HEART FAIWRE
Netherlands Institute for Continuing Cardiovascular Education (CVOI) self-assessment In collaboration with Mediselect and supported by the company Novartis, the textbook Heart Failure, edited by Dirk Jan van Veldhuisen and Adriaan Voors, was published in Autumn 2003.
This textbook was primarily intended for the cardiology training course (OCC) in 2003. In like manner, the CVOI intends to publish textbooks on Atherosclerosis and Thrombosis in 2004 and Electrocardiography and Electrophysiology in 2005.
Following publication ofthe book, brieffocused reviews of its chapters will be published in consecutive issues ofthe Netherlands Heart Journal. After each of these articles, there will be two multiple-choice questions, which can be answered in the section Questions & Answers ofthe website ofthe CVOI, www.cvoi.org. Correct answers will be honoured with 1 credit, while wrong answers to one or both questions will connect the participant to a section that presents and discusses the correct answers, after which the procedure can be repeated. Correct answers to both questions will automatically lead to registration of the CME credits in the Cardiologist Registration Accreditation System (CRAS) on the CVOI website. All textbooks contain eight chapters; participants can therefore obtain 16 credit points. This experiment that connects CME articles to web-based self-assessment programmes and accreditation may pave the way for similar future developments and a reliable verifiable accreditation of CME articles.
Heart failure: chapter
6
Pharmacological treatment
of
chronic heart failure
A.A. Voors, P.H.J.M. Dunselman, D.J. van Veldhuisen
Heart failure is basically a cardiac disorder, but the signs and symptoms of heart failure are related to dysfunction of several other organ systems. Therefore, heart failure is currently considered a systemic disorder where neurohormonal activation leads to pulmonary oedema, changes in skeletal muscles, increased sympathetic vasotonus, decreased peripheral vascularisation and even several molecular changes. Because ofits versatility, it is obvious that monotherapy will be insufficient in the pharmacological treatment ofheart failure. Therefore, most patients with chronic heart failure are currently treated with several agents,
A.A. Voors D.J. van Veldhulson Department of Cardiology, Groningen University Hospital P.H.J.M. Dunselman Department of Cardiology, Amphia Hospital, Breda Address for correspondence: A.A. Voors E-mail: [email protected]
512
each of which has a different mode of action. In this article, we will discuss the current pharmacological possibilities and evidence in the treatment ofpatients with chronic heart failure and systolic left ventricular
dysfunction. Diuretics
The beneficial effects of diuretics on haemodynamics and symptoms of chronic heart failure are well established.' However, no randomised clinical trial has demonstrated beneficial effects of diuretics on mortality. Nevertheless, diuretics remain the cornerstone of therapy in chronic heart failure for several reasons: 1. Symptomatic improvement; 2. All randomised clinical trials ofACE inhibitors, ,3blockers, aldosterone blockers and angiotensinreceptor blockers have been done in combination with diuretics; 3. There are several reports suggesting that diuretics can potentiate the effects of ACE inhibitors. Therefore, diuretics are recommended in all patients with chronic heart failure. Dose and choice of diuretic
Netherlands Heart Journal, Volume 12, Number 11, November 2004
HEART FAILURE
(loop-acting or thiazides or a combination) depends on volume status, renal function, and severity of heart failure. ACE Inhibitors Activation ofthe renin-angiotensin system (RAS) plays a key role in the pathogenesis of heart failure. The beneficial effects of ACE inhibitors can be explained by a reduction of: 1. Sodium and fluid retention; 2. Vasoconstriction; 3. Cardiac hypertrophy and dilatation; 4. Sympathetic activity; 5. Ventricular and supraventricular arrhythmias.
Several randomised clinical trials have demonstrated a clear mortality and morbidity benefit in patients with: 1. Severe (NYHA IV) chronic heart failure (CONSENSUS);2 2. Mild to moderate (NYHA II - III) chronic heart failure (V-HeFT II, SOLVD-treatment)34 3. Asymptomatic left ventricular dysfimction (SOLVD Prevention);5 4. Acute myocardial infarction and heart failure/left ventricular dysfunction (SAVE, AIRE, TRACE, SMILE).6-9 Therefore, ACE inhibitors are recommended in all patients with chronic heart failure, unless there is a serious contraindication. They need to be uptitrated to the (high) doses used in these clinical trials. A moderate increase in serum creatinine is not a reason for discontinuation.
Beablockers Less than a decade ago, ,3-blockers were contraindicated in patients with chronic heart failure. Based on sound pathophysiological arguments it was not considered a good idea to provide heart failure patients with a negative inotropic agent. However, several randomised clinical trials have proven otherwise. In the meantime, the evidence for a mortality and morbidity benefit of (-blockers in chronic heart failure is at least as good as with the ACE inhibitors. The most likely explanation of its beneficial effects is a decrease in chronic sympathetic overstimulation and changes in receptor density and sensibility.
Beta-blockers have proved to be beneficial in patients with: 1. Severe (NYHA III-IV) chronic heart failure
(COPERNICUS);'0 2. Mild to moderate (NYHA II - III) chronic heart failure (US-carvedilol, MERIT-HF, CIBIS-II);"-"3 3. Chronic heart failure and advanced age (SENIORS - unpublished). There is some evidence that the effects of carvedilol are more pronounced compared with metoprolol."4 Despite this overwhelming evidence, in a recent European survey it was demonstrated that only 30% of
Netherlands Heart Journal, Volume 12, Number 11, November 2004
the patients with chronic heart failure were treated with a (-blocker.'5 So, beside diuretics and ACE inhibitors, (3-blockers are recommended in all patients with chronic heart failure, unless there is a serious contraindication. They need to be slowly uptitrated ('start low, go slow') to the (high) doses used in these clinical trials.
Aldosterone blockers The potential beneficial effects ofaldosterone blockers in patients with chronic heart failure are: 1. Sodium and fluid excretion; 2. Decreased platelet aggregation; 3. Sympathetic inhibition; 4. Decreased collagen formation; 5. Reduction ofoxidative stress; 6. Improvement ofendothelial function; 7. Reduction ofcoronary inflammation; 8. Reduction ofdeleterious ventricular remodelling. In 1999, results of the Randomised Aldactone Evaluation Study (RALES) demonstrated a 30% mortality reduction when severe (NYHA III-IV) chronic heart failure patients were treated with spironolactone.'6 In addition, spironolactone reduced heart failure hospitalisation by 35%. Frequently observed side effects of spironolactone are gynaecomastia and sexual dysfunction. Eplerenone is another aldosterone blocker, but is more selective for the mineral corticoid receptor, and therefore has less side effects. Beneficial effects of eplerenone have been demonstrated in patients with heart failure after an acute myocardial infarction.'7 So, the evidence with aldosterone blockers is less powerful compared with the ACE inhibitors and (3-blockers. Nevertheless, aldosterone blockers (12.5 to 50 mg; slowly uptitrated) are recommended in (severe) symptomatic patients already on diuretics, ACE inhibitors and (3-blockers. Anglotensin-receptor blockers (ARBs) Despite recommended (high) doses ofACE inhibitors, a large number of chronic heart failure patients have increased angiotensin II concentrations. The effects of angiotensin II can be completely blocked by ARBs. ARBS have proven to be beneficial in: 1. Chronic heart failure patients who could not tolerate an ACE inhibitor (CHARM-alternative, ValHeFT-
subgroup);'8"19 2. Chronic heart failure patients in combination with an ACE inhibitor (ValHeFT, CHARM-added);'9'20 3. Patients with an acute myocardial infarction and heart failure/left ventricular dysfunction
(VALIANT).21 Therefore, ARBs are recommended in all patients who cannot tolerate an ACE inhibitor, unless contraindicated. Angio-oedema on ACE inhibitors is not a contraindication, although it does sometimes occur with ARBs. Furthermore, ARBs are recommended in symptomatic patients who are already
513
HEART FAILURE
on a diuretic, ACE inhibitor and (-blocker. The choice between an aldosterone blocker and an ARB depends on volume status, other specific patient characteristics, and personal preference.
Digoxin Digoxin has been used for the treatment of heart failure for more than 200 years. Despite this, its specific mode of action remains unknown. It is generally assumed that it increases intracellular sodium and calcium concentrations, and therefore increases cardiac contractility. Digoxin reduces the risk for hospitalisation for heart failure, but has no effect on mortality in chronic heart failure patients who are in sinus rhythm.22 Therefore, the indication for digoxin in patients with chronic heart failure is limited. In general, digoxin is advised in: 1. Patients with chronic heart failure and atrial fibrillation with a ventricular response >100 beats/min; 2. Patients with chronic heart failure who remain symptomatic despite optimal therapy with diuretics, ACE inhibitors, ,8-blockers, aldosterone blockers, and ARBs.
Vasodilators Before 1970, patients with chronic heart failure were treated with digoxin and diuretics. In 1986, results of the first Vasodilator Heart Failure Trial (V-HeFT-I) demonstrated an improved survival with nitrates and hydralazine compared with placebo, on top of standard treatment.23 Only five years later, the V-HeFT-II trial demonstrated superiority of enalapril over nitrates/hydralazine in chronic heart failure patients.3 Therefore, a combination of diuretics, digoxin, nitrates and hydralazine was indicated during a very short period of time. Today, this regimen is only indicated in patients where all other treatments fail.
Calcium antagonists Two randomised clinical trials in chronic heart failure patients with long-acting dihydropyridines demonstrated no differences in mortality compared with placebo.24-26 There is therefore neither an indication nor a contraindication for the use oflongacting dihydropyridines in chronic heart failure patients.
Conclusions Basically, all patients with chronic heart failure and left ventricular systolic dysfunction should be treated with diuretics, ACE inhibitors and (-blockers, unless contraindicated or not tolerated (figure 1). It is important to uptitrate ACE inhibitors and (-blockers to the high recommended doses that were used in the randomised clinical trials. If an ACE inhibitor is not tolerated or contraindicated, it is recommended to start anARB. Dose and choice ofdiuretics (loop-acting or thiazides or a combination) depends on volume
514
STEP 1
Optimize
CHF: Symptoms and LVEF
Netherlands Institute for Continuing Cardiovascular Education (CVOI) self-assessment In collaboration with Mediselect and supported by the company Novartis, the textbook Heart Failure, edited by Dirk Jan van Veldhuisen and Adriaan Voors, was published in Autumn 2003.
This textbook was primarily intended for the cardiology training course (OCC) in 2003. In like manner, the CVOI intends to publish textbooks on Atherosclerosis and Thrombosis in 2004 and Electrocardiography and Electrophysiology in 2005.
Following publication ofthe book, brieffocused reviews of its chapters will be published in consecutive issues ofthe Netherlands Heart Journal. After each of these articles, there will be two multiple-choice questions, which can be answered in the section Questions & Answers ofthe website ofthe CVOI, www.cvoi.org. Correct answers will be honoured with 1 credit, while wrong answers to one or both questions will connect the participant to a section that presents and discusses the correct answers, after which the procedure can be repeated. Correct answers to both questions will automatically lead to registration of the CME credits in the Cardiologist Registration Accreditation System (CRAS) on the CVOI website. All textbooks contain eight chapters; participants can therefore obtain 16 credit points. This experiment that connects CME articles to web-based self-assessment programmes and accreditation may pave the way for similar future developments and a reliable verifiable accreditation of CME articles.
Heart failure: chapter
6
Pharmacological treatment
of
chronic heart failure
A.A. Voors, P.H.J.M. Dunselman, D.J. van Veldhuisen
Heart failure is basically a cardiac disorder, but the signs and symptoms of heart failure are related to dysfunction of several other organ systems. Therefore, heart failure is currently considered a systemic disorder where neurohormonal activation leads to pulmonary oedema, changes in skeletal muscles, increased sympathetic vasotonus, decreased peripheral vascularisation and even several molecular changes. Because ofits versatility, it is obvious that monotherapy will be insufficient in the pharmacological treatment ofheart failure. Therefore, most patients with chronic heart failure are currently treated with several agents,
A.A. Voors D.J. van Veldhulson Department of Cardiology, Groningen University Hospital P.H.J.M. Dunselman Department of Cardiology, Amphia Hospital, Breda Address for correspondence: A.A. Voors E-mail: [email protected]
512
each of which has a different mode of action. In this article, we will discuss the current pharmacological possibilities and evidence in the treatment ofpatients with chronic heart failure and systolic left ventricular
dysfunction. Diuretics
The beneficial effects of diuretics on haemodynamics and symptoms of chronic heart failure are well established.' However, no randomised clinical trial has demonstrated beneficial effects of diuretics on mortality. Nevertheless, diuretics remain the cornerstone of therapy in chronic heart failure for several reasons: 1. Symptomatic improvement; 2. All randomised clinical trials ofACE inhibitors, ,3blockers, aldosterone blockers and angiotensinreceptor blockers have been done in combination with diuretics; 3. There are several reports suggesting that diuretics can potentiate the effects of ACE inhibitors. Therefore, diuretics are recommended in all patients with chronic heart failure. Dose and choice of diuretic
Netherlands Heart Journal, Volume 12, Number 11, November 2004
HEART FAILURE
(loop-acting or thiazides or a combination) depends on volume status, renal function, and severity of heart failure. ACE Inhibitors Activation ofthe renin-angiotensin system (RAS) plays a key role in the pathogenesis of heart failure. The beneficial effects of ACE inhibitors can be explained by a reduction of: 1. Sodium and fluid retention; 2. Vasoconstriction; 3. Cardiac hypertrophy and dilatation; 4. Sympathetic activity; 5. Ventricular and supraventricular arrhythmias.
Several randomised clinical trials have demonstrated a clear mortality and morbidity benefit in patients with: 1. Severe (NYHA IV) chronic heart failure (CONSENSUS);2 2. Mild to moderate (NYHA II - III) chronic heart failure (V-HeFT II, SOLVD-treatment)34 3. Asymptomatic left ventricular dysfimction (SOLVD Prevention);5 4. Acute myocardial infarction and heart failure/left ventricular dysfunction (SAVE, AIRE, TRACE, SMILE).6-9 Therefore, ACE inhibitors are recommended in all patients with chronic heart failure, unless there is a serious contraindication. They need to be uptitrated to the (high) doses used in these clinical trials. A moderate increase in serum creatinine is not a reason for discontinuation.
Beablockers Less than a decade ago, ,3-blockers were contraindicated in patients with chronic heart failure. Based on sound pathophysiological arguments it was not considered a good idea to provide heart failure patients with a negative inotropic agent. However, several randomised clinical trials have proven otherwise. In the meantime, the evidence for a mortality and morbidity benefit of (-blockers in chronic heart failure is at least as good as with the ACE inhibitors. The most likely explanation of its beneficial effects is a decrease in chronic sympathetic overstimulation and changes in receptor density and sensibility.
Beta-blockers have proved to be beneficial in patients with: 1. Severe (NYHA III-IV) chronic heart failure
(COPERNICUS);'0 2. Mild to moderate (NYHA II - III) chronic heart failure (US-carvedilol, MERIT-HF, CIBIS-II);"-"3 3. Chronic heart failure and advanced age (SENIORS - unpublished). There is some evidence that the effects of carvedilol are more pronounced compared with metoprolol."4 Despite this overwhelming evidence, in a recent European survey it was demonstrated that only 30% of
Netherlands Heart Journal, Volume 12, Number 11, November 2004
the patients with chronic heart failure were treated with a (-blocker.'5 So, beside diuretics and ACE inhibitors, (3-blockers are recommended in all patients with chronic heart failure, unless there is a serious contraindication. They need to be slowly uptitrated ('start low, go slow') to the (high) doses used in these clinical trials.
Aldosterone blockers The potential beneficial effects ofaldosterone blockers in patients with chronic heart failure are: 1. Sodium and fluid excretion; 2. Decreased platelet aggregation; 3. Sympathetic inhibition; 4. Decreased collagen formation; 5. Reduction ofoxidative stress; 6. Improvement ofendothelial function; 7. Reduction ofcoronary inflammation; 8. Reduction ofdeleterious ventricular remodelling. In 1999, results of the Randomised Aldactone Evaluation Study (RALES) demonstrated a 30% mortality reduction when severe (NYHA III-IV) chronic heart failure patients were treated with spironolactone.'6 In addition, spironolactone reduced heart failure hospitalisation by 35%. Frequently observed side effects of spironolactone are gynaecomastia and sexual dysfunction. Eplerenone is another aldosterone blocker, but is more selective for the mineral corticoid receptor, and therefore has less side effects. Beneficial effects of eplerenone have been demonstrated in patients with heart failure after an acute myocardial infarction.'7 So, the evidence with aldosterone blockers is less powerful compared with the ACE inhibitors and (3-blockers. Nevertheless, aldosterone blockers (12.5 to 50 mg; slowly uptitrated) are recommended in (severe) symptomatic patients already on diuretics, ACE inhibitors and (3-blockers. Anglotensin-receptor blockers (ARBs) Despite recommended (high) doses ofACE inhibitors, a large number of chronic heart failure patients have increased angiotensin II concentrations. The effects of angiotensin II can be completely blocked by ARBs. ARBS have proven to be beneficial in: 1. Chronic heart failure patients who could not tolerate an ACE inhibitor (CHARM-alternative, ValHeFT-
subgroup);'8"19 2. Chronic heart failure patients in combination with an ACE inhibitor (ValHeFT, CHARM-added);'9'20 3. Patients with an acute myocardial infarction and heart failure/left ventricular dysfunction
(VALIANT).21 Therefore, ARBs are recommended in all patients who cannot tolerate an ACE inhibitor, unless contraindicated. Angio-oedema on ACE inhibitors is not a contraindication, although it does sometimes occur with ARBs. Furthermore, ARBs are recommended in symptomatic patients who are already
513
HEART FAILURE
on a diuretic, ACE inhibitor and (-blocker. The choice between an aldosterone blocker and an ARB depends on volume status, other specific patient characteristics, and personal preference.
Digoxin Digoxin has been used for the treatment of heart failure for more than 200 years. Despite this, its specific mode of action remains unknown. It is generally assumed that it increases intracellular sodium and calcium concentrations, and therefore increases cardiac contractility. Digoxin reduces the risk for hospitalisation for heart failure, but has no effect on mortality in chronic heart failure patients who are in sinus rhythm.22 Therefore, the indication for digoxin in patients with chronic heart failure is limited. In general, digoxin is advised in: 1. Patients with chronic heart failure and atrial fibrillation with a ventricular response >100 beats/min; 2. Patients with chronic heart failure who remain symptomatic despite optimal therapy with diuretics, ACE inhibitors, ,8-blockers, aldosterone blockers, and ARBs.
Vasodilators Before 1970, patients with chronic heart failure were treated with digoxin and diuretics. In 1986, results of the first Vasodilator Heart Failure Trial (V-HeFT-I) demonstrated an improved survival with nitrates and hydralazine compared with placebo, on top of standard treatment.23 Only five years later, the V-HeFT-II trial demonstrated superiority of enalapril over nitrates/hydralazine in chronic heart failure patients.3 Therefore, a combination of diuretics, digoxin, nitrates and hydralazine was indicated during a very short period of time. Today, this regimen is only indicated in patients where all other treatments fail.
Calcium antagonists Two randomised clinical trials in chronic heart failure patients with long-acting dihydropyridines demonstrated no differences in mortality compared with placebo.24-26 There is therefore neither an indication nor a contraindication for the use oflongacting dihydropyridines in chronic heart failure patients.
Conclusions Basically, all patients with chronic heart failure and left ventricular systolic dysfunction should be treated with diuretics, ACE inhibitors and (-blockers, unless contraindicated or not tolerated (figure 1). It is important to uptitrate ACE inhibitors and (-blockers to the high recommended doses that were used in the randomised clinical trials. If an ACE inhibitor is not tolerated or contraindicated, it is recommended to start anARB. Dose and choice ofdiuretics (loop-acting or thiazides or a combination) depends on volume
514
STEP 1
Optimize
CHF: Symptoms and LVEF
