The renin-angiotensin system: the role of inhibitors, blockers, and genetic polymorphisms in the treatment and prevention of heart failure

The renin-angiotensin system (RAS) plays an important role in the pathogenesis and worsening of heart failure (HF). Blocking this system with angiotensin converting enzyme (ACE) inhibitors in patients with HF and left ventricular dysfunction reduces mortality and morbidity and these drugs are currently recommended as standard therapy. A more recently developed class of drug, angiotensin receptor blockers (ARBs) block the RAS at the receptor level, and may therefore provide more complete blockade. ARBs, either singly or in combination with ACE inhibitors, are currently being compared to either ACE inhibitor therapy alone or to placebo in randomized trials of patients with or at high risk of developing HF. With respect to large trials published to date directly comparing ARB versus ACE inhibitor therapy, neither the Losartan Heart Failure Survival Study (ELITE II) nor the Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) found differences in mortality or morbidity between the treatment groups. As regards combination ARB/ACE inhibitor therapy versus ACE inhibitor therapy alone, one completed study, the Valsartan Heart Failure Trial (Val-HeFT), found no differences in mortality but a decrease in HF-related hospitalizations in the combined therapy group. Four additional long-term trials (VALIANT, CHARM, ONTARGET, and TRANSCEND) should complete the totality of evidence regarding the role of ARBs in the treatment of HF. Since genetic polymorphisms affecting drug metabolizing enzymes or drug receptors are known to influence responses to drugs, exploration of these effects on treatment responses to ARBs and ACE inhibitors may provide for more targeted treatment of HF.     

The implications of a growing evidence base for drug use in elderly patients Part 2. ACE inhibitors and angiotensin receptor blockers in heart failure and high cardiovascular risk patients

Traditionally, angiotensin converting enzyme (ACE) inhibitors have been used for the management of patients with congestive cardiac failure. Studies performed over the last decade have demonstrated that (1) angiotensin receptor blockers (ARBs) are as effective as ACE inhibitors in reducing morbidity and mortality in cardiac failure; and (2) inhibition of the renin-angiotensin system provides beneficial effects in patients at high cardiovascular risk without cardiac failure. This review focuses on the applicability of the results of the main trials with ACE inhibitors and ARBs to the elderly population.     

The use of angiotensin receptor blockers in the treatment of chronic heart failure

Angiotensin receptor blockers (ARBs) have a pharmacological role in the treatment of heart failure through their blockade of the effects of angiotensin II. ARBs, however, lack the potential benefits of inhibiting the breakdown of bradykinin that is seen with ACE-Is. Historically, the medical literature assessing ARBs in the treatment of chronic heart failure have been short in duration and primarily focused on surrogate markers of disease severity. Recent, well-designed clinical trials have shed new light on the potential roles of ARBs in the treatment of chronic heart failure and their effects on mortality in this patient population. In comparison to captopril, losartan has been shown to have similar benefits in cardiovascular mortality and morbidity. In patients with systolic dysfunction who are intolerant to ACE-Is, candesartan has been shown to reduce cardiovascular mortality and hospital admissions for heart failure. In combination with ACE-Is, candesartan and valsartan have been shown to improve heart failure morbidity and, with candesartan, reduced cardiovascular mortality in those with systolic dysfunction. These 2 trials show conflicting mortality information regarding the use of triple therapy with ACE-Is, ARBs, and beta-blockers for systolic dysfunction. In patients with heart failure but preserved systolic dysfunction, candesartan showed no effects on mortality and only modest effects on morbidity.     

Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update

The angiotensin converting enzyme (ACE) inhibitors are widely used in the management of essential hypertension, stable chronic heart failure, myocardial infarction (MI) and diabetic nephropathy. There is an increasing number of new agents to add to the nine ACE inhibitors (benazepril, cilazapril, delapril, fosinopril, lisinopril, pentopril, perindopril, quinapril and ramipril) reviewed in this journal in 1990. The pharmacokinetic properties of five newer ACE inhibitors (trandolapril, moexipril, spirapril, temocapril and imidapril) are reviewed in this update. All of these new agents are characterised by having a carboxyl functional groups and requiring hepatic activation to form pharmacologically active metabolites. They achieve peak plasma concentrations at similar times (t(max)) to those of established agents. Three of these agents (trandolapril, moexipril and imidapril) require dosage reductions in patients with renal impairment. Dosage reductions of moexipril and temocapril are recommended for elderly patients, and dosages of moexipril should be lower in patients who are hepatically impaired. Moexipril should be taken 1 hour before meals, whereas other ACE inhibitors can be taken without regard to meals. The pharmacokinetics of warfarin are not altered by concomitant administration with trandolapril or moexipril. Although imidapril and spirapril have no effect on digoxin pharmacokinetics, the area under the concentration-time curve of imidapril and the peak plasma concentration of the active metabolite imidaprilat are decreased when imidapril is given together with digoxin. Although six ACE inhibitors (captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril) have been approved for use in heart failure by the US Food and Drug Administration, an overview of 32 clinical trials of ACE inhibitors in heart failure showed that no significant heterogeneity in mortality was found among enalapril, ramipril, quinapril, captopril, lisinopril, benazepril, perindopril and cilazapril. Initiation of therapy with captopril, ramipril, and trandolapril at least 3 days after an acute MI resulted in all-cause mortality risk reductions of 18 to 27%. Captopril has been shown to have similar morbidity and mortality benefits to those of diuretics and beta-blockers in hypertensive patients. Captopril has been shown to delay the progression of diabetic nephropathy, and enalapril and lisinopril prevent the development of nephropathy in normoalbuminuric patients with diabetes. ACE inhibitors are generally characterised by flat dose-response curves. Lisinopril is the only ACE inhibitor that exhibits a linear dose-response curve. Despite the fact that most ACE inhibitors are recommended for once-daily administration, only fosinopril, ramipril, and trandolapril have trough-to-peak effect ratios in excess of 50%.     

Angiotensin II receptor blockers in heart failure

Heart failure remains a significant cause of morbidity and mortality, despite major advances in therapy. Angiotensin II, the principal mediator of the renin-angiotensin system, exerts both short-term (e.g., hemodynamic, renal) and long-term (e.g., inflammation, cardiac remodeling) effects in the pathophysiology of cardiovascular disease. The effects of angiotensin II appear to be more completely inhibited by angiotensin II receptor blockers (ARBs), which act at the subtype 1 receptor level, than by angiotensin-converting enzyme (ACE) inhibitors because pathways other than that of ACE contribute to the generation of angiotensin II. Evidence demonstrates that ARBs, when added to conventional treatment for patients with heart failure, are associated with a reduction in morbidity and mortality as well as an improvement in quality of life. Clinical trials of ARB therapy indicate that these agents are generally well tolerated, both alone and in combination with other neurohormonal inhibitors. The current role of ARBs in heart failure is as an alternative for patients who cannot tolerate therapy with an ACE inhibitor. A number of ongoing clinical studies are likely to further define or expand the role of ARBs in the treatment of cardiovascular disease.     

Candesartan cilexetil: a review of its use in the management of chronic heart failure

Candesartan cilexetil is the orally administered pro-drug of candesartan, a highly selective antagonist of the angiotensin II subtype 1 receptor that mediates the pressor activities of angiotensin II. Candesartan cilexetil is widely used for the treatment of hypertension and has recently been approved in Europe for the treatment of chronic heart failure (CHF) in patients with impaired left ventricular (LV) systolic function.Results of the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) programme suggest that oral candesartan cilexetil reduces morbidity and mortality in patients with CHF and LV ejection fraction (LVEF) < or =40%. There are cardiovascular benefits when candesartan cilexetil is administered as an alternative to an ACE inhibitor, or as an add-on to current treatment regimens that include an ACE inhibitor, in symptomatic CHF. While tolerability is generally good, renal monitoring is required. The recent approval of candesartan cilexetil as both add-on and alternative therapy to ACE inhibitors in patients with CHF and impaired LV systolic function recognises the cardiovascular benefits of candesartan cilexetil in both types of treatment regimens.     

Role of valsartan and other angiotensin receptor blocking agents in the management of cardiovascular disease.

Blockade of the renin-angiotensin system by angiotensin converting enzyme (ACE) inhibitors reduces mortality and morbidity in patients post-myocardial infarction as well as in chronic heart failure and hypertension. ACE inhibitors also have a well-established place in the treatment of diabetic nephropathy. Angiotensin receptor blockers (ARBs) have been developed to produce a more complete blockade of the actions of angiotensin II as compared to other drug classes, as well as an improved side effect profile. This article provides an overview of the place of ARBs in general and of the ARB valsartan in particular, and draws comparisons to ACE inhibitors in the treatment of cardiovascular diseases.     

Effects of ACE Inhibitors or ↓-Blockers in Patients Treated with the Fixed-Dose Combination of Isosorbide Dinitrate/Hydralazine in the African-American Heart Failure Trial

BACKGROUND: In the A-HeFT (African-American Heart Failure Trial), treatment of African-American patients with New York Heart Association (NYHA) class III/IV heart failure (HF) with fixed-dose combination (FDC) of isosorbide dinitrate/hydralazine (I/H) reduced mortality and morbidity and improved patient reported functional status compared with standard therapy alone. OBJECTIVE: To examine the benefit of FDC I/H in subgroups based on baseline drug therapy and to investigate whether ACE inhibitors and/or angiotensin receptor antagonists (angiotensin receptor blockers) [ARBs] or beta-adrenoceptor antagonists (beta-blockers) provided additional benefit in FDC I/H-treated African-American patients with HF. STUDY DESIGN: The A-HeFT was a double-blind, placebo-controlled study enrolling 1050 patients stabilized on optimal HF therapies and with NYHA class III/IV HF with systolic dysfunction conducted during the years 2001-4 with up to 18 months follow-up. The primary endpoint was a composite of mortality, first HF hospitalization, and improvement of quality of life at 6 months. Secondary endpoints included mortality, hospitalizations, and change in quality of life. Prospective Kaplan-Meier survival analyses were used for differences between FDC I/H and placebo groups and retrospective analyses were conducted within FDC I/H-treated and placebo groups. RESULTS: Subgroup analysis for mortality, event-free survival (death or first HF hospitalization), and HF hospitalization showed that FDC I/H, compared with placebo, was effective with or without ACE inhibitors or beta-blockers or other standard medications with all-point estimates favoring the FDC I/H group. Within the placebo-treated group, beta-blockers or ACE inhibitors and/or ARBs were efficacious in improving survival (hazard ratio [HR] 0.33; p<0.0001 for [beta]-blocker use and HR 0.39; p=0.01 for ACE inhibitor and/or ARB use). However, within the FDC I/H-treated group, use of beta-blockers, but not ACE inhibitors and/or ARBs, provided additional significant benefit for survival (HR 0.44; p=0.029 and HR 0.60; p=0.34, respectively), event-free survival (HR 0.62; p=0.034 and HR 0.72; p=0.29, respectively) and the composite score of death, HF hospitalization and change in quality of life (p=0.016 and p=0.13, respectively). CONCLUSION: Based on the analysis of baseline medication use in the A-HeFT, FDC I/H was superior to placebo with or without beta-blockers or ACE inhibitor. However, beta-blockers but not ACE inhibitors and/or ARBs provided additional significant benefit in African-Americans with HF treated with FDC I/H. These analyses are hypotheses generating and their confirmation in clinical trials needs to be considered.     

The therapeutic potential of angiotensin II receptor blockers in the treatment of heart failure

In clinical heart failure (HF) the renin-angiotensin-aldosterone system is an important component of neurohormonal activation. Angiotensin-converting enzyme inhibitors have been shown to be of great clinical benefit in reducing the production of angiotensin II. However, they do not fully suppress angiotensin II production in HF because there are other pathways through which angiotensin II can be produced. Theoretically, angiotensin II receptor blockers (ARBs) have great potential because of their ability to directly block angiotensin II produced through any pathway. A large body of literature has accumulated examining the effects of ARBs in HF. The earlier, smaller studies examined outcomes such as symptoms, neurohormonal concentrations and cardiac function. More recent, larger studies have examined the effects of ARBs on mortality and morbidity. This paper reviews the data defining the role of ARBs in the treatment of HF patients, focusing more on the large randomised clinical outcome trials.     

VALIANT (VALsartan In Acute myocardial iNfarcTion) trial

Angiotensin-converting enzyme inhibitors (ACE-Is) are an evidence-based treatment for patients who after myocardial infarction (MI) present with either heart failure (HF) or left ventricular systolic dysfunction, or both. An alternative could be a more complete inhibition of the renin-angiotensin system through the blockade of the angiotensin type 1 receptors. The effect of valsartan or captopril, or the combination of the two in post-MI HF or systolic dysfunction or both, has been evaluated in the VALIANT (VALsartan In Acute myocardial iNfarcTion) trial. Total mortality and the combined secondary end point of cardiovascular death, MI or HF were not significantly different in the three groups after 24.7 months of follow-up. Valsartan was not inferior to captopril in terms of total mortality and cardiovascular death, MI and HF. Valsartan can be considered an alternative treatment to ACE-I in these patients.     

Angiotensin II receptor antagonists and heart failure: angiotensin-converting-enzyme inhibitors remain the first-line option

(1) Some angiotensin-converting-enzyme inhibitors (ACE inhibitors) reduce mortality in patients with heart failure (captopril, enalapril, ramipril and trandolapril), and in patients with recent myocardial infarction and heart failure or marked left ventricular dysfunction (captopril, ramipril and trandolapril). (2) Angiotensin II receptor antagonists, otherwise known as angiotensin receptor blockers, have haemodynamic effects similar to ACE inhibitors, but differ in their mechanism of action and certain adverse effects. (3) Five clinical trials have evaluated angiotensin II receptor antagonists (candesartan, losartan and valsartan) in terms of their effect on mortality and on the risk of clinical deterioration in patients with symptomatic heart failure, but without severe renal failure, hyperkalemia or hypotension. In these trials, candesartan and valsartan were used at much higher doses than those recommended for the treatment of arterial hypertension. (4) In patients with heart failure who were not taking an angiotensin II receptor antagonist or an ACE inhibitor at enrollment, no significant difference was found between losartan and captopril in terms of mortality or the risk of clinical deterioration. (5) In patients with heart failure who had stopped taking an ACE inhibitor because of adverse effects, candesartan had no effect on mortality as compared with placebo, but it did reduce the risk of clinical deterioration (3 fewer hospitalisations per year per 100 patients). However, candesartan was associated with adverse effects such as renal failure and hyperkalemia, especially in patients who had experienced these same adverse effects while taking an ACE inhibitor. (6) In patients with heart failure who were already taking an ACE inhibitor, adjunctive candesartan or valsartan treatment did not influence mortality in comparison to the addition of a placebo. Adding candesartan or valsartan reduced the risk of hospitalisation (between 1 and 3 fewer hospitalisations per year per 100 patients), but increased the risk of renal failure and hyperkalemia. (7) In patients with heart failure and incapacitating dyspnea despite ACE inhibitor + diuretic combination therapy, there are no trials comparing the addition of an angiotensin II receptor antagonist versus spironolactone. Adjunctive spironolactone therapy prevents 5 to 6 deaths per year per 100 patients in this setting. (8) In patients with heart failure who do not have markedly altered cardiac contractility, candesartan appears to have no clinical advantages over placebo. (9) In some of these trials, mortality was higher with angiotensin II receptor antagonist therapy than with placebo among patients who were already taking a betablocker. (10) Two trials have compared an angiotensin II receptor antagonist with an ACE inhibitor in patients with recent myocardial infarction who had heart failure or an altered left ventricular ejection fraction, but who did not have hypotension or severe renal failure. However, there are no placebo-controlled randomised trials assessing the effects of angiotensin II receptor antagonists on mortality. (11) In patients with recent myocardial infarction, these trials showed no difference in mortality between angiotensin II receptor antagonist treatment (losartan or valsartan) and captopril. They did not rule out the possibility that these angiotensin II receptor antagonists are moderately less effective than captopril. Adding valsartan to ongoing captopril therapy did not reduce mortality or morbidity as compared with placebo, but did increase the risk of adverse effects. (12) Overall, these trials confirm the advantage of angiotensin II receptor antagonists over ACE inhibitors with respect to some adverse effects (cough, skin rash, etc.). However, the two drug classes share certain serious adverse effects such as hyperkalemia, renal failure and hypotension. In one trial, angioedema was less frequent with angiotensin II receptor antagonist therapy (one less case per 500 patients).     

Angiotensin Antagonism in Patients with Heart Failure

Chronic heart failure (CHF) is a major cause of morbidity and mortality in western society. It is now widely accepted that the renin-angiotensin-aldosterone system (RAAS) and, in particular, angiotensin II (A-II) play a key role in the pathophysiology of CHF. Large-scale clinical trials have demonstrated that inhibitors of angiotensin-converting enzyme (ACE), the principal enzyme responsible for A-II production, improve symptoms and survival in patients with CHF. This enzyme is also responsible for the breakdown of the vasodilator hormone bradykinin. Administration of ACE inhibitors is associated with increased plasma bradykinin levels and this is thought to contribute to the vascular changes associated with ACE inhibitor therapy. However, RAAS inhibition with ACE inhibitors remains incomplete because ACE inhibitors do not block the non-ACE-mediated conversion of angiotensin I to A-II. Angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) antagonize the action of A-II at the A-II type 1 (AT(1)) receptor, whilst allowing the potentially beneficial actions of A-II mediated via the A-II type 2 (AT(2)) receptor. Evidence that the clinical benefit demonstrated with ACE inhibitors in patients with CHF may extend to ARBs has only emerged recently. Combination therapy with both an ACE inhibitor and an ARB has a number of potential advantages and has been investigated in several large-scale clinical trials recently. In patients with CHF, first-line therapy should include an ACE inhibitor and a beta-adrenoceptor antagonist. The addition of an ARB provides symptomatic relief but has not been shown to improve survival. Where an ACE inhibitor is not tolerated, treatment with an ARB would seem an appropriate alternative. There is insufficient data to support the routine use of ARBs as first-line therapy in the management of CHF.     

ACE inhibitors,angiotensin receptor blockers and direct renin inhibitors in combination: a review of their role after the ONTARGET trial

ABSTRACT

Background: Clinical trials have shown organ-protective effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs); however, cardiovascular mortality and morbidity rates, and decline in renal function remain high. In the ONTARGET trial in patients with hypertension at high cardiovascular risk, ACE inhibitor/ARB combination therapy provided no significant clinical outcome benefits over monotherapy, and was associated with a worse safety and tolerability profile. These results raise the question of whether ACE inhibitor/ARB, direct renin inhibitor (DRI)/ACE inhibitor and DRI/ARB combinations are of clinical value.

Scope: Using PubMed and EMBASE databases, we conducted a systematic review of clinical trials published before June 2008 evaluating dual intervention with ACE inhibitors and ARBs, and compared these with trials of DRI/ACE inhibitor or DRI/ARB combinations.

Findings: A total of 70 studies met the inclusion criteria for this analysis. In patients with hypertension, ACE inhibitor/ARB combinations provided limited additional reductions in blood pressure (BP) over monotherapy. Outcomes benefits were unclear: VALIANT and ONTARGET demonstrated no enhanced outcome benefit of combination therapy over monotherapy; Val-HeFT and CHARM-Added showed reduced morbidity/mortality in patients with heart failure, but at the expense of poorer tolerability. Combination therapy with the DRI aliskiren and an ACE inhibitor or ARB provided significant additional BP reductions over monotherapy in patients with mild-to-moderate hypertension, and reduced surrogate markers of organ damage in patients with heart failure or diabetic nephropathy, with generally similar safety and tolerability to the component monotherapies. No morbidity and mortality data for DRI/ACE inhibitor or DRI/ARB combinations are currently available.

Conclusions: ACE inhibitor/ARB combinations showed equivocal effects on clinical outcomes. DRI/ACE inhibitor and DRI/ARB combinations reduced markers of organ damage, but longer-term trials are required to establish whether more complete renin--angiotensin--aldosterone system control with aliskiren-based therapy translates into improved outcome benefits.     

Treatment of heart failure in patients with diabetes mellitus

Patients with diabetes mellitus have an increased morbidity and mortality from cardiovascular disease. Both coronary artery disease and congestive heart failure (CHF) are largely responsible for the increased cardiovascular adverse events in patients with diabetes. This review discusses the pathophysiology of CHF, the mechanisms of left ventricular (LV) dysfunction and the neurohormonal mechanisms involved in both LV dysfunction and CHF. Diabetes with and without hypertension is an important cause of LV dysfunction and CHF. Diabetes may be responsible for the metabolic and ultrastructural causes of LV dysfunction, while hypertension may be responsible for the marked fibrotic changes that are found. Experimental induction of diabetes in animals has shed light on the biochemical and ultrastructural changes seen. The role of insulin to reverse both metabolic and structural changes is reviewed both from experimental data and with the limited amount of clinical data available. The therapy of CHF in patients with diabetes is similar to that of patients without diabetes, with therapy directed toward the use of beta-blockers and angiotensin converting enzyme (ACE) inhibitors. As the morbidity and mortality are higher in patients with diabetes, several studies have pointed out the importance of this subgroup where the opportunity to make a significant clinical impact exists. A significant opportunity exists to reduce morbidity and mortality with beta-blockers and ACE inhibitors when ischaemia and CHF are both present. However, studies in patients diabetes have been limited to post hoc subgroup analyses and rarely as predefined subgroups. Clinical trials involving patients with diabetes with and without hypertension and LV dysfunction are clearly needed in the future to adequately address the needs of this high risk subgroup.     

Perindopril versus angiotensin II receptor blockade in hypertension and coronary artery disease: implications of clinical trials

The renin-angiotensin-aldosterone system (RAAS) is now known to play a key role in the pathogenesis of hypertension and a range of other cardiovascular diseases. Two groups of drugs, the ACE inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) have been developed with the aim of improving clinical outcomes by regulating the RAAS in patients with cardiovascular disease. Initial assumptions were that these two drug types might be interchangeable, but ongoing research has revealed differences between them in terms of pharmacology and outcomes in clinical trials. Although both groups of drugs lower blood pressure, studies of the ACE inhibitor perindopril have revealed preservation of beneficial vascular and endothelial effects mediated by bradykinin and nitric oxide. The selective blockade exerted by ARBs is not associated with these effects. Furthermore, examination of clinical endpoints in major clinical trials has provoked discussion about outcomes comparing ACE inhibitors and ARBs, with recent debate focusing on the incidence of myocardial infarction (MI) in patients receiving these agents. Whether there is an actual difference in protection from MI remains unresolved, although available data confirm the benefit and safety of ACE inhibitors, in particular perindopril, for myocardial protection.     

Congestive Heart Failure

Left ventricular systolic dysfunction is associated with neurohormonal activation which contributes to progressive ventricular remodeling and worsening clinical heart failure. Renin-angiotensin-aldosterone and sympathetic nervous systems are activated, not only in patients with clinically overt heart failure, but also in patients with asymptomatic or minimally symptomatic left ventricular systolic dysfunction. Activation of the angiotensin and adrenergic systems produces deleterious effects on systemic and coronary hemodynamics, promotes myocyte hypertrophy and fibroblast growth, and myocyte necrosis and apoptosis. Thus, therapy of heart failure should consist of pharmacologic agents not only to relieve symptoms but also to prevent and attenuate ventricular remodeling and progressive heart failure, thereby improving prognosis. In patients who are symptomatic, ACE inhibitors along with digitalis and diuretics as initial therapy (triple therapy) have the greater potential to improve exercise tolerance and decrease the incidence of treatment failure compared with diuretics alone or a combination of diuretics and digitalis. Diuretics alone should not be considered for long-term therapy as plasma renin activity, angiotensin II, aldosterone, norepinephrine and vasopressin levels may increase. ACE inhibitors decrease mortality in patients with heart failure resulting from left ventricular systolic dysfunction. The results of presently available studies indicate that angiotensin II receptor blockers (ARBs) do not provide any advantage over ACE inhibitors regarding survival benefit but may be better tolerated. Long-term adrenergic inhibition with the use of ß-adrenoceptor antagonists added to ACE inhibitors is associated with attenuation of ventricular remodeling, improvement in ventricular function and clinical class and survival of patients with symptomatic systolic left ventricular failure. Thus, initial pharmacotherapy for systolic heart failure should consist of: (i) maximal tolerated dosages of ACE inhibitors; (ii) ARBs if ACE inhibitors are not tolerated because of intractable cough or angioedema; (iii) adequate dosages of hydralazine and isosorbide dinitrate if ACE inhibitors or ARBs are not tolerated; (iv) relatively low dosages of digoxin (serum concentrations of ≤ 1.0 ng/dl) if not contraindicated; and (v) diuretics to relieve congestive symptoms. Addition of spironolactone to ACE inhibitors can result in a significant reduction in the risk of sudden death in patients with symptomatic severe heart failure. Myocardial infarction resulting from ischemic heart disease is the most common cause of systolic left ventricular failure and the therapeutic modalities with potential to reduce the risks of myocardial infraction, such as risk factor modification, adequate control of diabetes and hypertension, antiplatelet agents and lipid-lowering agents, should also be included in the initial therapy.     

Pharmacotherapy for heart failure with left ventricular dysfunction: beyond angiotensin-converting enzyme inhibitors and beta-blockers

Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers make up the cornerstone of therapy for patients with heart failure involving left ventricular dysfunction. These drug classes have been proven to decrease morbidity and mortality in patients with heart failure. Unfortunately, many patients remain symptomatic and experience disease progression despite taking both an ACE inhibitor and a beta-blocker. Others may be unable to tolerate one or both of these agents. In recent years, several other drug classes have been shown to provide additional morbidity and mortality benefits in patients with heart failure. These include angiotensin II receptor blockers (ARBs), aldosterone antagonists, and the combination of isosorbide dinitrate plus hydralazine. To select the most appropriate drug therapy for patients with heart failure, clinicians should consider results from clinical trials in specific patient populations, adverse-event profiles, tolerability, cost, and dosing regimens.     

ACE inhibitors and angiotensin receptor antagonists and the incidence of new-onset diabetes mellitus: an emerging theme

The prevalence of type 2 diabetes mellitus continues to rise. Given the associated co-morbidities of obesity, hypertension and cardiovascular disease, the rising incidence of diabetes has important health consequences and efforts to reduce this incidence are critical. Although lifestyle modifications, including weight loss and exercise, are instrumental in the prevention of diabetes, pharmacological therapies that reduce the incidence of diabetes have the significant potential to lower risk.The results of several large clinical trials have demonstrated that treatment with ACE inhibitors and angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) may prevent or delay the onset of diabetes. These trials have demonstrated an approximately 15-30% reduction in the new onset of diabetes in those receiving ACE inhibitors and ARBs when compared with placebo or other active therapy. Although the exact mechanism underlying the effects are not entirely clear, multiple animal and human studies have demonstrated that the renin-angiotensin system plays an important role in glucose homeostasis. Although future prospective studies to clarify the role of ACE inhibitors and ARBs in preventing diabetes are ongoing, there is substantial existing evidence from completed trials that these agents may prevent the onset of diabetes.     

Left Ventricular Diastolic Dysfunction in Diabetic Patients

Patients with signs and symptoms of heart failure and a preserved left ventricular (LV) systolic function may have significant abnormalities in diastolic function. This condition is called diastolic heart failure (DHF) and is observed in about 40% of patients with chronic heart failure (CHF). Diabetes mellitus is one of the major risk factors for DHF. Diastolic dysfunction is observed in about 40% of patients with diabetes mellitus and correlates with poor glycemic control. Suggested mechanisms for diastolic dysfunction in the diabetic heart are: (i) abnormalities in high-energy phosphate metabolism; (ii) impaired calcium transport; (iii) interstitial accumulation of advanced glycosylation end products; (iv) imbalance in collagen synthesis and degradation; (v) abnormal microvascular function, (vi) activated cardiac renin-angiotensin system; (vii) decreased adiponectin levels; and (viii) alteration in the metabolism of free fatty acids and glucose. Because most large, randomized clinical trials in CHF have enrolled only patients with systolic dysfunction, the specific management of diastolic dysfunction is largely unknown. The CHARM-Preserved (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity-Preserved) trial, the only mega trial specific for DHF (LV ejection fraction >40%), showed that the angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]) candesartan cilexetil reduced hospital admissions for CHF but not cardiovascular death. Currently, the pharmacologic treatment used in systolic heart failure is also recommended in DHF and includes administration of diuretics and nitrates for pulmonary congestion, and long-term management with ACE inhibitors, ARBs, aldosterone antagonists, and beta-adrenoceptor antagonists. Poor glycemic control is associated with a high incidence of heart failure in diabetic patients, but the preferable antihyperglycemic regimen for DHF in patients with diabetes mellitus needs to be determined in further studies.