Newer drug therapies in heart failure

Heart failure is a significant cause of morbidity and mortality. There are recent, clear, evidence-based guidelines for its management and newer therapies are becoming available.

eart failure is a condition which carries significant morbidity and mortality and which often co-exists with other long term conditions.¹ Practice nurses deliver a great deal of the care for long term conditions in primary care and are likely to encounter heart failure as a result. The importance of delivering evidence based care is underlined by the Quality and Outcomes Framework, which stresses that patients who have a diagnosis of left ventricular systolic dysfunction (LVSD) should be treated with medication which has been shown to improve morbidity and mortality.² All nurses should therefore be aware of the relevant medication recommended for heart failure, even if they do not prescribe themselves. This includes being aware of newer or lesser-used therapies which may be useful for patients who cannot tolerate standard therapeutic options.

CURRENT TREATMENTS

In 2010 NICE updated its guideline on the management of heart failure.¹ This guideline included advice about how to use an evidence based approach to the prescribing of drug therapies aimed at relieving symptoms and reducing morbidity and mortality. It also included suggestions for alternative drugs that could be used if standard treatment options were not adequate. Since this guideline was published, newer therapeutic options have also been identified. This article will discuss the evidence for the use of these alternative or new therapies in LVSD, along with possible scenarios where their use could be considered.

PATHOPHYSIOLOGY AND FIRST LINE DRUGS

Heart failure is a syndrome of signs and symptoms which occur when the pump mechanism of the heart is failing to keep up with the physiological needs of the body.² Although heart failure is more likely in older people there are other possible causes, including coronary heart disease, hypertension, valve disorders and viral, alcoholic and chemotherapy-related cardiomyopathies,1 which may make younger individuals susceptible as well.

Cardiac output drops as the left ventricle struggles to pump blood around the body. The subsequent reduction in arterial pressure is registered by baroreceptors in the aortic arch and other areas, and by the kidneys.² The body interprets this drop in pressure as a loss of circulatory volume, and responds by activating both the renin angiotensin aldosterone system (RAAS) and the sympathetic nervous system (SNS). These systems encourage fluid and salt retention and vasoconstriction in order to increase the circulatory volume that the body, mistakenly in the case of heart failure, believes to be needed. In reality, the extra circulatory volume produced puts even more pressure on the struggling heart. The focus of first line drug treatments for heart failure is, therefore, to reduce the activity of the RAAS and SNS to prevent overloading of the failing heart.³

ACE inhibitors and beta blockers

First line drug therapy for heart failure consists of an angiotensin converting enzyme (ACE) inhibitor and a beta ()-blocker. Both these drugs are used at the highest dose tolerated by the individual. Their use is recommended based on solid evidence that they improve symptoms and reduce mortality.^4-6 Diuretics are advocated for symptom relief but, in contrast to ACE inhibition and -blockade, there is a lack of convincing evidence that they improve mortality.¹

Angiotensin II is a powerful vasoconstrictor, which increases the preload on the heart. ACE inhibitors target the RAAS by inhibiting the conversion of angiotensin I to angiotensin II. Down-regulation of the RAAS with ACE inhibitors therefore reduces the preload and takes pressure off the failing heart.

-blockers target the SNS. One of their effects is to slow the heart rate. Studies have shown that their use in the treatment of heart failure improves mortality.^7,8

Both these classes of drugs require careful consideration of possible contraindications, special precautions and potential side effects before initiation.¹ They also require careful dose titration and ongoing monitoring. -blockers, in particular, can be poorly tolerated due to side effects such as bronchoconstriction, cold extremities and erectile dysfunction. Furthermore, up to 1 in 3 people will suffer an exacerbation of their heart failure symptoms after being started on this class of drug.¹⁰ A 'start low, go slow' policy is therefore advocated in order to minimise the risk of side effects and increase the chances of -blockers being eventually tolerated at higher doses. In some people this will involve combating side effects such as fluid retention and breathlessness with extra doses of diuretics. It may also be necessary to treat people with smaller doses of -blockers if that is all they can tolerate. However, compelling evidence for reductions in mortality means that these important drugs should be offered to all patients who are able to tolerate them, even if smaller doses have to be used. -blockers currently licensed for use in heart failure include bisoprolol and nebivolol, and the non-selective alpha1-/-blocker, carvedilol.¹¹

IVABRADINE FOR HEART FAILURE

Ivabradine was initially used in coronary heart disease when -blockers could not be tolerated, or were contraindicated. Subsequently it has been shown to benefit heart failure patients too, where it may be used instead of -blockers in patients who do not tolerate them, or in conjunction with -blockade.

Ivabradine reduces the heart rate through inhibition of the If ionic current, which impacts on pacemaker activity in the sinoatrial (SA) node. Blocking this channel results in a slower pulse rate, improved blood flow to the myocardium and improved outcomes.¹¹

The SHIFT study

The 'Systolic Heart Failure treatment with If inhibitor Trial' (SHIFT) was designed to determine whether or not ivabradine would confer additional benefits to heart failure patients when used alongside optimal, guideline-based heart failure treatments.¹²

A raised resting pulse rate of more than 70 beats per minute is recognised as being a risk factor for mortality and morbidity in cardiovascular diseases, including heart failure.^13,14 In spite of current evidence based treatment, which includes the use of -blockers at optimised doses, more than half of the patients with heart failure and low ejection fraction still have an elevated heart rate.

The aim of SHIFT was to look at the impact of ivabradine on events such as cardiovascular death or hospitalisation for worsening heart failure. LVSD was defined as being evident by the presence of an ejection fraction of 35% or less. A total of 6,505 patients from 37 countries were studied for a median duration of 22.⁹ months, and up to 41.⁷ months. The study population included patients with symptomatic chronic heart failure (New York Heart Association [NYHA] class II-IV) (Figure 1) who had been stable for at least four weeks prior to starting in the study.¹⁵ The patients had to have had a previous episode of hospitalisation for worsening heart failure in the year leading up to the study and there was a run-in period to entry into the study to ensure that they were on maximum tolerated doses of -blockers. It is interesting to note, however, that only 26% of participants achieved their target -blocker dose.

During the median follow-up period (22.⁹ months) the composite end point of the study (cardiovascular death or hospitalisation with worsening heart failure) occurred in 24.5% of ivabradine-treated patients compared with 28.7% of patients in the placebo group (hazard ratio 0.82, 95% confidence interval 0.⁷⁵ to 0.90, P<0.0001). The number needed to treat (NNT) is 23 over 22.⁹ months; i.e. 23 patients need to be treated with ivabradine for 22.⁹ months in order to prevent one cardiovascular death or hospitalisation for worsening heart failure.

In patients with a heart rate of 70 bpm or more who were already receiving standard heart failure therapy, the addition of ivabradine significantly reduced the risk of cardiovascular death and hospitalisation for heart failure. Ivabradine also improved quality of life and reversed left ventricular remodelling. Patients with a higher baseline heart rate (75 bpm or more) who were prescribed ivabradine in the trial showed a 17% reduction in cardiovascular deaths and a 17% reduction in total deaths.

These improved outcomes were observed across the board in the ivabradine-treated group, irrespective of age, sex, NYHA level, the presence of co-morbidities such as diabetes and hypertension and whether or not the heart failure was related to ischaemic heart disease. Current treatment with -blockers at randomisation also did not affect outcomes.

In terms of safety and tolerability, serious adverse events were noted to occur more frequently in the placebo group than in the active treatment group. Doses of between 2.5mg bd and 7.5mg bd were used and over three quarters of patients were able to tolerate the target dose of 7.⁵ mg twice daily.

In February 2012, as a result of the SHIFT study, the European Medicine Agency added a new indication for ivabradine, stating that it can be used for treating heart failure in patients who are in sinus rhythm and who have a heart rate of 75 bpm or more. Shortly afterwards, the European Society for Cardiology (ESC) included ivabradine in its guideline for the treatment of patients with chronic symptomatic systolic heart failure (NYHA class II-IV) and a heart rate equal to or greater than 70 bpm.¹⁶ Ivabradine is licensed to be used in combination with standard therapy, including ACE inhibitors, -blockers and aldosterone antagonists (e.g. spironolactone), but may also be prescribed when -blocker therapy is contraindicated or not tolerated. The latest ESC guideline for heart failure places ivabradine above digoxin in the treatment algorithm, and NICE is currently reviewing ivabradine in heart failure, and the technology appraisal is due for publication in November this year.

ALDOSTERONE ANTAGONISTIS: AN UPDATE

The 2012 ESC guideline for heart failure16 has come out in strong support of aldosterone antagonists, in preference to the use of angiotensin receptor blockers (ARBs). NICE currently recommends either of these drugs, or hydralazine with a nitrate, as an optional add-in therapy if treatment with an ACE inhibitor and a -blocker does not control symptoms. Aldosterone antagonists include spironolactone and eplerenone (which is licensed for post-myocardial use only). The recommendations for the use of aldosterone antagonists are based on the results of trials such as EPHESUS,17 RALES,18 and, more recently, EMPHASIS-HF.¹⁹

In the RALES trial,18 patients with a diagnosis of LVSD (ejection fraction <35%) who were classed as NYHA III-IV were given spironolactone 25mg, increasing to 50mg after 8 weeks if heart failure symptoms persisted. Concurrent use of ACE inhibitors (if tolerated) and loop diuretics was allowed. The trial showed that blocking aldosterone activity in these patients reduces both morbidity and mortality.

EPHESUS17 looked at eplerenone versus placebo in patients who had a diagnosis of LVSD up to 2 weeks post-MI. They were given 25-50mg eplerenone, with care being taken to monitor potassium levels. Optimal medical treatment was continued, using ACE inhibitors, -blockers, ARBs and diuretics in line with current guidelines. The results of the trial showed that overall mortality was reduced by 15%. Cardiovascular deaths and admissions for cardiovascular events were also significantly reduced.

EMPHASIS-HF19 looked at patients with NYHA Class II heart failure (i.e. those with few symptoms) who had LVSD (ejection fraction <35%) to see if eplerenone was as useful in this group as it had been in the more severe cases in the EPHESUS study. A dose of 25-50mg versus placebo was used. The results were so convincing that the trial was stopped at 21 months. Interestingly, an additional finding was that new onset atrial fibrillation or flutter was reduced in the active treatment group.

The potential side effects of aldosterone antagonists may have made some clinicians reluctant to consider them. Aldosterone antagonists, because they affect androgen receptors, can cause feminisation in male patients (gynaecomastia, testicular atrophy and sexual dysfunction) and menstrual irregularity and breast tenderness and enlargement in women. These drugs often increase serum potassium levels and may cause potentially life-threatening hyperkalaemia, especially when used with other drugs that affect electrolyte balance. Hyperkalaemia may also occur if potassium based salt substitutes, such as Lo-salt, are used concurrently and patients should be advised to avoid these. It is advisable to periodically screen the serum potassium level of patients taking these drugs. Other common side effects include urinary frequency, ataxia, drowsiness, dry skin and rashes.

The NICE guideline currently suggests that it is left to specialists to initiate aldosterone antagonists. However, this may change in the future, as a result of greater use, experience and awareness of both risks and benefits of these drugs, particularly if they take precedence over other 'add-in' drugs.

FUTURE THERAPIES

Another completely new class of drug is being investigated for its potential benefits in treating heart failure. Systolic heart failure is characterised by reduced myocardial contractility and shortening of ventricular systole. Cardiac myosin activators (CMAs) target proteins involved in muscle contraction. The action of CMAs in the heart leads to a prolonged contraction of the left ventricle and therefore increases the volume of blood pumped out of the heart in each episode of systole. Omecamtiv mercabil is the first drug in this class and initial studies have indicated that it may be useful for improving cardiac function in people with LVSD.²⁰ Further studies will be needed, but CMAs look promising for the future.

CONCLUSION

In summary, although novel treatment options for heart failure, such as CMAs are being studied, both the NICE guideline from 2010 and the updated ESC guideline from 2012 reiterate the importance of ACE inhibitors and -blockers as first line treatments for LVSD. The ESC guidelines now suggest that aldosterone antagonists should take priority as the next add-in drug, unless contraindicated. NICE still gives alternative choices such as adding in an ARB or hydralazine with a nitrate. The ESC has also highlighted ivabradine as a useful new addition to the drug treatment armoury for heart failure, ahead of digoxin. It remains to be seen whether NICE will follow suit.

KNOWLEDGE CHECKER

[bold] 1. List some of the main causes of heart failure.

Heart failure is more common in older people and in people with a history of coronary heart disease, hypertension and valve disorders.

[bold] 2. Name two of the systems that are activated by the failing heart in heart failure?

The renin angiotensin aldosterone system (RAAS) and the sympathetic nervous system (SNS).

[bold] 3. Which drugs are given first line to improve morbidity and mortality in heart failure?

First line drug therapies for heart failure are ACE inhibitors and beta()-blockers; both should be prescribed at the highest dose tolerated by the individual patient.

[bold] 4. List some commonly occurring side effects of -blockers.

Side effects of -blockers include bronchoconstriction, cold extremities and erectile dysfunction.

[bold] 5. Which -blockers are currently licensed for use in heart failure?

-blockers currently licensed for use in heart failure include bisoprolol and nebivolol, and the non-selective alpha1-/-blocker, carvedilol.

[bold] 6. Ivabradine is a new therapy option for treating heart failure. How does ivabradine work?

Ivabradine reduces the heart rate through inhibition of the If ionic current, which impacts on pacemaker activity in the sinoatrial (SA) node. Blocking this channel results in a slower pulse rate, improved blood flow to the myocardium and improved outcomes including reductions in cardiovascular death and hospitalization for worsening heart failure.

[bold] 7. In the SHIFT study, the number needed to treat with ivabradine was 23; what does this mean?

This means that 23 patients need to be treated with ivabradine for a median of 22.⁹ months in order to avoid one cardiovascular death or hospitalization for worsening heart failure.

[bold] 8. The European Society of Cardiology has included ivabradine in its 2012 guideline. Where does this guideline say ivabradine can be used?

The ESC included ivabradine in its guideline for the treatment of patients with chronic symptomatic systolic heart failure (NYHA class II-IV) and a heart rate >=70 bpm. Ivabradine is licensed to be used in combination with standard therapy including ACE inhibitors, -blockers and aldosterone antagonists (e.g. spironolactone) but may also be prescribed when -blocker therapy is contraindicated or not tolerated.

[bold] 9. Which two drugs fall into the class of aldosterone antagonists? How do NICE and ESC guidelines differ in their recommendations regarding their use?

Aldosterone antagonists include spironolactone and eplerenone (which is licensed for post-myocardial use only). The 2012 ESC guideline for heart failure has come out in strong support of aldosterone antagonists, in preference to the use of angiotensin receptor blockers (ARBs). NICE currently recommends either of these drugs, or hydralazine with a nitrate, as an optional add-in therapy if treatment with an ACE inhibitor and a -blocker does not control symptoms.

[bold] 10. How do cardiac myosin activators (CMAs) work?

The action of CMAs in the heart leads to a prolonged contraction of the left ventricle and therefore increases the volume of blood pumped out of the heart in each episode of systole; initial studies suggest that these drugs may be useful for improving cardiac function in people with LVSD.

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