Ivabradine: Current and Future Treatment of Heart Failure

In heart failure (HF), the heart cannot pump blood efficiently and is therefore unable to meet the body's demands of oxygen, and/or there is increased end‐diastolic pressure. Current treatments for HF with reduced ejection fraction (HFrEF) include angiotensin‐converting enzyme (ACE) inhibitors, angiotension receptor type 1 (AT₁) antagonists, β‐adrenoceptor antagonists, aldosterone receptor antagonists, diuretics, digoxin and a combination drug with AT₁ receptor antagonist and neprilysin inhibitor. In HF, the risk of readmission for hospital and mortality is markedly higher with a heart rate (HR) above 70 bpm. Here, we review the evidence regarding the use of ivabradine for lowering HR in HF. Ivabradine is a blocker of an I funny current (I(f)) channel and causes rate‐dependent inhibition of the pacemaker activity in the sinoatrial node. In clinical trials of HFrEF, treatment with ivabradine seems to improve clinical outcome, for example improved ejection fraction (EF) and less readmission for hospital, but the effect appears most pronounced in patients with HRs above 70 bpm, while the effect on cardiovascular death appears less consistent. The adverse effects of ivabradine include bradycardia, atrial fibrillation and visual disturbances, but ivabradine avoids the negative inotrope effects observed with β‐adrenoceptor antagonists. In conclusion, in patients with stable HFrEF with EF<35% and HR above 70 bpm, ivabradine improves the outcome and might be a first choice of therapy, if beta‐adrenoceptor antagonists are not tolerated. Further studies must show whether that can be extended to HF patients with preserved EF.     

Comparative pharmacology of the angiotensin II receptor antagonists

The non-peptide angiotensin II (AII) receptor antagonists are a new class of compounds that are continuing to be developed as therapeutic agents for the treatment of hypertension, heart failure (HF) and chronic renal disease (CRD). Several of these compounds are currently available for therapeutic use in the USA and the European community with several more in clinical trials and in development. Compounds in this new class are as effective as angiotensin converting enzyme (ACE) inhibitors in treating hypertensive patients and appeared to have a similar therapeutic profile to ACE inhibitors in patients with HF and CRD. One clinical advantage of the AII receptor antagonists over ACE inhibitors is an improved side-effect profile with the absence of the persistent dry cough associated with ACE inhibitor therapy. To date, it is clear that the AII receptor antagonists are effective antihypertensive agents. Clinical trials are currently in progress to determine the therapeutic efficacy of these drugs in the treatment of HF and progressive renal disease.     

Emerging therapies for heart failure

Although multiple advancements have been made in the treatment of heart failure (HF), mortality rates remain alarmingly high. The accepted arsenal of therapeutics includes a diuretic, digitalis, a beta-blocking agent and an inhibitor of the renin-angiotensin-aldosterone system. Despite the employment of a vast array of agents, nearly 300,000 patients in the US die annually with HF as a primary or contributory cause of death. Additional molecular targets are being evaluated in preclinical and clinical settings including vasopeptidase inhibitors, endothelin-1 receptor antagonists, arginine vasopressin antagonists, selective aldosterone blockers, TNF-alpha blockers and matrix metalloproteinase inhibitors. Although these approaches hold promise as viable therapeutics, a thorough evaluation of clinical benefit from these agents requires additional trials. Future disease-modifying approaches will also undoubtedly include cell transplantation and gene therapy. It is likely that notable advances in HF treatment will come from agents that attenuate myocardial remodelling. Indeed, maintenance or improvement of cardiac structure can attenuate HF development and improve mortality.     

Present and future pharmacotherapy for heart failure

The pharmacotherapy currently recommended by the American College of Cardiology and the American Heart Association for heart failure (HF) is a diuretic, an angiotensin-converting enzyme inhibitor (ACEI), a beta-adrenoceptor antagonist and (usually) digitalis. This current treatment of HF may be improved by optimising the dose of ACEI used, as increasing the dose of lisinopril increases its benefits in HF. Selective angiotensin receptor-1 (AT(1)) antagonists are effective alternatives for those who cannot tolerate ACEIs. AT(1) antagonists may also be used in combination with ACEIs, as some studies have shown cumulative benefits for the combination. In addition to being used in Stage IV HF patients, in whom it has a marked benefit, spironolactone should be studied in less severe HF and in the presence of beta-blockers. The use of carvedilol, extended-release metoprolol and bisoprolol should be extended to severe HF patients as these agents have been shown to decrease mortality in this group. The ancillary properties of carvedilol, particularly antagonism at prejunctional beta -adrenoceptors, may give it additional benefits to selective beta(1)-adrenoceptor antagonists. Celiprolol and bucindolol are not the beta-blockers of choice in HF, as they do not decrease mortality. Although digitalis does not reduce mortality, it remains the only option for a long-term positive inotropic effect, as the long-term use of the phosphodiesterase inhibitors is associated with increased mortality. The calcium sensitising drug levosimendan may be useful in the hospital treatment of decompensated HF to increase cardiac output and improve dyspnoea and fatigue. The antiarrhythmic drug amiodarone should probably be used in patients at high risk of arrhythmic or sudden death, although this treatment may soon be superseded by the more expensive implanted cardioverter defibrillators, which are probably more effective and have fewer side effects. The natriuretic peptide nesiritide has recently been introduced for the hospital treatment of decompensated HF. Novel drugs that may be beneficial in the treatment of HF include the vasopeptidase inhibitors and the selective endothelin-A receptor antagonists but these require much more investigation. However, disappointing results have been obtained in a large clinical trial of the tumour necrosis factor alpha antagonist etanercept, where no likelihood of a difference between placebo and etanercept was observed. Small clinical trials with recombinant growth hormone to thicken ventricles in dilated cardiomyopathy have given variable results.     

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.     

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 in Heart Failure

ACE inhibitors have significantly decreased cardiovascular mortality, myocardial infarction (MI), and hospitalizations for heart failure (HF) in patients with asymptomatic or symptomatic left ventricular (LV) systolic dysfunction. Furthermore, the extended 12-year study of the SOLVD (Studies Of Left Ventricular Dysfunction) Prevention and Treatment trials (X-SOLVD) demonstrated a significant benefit with a reduction of cumulative all-cause death compared with placebo (50.9% vs 56.4%) [hazard ratio (HR) 0.86; 95% CI 0.79, 0.93; p < 0.001]. The survival benefits and significant reductions in cardiovascular morbidity related to treatment with ACE inhibitors are likely achieved by titrating the dose of ACE inhibitors to the target dose achieved in clinical trials. Although the ATLAS (Assessment of Treatment with Lisinopril And Survival) study, which randomly allocated HF patients to low- or high-dose lisinopril, showed no significant difference between groups for the primary outcome of all-cause mortality (HR 0.92; 95% CI 0.82, 1.03), the predetermined secondary combined outcome of all-cause mortality and HF hospitalization was reduced by 15% for the patients receiving high-dose lisinopril compared with low-dose (p < 0.001) with a 24% reduction in HF hospitalization (p = 0.002). Despite the use of ACE inhibitors, blockade of the renin angiotensin aldosterone system (RAAS) remains incomplete, with evidence of continued production of angiotensin II by non-ACE-dependent pathways. The safety and potential benefits of angiotensin receptor antagonists (angiotensin receptor blockers [ARBs]) in patients with impaired systolic function have been assessed in moderate to large clinical trials. In patients with impaired LV systolic function and HF, combination therapy with ARBs with recommended HF therapy including ACE inhibitors in patients who remain symptomatic may be considered for its morbidity benefit. Based on the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity)-Added data, candesartan cilexetil in addition to standard HF therapy results in a further reduction of cardiovascular mortality. Close monitoring of renal function and serum potassium levels is needed in this setting. The VALIANT (VALsartan In Acute myocardial iNfarction Trial) results suggest that valsartan is as effective as captopril in patients following an acute MI with HF and/or LV systolic dysfunction and may be used as an alternative treatment in ACE inhibitor-intolerant patients. There was no survival benefit with valsartan-captopril combination compared with captopril alone in this trial. Despite these results, ACE inhibitors remain the first-choice therapeutic agent in post-MI patients, and ARBs can be used in patients with clear intolerance. Although the use of ACE inhibitors may be appealing in patients with HF and preserved LV systolic function, there is currently no evidence from large clinical trials to support this.     

Present and future pharmacotherapy for heart failure

The pharmacotherapy currently recommended by the American College of Cardiology and the American Heart Association for heart failure (HF) is a diuretic, an angiotensin-converting enzyme inhibitor (ACEI), a β-adrenoceptor antagonist and (usually) digitalis. This current treatment of HF may be improved by optimising the dose of ACEI used, as increasing the dose of lisinopril increases its benefits in HF. Selective angiotensin receptor-1 (AT₁) antagonists are effective alternatives for those who cannot tolerate ACEIs. AT₁ antagonists may also be used in combination with ACEIs, as some studies have shown cumulative benefits for the combination. In addition to being used in Stage IV HF patients, in whom it has a marked benefit, spironolactone should be studied in less severe HF and in the presence of β-blockers. The use of carvedilol, extended-release metoprolol and bisoprolol should be extended to severe HF patients as these agents have been shown to decrease mortality in this group. The ancillary properties of carvedilol, particularly antagonism at prejunctional β-adrenoceptors, may give it additional benefits to selective β₁-adrenoceptor antagonists. Celiprolol and bucindolol are not the β-blockers of choice in HF, as they do not decrease mortality. Although digitalis does not reduce mortality, it remains the only option for a long-term positive inotropic effect, as the long-term use of the phosphodiesterase inhibitors is associated with increased mortality. The calcium sensitising drug levosimendan may be useful in the hospital treatment of decompensated HF to increase cardiac output and improve dyspnoea and fatigue. The antiarrhythmic drug amiodarone should probably be used in patients at high risk of arrhythmic or sudden death, although this treatment may soon be superseded by the more expensive implanted cardioverter defibrillators, which are probably more effective and have fewer side effects. The natriuretic peptide nesiritide has recently been introduced for the hospital treatment of decompensated HF. Novel drugs that may be beneficial in the treatment of HF include the vasopeptidase inhibitors and the selective endothelin-A receptor antagonists but these require much more investigation. However, disappointing results have been obtained in a large clinical trial of the tumour necrosis factor α antagonist etanercept, where no likelihood of a difference between placebo and etanercept was observed. Small clinical trials with recombinant growth hormone to thicken ventricles in dilated cardiomyopathy have given variable results.     

Pharmacotherapy for prostate cancer,with emphasis on hormonal treatments

For more than half a century, hormonal therapy has been one of the cornerstones of prostate cancer therapy. However, the position and timing of androgen deprivation therapy is continuously challenged. Nowadays, it is often combined with other types of treatment in a multi-modal approach, especially with radiation therapy. Besides the well-known luteinising hormone-releasing hormone agonists, several developments have been introduced (e.g., luteinising hormone-releasing hormone antagonists or improved depot formulations achieving a better pharmacokinetic slope and lower testosterone levels). Research developments include a better understanding of the different gonadotropin-releasing hormone isoforms, the ligand-independent transformation of the androgen receptor and androgen receptor overexpression in hormone-insensitive disease. Prostate cancer, previously thought to be chemotherapy insensitive, is now treated at the metastatic stage by taxane-based chemotherapies. The combination of hormonal therapy and chemotherapy is currently studied at various stages of the disease, as early as localised or locally advanced prostate cancer. It is very likely that, in the future, pharmacological treatment for prostate cancer will include combination therapies rather than monotherapies. The authors suggest an in-depth re-evaluation of the place of androgen deprivation therapy in prostate cancer.     

Pharmacotherapy for prostate cancer, with emphasis on hormonal treatments

For more than half a century, hormonal therapy has been one of the cornerstones of prostate cancer therapy. However, the position and timing of androgen deprivation therapy is continuously challenged. Nowadays, it is often combined with other types of treatment in a multi-modal approach, especially with radiation therapy. Besides the well-known luteinising hormone-releasing hormone agonists, several developments have been introduced (e.g., luteinising hormone-releasing hormone antagonists or improved depot formulations achieving a better pharmacokinetic slope and lower testosterone levels). Research developments include a better understanding of the different gonadotropin-releasing hormone isoforms, the ligand-independent transformation of the androgen receptor and androgen receptor overexpression in hormone-insensitive disease. Prostate cancer, previously thought to be chemotherapy insensitive, is now treated at the metastatic stage by taxane-based chemotherapies. The combination of hormonal therapy and chemotherapy is currently studied at various stages of the disease, as early as localised or locally advanced prostate cancer. It is very likely that, in the future, pharmacological treatment for prostate cancer will include combination therapies rather than monotherapies. The authors suggest an in-depth re-evaluation of the place of androgen deprivation therapy in prostate cancer.     

Current and emerging pharmacologic options for the management of patients with chronic and acute decompensated heart failure

Introduction: For many years heart failure (HF) was known as a fatal disease with an ominous prognosis. In the last decades better understanding of the pathophysiological mechanisms underlying HF has resulted in major breakthrough in the management and improvement in the natural history of this clinical syndrome.

Areas covered: The review is focused on current and upcoming pharmacological therapies in patients with chronic and acute HF, starting with brief overview of drugs which improve the outcomes in patients with chronic HF with reduced ejection fraction (EF) including neurohormonal antagonists, angiotensin receptor neprilysin inhibitor and If- channel inhibitor, then presenting the summary of symptomatic treatment, the pharmacotherapy in chronic HF with preserved and mid-range EF and in acute HF. Finally, we report the emerging pharmacologic options and ongoing clinical trials and future directions in pharmacotherapy.

Expert commentary: The guidelines-recommended therapies in HF with reduced EF need to be widely implemented into the everyday clinical practice. Better clinical characterization of HF with preserved, mid-range EF and acute HF, with better understanding of the underlying pathophysiological mechanisms may ultimately result in a development of effective strategies improving ominous outcomes in these patients.     

Emerging drugs in the management of hypertension

Hypertension is a global health problem, affecting developing and developed countries alike. Most patients with hypertension are undiagnosed, and most diagnosed patients are either untreated or inadequately treated. Randomised controlled trial evidence suggests diuretic therapy for hypertension is as effective as newer drugs in reducing cardiovascular events. There is good evidence for the use of specific classes of drugs in hypertensive patients with a variety of associated clinical conditions, but for uncomplicated cases, the current emphasis in hypertension management is on blood pressure lowering rather than drug class. Individual patients vary in their responses to different drug classes, and optimal therapy for the individual is determined by trial and error. Pharmacogenomics may assist in tailoring therapy for individuals in the future. Emerging drugs include newer members of classes already established in clinical practice, for example, angiotensin II receptor antagonists, aldosterone receptor antagonists, calcium antagonists and centrally acting drugs; newer fixed-dose combination therapies; and more novel therapies, for example, endothelin (ET) receptor antagonists, activators of nitric oxide (NO)-sensitive guanylyl cyclase and vasopeptidase inhibitors.     

Emerging drugs in the management of hypertension

Hypertension is a global health problem, affecting developing and developed countries alike. Most patients with hypertension are undiagnosed, and most diagnosed patients are either untreated or inadequately treated. Randomised controlled trial evidence suggests diuretic therapy for hypertension is as effective as newer drugs in reducing cardiovascular events. There is good evidence for the use of specific classes of drugs in hypertensive patients with a variety of associated clinical conditions, but for uncomplicated cases, the current emphasis in hypertension management is on blood pressure lowering rather than drug class. Individual patients vary in their responses to different drug classes, and optimal therapy for the individual is determined by trial and error. Pharmacogenomics may assist in tailoring therapy for individuals in the future. Emerging drugs include newer members of classes already established in clinical practice, for example, angiotensin II receptor antagonists, aldosterone receptor antagonists, calcium antagonists and centrally acting drugs; newer fixed-dose combination therapies; and more novel therapies, for example, endothelin (ET) receptor antagonists, activators of nitric oxide (NO)-sensitive guanylyl cyclase and vasopeptidase inhibitors.     

Sarcoplasmic reticulum and cardiac oxidative stress: an emerging target for heart disease

The sarcoplasmic reticulum (SR) is a major player in maintaining cardiac function, as it is intimately involved in the regulation of Ca2+-movements on a beat-to-beat basis. SR dysfunction due to abnormalities in SR protein content has been reported in different cardiac diseases such as ischaemic heart disease, myocardial infarction, congestive heart failure and various cardiomyopathies; thus the genes expressing the SR Ca2+-pump, Ca2+-channels, calsequestrin, phospholamban and other regulatory proteins are considered important targets for drug development. In our experience, ischaemic preconditioning (IP) and pharmacological therapies, such as anti-oxidants, beta-adrenergic receptor blockers, angiotensin receptor (AT-1) blockers, angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers are effective therapies that improve cardiac performance in the failing heart by improving SR function. Accordingly, this paper is intended to shed light on the knowledge in the field of cardiac therapy targeted to improve and protect SR function.     

Mechanisms of sympathetic activation in heart failure

1. Heart Failure (HF) is a serious, debilitating condition with poor survival rates and an increasing level of prevalence. A characteristic of HF is a compensatory neurohumoral activation that increases with the severity of the condition. 2. The increase in sympathetic activity may be beneficial initially, providing inotropic support to the heart and peripheral vasoconstriction, but in the longer term it promotes disease progression and worsens prognosis. This is particularly true for the increase in cardiac sympathetic nerve activity, as shown by the strong inverse correlation between cardiac noradrenaline spillover and prognosis and by the beneficial effect of beta-adrenoceptor antagonists. 3. Possible causes for the raised level of sympathetic activity in HF include altered neural reflexes, such as those from baroreceptors and chemoreceptors, raised levels of hormones, such as angiotensin II, acting on circumventricular organs, and changes in central mechanisms that may amplify the responses to these inputs. 4. The control of sympathetic activity to different organs is regionally heterogeneous, as demonstrated by a lack of concordance in burst patterns, different responses to reflexes, opposite responses of cardiac and renal sympathetic nerves to central angiotensin and organ-specific increases in sympathetic activity in HF. These observations indicate that, in HF, it is essential to study the factors causing sympathetic activation in individual outflows, in particular those that powerfully, and perhaps preferentially, increase cardiac sympathetic nerve activity.     

Angiotensin II, angiotensin II antagonists and spironolactone and their modulation of cardiac repolarization

Angiotensin II and aldosterone produce pro-arrhythmic effects by several mechanisms, including the modulation of voltage-dependent K(+) channels involved in human cardiac repolarization. Drugs that inhibit the renin-angiotensin-aldosterone system exert anti-arrhythmic actions that are related to the blockade of the pro-arrhythmic actions of angiotensin II and aldosterone. These anti-arrhythmic actions include inhibition of electrical and structural cardiac remodeling, inhibition of neurohumoral activation, reduction of blood pressure and stabilization of electrolyte disturbances. In this article, several angiotensin II AT(1) receptor antagonists (candesartan, E3174, eprosartan, irbesartan and losartan) and aldosterone receptor antagonists (canrenoic acid and spironolactone) that directly modulate the activity of the voltage-dependent K(+) channels are reviewed; the effects of these antagonists might be useful in the prevention and treatment of cardiac arrhythmias.     

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).     

The pharmacotherapy implications of ventricular assist device in the patient with end-stage heart failure

Advances in mechanical circulatory support, such as the use of ventricular assist devices (VADs), have become a means for prolonging survival in end-stage heart failure (HF). VADs decrease the symptoms of HF and improve quality of life by replacing some of the work of a failing heart. They unload the ventricle to provide improved cardiac output and end-organ perfusion, resulting in improvement in cardiorenal syndromes and New York Heart Association functional class rating. VADs are currently used asa bridge to heart transplantation, a bridge to recovery of cardiac function, or as destination therapy. Complications of VAD include bleeding, infections, arrhythmias, multiple organ failure, right ventricular failure, and neurological dysfunction. Patients with VAD have unique pharmacotherapeutic requirements in terms of anticoagulation, appropriate antibiotic selection, and continuation of HF medications. Pharmacists in acute care and community settings are well prepared to care for the patient with VAD. These patients require thorough counseling and follow-up with regard to prevention and treatment of infections, appropriate levels of anticoagulation, and maintenance of fluid balance. A basic understanding of this unique therapy can assist pharmacists in attending to the needs of patients with VAD.     

Sarcoplasmic reticulum and cardiac oxidative stress: an emerging target for heart disease

The sarcoplasmic reticulum (SR) is a major player in maintaining cardiac function, as it is intimately involved in the regulation of Ca²⁺-movements on a beat-to-beat basis. SR dysfunction due to abnormalities in SR protein content has been reported in different cardiac diseases such as ischaemic heart disease, myocardial infarction, congestive heart failure and various cardiomyopathies; thus the genes expressing the SR Ca²⁺-pump, Ca²⁺-channels, calsequestrin, phospholamban and other regulatory proteins are considered important targets for drug development. In our experience, ischaemic preconditioning (IP) and pharmacological therapies, such as anti-oxidants, β-adrenergic receptor blockers, angiotensin receptor (AT-1) blockers, angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers are effective therapies that improve cardiac performance in the failing heart by improving SR function. Accordingly, this paper is intended to shed light on the knowledge in the field of cardiac therapy targeted to improve and protect SR function.     

Stroke: antithrombin versus antiplatelet therapy

The success of thrombolytic therapy for acute stroke has demonstrated that neurologic outcome can be improved with timely treatment. However, the severely restricted use of thrombolytics has reinforced the need to develop alternative and complementary therapies. Antithrombin and antiplatelet agents represent promising therapeutic approaches for stroke management. Antiplatelet therapy has modestly improved outcome in both acute stroke (aspirin) and in secondary stroke prevention (aspirin with or without dipyridamole; adenosine receptor antagonists), although bleeding and other adverse events associated with antithrombin therapy have largely negated their potential benefit. These findings have prompted innovative solutions to the pharmacokinetic and pharmacodynamic challenges that are crucial to advancing these strategies for acute, primary and secondary stroke therapy. Currently, inhibitors of the platelet surface glycoprotein IIb/IIIa (GP IIb/IIIa, fibrinogen) receptor are being examined in clinical trials while antithrombin therapies focus on thrombin antagonists and inhibitors as well as inhibitors of Factor Xa. Further advances in stroke treatment will include combination therapies. Additionally, the successful design of future drug therapies will result from a more complete understanding of the activity of these agents not only on platelet function and the coagulation cascade, but also for their effects on the endothelium and within the brain parenchyma. The sum of these activities will allow for the maintenance of cerebral blood flow, blood-brain barrier integrity and neuronal function.