The different forms of heart failure (HF) (systolic and diastolic, left and right ventricular ([LV/RV] dysfunction, acute and chronic – see Chapter 1) require somewhat different treatment approaches.
While successful evidence-based therapy now exists for HF due to LV systolic dysfunction, the search for the ‘holy grail’ in diastolic HF (heart failure with preserved ejection fraction [HFpEF]) continues. Several large studies of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) have not been successful. In general, the management of HFpEF should be directed towards the underlying cause (e.g. lowering blood pressure in patients with hypertension, revascularization in patients with coronary ischemia). Symptoms of congestion should be managed with diuretics (see pages 95–7). The recent TOPCAT trial of the mineraloreceptor antagonist spironolactone in patients with HFpEF showed an overall neutral effect on primary composite endpoints (mortality and HF hospitalization). Interestingly, a post hoc analysis showed regional differences in outcome, and patients from American centers had a significant reduction in cardiac events.
In this chapter, we outline the evidence-based medical therapy for heart failure with reduced ejection fraction (HFrEF) (Figure 7.1).
Figure 7.1 Recommended therapy for patients with heart failure with reduced ejection fraction (HFrEF) and mild-to-moderate symptoms (class I and II NYHA). ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; ARNI, angiotensin receptor/neprilysin inhibitor; CRT. cardiac resynchronization therapy; H-ISDN, hydralazine/isosorbide dinitrate; HR, heart rate; ICD, implantable cardioverter defibrillator; LVAD, left ventricular assist device; MR, mineralocorticoid receptor; VT/VF, ventricular tachycardia/fibrillation.
General management principles
Knowledge of LV and RV function is essential to the application of medical therapy. If LV/RV systolic dysfunction is confirmed, causes should be sought, as ultimately the treatment of HF due to valvular heart disease, myocardial infarction (MI) or severe pulmonary disease will vary because of the different mechanism and ventricle involved. A search for aggravating factors such as drugs (calcium-channel antagonists, namely diltiazem and verapamil; non-steroidal anti-inflammatory drugs [NSAIDs]; cyclooxygenase [COX]-2 inhibitors; class 1 antiarrhythmics; thiazolidinediones) and concomitant problems (arrhythmia, anemia, infection, thromboembolism, thyroid disease) should also be performed and the prescribed therapy modified accordingly.
Monitoring. Successful safe HF therapy requires specific and regular monitoring, including measurement of weight or fluid balance (daily), heart rate, blood pressure (lying and standing), and respiratory rate and oxygen saturation. Regular serum creatinine and electrolyte measurements should be performed according to the clinical scenario, primarily if the patient is on intravenous diuretics, and potassium and magnesium must be replaced if the patient is hypokalemic or hypomagnesemic.
Imaging results (chest X-ray and echocardiography) are helpful for assessing the response to treatment.
First-line therapy
Diuretics (in patients with fluid retention/pulmonary congestion) are the oldest agents used in HF therapy. They are very successful in limiting the symptoms of fluid retention but have not been proved to reduce mortality in HF. Symptomatic systolic HF should be treated with a combination of an ACE inhibitor and a diuretic to maintain euvolemia.
Oral diuretics. In mild and stable forms of HF, the oral route should be used first. Loop diuretics and thiazides are prescribed most frequently (Table 7.1). Loop diuretics act on the ascending loop of Henle in the kidney. Dose escalation and addition of a thiazide diuretic may be required if the edema is resistant. However, there is a risk of significant diuresis when a loop diuretic and thiazide are used in combination. Daily weight monitoring and frequent electrolyte measurement should be employed in such cases, with prompt replacement of potassium when required.
TABLE 7.1 Examples of oral diuretic treatment for heart failure | ||
Initial dose | ||
Loop diuretics | ||
Furosemide | 40–80 mg od or bd | |
Bumetanide | 1–2 mg od or bd | |
Torasemide (torsemide) | 10–20 mg od | |
Thiazides | ||
Hydrochlorothiazide | 25–50 mg od | |
Bendroflumethiazide | 2.5–10 mg od | |
Quinazolone diuretics | ||
Metolazone | 2.5–5 mg od | |
Potassium-sparing diuretics | ||
Amiloride | 5–10 mg od | |
Triamterene | 100 mg bd | |
Aldosterone antagonists (see Table 7.8) | ||
Other diuretics | ||
Acetazolamide | 250–375 mg od or alternate days | |
bd, twice daily; od, once daily. | ||
Metolazone is a strong diuretic often used in combination with loop diuretics when loop diuretics alone do not work.
Potassium-sparing diuretics are weak diuretics when used alone and are most frequently used in the treatment of ascites caused by end-stage liver disease. The aldosterone antagonists have an important role in the management of HF (see pages 104–6).
Parenteral diuretics. Intravenous diuretics are reserved for patients with acute LV dysfunction or those presenting with edema resistant to oral diuretics. Furosemide can be administered by continuous infusion or boluses. The usual starting dose for intravenous boluses is 40–80 mg at a continuous infusion rate of 5–10 mg/hour. In fluid-overloaded patients, the aim is to achieve an increase in urine output and a weight reduction of 0.5–1.0 kg/day. Peak diuresis should be achieved within 2 hours and last for 6–8 hours.
Subcutaneous furosemide has been used off-label in the palliative care setting in some countries for several years. Developments in this area are discussed on pages 145–6.
ACE inhibitors block tissue angiotensin-converting enzyme, which is responsible for the conversion of angiotensin I to angiotensin II, and the breakdown of bradykinin. This causes vasodilation and decreases intraglomerular pressure.
There is strong evidence that ACE inhibitors maximize blockade of the renin–angiotensin–aldosterone system and prevent progression of the disease in all stages of HF with systolic dysfunction (LV ejection fraction [LVEF] < 40%). All patients with systolic LV dysfunction, including asymptomatic patients (NYHA class I), should be treated with ACE inhibitors at target doses (Table 7.2). If target doses are not reached (poorly tolerated), then lower doses are still beneficial. If ACE inhibitors are contraindicated (Table 7.3) or cause specific side effects (cough), then an ARB should be used instead. Absolute and relative contraindications and drug interactions are shown in Table 7.3. There is no convincing evidence for the use of ACE inhibitors in HFpEF.
TABLE 7.2 Examples of ACE inhibitor treatment for heart failure | ||
Starting dose | Target dose | |
Enalapril | 2.5 mg bd | 20 mg bd |
Lisinopril | 2.5–5 mg od | 20–35 mg od |
Ramipril | 1.25 mg bd | 5 mg bd |
Trandolapril | 0.5 mg od | 4 mg od |
Captopril | 6.25 mg tds | 50 mg tds |
Perindopril | 2.5 mg od | 10 mg od |
ACE, angiotensin-converting enzyme; bd, twice daily; od, once daily; tds, three times daily. | ||
TABLE 7.3 Contraindications and drug interactions of ACE inhibitors | ||
Absolute contraindications | Relative contraindications | Drug interactions |
• History of anaphylaxis • Angioneurotic edema • Known bilateral renal artery stenosis • Acute kidney failure | • Significant hyperkalemia (> 5.0 mmol/L) • Significant renal dysfunction (eGFR < 30 mL/min) • Symptomatic or severe asymptomatic hypotension (systolic BP < 90 mmHg) • Hyponatremia with volume depletion | • K+ supplements or K+-sparing diuretics (e.g. triamterene) • Aldosterone antagonists (spironolactone) • ARBs • NSAIDs |
ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; BP, blood pressure; eGFR, estimated glomerular filtration rate; K+, potassium; NSAID, non-steroidal anti-inflammatory drug. | ||
The SOLVD-T trial randomized 2569 patients already receiving conventional treatment for HF to enalapril, 2.5–20 mg daily, or placebo. There were significant reductions in mortality in the enalapril group (the largest reduction was in those with progressive HF) and fewer patients were hospitalized for worsening HF in this group.
The ATLAS trial was undertaken with the precise objective of comparing two dosages of lisinopril (2.5–5 mg daily and 32.5–35 mg daily) on the morbidity and mortality of patients with LV systolic dysfunction. In total, 3000 patients with NYHA class II–IV were followed up for 4.5 years. The high-dose group had a significant 12% lower risk of death or hospitalization for any reason, and 24% fewer cases of hospitalization for HF.
Other trials. SAVE, AIRE and TRACE have all clearly demonstrated the benefits of ACE inhibitors in reducing mortality and morbidity in patients with systolic HF after MI.
Angiotensin-receptor blockers are first-line treatments in patients with NYHA class II–IV HF who are intolerant to an ACE inhibitor, and second-line treatment after optimal ACE inhibitor and beta-blocker therapy in patients with NYHA class III or IV (Table 7.4). Absolute and relative contraindications and drug interactions are shown in Table 7.5.
TABLE 7.4 Examples of ARB treatment for heart failure | ||
Starting dose | Target dose | |
Candesartan | 4 or 8 mg od | 16 mg bd |
Valsartan | 40 mg bd | 160 mg bd |
Irbesartan | 75 mg od | 300 mg od |
ARB, angiotensin-receptor blocker; bd, twice daily; od, once daily. | ||
TABLE 7.5 Contraindications and drug interactions for angiotensin receptor blockers | ||
Absolute contraindications | Relative contraindications | Drug interactions |
• Acute/severe renal failure • Acute/severe liver failure | • Significant hyperkalemia (> 5.0 mmol/L) • Symptomatic or severe asymptomatic hypotension (systolic BP < 90 mmHg) | • K+ supplements or K+-sparing diuretics (e.g. triamterene) • Aldosterone antagonists (spironolactone, eplerenone); ACE inhibitors; NSAIDs |
ACE, angiotensin-converting enzyme; BP; blood pressure; NSAID, non-steroidal anti-inflammatory drug. | ||
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