Epidemiology, pathophysiology, prognosis, and treatment of systolic and diastolic heart failure

Underlying causes, risk factors, and precipitating causes of heart failure (HF) should be treated. Drugs known to precipitate or aggravate HF such as nonsteroidal antiinflammatory drugs should be stopped. Patients with HF and a low left ventricular ejection fraction (systolic heart failure) or normal ejection fraction (diastolic HF) should be treated with diuretics if fluid retention is present, with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker if the patient cannot tolerate an ACE inhibitor because of cough, angioneurotic edema, rash, or altered taste sensation, and with a beta blocker unless contraindicated. If severe systolic HF persists, an aldosterone antagonist should be added. If HF persists, isosorbide dinitrate plus hydralazine should be added. Calcium channel blockers should be avoided if systolic HF is present. Digoxin should be avoided in men and women with diastolic HF if sinus rhythm is present and in women with systolic HF. Digoxin should be given to men with systolic HF if symptoms persist, but the serum digoxin level should be maintained between 0.5 and 0.8 ng/mL.     

Drug treatment of systolic and of diastolic heart failure in elderly persons

Underlying causes, risk factors, and precipitating causes of heart failure (HF) should be treated. Patients with HF and an abnormal left ventricular ejection fraction (systolic HF) or normal left ventricular ejection fraction (diastolic HF) should be treated with diuretics if fluid retention is present, with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker if the patient cannot tolerate an ACE inhibitor because of cough, angioneurotic edema, rash, or altered taste sensation, and with a beta blocker unless contraindicated. If severe systolic HF persists, an aldosterone antagonist should be added. If HF persists, isosorbide dinitrate plus hydralazine should be added. Calcium channel blockers should be avoided if systolic HF is present. Digoxin should be avoided in men and women with diastolic HF if sinus rhythm is present and in women with systolic HF. Digoxin should be given to men with systolic HF if symptoms persist, but the serum digoxin level should be maintained between 0.5 and 0.8 ng/ml. Cardiac synchronized pacing should be considered in patients with severe systolic HF despite optimal medical therapy, with sinus rhythm, and with ventricular dyssynchrony.     

ACE Inhibitor‐Related Angioedema: Can Angiotensin‐Receptor Blockers Be Safely Used?

Angioedema is a well-recognized side effect of angiotensin-converting enzyme (ACE) inhibitor therapy. Angioedema can also be seen with angiotensin receptor blocker therapy but much less frequently than is the case with ACE inhibitors. For unclear reasons, ACE inhibitor-related angioedema occurs more commonly in black patients. Angioedema can be life threatening but more times than not its occurrence can be managed with conservative treatment measures including discontinuation of the medication and/or administration of an antihistamine. Occasionally, epinephrine and/or steroid therapy may be warranted. In a patient having experienced ACE inhibitor-related angioedema, angiotensin receptor blockers should be used cautiously if at all. If angiotensin receptor blocker therapy is being considered in a patient with prior ACE inhibitor-related angioedema there should be some justification for the use. Such justification might include the presence of heart failure or proteinuric nephropathic states among other considerations.     

ACE Inhibitor-Related Angioedema: Can Angiotensin-Receptor Blockers Be Safely Used?

Angioedema is a well-recognized side effect of angiotensin-converting enzyme (ACE) inhibitor therapy. Angioedema can also be seen with angiotensin receptor blocker therapy but much less frequently than is the case with ACE inhibitors. For unclear reasons, ACE inhibitor-related angioedema occurs more commonly in black patients. Angioedema can be life threatening but more times than not its occurrence can be managed with conservative treatment measures including discontinuation of the medication and/or administration of an antihistamine. Occasionally, epinephrine and/or steroid therapy may be warranted. In a patient having experienced ACE inhibitor-related angioedema, angiotensin receptor blockers should be used cautiously if at all. If angiotensin receptor blocker therapy is being considered in a patient with prior ACE inhibitor-related angioedema there should be some justification for the use. Such justification might include the presence of heart failure or proteinuric nephropathic states among other considerations.     

Hypertension and coronary artery disease: a summary of the American Heart Association scientific statement

The American Heart Association scientific statement on the treatment of hypertension in the prevention and management of ischemic heart disease was published recently. The main recommendations were as follows: (1) For most adults with hypertension, the blood pressure (BP) goal is <140/90 mm Hg but should be <130/80 [corrected] mm Hg in patients with diabetes mellitus, chronic kidney disease, known coronary artery disease (CAD), CAD equivalents (carotid artery disease, abdominal aortic aneurism, and peripheral vascular disease), or 10-year Framingham risk score of >/=10%. For those with left ventricular dysfunction, the recommended BP target is <120/80 mm Hg. (2) For primary CAD prevention, any effective antihypertensive drug or combination is indicated, but preference is given to angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazide diuretics. (3) For the management of hypertension in patients with established CAD (stable or unstable angina, non-ST-segment elevation myocardial infarction, ST-segment elevation myocardial infarction), beta-blockers and ACE inhibitors (or ARBs) are the basis of treatment. If further BP lowering is needed, a thiazide diuretic and/or a dihydropyridine CCB (not verapamil or diltiazem) can be added. If a beta-blocker is contraindicated or not tolerated, diltiazem or verapamil can be substituted. (4) If there is left ventricular dysfunction, recommended therapy consists of an ACE inhibitor or ARB, a beta-blocker, and either a thiazide or loop diuretic. In patients with more severe heart failure, an aldosterone antagonist and hydralazine/isosorbide dinitrate (in black patients) should be considered.     

Managing the hypertensive patient with ischemic heart disease

Thiazide diuretics, b-blockers, calcium channel blockers, and angiotensin converting enzyme (ACE) inhibitors are all superior to placebo for the primary prevention of coronary events in patients with hypertension. Recent studies have shown that ACE inhibitors are better than other antihypertensive agents in lowering overall cardiovascular morbidity and mortality, especially stroke. Blood pressure should be aggressively lowered (to < 140/90 mm Hg), especially in diabetic patients (to < 130/80 mm Hg), but care should be exercised in lowering the diastolic blood pressure below 65 mm Hg in patients with significant occlusive coronary artery disease. Hypertension in patients with stable angina should be treated with a b-blocker (alternatively a calcium channel blocker) together with an ACE inhibitor. Patients with hypertension and acute coronary syndrome (unstable angina or myocardial infarction) should be treated with a b-blocker, and with an ACE inhibitor if there is left ventricular dysfunction. A thiazide diuretic and/or a dihydropyridine calcium channel blocker could be added for blood pressure control. Calcium channel blockers should be avoided if there is significant left ventricular dysfunction.     

ACE Inhibitors and Chronotherapy

Chronotherapy can improve the effectiveness and reduce the adverse reactions of drugs and actually is used for several conditions including cardiovascular diseases. Although angiotensin converting enzyme (ACE) inhibitors are available for the therapy of patients with hypertension and/or heart failure, these agents have some characteristic adverse effects such as angioedema and dry cough. It has been reported that the dosing of ACE inhibitor at an inactive period has a better protective effect against cardiac hypertrophy in hypertensive rats, and changing dosing time from morning to evening reduces the severity and frequency of the drug-induced dry cough of hypertensive patients treated in the morning. Thus, the dosing of ACE inhibitors in the inactive span is more effective and safe. Dosing in the evening may be an alternative for hypertensives with dry cough with a morning dose of ACE inhibitors, if one ascertains that no circadian hyperamplitude tension is induced by the evening dose of this or any other antihypertensive drug.     

ACE inhibitors and chronotherapy

Chronotherapy can improve the effectiveness and reduce the adverse reactions of drugs and actually is used for several conditions including cardiovascular diseases. Although angiotensin converting enzyme (ACE) inhibitors are available for the therapy of patients with hypertension and/or heart failure, these agents have some characteristic adverse effects such as angioedema and dry cough. It has been reported that the dosing of ACE inhibitor at an inactive period has a better protective effect against cardiac hypertrophy in hypertensive rats, and changing dosing time from morning to evening reduces the severity and frequency of the drug-induced dry cough of hypertensive patients treated in the morning. Thus, the dosing of ACE inhibitors in the inactive span is more effective and safe. Dosing in the evening may be an alternative for hypertensives with dry cough with a morning dose of ACE inhibitors, if one ascertains that no circadian hyperamplitude tension is induced by the evening dose of this or any other antihypertensive drug.     

Treatment of heart failure with abnormal left ventricular systolic function in the elderly

This article summarizes the four stages of heart failure (HF) as defined by the American College of Cardiology and the American Heart Association and discusses the treatments for elderly patients with HF and abnormal left ventricular systolic function. The article explains the important role of diuretics, the first-line drugs in the treatment of older patients with HF and volume overload. Other treatments described include angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, aldosterone antagonists, isosorbide dinitrate plus hydralazine, digoxin, and calcium channel blockers. The article explains the role each of these plays and reports on studies that have examined and compared various treatments.     

Angioedema associated with angiotensin-converting enzyme inhibitor use: outcome after switching to a different treatment

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are associated with angioedema episodes that are potentially life-threatening. Few data are available on the outcome of patients reporting this adverse effect when they are switched to another drug. Scattered reports of angioedema associated with angiotensin II receptor blocker (ARB) use question the safety of using these drugs in patients with ACE inhibitor-related angioedema. We describe 64 consecutive patients with ACE inhibitor-related angioedema, the outcome after discontinuing this treatment, and the safety of using ARBs. METHODS: Retrospective analysis of 64 consecutive patients (January 1993 to June 2002) presenting with angioedema onset while receiving treatment with an ACE inhibitor. RESULTS: Patients were recommended to stop ACE inhibitor use, substituting it upon advice of the physician. Fifty-four patients were available for follow-up (median follow-up, 11 months; range, 1-80 months): 26 had switched to an ARB, 14 to a calcium antagonist, and 14 to other antihypertensive drugs. Angioedema disappeared or drastically reduced upon withdrawal of the ACE inhibitor in 46 patients (85%). For the remaining 8 patients, angioedema was due to a cause other than ACE inhibitor use in 2; angioedema persisted independent of the treatment and without apparent cause (idiopathic angioedema) in 4; angioedema persisted after switching to an ARB and disappeared upon its withdrawal in 2. CONCLUSIONS: Stopping ACE inhibitor use without further assessments is a successful measure in the large majority of patients developing angioedema while taking this drug. Only a small percentage of patients with ACE inhibitor-related angioedema continue with this symptom when switched to an ARB.     

Treatment of heart failure with abnormal left ventricular systolic function in the elderly

This article summarizes the four stages of heart failure (HF) as defined by the American College of Cardiology and the American Heart Association and discusses the treatments for elderly patients with HF and abnormal left ventricular systolic function. The article explains the important role of diuretics, the first-line drugs in the treatment of older patients with HF and volume overload. Other treatments described include angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, aldosterone antagonists, isosorbide dinitrate plus hydralazine, digoxin, and calcium channel blockers. The article explains the role each of these plays and reports on studies that have examined and compared various treatments.     

Pharmacological treatment of chronic heart failure according to the 2005 guidelines of the European Society of Cardiology

Recently, the updated guidelines for the diagnosis and treatment of chronic heart failure were published. This review focuses on the pharmacological treatment. Basically, all patients with chronic heart failure and left ventricular systolic dysfunction should be treated with diuretics, ACE-inhibitors and beta-blockers, unless contra-indicated or not tolerated. It is important to uptitrate ACE-inhibitors and beta-blockers to the high recommended doses that were used in the randomised clinical trials. If an ACE-inhibitor is not tolerated or contra-indicated, it is recommended to start an angiotensin receptor blocker (ARB). Dose and choice of diuretics (loop acting or thiazides or combination) depends on volume status, renal function, and severity of heart failure. If patients remain symptomatic (NYHA class II), an ARB can be added, mainly to reduce worsening of heart failure and related hospitalisation. If patients remain severely symptomatic (NYHA class III), it is recommended to either add an aldosterone blocker, an ARB or both. The choice between an aldosterone blocker and an ARB depends on volume status, other specific patient characteristics, side effects, and personal preference. If all other therapies fail, one might consider nitrates, hydralazine and/or digoxin, while digoxin is always recommended in chronic heart failure patients with atrial fibrillation. Therefore, treatment of chronic heart failure is relatively simple. Although individual patient characteristics should always be taken into account, the current recommendations apply to all patients with chronic heart failure, irrespective its underlying cause.     

Angioedema in heart failure: occurrence with ACE inhibitors and safety of angiotensin receptor blocker therapy

Angioedema is a well-known side effect of treatment with an angiotensin-converting enzyme (ACE) inhibitor and one that we have been willing to accept in view of the incidence of the problem and the clear benefits of this class of agents in numerous clinical situations. Angioedema is also seen with angiotensin receptor blocker (ARB) therapy but much less frequently than with ACE inhibitors. The mechanism for angioedema with ARB therapy remains poorly defined. ACE inhibitor-related angioedema occurs more commonly in black patients. The basis for an increased risk of angioedema in black patients remains unclear. Angioedema can be life-threatening but more times than not it can be managed with conservative treatment measures including specifically the discontinuation of the medication and/or administration of an antihistamine and/or epinephrine. Occasionally, maneuvers to protect the integrity of the airway may be needed. In a heart failure patient having previously experienced ACE inhibitor-related angioedema, ARBs should be used cautiously since angioedema has been reported with ARB therapy in heart failure patients. The need to reduce renin-angiotensin aldosterone system activity in a heart failure patient would seem to justify the small risk of angioedema with ARB therapy in a patient having previously experienced ACE inhibitor-related angioedema.     

Neurohormonal Intervention to Reduce Sudden Cardiac Death in Heart Failure: What is the Optimal Pharmacologic Strategy?

Sudden cardiac death (SCD) accounts for up to 50% of deaths in patients with heart failure (HF), depending on severity of symptomatic impairment and left ventricular dysfunction. Neurohormonal therapy directed at the renin-angiotensin-aldosterone system may reduce the propensity to SCD through improved hemodynamic responsiveness, reduced sympathetic tone in the myocardium and inhibition of cardiac remodelling. Angiotensin converting enzyme (ACE) inhibitors reduce overall mortality in chronic HF, the greatest benefit appearing to arises from reduction of HF progression rather than SCD. In HF patients who experience myocardial infarction (MI) reduced incidence in SCD may make a more marked contribution to the mortality benefits of ACE inhibition. Addition of beta-blocker therapy to ACE inhibition has consistently resulted in a reduction in SCD in patients with either mild-to-moderate or severe HF, and in the presence or absence of MI; the reduction in SCD is of the order of one-third versus placebo. Aldosterone blockade reduces the risk of SCD in advanced chronic heart failure (when added to ACE inhibitor) and in HF associated with acute MI (when given in addition to both ACE inhibitor and beta blocker). The evidence base suggests that for maximal SCD risk reduction in HF, beta-blocker therapy is advisable in combination with standard ACE inhibitor therapy, with addition of aldosterone blockade to this regimen for particular groups of heart failure patients.     

Neurohormonal intervention to reduce sudden cardiac death in heart failure: what is the optimal pharmacologic strategy?

Sudden cardiac death (SCD) accounts for up to 50% of deaths in patients with heart failure (HF), depending on severity of symptomatic impairment and left ventricular dysfunction. Neurohormonal therapy directed at the renin-angiotensin-aldosterone system may reduce the propensity to SCD through improved hemodynamic responsiveness, reduced sympathetic tone in the myocardium and inhibition of cardiac remodelling. Angiotensin converting enzyme (ACE) inhibitors reduce overall mortality in chronic HF, the greatest benefit appearing to arises from reduction of HF progression rather than SCD. In HF patients who experience myocardial infarction (MI) reduced incidence in SCD may make a more marked contribution to the mortality benefits of ACE inhibition. Addition of beta-blocker therapy to ACE inhibition has consistently resulted in a reduction in SCD in patients with either mild-to-moderate or severe HF, and in the presence or absence of MI; the reduction in SCD is of the order of one-third versus placebo. Aldosterone blockade reduces the risk of SCD in advanced chronic heart failure (when added to ACE inhibitor) and in HF associated with acute MI (when given in addition to both ACE inhibitor and beta blocker). The evidence base suggests that for maximal SCD risk reduction in HF, beta-blocker therapy is advisable in combination with standard ACE inhibitor therapy, with addition of aldosterone blockade to this regimen for particular groups of heart failure patients.     

Heart failure drug utilization patterns for Medicaid patients before and after a heart failure-related hospitalization

The authors examined heart failure (HF) drug utilization patterns in Medicaid patients before and after a HF-related hospitalization. This was a retrospective claims analysis of Kansas Medicaid beneficiaries hospitalized for HF between July 1, 2000, and March 31, 2001. HF drugs were tracked 6 months prior and 6 months following the admission. Angiotensin-converting enzyme (ACE) inhibitor doses were compared with target ranges. The cohort of 135 patients had a mean age of 53.6 years and was predominantly female (66.7%) and Caucasian (70.4%) with a high prevalence of cardiovascular comorbidities. Before hospitalization, less than one third of patients were receiving ACE inhibitors, angiotensin receptor blockers, beta blockers, digoxin, or vasodilators. Following hospitalization, increased utilization was observed for beta blockers, digoxin, and angiotensin receptor blockers, but overall usage remained low. ACE inhibitors and vasodilator use remained constant. ACE-inhibitor doses were below target ranges before and after hospitalization. In this Medicaid cohort, HF-related hospitalizations did not lead to improved HF therapy.     

Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition

INTRODUCTION: The beneficial effects of ACE inhibitors are generally ascribed to blockade of neurohormonal activation. However, especially in chronic heart failure (CHF) patients plasma angiotensin II and aldosterone levels can be elevated despite ACE inhibition, the so-called ACE escape. In the present study, we aimed to identify the frequency and determinants of ACE escape in CHF patients. METHODS: We studied 99 stable chronic heart failure patients (NYHA class III and IV, 66% ischemic etiology) receiving long-term therapy with ACE inhibitors. In all patients, cardiac, renal, and neurohormonal parameters were measured. ACE escape was defined as plasma angiotensin level > or = 16 pmol/L. RESULTS: Mean (+/- SD) left ventricular ejection fraction of our 99 patients (79 men and 20 women, age 69 +/- 12 years) was 28 +/- 10%. In addition to an ACE inhibitor, 93% of patients received diuretics, 71% a beta-blocker, and 49% spironolactone. None of the patients used an angiotensin receptor blocker. In our population, 45% of the patients had an angiotensin II plasma concentration higher than 16 pmol/L (median concentration was 14.1 pmol/L). Spironolactone use was an independent predictor of elevated plasma angiotensin II levels. Furthermore, spironolactone users had significantly higher plasma active renin protein and aldosterone levels. Plasma angiotensin II concentration was positively correlated to active renin, plasma angiotensin I and plasma aldosterone. No correlation was found between plasma angiotensin II levels and serum ACE activity, dose of ACE inhibitor, or duration of use. CONCLUSION: In a group of severe chronic heart failure patients, 45% had elevated plasma angiotensin II levels independent of serum ACE activity despite long-term ACE inhibitor use. Although a causal link could not be proven, an association was found between spironolactone use and active renin protein, angiotensin II and aldosterone levels, suggesting that escape from ACE is mainly caused by a feedback mechanism.     

Low-Dose Aldosterone Blockade as a New Treatment Paradigm for Controlling Resistant Hypertension

Treatment of resistant hypertension requires confirmation of true resistance, diagnosis and treatment of secondary causes of hypertension, adoption of appropriate lifestyle modifications, and effective use of multidrug antihypertensive regimens. Excessive volume retention often underlies resistant hypertension, so diuretics are generally necessary to achieve blood pressure (BP) goals. Although treatment regimens consisting of 3 or more agents have not been systematically evaluated, the author has found a triple regimen consisting of a thiazide diuretic, a calcium channel blocker, and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) to be generally effective and well tolerated. Although hydrochlorothiazide is more widely used, chlorthalidone provides better BP reduction and should be preferentially used in patients with resistant hypertension, particularly if the patient remains uncontrolled on hydrochlorothiazide. Recent studies have demonstrated that low doses of aldosterone antagonists, when added to multi-drug regimens that include a thiazide diuretic and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, provide significant additional BP reduction, seemingly exceeding what would be expected with addition of alternative classes of agents. The degree of BP reduction induced by aldosterone blockade has been similar in patients with and without evidence of aldosterone excess. Aldosterone antagonists are generally safe and well tolerated. The most common adverse effect of low-dose spironolactone has been breast tenderness, occurring in about 10% of men. Hyperkalemia is uncommon, but can occur, necessitating biochemical monitoring. Risk of hyperkalemia is increased in patients with chronic kidney disease or diabetes, elderly patients, and patients already receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.     

CCS/CHFS Heart Failure Guidelines Update: Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction

In this update of the Canadian Cardiovascular Society heart failure (HF) guidelines, we provide comprehensive recommendations and practical tips for the pharmacologic management of patients with HF with reduced ejection fraction (HFrEF). Since the 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of HF, substantial new evidence has emerged that has informed the care of these patients. In particular, we focus on the role of novel pharmacologic therapies for HFrEF including angiotensin receptor-neprilysin inhibitors, sinus node inhibitors, sodium glucose transport 2 inhibitors, and soluble guanylate cyclase stimulators in conjunction with other long established HFrEF therapies. Updated recommendations are also provided in the context of the clinical setting for which each of these agents might be prescribed; the potential value of each therapy is reviewed, where relevant, for chronic HF, new onset HF, and for HF hospitalization. We define a new standard of pharmacologic care for HFrEF that incorporates 4 key therapeutic drug classes as standard therapy for most patients: an angiotensin receptor-neprilysin inhibitor (as first-line therapy or after angiotensin converting enzyme inhibitor/angiotensin receptor blocker titration); a β-blocker; a mineralocorticoid receptor antagonist; and a sodium glucose transport 2 inhibitor. Additionally, many patients with HFrEF will have clinical characteristics for which we recommended other key therapies to improve HF outcomes, including sinus node inhibitors, soluble guanylate cyclase stimulators, hydralazine/nitrates in combination, and/or digoxin. Finally, an approach to management that integrates prioritized pharmacologic with nonpharmacologic and invasive therapies after a diagnosis of HFrEF is highlighted.     

Safety and tolerability of the direct renin inhibitor aliskiren: a pooled analysis of clinical experience in more than 12,000 patients with hypertension

While the safety of renin-angiotensin system (RAS)-blocking drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers is well known, less is known about the new direct renin inhibitor aliskiren. The authors pooled data from 12 randomized controlled trials of aliskiren in patients with hypertension and analyzed the incidence and types of adverse events (AEs) and laboratory abnormalities. Studies were characterized as short-term (≤2 months) placebo-controlled or long-term (>2 months) active-controlled. Relative risks for AEs of particular interest for RAS blockers were calculated. In short-term studies, AEs occurred in similar proportions of aliskiren 150 mg and 300 mg (33.6% and 31.6%, respectively) and placebo treatment groups (36.8%). In long-term studies, a lower proportion of patients treated with aliskiren 150 mg and 300 mg had AEs (33.7% and 43.2%, respectively) than those treated with ACE inhibitors (60.1%), angiotensin receptor blockers (53.9%), and thiazide diuretics (48.9%). Events of special interest, including angioedema, hyperkalemia, and diarrhea occurred in similar proportions of patients taking aliskiren, placebo, and comparator agents. In studies of up to 36 weeks, patients treated with aliskiren were significantly less likely to develop cough than those treated with ACE inhibitors. At the registered doses of 150 mg and 300 mg daily, aliskiren has safety and tolerability profiles similar to placebo, other RAS blockers, and diuretics. Cough rates are lower with aliskiren compared with ACE inhibitors.