and tissue Ang‐II concentrations to pretreatment levels, a process termed angiotensin II escape. ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ One suggested explanation for Ang‐II escape focuses on the ability of tissue‐based enzymes, such as chymase, cathepsin G, and chymostatin‐sensitive angiotensin‐generating enzyme to generate Ang‐II from any of a diverse group of peptide substrates. ⁶⁸ Because this mode of Ang‐II generation is independent of ACE, it can go on in an unbridled fashion despite the presence of an ACE inhibitor.

These alternate, non–ACE‐dependent pathways for production of Ang‐II can upregulate in the face of chronic ACE inhibition, although the exact stimulus for this has not been identified. ⁶⁹ In addition, ACE activity increases in damaged tissues, such as atheromatous lesions that have undergone angioplasty, and this usual pathway for production of Ang‐II goes incompletely suppressed even with high‐dose ACE inhibitor therapy. ⁷⁰ , ⁷¹ The relevance of Ang‐II escape is unclear. In the treatment of hypertension and HF there is scant evidence to support a role for Ang‐II escape in disabling the response to an ACE inhibitor. ⁶³ , ⁷² If Ang‐II escape with an ACE inhibitor is ever to be truly relevant to clinical practice, it will be on the basis of sub‐optimal tissue protection, a process that cannot be easily quantified.

ACE doubles as kininase‐II, which controls the proteolytic breakdown of bradykinin and similar small vasoactive peptides. For that reason, ACE inhibition inhibits the breakdown of bradykinin, which then promotes release of the potent vasodilator nitric oxide via activation of the endothelial based B₂ receptor. It is generally accepted that at least part of the BP lowering seen with ACE inhibition is mediated by bradykinin. ⁷³ ARBs do not affect bradykinin by the ACE degradative pathway, which is an action that sets ACE inhibitors apart from ARBs. Alternatively, Ang‐II type 2 receptor stimulation, as occurs with ARB therapy, can increase renal interstitial fluid bradykinin concentrations—a process potentiated by coadministration of an ACE inhibitor. ⁷⁴ , ⁷⁵

Interpretive Consideration in Combining ACE Inhibitors and ARBs

The basis for combining an ACE inhibitor with an ARB is to arrive at a therapeutic outcome better than that seen with either drug alone. There are, however, interpretive pitfalls with this drug combination when viewed simply as one drug being added to the other. Understanding the response to the combination of an ACE inhibitor and an ARB requires that some consideration be given to the pharmacology of individual class members, time of day of dosing, the dosing sequence effect, and/or the timing of response ascertainment.

There are close to 2 dozen ACE inhibitors and ARBs on the world market. Drugs within each of these classes have differing durations of action; thus, the combination of a short‐acting ACE inhibitor such as enalapril with a long‐acting ARB such as telmisartan can result in a greater end‐of‐day response. This can be mistaken for an additive response when in point of fact it may simply represent a more enduring response to a prolonged half‐life compound. As such, when the ACE inhibitor and ARB given are both long‐acting, there does not appear to be significant additivity in how the combination reduces BP. ²¹ The timing of drug administration should also be taken into account in assessing a combination therapy response. As such, giving an ACE inhibitor and an ARB at separate times may prove more effective than giving both medications simultaneously. This approach may, however, differ little from split‐dosing a single agent.

The sequence in which these medications are given may dictate the final BP and/or antiproteinuric response. ³⁸ The decrease in BP that occurs with an ACE inhibitor is linked to both a reduction in Ang‐II levels and a variable increase in bradykinin effect. ⁶³ If the latter is an important contributor to BP reduction, then adding the ARB after the ACE inhibitor may have minimal effect, whereas the reverse order of treatment may offer an additional mechanistic basis for BP reduction. The same sequencing effect could apply to the BP‐independent effects of combination therapy. Finally, if a response occurs to an ACE inhibitor and ARB combination, then its timing can provide mechanistic insight. For example, if BP drops shortly after adding one drug to the other, a direct pharmacokinetic/pharmacodynamic effect seems likely. If a response takes several weeks to arise, then the combination of these drugs may have accelerated vascular remodeling more so than if either drug had been given alone—a process that might have occurred, however, with simple dose titration of one or the other of these medication classes. Thus, exploring the dose‐response curves of an ACE inhibitor and ARB combination is a prerequisite to determining whether true additivity exists. ¹⁹ , ³⁷

CLINICAL TRIALS

Hypertension

The efficacy of both ACE inhibitors and ARBs as antihypertensive agents is unquestioned. ¹ , ⁶³ In head‐to‐head comparisons, ACE inhibitors and ARBs reduce BP similarly. ¹ In contradistinction to the considerable information on monotherapy with these drug classes, there is limited information about the BP‐lowering effects of combined ACE inhibitor and ARB therapy. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ⁴⁹ Of the currently published trials, many are poorly generalizable in that they have been too short, studied only a small sample of patients without an adequate racial or age diversity, and/or did not use medication doses commonly employed in clinical practice. Moreover, in most instances there has been a failure to compare ACE inhibitor and ARB therapy to more traditional standard‐of‐care combinations. ²⁰ In interpreting the BP response to ACE inhibitor and ARB combination therapy, it should also be recognized that a high‐sodium diet blunts the antihypertensive effect of such therapy. ¹³ , ¹⁸

In one such example, 20 patients received monotherapy with a submaximal dose of benazepril (20 mg/d) for a total of 6 weeks. If average awake ambulatory diastolic BPs remained >85 mm Hg, subjects were randomized to either a submaximal dose of valsartan (80 mg/d) or matching placebo in a blinded manner for an additional 5 weeks, while continuing to receive background benazepril at the same dose. Patients then crossed over to the alternative regimen for a second 5‐week period. Valsartan added to benazepril reduced BP by 6.5±12.6/4.5±8.0 mm Hg (systolic/diastolic) and 7.1±9.4/5.6±6.5 mm Hg (over placebo) for average awake and nocturnal BPs, respectively. ¹⁶

Another example of why it is difficult to interpret the literature on combination ACE inhibitor and ARB therapy can be seen in an 8‐week, open‐label experience trial assessing the impact of adding the ARB candesartan cilexetil (dose range, 16–32 mg) in 473 patients receiving ACE inhibitor monotherapy. ¹⁵ The incremental reduction in BP with the addition of candesartan to an ACE inhibitor was 15.3/10.0 mm Hg, which at first appears to be a dramatic response. These studies, however, were neither placebo‐controlled (which would increase the likelihood of expectation bias) nor was the ACE inhibitor dose in any way standardized (making pretreatment ACE inhibitor underdosing a possibility). ¹⁵

There appears to be little reason to consider the use of an ACE inhibitor in combination with an ARB in the patient with stage I hypertension, since most patients will achieve goal BP with monotherapy (with either of these drug classes) or with addition of a diuretic to either drug class. Overall, a recent meta‐analysis of studies examining the combination of an ACE inhibitor and an ARB found that ambulatory BP was reduced by 4.7/3.0 mm Hg compared with ACE inhibitor monotherapy and fell by 3.8/2.7 mm Hg compared with ARB monotherapy. ²¹ These changes in BP are of an insufficient magnitude to justify use of these 2 classes of drugs as preferred 2‐drug therapy. In that regard, a recent study compared the additional BP reduction with a diuretic (chlorthalidone 12.5 mg/d), an ACE inhibitor (benazepril 20 mg/d), and a calcium channel blocker (amlodipine 5 mg/d) in patients with ambulatory BP not controlled by valsartan (160 mg) monotherapy. It was observed after 5 weeks of treatment that the additional BP reduction was: benazepril (reduction of 8.6±8.8/6.3±6.7 mm Hg), amlodipine (reduction of 15.2±12.9/9.9±6.8 mm Hg), and chlorthalidone (reduction of 13.5±11.6/9.5±7.7 mm Hg). ²⁰

Existing studies also fail to resolve the issue of whether these drug classes should be more routinely combined in the management of the complex hypertensive patient when an ACE inhibitor or ARB is being added to 3‐ or 4‐drug regimens, which already have one or the other of these drug classes in place. ¹⁷ Additional studies are needed to determine whether there are subgroups of hypertensive patients that are particularly responsive to the combination of an ACE inhibitor and an ARB.

Renal Disease

The combination of an ACE inhibitor and an ARB has been occasionally used in progressive CKD, seeking an antiproteinuric effect beyond that seen with a single agent. ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ The effect of combination therapy on protein excretion has been explored in a number of studies. For example, in a study of normotensive patients with biopsy‐proven IgA nephropathy and nonnephrotic proteinuria, the combination of losartan and an ACE inhibitor produced a 73% reduction in protein excretion (ACE inhibitor, 38%; losartan, 30%). In this study, no further reduction in proteinuria was seen with a doubling in the dose of either agent. The observed change could not be explained by either a decline in systemic BP or a fall in creatinine clearance and occurred within 4 weeks of beginning combination therapy. ²⁶

Recently, the Candesartan and Lisinopril Microalbuminuria (CALM) study ²⁵ yielded similar observations. This study evaluated the effect of combining candesartan and lisinopril (each given at one half the usual maximal dose) on microalbuminuria in 199 patients with type 2 diabetes. In this study, the reduction in the urine albumin/creatinine ratio with the combination of candesartan (16 mg/d) and lisinopril (20 mg/d) was significantly greater (50% decrease) than that observed with either agent alone (24% and 39% decrease with candesartan and lisinopril, respectively). As can be the case with combination therapy, BP values were somewhat lower than those obtained with either agent alone. After 24 weeks of therapy, diastolic BP was reduced to a greater degree with combination therapy (16.3‐mm Hg reduction) than with either candesartan (10.4‐mm Hg reduction) or lisinopril (10.7‐mm Hg reduction) alone.

The importance of BP reduction in considering the additive antiproteinuric effects of combination therapy cannot be overstated. ²³ , ²⁴ , ²⁵ , ²⁷ , ⁴⁰ , ⁴² , ⁴³ , ⁴⁶ The link between BP reduction and the antiproteinuric effect of combination therapy may go unnoticed if only office‐based values are relied on, as these can have a high degree of variability. ⁴² , ⁴³ A recent study by Russo et al ²⁷ found no correlation between office trough BP measurements and the antiproteinuric effect of the combination of enalapril and losartan. On the other hand, there was a highly correlated relationship between mean ambulatory BP values and the extent to which urinary protein excretion fell.

Insight into the potential mechanism(s) of the additive antiproteinuric effect with combination therapy can be obtained from a series of recent studies that explore combination therapy‐related changes in growth factors, neurohormones, and renal hemodynamics. ²³ , ³³ , ⁴³ , ⁶⁷ , ⁷⁶ In the interpretation of the renal effects of combination therapy, it must be appreciated that the components of the tissue‐specific RAS are highly compartmentalized within the kidney. ⁷⁷ As such, renal tissue ACE may not be inhibited by plasma concentrations of ACE inhibitors that are achieved with currently used doses. Consequently, renal Ang‐II formation may proceed in an unchecked fashion despite ACE inhibitors being given in doses that maximally reduce BP.

Agarwal et al ³³ observed increased urinary levels of the profibrogenic cytokine transforming growth factor‐β₁ in proteinuric patients with CKD, despite high‐dose ACE inhibition (lisinopril 40 mg/d). The elevated levels of transforming growth factor‐β₁ declined by 38% after 1 month of add‐on therapy with losartan (50 mg/d), an alteration independent of changes in BP and/or mean urinary protein excretion. ³³ Komine et al ⁶⁷ have also shown that the renal production of Ang‐II is more completely suppressed when losartan is added to captopril. Other studies have shown a considerable reduction in plasma aldosterone concentrations beyond that observed with either an ACE inhibitor or an ARB alone. ³⁹ Campbell et al ³⁷ have also shown that the additive antiproteinuric response with combination therapy is marked by further reductions in renal vascular resistance but no change in glomerular permselectivity as determined by dextran sieving. ³⁷ Finally, Delles et al ⁷⁶ have shown that 1 week of treatment with the combination of submaximal amounts of enalapril (10 mg) and eprosartan (300 mg) increased renal plasma flow by a nitric oxide–dependent mechanism. ⁷⁶

In 2003, the COOPERATE study ⁴¹ provided the first long‐term trial results addressing the effect of dual blockade of the RAS on combined renal end points. This double‐blind randomized study of 263 patients with nondiabetic renal disease demonstrated that 11% of patients on 100 mg of losartan and 3 mg of trandolapril doubled their serum creatinine or reached end‐stage renal disease during a median of 3 years of follow‐up, whereas 23% reached the primary end point during treatment with either drug as monotherapy. ⁴¹ Additional studies involving more diverse patient populations are needed, however, to establish whether long‐term cardiovascular and renal outcomes are truly improved with combination therapy. ⁴⁶

Finally, the optimal dose and time relationship, as well as the specific drug makeup, of an ACE inhibitor and ARB combination remains to be determined. ³⁵ , ⁴³ , ⁴⁴ , ⁴⁶ It is clear that dose titration with an RAS blocker to a maximally effective dose, followed by add‐on therapy, is effective in incrementally reducing protein excretion ³⁸ , ⁴⁵ , ⁷⁸ —a process that may be greater in patients with non‐diabetic renal disease compared with patients with diabetes. ⁴⁶ This approach differs from that used in many studies where one drug of the combination is added to subhypotensive (and presumably less‐than‐optimal antiproteinuric) doses of the other. ²⁶ , ⁴⁴ Despite the considerable uncertainty surrounding the use of combination ACE inhibitor and ARB therapy, such dual blockade appears to be generally safe and well tolerated ²¹ , ⁴⁰ , ⁴⁶ ; however, hyperkalemia and/or acute renal failure can occur with combination therapy. ⁷⁸ , ⁷⁹

Congestive HF

The grounds for combination therapy with an ACE inhibitor and an ARB in HF are stronger than is the case for their combined use in hypertension. HF is a disease state characterized by considerable activation of the RAS, particularly in the later stages of the disease. Ang‐II escape is a not infrequent development in the ACE inhibitor‐treated HF patient. ⁶⁴ , ⁶⁶ , ⁸⁰ Consequently, high‐dose ACE inhibitor therapy or combined ACE inhibitor and ARB therapy has been encouraged, at least in part, because of the need to eliminate Ang‐II effect in as complete a manner as possible. ⁶¹ , ⁸¹

Results of several short‐term trials, all with small numbers of patients and most with mild HF, have consistently shown that combined therapy with an ACE inhibitor and an ARB additively decreases BP, improves ventricular remodeling parameters, increases oxygen consumption during exercise, and reduces plasma aldosterone and norepinephrine concentrations. ⁴⁸ , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ These positive effects on surrogate hemodynamic and neurohumoral parameters provided the foundation for subsequent studies, which then sought to determine whether combination therapy was associated with long‐term survival benefits.

Few data are currently available to evaluate the effect of combined therapy on systolic HF‐related morbidity and mortality. The Valsartan Heart Failure Trial (Val‐HeFT) ⁵⁸ and Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM‐Added) ⁵⁹ studies demonstrated that by combining an ARB with an ACE inhibitor an additive effect on indices of HF‐related morbidity and mortality can be achieved. ⁵⁸ , ⁵⁹ A recent post hoc analysis of Val‐HeFT ⁸² has also demonstrated a trend toward a more pronounced effect of combination therapy in patients with a left ventricular ejection fraction (LVEF) <30%, suggesting that combination therapy is more effective in severe HF with a highly activated RAS.

Based on the above findings, the American College of Cardiology/American Heart Association (ACC/AHA) guidelines state that one can consider the addition of an ARB to conventional treatment, including an ACE inhibitor, in patients with a reduced LVEF who are persistently symptomatic. This is an evidence level B recommendation (class IIb), meaning that its usefulness/efficacy is less well established by evidence/opinion. This is important, since the addition of an aldosterone antagonist to an ACE inhibitor is the preferred approach in severely symptomatic HF. Three‐drug therapy with an ACE inhibitor, an ARB, and an aldosterone antagonist is currently not recommended because of both a lack of data and concern over the development of hyperkalemia (class III, evidence level C). ⁸³

High‐Risk Coronary Artery Disease

The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) ⁸⁴ , ⁸⁵ will more definitively answer many of the questions surrounding the use of combination ACE inhibitor and ARB therapy. ONTARGET is a double‐blind, parallel‐group study that randomized 25,620 patients in 40 countries to 1 of 3 treatment arms: (1) telmisartan 80 mg, (2) ramipril 10 mg, or (3) telmisartan 80 mg plus ramipril 10 mg, with subjects being followed for 3.5–5.5 years. ⁸⁶ Participating patients were to be similar to patients studied in the Heart Outcomes Prevention Evaluation (HOPE) study, ⁷ and as such were to be older than 55 and with a history of: (1) coronary artery disease; (2) stroke; (3) peripheral vascular disease; or (4) diabetes mellitus with end organ damage (microalbuminuria, ankle–brachial index <lt;0.8, or left ventricular hypertrophy). Patients with symptomatic HF were excluded from this study. ⁸⁶

The primary end point for ONTARGET is a composite of cardiovascular death, myocardial infarction, stroke, and hospitalization for HF, with combination therapy (telmisartan 80 mg/ramipril 10 mg) being compared with ramipril 10 mg alone. A separate analysis is to determine whether telmisartan 80 mg daily is at least as effective (ie, not inferior) as ramipril 10 mg daily. Secondary end points of some particular interest will examine the impact of the various dosing strategies on the development of diabetes mellitus, nephropathy, dementia, and atrial fibrillation. These secondary end points all appear to have some particular level of association with Ang‐II. Several substudies will explore other functional and morphologic consequences of ACE inhibition, Ang‐II receptor blockade, and the combination of both strategies. ⁸⁶

The HOPE study has set the standard for a drug class providing cardiovascular protection in a fashion independent of BP reduction. ⁷ The HOPE study, by way of its positive findings with ramipril, identified a central role for Ang‐II in the development of atherosclerosis‐related events. ONTARGET proposes to extend the findings of the HOPE study by implementing the 3 aforementioned treatment approaches for hindering the effects of Ang‐II: inhibiting ACE, blocking the Ang‐II type 1 receptor, and combining both strategies. The fact that combination therapy typically has a minimal effect on BP is an important consideration for the ONTARGET study. ²¹ Ultimately, for any between‐group differences in ONTARGET to be viewed as BP‐independent, there must be fairly equal BP values between treatment groups.

The baseline data for ONTARGET allow a preliminary comparison of patient demographics between it and the HOPE study. ⁸⁷ The demographic comparability (or not) of these 2 studies will be of some importance in the interpretation of the end‐of‐study findings. One difference in the patient demographics between these 2 studies is that there is a greater ethnic diversity in ONTARGET, with 19% of recruited subjects from Asian countries. The surgical histories of patients in these 2 trials, moreover, reflect the changing trends in cardiovascular surgery in that a higher proportion of patients in HOPE had undergone coronary bypass grafting, whereas there were more percutaneous coronary interventions in ONTARGET. The baseline supine BP readings at run‐in were also somewhat higher in ONTARGET (143/82 mm Hg) compared with HOPE (139/79 mm Hg). At the point of randomization, however, BP values averaged 134/77 mm Hg in ONTARGET. Finally, the baseline use of statins (60.7% vs 28.9%), β‐blockers (56.9% vs 39.5%), and/or ACE inhibitors (57.5% vs 11.6%) were each considerably higher in ONTARGET than in HOPE. ⁸⁷

CONCLUSIONS

ACE inhibitors and ARBs are effective and generally well tolerated antihypertensive agents. Moreover, these compounds have an established track record for success in the treatment of HF and proteinuric nephropathies. Whereas the combination of an ACE inhibitor and an ARB has limited utility for incremental BP reduction, these drug classes in combination do offer some benefit in patients with either HF or a proteinuric nephropathy. The therapeutic position of ACE inhibitor and ARB combination therapy in the high‐risk cardiac patient is yet to be determined. The results of ongoing studies using the drugs ramipril and telmisartan, singly and in combination, will provide important information as to best‐practice treatment options in the high‐risk cardiac patient.