|Domenic A. Sica, MD, J Clin Hypertens 5(6):414-420, 2003
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are commonly prescribed for the management of hypertension. In addition, each of these drug classes has been shown to be effective in the treatment of congestive heart failure, proteinuric chronic kidney disease, and most recently the high-cardiac-risk profile patient. The individual success of each of these drug classes has fueled the theory that given together, the overall biologic effect of both would surpass that of either given alone. The foundation of this premise, although biologically plausible, has yet to be proven in a compelling enough fashion to support the everyday use of these two drug classes in combination. Additional clarifying studies are required to establish whether specific patient subsets exist that might benefit from such combination therapy.
Inhibition of the renin-angiotensin system (RAS) by administration of either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) reduces blood pressure (BP) to a similar extent in hypertensive patients. Both ACE inhibitors and ARBs impede the progressive deterioration in renal function, which underscores renal injury, particularly in patients with diabetic nephropathy.[2-4] The renoprotective effects of these drugs, in part, relates to their ability to reduce proteinuria.[5-6] ACE inhibitors also improve the prognosis of patients with a high risk of atherothrombotic cardiovascular events, not unlike the effects that have been observed with ARBs.[7-10] Moreover, ACE inhibitors and ARBs are both of benefit in conditions of left ventricular dys-function.[11-12] It was just a matter of time before ACE inhibitors and ARBs were given together as combination therapy, due to evidence suggesting that these agents are complementary in their actions. Unfortunately, there are few published studies that permit an assessment of combined ACE inhibitor and ARB therapy. Of the available studies in hypertension, the observed results have been inconsistent and poorly generalizable.[12-21] The studies of combination therapy in proteinuric chronic kidney disease (CKD)[21-41] have proven more interesting, as has been the case for combination ACE inhibitor and ARB combination therapy in congestive heart failure (CHF).[42-56] This review summarizes the basis for combined use of ACE inhibitors and ARBs, and describes the results of available clinical trials in which such combinations have been examined.
Theoretical Basis for Combining ACE Inhibitors and ARBS
The pharmacologic actions of ACE inhibitors and ARBs have been well characterized. The BP reduction and/or tissue protection derived from interrupting the RAS with either an ACE inhibitor or an ARB are, in large measure, an extension of compound-specific pharmacokinetic/pharmacodynamic properties.[57-58]
Numerous factors influence the final response to these drug classes, including where inhibition occurs in the RAS, any compensatory changes in RAS activity that arise from such blockade, and any additional unique effects on non-RAS systems that may emerge.
Administration of an ACE inhibitor initially reduces both circulating and tissue concentrations of angiotensin-II (Ang-II) by blocking the enzymatic conversion of angiotensin-I to Ang-II via ACE. However, long-term treatment with an ACE inhibitor is accompanied by a gradual return of circulating and tissue Ang-II concentrations to pretreatment levels, a phenomenon termed "angiotensin-II escape."[59-62] One suggested explanation for Ang-II escape centers on the capacity of enzymes in human tissues, such as chymase, cathepsin G, and chymostatin-sensitive angiotensin generating enzyme (CAGE), to form Ang-II from a variety of peptide substrates. Since this mode of Ang-II generation is independent of ACE, it can proceed in an unbridled fashion irrespective of the presence of an ACE inhibitor.
These alternative non-ACE-dependent pathways for production of Ang-II can upregulate with chronic ACE inhibition, although the precise stimulus for this remains unclear. In addition, ACE activity increases in diseased tissues, such as atheromatous lesions that have been subjected to angioplasty. This traditional pathway for production of Ang-II is incompletely suppressed even by high-dose ACE inhibitor therapy.[65-66] Despite strong evidence in support of the concept of Ang-II escape in CHF, escape from the BP-reducing effects of an ACE inhibitor has yet to be described.[58,67] If Ang-II escape with ACE inhibitors is ever to be of relevance to clinical practice, it will not be on the basis of loss of BP control, an easily measured and treated parameter; rather, it is likely to be as a consequence of "suboptimal tissue protection."
ACE is also known as kininase-II, which is largely in control of the proteolytic breakdown of bradykinin and similar small vasoactive peptides. Accordingly, ACE inhibition inhibits the breakdown of bradykinin to biologically inactive products. The resultant increase in bradykinin promotes release of the potent vasodilator nitric oxide (NO) via activation of the endothelial-based B2 receptor. It is generally accepted that at least part of the vasodepressor response to ACE inhibition is bradykinin-mediated. Blockade of the Ang-II AT1 receptor with an ARB does not affect bradykinin. An ARB has little affect on the generation of Ang-II, but effectively blocks its action. This clearly differentiates ACE inhibitors and ARBs, pharmacologically. Alternatively, AT2 receptor stimulation, as a sequelae to ARB therapy, can increase renal interstitial fluid bradykinin concentrations. This process is potentiated by coadministration of an ACE inhibitor.
Interpretative Issues in Combining ACE Inhibitors and ARBS
The basis for combining an ACE inhibitor with an ARB is to realize a therapeutic outcome superior to that seen with either drug administered alone. The theoretical premise behind the combination of these two drug classes is plausible to a degree, but there are pitfalls that may be encountered if only superficial analyses of response are performed.
First, there are a number of ACE inhibitors and ARBs marketed worldwide. 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 candesartan, can achieve a more prolonged response. This can be mistaken for an additive response when in reality it is little more than a mixing of drugs with different half-lives for a sustained effect on BP.
Secondly, the time of day that drugs in these classes are administered should be considered in assessing a response. Split dosing of these drug classes, with one being given in the morning and the other given in the evening, may be considered more effective than giving both drugs simultaneously. In reality, this approach may differ little from split-dosing a single agent.
Third, the sequence in which these medications are given may determine the final BP or antiproteinuric response. The fall in BP that occurs with an ACE inhibitor relates to both a reduction in Ang-II levels and a variable increase in bradykinin effect. If the latter is an important contributor to BP reduction, then the order in which an ACE inhibitor is added may dictate the pattern of response. Theoretically, adding the ARB after the ACE inhibitor may have little effect on bradykinin levels, whereas beginning treatment with an ARB then adding the ACE inhibitor may uncover an additional vasodepressor response to bradykinin.
Finally, the time course of response to the combination of an ACE inhibitor and an ARB is mechanistically relevant. For example, if the combination of these drugs results in a drop in BP shortly after beginning combination therapy, a direct pharmacokinetic/pharmacodynamic effect is likely. If a response occurs, but it takes several weeks, then the possibility exists that the combination of these drugs encouraged earlier vascular remodeling more than if either drug had been given alone. The most relevant question that remains when the combination of an ACE inhibitor with an ARB results in a positive response is whether the same would have occurred with simple dose titration of one or the other of the medications. Thus, exploring the dose-response curves of this combination is a necessary exercise before considering the combination of these classes.[19,37]
The efficacy of both ACE inhibitors and ARBs as anti-hypertensive agents is well established.[1,58] In head-to-head comparisons, ACE inhibitors and ARBs reduce BP comparably. In contradistinction to the wealth of information on monotherapy with these drugs, there is sparingly little information about the efficacy of combined ACE inhibitor and ARB therapy.[12-21,44] Moreover, the trials currently published cannot be generalized, since in many instances they have studied only a small number of patients followed for a short period of time. Inherent limitations in a number of these trials include dose selection that does not mimic clinical practice, failure to compare the combination of ACE inhibitor and ARB to other more commonly used combinations, as well as an absence of racial and age diversity in the sampled populations. Moreover, in interpreting any such findings it should be recognized that a high sodium diet will attenuate the effect of either drug class given individually as well as the vasodepressor response to the combination of an ACE inhibitor and an ARB.[13,18]
In one such example, 20 patients received monotherapy with benazepril, an ACE inhibitor, for 6 weeks. If average awake ambulatory diastolic BPs remained >85 mm Hg, subjects were randomized to either valsartan, an ARB, 80 mg/d or matching placebo in a blinded manner for 5 weeks while continuing to receive background benazepril.
The 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) over placebo for average awake ambulatory BP. Nocturnal systolic and diastolic BPs were also similarly reduced by 7.1±9.4/5.6±6.5.
In a larger, 8-week, open-label experience trial, the efficacy of the ARB candesartan cilexetil, in a dose range of 16-32 mg, was evaluated in 473 patients receiving ACE inhibitor monotherapy. The incremental reduction in BP with the addition of candesartan to an ACE inhibitor was 15.3/10.0 mm Hg. At first glance this would appear to be a significant response. However, it is important to recognize that these studies were not placebo controlled. A placebo effect could have easily contributed to the observed incremental response by virtue of "expectation bias." Furthermore, these studies employed a variety of ACE inhibitors given over a wide range of doses. The nature of this study precluded identifying the background ACE inhibitors and their doses; thus, in these studies it is possible that background therapy with an ACE inhibitor was not maximized before the addition of candesartan. African Americans had a clinically important but somewhat reduced BP response when candesartan was added to an ACE inhibitor although neither the exact number of African-American patients nor their response was reported. Finally, there were 127 patients with isolated systolic hypertension in this clinical experience trial. They experienced a 13.4/4.3 mm Hg drop in BP when candesartan was added to monotherapy.
There appears to be little reason to consider the use of an ACE inhibitor in combination with an ARB in stage I hypertensives; most patients with BPs below 160/100 mm Hg are likely to achieve goal BP with monotherapy or with an RAS antagonist with a diuretic. Existing studies also fail to resolve the question of whether these drug classes should be routinely combined in the management of the complex hypertensive. Additional studies are needed to determine whether there are subgroups of hypertensive patients that are uniquely responsive to the combination of an ACE inhibitor and an ARB.
One study, which will definitively answer many of the questions surrounding the use of combination ACE inhibitor and ARB therapy, is the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). This is a double-blind, parallel-group study involving 23,400 patients in 40 countries over a 5.5-year period. It will compare three treatment arms: 1) an ARB (telmisartan 80 mg); 2) an ACE inhibitor (ramipril 10 mg); and 3) telmisartan 80 mg plus ramipril (10 mg) in patients >55 years of age with a history of coronary artery dis-ease, stroke, peripheral vascular disease, or diabetes mellitus with end organ damage (microalbuminuria, ankle-brachial index <0.8, or left ventricular hypertrophy). Patients with CHF will be excluded in this trial.
In a parallel study, patients unable to tolerate an ACE inhibitor will be randomized to receive 80 mg telmisartan or placebo (the Telmisartan Randomized Assessment Study in ACE-intolerant patients with Cardiovascular Disease [TRANSCEND]). The primary end point for both trials is a composite of cardiovascular death, myocardial infarction (MI), stroke, and hospitalization for heart failure. Secondary end points will investigate reductions in the development of diabetes mellitus, nephropathy, dementia, and atrial fibrillation. The population of the ONTARGET trial is at three-fold greater risk for coronary artery disease-related events than those in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), so between 4000 and 5000 primary end points are anticipated. Both the ONTARGET and TRANSCEND trials are expected to be completed by 2007.
The combination of an ACE inhibitor and an ARB has been occasionally used in progressive renal disease, particularly for an antiproteinuric effect beyond that seen with a single agent.[21-41] Insight into the potential mechanism(s) of the antiproteinuric effect with combination therapy can be gained from several recent studies.[22,62,71]
Agarwal et al. observed increased urinary levels of transforming growth factor b1 (TGF b1) in proteinuric patients with renal failure despite maximal ACE inhibition (lisinopril 40 mg/d). The elevated levels of TGF b1 declined by 38% after 1 month of add-on therapy with the ARB losartan (50 mg/d). Komine et al. have also shown that renal Ang-II production is incompletely suppressed with the ACE inhibitor captopril and that addition of the ARB losartan more completely suppresses production of Ang-II. Additional studies have shown a significant reduction in plasma aldosterone concentrations beyond that observed with either drug class alone. These synergistic effects on aldosterone and Ang-II may have important implications in long-term renoprotection. Campbell et al. have also shown that the additive antiproteinuric response with combination therapy is associated with further reductions in renal vascular resistance but no change in glomerular permselectivity as determined by dextran sieving. Finally, Delles et al. have shown that 1 week of treatment with the combination of enalapril (10 mg), an ACE, and eprosartan (300 mg), an ARB (these doses represented one half the usual dose of each drug), increased renal plasma flow by a nitric oxide-dependent mechanism.
The effect of combination therapy on protein excretion has been probed in a number of studies. For example, in an early study of normotensive patients with biopsy-proven IgA nephropathy and non-nephrotic proteinuria, the combination of losartan with an ACE inhibitor produced an average 73% greater reduction in proteinuria than either agent alone (ACE inhibitor 38% and losartan 30%). In this study, no further reduction in proteinuria was observed by doubling the dose of either the ACE inhibitor or of losartan. The observed change could not be explained by either a decline in systemic BP or a fall in glomerular filtration rate and developed within 4 weeks of beginning combination therapy.
Recently, the randomized Candesartan and Lisinopril Microalbuminuria (CALM) study, which evaluated the effect of combining candesartan and lisinopril on microalbuminuria in 199 type 2 diabetic patients, yielded similar observations. Twelve weeks of combination therapy was begun after 12 weeks of monotherapy with either candesartan or lisinopril, each given at one half the usual maximal dose. In this study, the reduction in urinary 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 is often the case with combination therapy, BP values were lower than those obtained with either agent alone, which make interpretations of the findings difficult. After 24 weeks of therapy, diastolic BP was reduced to a greater degree with combination therapy (-16.3 mm Hg) than with either candesartan (-10.4 mm Hg) or lisinopril (-10.7 mm Hg) alone.
The importance of BP reduction in the additive antiproteinuric effects of combination therapy cannot be overemphasized.[22-24,26,39,41] The relationship between BP and the antiproteinuric effect of combination therapy may not be detected if only office-based readings are used, as these have a high degree of intrinsic variability. A recent study by Russo et al. noted no relationship between office measurements of trough BP and the antiproteinuric effect of combination therapy with enalapril and losartan. However, there was a significant and highly correlated relationship between mean ambulatory BPs and the degree to which urinary protein excretion fell. The degree to which BP is lowered by combined ACE inhibitor and ARB therapy will persist is an important consideration in defining the mechanism of the additive antiproteinuric effects of combination therapy even when BP isotherwise stated not to change.
Recently, the Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in nondiabetic renal disease (COOPERATE) study provided the first long-term trial results addressing the effect of dual blockade on primary renal end points. This double-blind randomized study of 263 patients with nondiabetic renal disease demonstrated that only 11% of patients on 100 mg losartan and 3 mg trandolapril (an ACE inhibitor), 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 monotherapy. However, additional studies involving more diverse patient populations are required to determine whether long-term cardiovascular and renal out-come measures are more favorably impacted on a broader basis with combination therapy.
Finally, the optimal dose and time relationship, as well as the specific drug make-up, of an ACE inhibitor and ARB combination remain to be determined. It is clear that dose titration with a RAS blocker to a maximally effective dose, followed by add-on therapy is highly effective in reducing proteinuria. 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. Despite the considerable uncertainty surrounding the use of combination ACE inhibitor and ARB therapy, such dual blockade appears to be safe and well tolerated.
Congestive Heart Failure
The rationale for combination therapy with an ACE inhibitor and an ARB in CHF is stronger than that for their combined use in hypertension. CHF is a disease state characterized by significant activation of the RAS, particularly in the later stages of the disease. Ang-II escape is a not infrequent occurrence in the ACE inhibitor treated CHF patient.[61,64,72] Consequently, high-dose ACE inhibitor therapy or combined ACE inhibitor and ARB therapy has been advocated, in part, because of the necessity to reduce either the generation or the effects of Ang-II escape as completely as possible.
Results of several short-term trials, all with small numbers of patients and a number of them with mild heart failure, have consistently shown that combined therapy with an ACE inhibitor and an ARB additively decreases BP, improves ventricular remodeling, increases oxygen consumption during exercise, and reduces plasma aldosterone and norepinephrineconcentrations. [42-44,46-53] These favorable effects on surrogate hemodynamic and neurohumoral parameters of CHF occur without apparent loss of drug regimen tolerability or increased adverse effects. Hemodynamic, neurohumoral, and clinical findings, however, do not necessarily equate with long-term survival benefits.
Few data are currently available to evaluate the effect of combined therapy on heart failure-related mortality.[55-56] In the recently concluded Valsartan Heart Failure Trial (Val-HeFT), valsartan was compared with placebo on top of background ACE inhibitor therapy in a cohort of 5010 patients with New York Heart Association class II-IV heart failure (primarily Class IIIII). In both treatment arms, 93% of subjects were receiving ACE inhibitors. After randomization, valsartan was given at a dose of 40 mg b.i.d. and titrated to 160 mg b.i.d. The two primary outcome measures were all-cause mortality or a combined end point (all-cause mortality, which included sudden cardiac death with resuscitation, hospitalization for heart failure, and worsening heart failure requiring inotropic or vasodilating agents). Compared with placebo, valsartan reduced the combined mortality/morbidity end point by13.3% and hospitalization for heart failure by 27.5%, although all-cause mortality was not significantly reduced.
In the recently completed Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM)-Added trial, the combination of the ARB, candesartan, with ACE inhibitors was investigated in 2548 patients with New York Heart Association class II-IV heart failure (primarily Class II-III). Candesartan was given in a dose of either 4 or 8 mg daily and titrated to a dose of 32 mg/d. The primary outcome was cardiovascular death or unplanned admission to hospital for the management of worsening CHF. Several secondary outcomes were evaluated. Candesartan reduced each of the components of the primary outcome significantly, as well as the total number of admissions for CHF. The benefits of candesartan when added to ACE therapy were similar in all predefined subgroups, including patients receiving baseline b-blocker therapy. However, the benefits of combination therapy with candesartan were obtained with a somewhat higher rate of hypotension, hyperkalemia, and increase in serum creatinine, indicating the need for careful monitoring of renal function and potassium. The same safety observation can be drawn from the recently completed Valsartan in Acute Myocardial Infarction (VALIANT) trial, which explored the effect of captopril, valsartan, and the combination of these two drugs on mortality and cardiovascular morbidity among MI patients complicated by left ventricular systolic dysfunction. In this trial, combining valsartan with captopril increased the rate of adverse events without improving survival.
Practice guidelines in CHF management have not been updated to outline when and in whom an ARB should be added to an ACE inhibitor, particularly in view of the recent CHARM results. Such guidelines must ultimately consider the sequence of drugs to be added, given the expanding role of low-dose b-blocker therapy in CHF management. Since no significant improvement was seen in Val-HeFT when valsartan was given to patients receiving both an ACE inhibitor and a b blocker, ARB therapy may become third-line therapy in CHF management unless a CHF patient is completely intolerant of ACE inhibition, in which case an ARB can be substituted for the ACE inhibitor. However, the poor out-come with triple therapy (ACE inhibitor, valsartan, and a b-blocker in Val-HeFT was not observed with similar triple-drug therapy in CHARM, suggesting that the finding in Val-HeFT may be spurious. If there is evidence of partial intolerance to an ACE inhibitor at the early stage of dose titration -- such as a precipitous drop in renal function or an excessive drop in BP -- the addition of an ARB to a reduced dose of an ACE inhibitor may succeed where dose titration alone has failed.
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