Treatment Of Chronic Heart Failure
Therapy of chronic heart failure (CHF) is designed to: (i) improve the quality of life by reducing symptoms; (ii) lengthen survival; and (iii) slow the progression of cardiac deterioration. CHF typically has an underlying cause such as ischaemic heart disease, and may be exacerbated by specific precipitating factors such as infection or arrhythmias, as well as by myocardial abnormalities which develop as CHF progresses (e.g. valvular dysfunction). As well as the symptoms of CHF per se, both underlying and precipitating factors should, if possible, be treated. Restricting activity and reducing dietary sodium help to lessen cardiac workload and fluid retention.
The sympathetic and renin–angiotensin–aldosterone (RAA) systems activated in response to reduced pump function initially help to maintain cardiac output, but also drive the progression of cardiac deterioration (Figure 47; see also Chapter 46). Therapy mainly involves inhibiting these systems, and is initiated with angiotensin-converting enzyme inhibitors (ACEI) or β-blockers, which slow CHF progression, lengthen survival time and improve haemodynamic parameters. Angiotensin receptor blockers (ARBs) are used as an alternative in patients who cannot tolerate ACEI. If symptoms are not adequately controlled with one of these three types of drugs, one of the other classes is then also prescribed. Typically, a drug targeting the RAA system is combined with a β-blocker, although the ACEI–ARB combination can be used in β-blocker intolerant patients. Combining all three classes has been shown not to be beneficial and potentially increases side effects, so is not recommended. A diuretic can also be used to control fluid accumulation and digoxin may be used to support cardiac function and reduce symptoms. In severe or refractory CHF, or when existing therapy fails to control symptoms adequately, an aldosterone antagonist such as spironolactone or eplerenone is recommended.
Positive inotropes such as dobutamine, dopamine or milrinone may be used temporarily if decompensation (an acute worsening of heart failure) occurs, as can intra-aortic balloon counterpulsation (see Chapter 45).
Device therapy is playing an increasingly important role in treating chronic heart failure. Implantable cardiac defibrillators are used in many patients with moderate to severe CHF, as ∼50% of patients will have sudden cardiac death, which is mainly caused by ventricular fibrillation (see Chapter 50). Cardiac resynchronization therapy, which involves implantation of a pacemaker that stimulates both ventricles to contract simultaneously, can also be used in patients with moderate to severe CHF who show evidence of asynchronous ventricular contraction.
A ventricular assist device (a pump that takes over part or all of the heart’s pumping action) can be used as a bridge for patients awaiting cardiac transplant, or as a destination device to lengthen survival if transplant is not possible.
ACEI and other vasodilators
As described in Chapter 29, angiotension II causes vasoconstriction and promotes fluid retention via multiple mechanisms. ACEI, which inhibit the conversion of angiotensin I to angiotensin II, therefore dilate arteries and veins, and reduce blood volume and oedema. Arterial vasodilatation decreases afterload and cardiac work, and improves tissue perfusion by increasing stroke volume and cardiac output. Venous dilatation and reduction of fluid retention diminish pulmonary congestion, oedema and central venous pressure (CVP) (preload). Reduction of preload lowers ventricular filling pressure, therefore lowering cardiac wall stress, workload and ischaemia. ACEI also delay abnormal cardiac hypertrophy and fibrosis, which are thought to be promoted by angiotensin II.
Angiotensin (AT1) receptor blockers such as losartan are used in patients unable to tolerate the cough or renal dysfunction occasionally caused by ACEI. The combination of the vasodilators isosorbide dinitrate (see Chapter 41) and hydralazine, although not as effective as an ACEI in prolonging survival, can be used instead of an ACEI or ARB for patients in whom blocking the RAA system is contraindicated. Hydralazine causes mainly arterial vasodilatation, possibly via inhibition of Ca2+ release from the sarcoplasmic reticulum.
The 1993 MDC study reported that the β1-selective antagonist metoprolol reduced mortality when added to conventional therapy for mild to moderate CHF. The benefits of adding metoprolol to standard therapy (ACEI and diuretics) were confirmed in the 1999 MERIT-HF study, which showed that this drug reduced 1-year mortality by 34% in patients with mild to severe CHF. Bisoprolol, another β1-selective antagonist, was shown by the 1999 CIBIS-II trial to similarly diminish mortality. Carvedilol is a non-selective β-blocker that has additional α-antagonist and antioxidant properties, and has also been shown to prolong survival in CHF. The 2003 COMET trial showed that when given to patients being treated with ACEI and diuretics, carvedilol extended survival to a greater extent than did metoprolol.
Long-term treatment with β-blockers has been shown to increase ejection fraction, reduce systolic and diastolic volume, and eventually cause regression of left ventricular hypertrophy. Other beneficial effects of β-blockers in CHF probably include reduced ischaemia and a reduction in heart rate, thus improving myocardial perfusion, inhibition of the deleterious effects of excess catecholamines on myocardial structure and metabolism, and reduction of cytokine release. β-Blockers appear to be particularly effective in reducing sudden death in those with CHF, suggesting that the prevention of ventricular fibrillation (see Chapters 48, 50 and 51) constitutes an important part of their action.
The negative inotropic effect of β-blockers is potentially hazardous in some patients with CHF, because cardiac function is already compromised. Therapy is therefore initiated with low doses which are carefully elevated over several weeks or months. Because only the three β-blockers described above have as yet been shown to lengthen survival in CHF, they are the only ones recommended for its treatment.
Ivabradine, although not a β-blocker, also lowers the heart rate (see Chapter 40). The 2010 SHIFT study showed that adding ivabradine to current gold standard treatment significantly reduced death from heart failure in patients with moderate to severe CHF.
Aldosterone levels initially fall during ACEI treatment, but often rise again (‘escape’) during prolonged treatment. Aldosterone has a number of effects that worsen CHF and its consequences: inducing cardiac fibrosis and remodelling, reducing nitric oxide release, increasing Na+ retention, and promoting arrhythmias by decreasing plasma K+ and cardiac noradrenaline release.
The aldosterone antagonist spironolactone was shown in the 1999 RALES trial to reduce mortality when added to ACEI in severe CHF. Its use is now recommended in patients with more severe heart failure and good renal function. As it can cause hyperkalaemia, careful monitoring of plasma K+ levels is important.
Spironolactone also causes antiandrogenic side effects such as gynaecomastia. The more selective aldosterone antagonist eplerenone is also used, and has fewer side effects.
Diuretics reduce fluid accumulation by increasing renal salt and water excretion. Preload, pulmonary congestion and systemic oedema are thereby relieved. Loop diuretics inhibit the Na+–K+– 2Cl− symport in the thick ascending loop of Henle. Na+ and Cl− reabsorption is thereby inhibited, and the retention of these ions in the tubule promotes fluid loss in the urine. Diuretics are com- monly used in CHF, including furosemide, bumetanide, torasemide and ethacrynic acid. Thiazide and thiazide-related diuretics (see Chapter 38), particularly metolazone, are sometimes combined with a loop diuretic.
Both loop and thiazide diuretics can cause hypokalaemia and metabolic alkalosis because the increased Na+ retained in the tubular fluid is partly exchanged for K+ and H+ in the distal nephron. This process is stimulated by aldosterone (see Chapter 29), and diuretic-induced hypokalaemia can be controlled by an ACEI or an aldosterone antagonist. Hypokalaemia can also be treated with K+ supplements, or the use of K+-sparing diuretics such as amiloride or triamterene. These inhibit Na+ reabsorption in the collecting duct. Long-term use of loop diuretics can result in hypovolaemia, reduced plasma Mg2+, Ca2+ and Na+, and hyperuricaemia and hyperglycaemia. This is more common in the elderly, who may require high doses of diuretics to overcome diuretic resistance.
Cardiac glycosides include ouabain, digitoxin and digoxin, which is used most widely. Digoxin improves CHF symptoms, but does not prolong life. Cardiac glycosides inhibit the Na+ pump in cardiac muscle, thereby indirectly inhibiting the Na+–Ca2+ antiport and thus increasing intracellular Ca2+ (see Chapter 12). The rise in Ca2+ enhances contractility and shortens action potential duration and refractory period in atrial and ventricular cells by stimulating K+ channels. Digoxin has been shown to increase baroreceptor responsiveness, thereby reducing sympathetic tone.
Digoxin also acts on the nervous system to increase vagal tone. This slows both sinoatrial node activity and atrioventricular node (AVN) conduction, and can be useful in treating atrial arrhyth- mias (see Chapter 51). It is therefore mainly used in patients with both CHF and atrial fibrillation.
Even a small (two to threefold) excess of digoxin over the optimal therapeutic concentration can cause arrhythmias. This occurs because an excessive rise in [Ca2+]i causes oscillations in membrane potential after action potentials. These delayed afterdepolarizations can trigger ectopic beats (see Chapter 48), and at higher doses can cause ventricular tachycardia. Inhibition of the Na+ pump also decreases intracellular K+, causing depolarization and facilitating arrhythmias. In addition, excess digoxin can increase vagal tone enough to block conduction at the AVN, and can also raise sympathetic tone, again favouring arrhythmias. Digoxin toxicity is enhanced by hypokalaemia (low plasma K+), because K+ decreases the affinity of digoxin for the Na+ pump. Digoxin also causes toxic gastrointestinal effects, including anorexia, nausea and vomiting. Acute toxicity can be treated with intravenous K+, anti-arrhythmics (e.g. lidocaine) and digoxin specific antibodies.