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Treating heart failure - Chronic Heart Failure - NCBI Bookshelf

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National Clinical Guideline Centre (UK). Chronic Heart Failure: National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care: Partial Update [Internet]. London: Royal College of Physicians (UK); 2010 Aug. (NICE Clinical Guidelines, No. 108.)

Chronic Heart Failure: National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care: Partial Update [Internet].

Show detailsNICE Clinical Guidelines, No. 108. National Clinical Guideline Centre (UK). London: Royal College of Physicians (UK); 2010 Aug. < PrevNext >

5Treating heart failure

Introduction

Until 1986 the management of most patients with heart failure had relied on the symptomatic relief of the features of congestion by the use of diuretics, with or without digoxin. These measures had no impact on patients’ poor prognosis. Since then, several hypotheses into the management of heart failure have been developed, including the haemodynamic, the neuro-endocrine and the inflammatory hypotheses. Several classes of drugs have been introduced, with significant impact on patients’ morbidity and mortality. Medical therapy is now available with two aims:

  1. Improving the patients’ morbidity: by reducing the patient’s symptoms, improving their exercise tolerance, reducing their hospitalisation rate and improving their quality of life.
  2. Improving the patient’s prognosis, through the reduction of all cause mortality or their heart failure-related mortality.

Therapeutics available for heart failure have expanded since 1986 and include a wide array of medication that are not without side effects. This is one of the many reasons why the decisions on the management of heart failure have to take into account patients’ preferences.r These preferences do change with time and with the varying perspectives that patients may have on their condition and their lives. Involving the patient in management decisions requires that the provision of information to patients and their carers becomes an integral component of management of patients, and their rehabilitation.

Apart from a small number of recent advances in the understanding and therapy of heart failure with preserved left ventricular ejection fraction, most of the evidence supporting the therapeutic interventions in heart failure come from trials that recruited patients with heart failure due to left ventricular systolic dysfunction (LVSD).

The complexity of both the diagnostic process and the therapeutic options, as well as the continuing difficulties in the diagnosis and management of heart failure with preserved left ventricular ejection fraction, dictate the recurrent involvement of specialists. In addition, the role of the multidisciplinary team in the continuing management of heart failure patients is pivotal.

The partial update includes topics where new evidence has emerged since the publication of the heart failure guidelines of 2003.

The guidance for the treatment of heart failure is presented under the following headings:

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5.1 Lifestyle 5.2 Pharmacological treatment of heart failure 5.3 Invasive procedures 5.4 Treatment algorithm

5.1. Lifestyle

This topic (with the exception of rehabilitation which is covered in Chapter 6) was not within the scope of the partial update (2010). For more information on the following aspects of lifestyle please refer to Appendix M, the 2003 Guideline22:

  • Exercise training (7.1.1)
  • Smoking (7.1.3)
  • Alcohol (7.1.4)
  • Diet and nutrition (7.1.5)
  • Natural supplementary therapies (7.1.6)
  • Sexual activity (7.1.7)
  • Vaccination (7.1.8)
  • Air travel (7.1.9)
  • Driving regulations (7.1.10)

5.1.1. Recommendations on lifestyle

Exercise training

Please see Chapter 6 Rehabilitation

Smoking

For guidance on smoking cessation refer to the following NICE guidance:

R18.

Patients should be strongly advised not to smoke. Referral to smoking cessation services should be considered. [2003].

Alcohol

R19.

Patients with alcohol-related heart failure should abstain from drinking alcohol. [2003]

R20.

Healthcare professionals should discuss alcohol consumption with the patient and tailor their advice appropriately to the clinical circumstances. [2003]

Sexual activity

R21.

Healthcare professionals should be prepared to broach sensitive issues with patients, such as sexual activity, as these are unlikely to be raised by the patient. [2003]

Vaccination

R22.

Patients with heart failure should be offered an annual vaccination against influenza. [2003]

R23.

Patients with heart failure should be offered vaccination against pneumococcal disease (only required once). [2003]

Air travel

R24.

Air travel will be possible for the majority of patients with heart failure, depending on their clinical condition at the time of travel. [2003]

Driving regulations

R25.

Large Goods Vehicle and Passenger Carrying Vehicle licence: physicians should be up to date with the latest Driver and Vehicle Licensing Agency guidelines. Check the website for regular updates: www​.dft.gov.uk/dvla. [2003]

5.2. Pharmacological treatment of heart failure

Introduction

Pharmacological interventions in heart failure were driven by symptomatic therapy for many decades. The two pillars of therapy were diuretics and digoxin. Attempts to improve patient outcomes were doomed to fail until the pathophysiology underpinning heart failure started to be addressed through the use of agents that attempted to correct the haemodynamic disturbances and neuro-endocrine over-activity. This has led to major advances in the pharmacological management of heart failure. The morbidity and mortality rates of heart failure have progressively fallen through the accumulative effects of several classes of agents including angiotensin converting enzyme inhibitors, beta-blockers, aldosterone antagonists, combined arterial and venous dilators (combined hydralazine and nitrates) and angiotensin receptor blockers. These advances have been achieved in the treatment of heart failure associated with reduced left ventricular ejection fraction or HF with LVSD, which comprises almost 50% of the heart failure patient population.

Since the late 1990s, research effort has focussed on patients with heart failure who have either a normal left ventricular ejection fraction, or no significant reduction of the left ventricular ejection fraction. These patients are said to have heart failure with preserved left ventricular ejection fraction (HFPEF). There are several theories to explain this syndrome. Some believe this is caused by pure diastolic dysfunction. Others propose a type of systolic dysfunction that affects the long axis of the left ventricle, which can be missed when the concentric contraction of the left ventricle is assessed, as this would not be reduced. Different imaging modalities produce varied estimates of the left ventricular ejection fraction, and some believe that the normal ejection fraction rises with age. Therefore, it is possible that some patients are mislabelled as having HFPEF.

Further research is needed into the detection of HFPEF and a better understanding of the pathophysiological processes. This may lead to more successful therapeutic interventions. Up until now, research on how to treat patients with HFPEF has primarily been concerned with testing agents used in the treatment of HF with LVSD.

Where there are studies specifically addressing HFPEF, these are highlighted in separate sub-sections.

Valve disease, atrial fibrillation and other causes of heart failure (including congenital heart disease, cardiomyopathies and specifc cardiac muscle disease such as amyloid disease) were not reviewed in this 2010 partial update. For more information see Section 7.6.1 of the 2003 Guideline 22 and Atrial fibrillation. NICE clinical guidance 36 (2006) available from www.nice.org.uk/CG36

The decision on which drugs to include in the update of the guideline was made following consultation of the scope. A review of new evidence published after 2003 was carried out in order to determine whether any changes to current recommendations where likely to be required. Decisions on which drugs required a full review of the literature were made as a result of this exercise and whether other NICE guidance relevant for a heart failure population was already available.

The following agents were not considered in the update. For more information refer to Appendix M, the 2003 Guideline22:

  • Amiodarone (7.2.7)
  • Anticoagulants (7.2.8)
  • Inotropic agents (7.2.12)
  • Calcium channel blockers (7.2.13)
  • Diuretics (7.2.1)
  • Digoxin (7.2.5)
  • Statins (7.2.10)
  • Others (Nesiritide, Levosimendan, d-sotalol, epoproserol, magnesium supplementation, vitamin E supplementation, interferon/thymomodulin, human recominant growth hormone, L-cartinine, pentoxifylline, and immunosuppressants (7.2.14)

Drugs reviewed in partial update

5.2.1. Angiotensin converting enzyme inhibitors (ACEI)

The evidence for the use of angiotensin converting enzyme inhibitors (ACEI) in HF with LVSD had been appraised in 2003. There is evidence to support the use of ACEI in all patients with HF with LVSD. ACEI improve symptoms, reduce hospitalisation rate, and improve survival rate. This is applicable in all age groups.

The GDG considered the impact of the new evidence looking at the sequence of therapy in relation to ACEI and beta-blockers, within the section on beta-blockers (Section 5.2.2).

The GDG also looked at the combination of ACEI with angiotensin receptor blockers (ARB) (Section 5.2.6).

Angiotensin Converting Enzyme Inhibitors in HFPEF

Clinical question:

ACE: What is the efficacy and safety of ACEI in people with heart failure and preserved left ventricular ejection fraction?

5.2.1.1. Clinical introduction

ACEI are effective agents in the treatment of heart failure with LVSD, of hypertension and in reducing adverse cardiovascular events in patients with ischaemic heart disease and diabetes mellitus 51,52.

Patients with HFPEF have similar symptoms and almost the same outcomes as those with LVSD. Not infrequently they report a history of hypertension. Some of these patients will have diabetes mellitus or ischaemic heart disease.

Reasons for Review

Since the publication of the 2003 guidelines on chronic heart failure, evidence on the use of ACEI in the management of patients with HFPEF, especially the elderly, has been published.

5.2.1.2. Clinical Methodological introduction

ACE I: Angiotensin Converting Enzyme (ACEI) inhibitor vs. Placebo

Populations
Background medication
  • Beta Blockers >60% 54
  • Beta Blockers <20% 53
Intervention
Comparison

5.2.1.3. Clinical evidence statements

Compared with placebo, ACE inhibitors significantly reduced:

  • HF hospitalisation (follow-up one year) [moderate quality]

There was no significant difference between ACE inhibitors and placebo for:

  • All cause mortality or unplanned hospitalisation (follow-up 12 months) [moderate quality]
  • All cause mortality (follow-up 6 to 12 months and 12 to 54 months) [moderate quality]
  • CV mortality (follow-up one year and 12 to 54 months) [moderate quality]
  • HF hospitalisation (follow-up 12 to 54 months) [moderate quality]
  • Adverse events (follow up 6 to 18 months) [moderate quality]
  • Quality of life (follow-up 6 months) [moderate quality]
  • NYHA class (follow-up 6 months) [moderate quality]

The evidence profile below summarises the quality of the evidence and outcome data from 2 randomised-control trials (RCT) 53,54 comparing ACE inhibitors vs. placebo in HFPEF.

Evidence Profile

ACE inhibitors vs placebo in HFPEF. Question: Should ACE inhibitors vs placebo be used for CHF? Bibliography: Zi M, Carmichael N, Lye M. The effect of quinapril on functional status of elderly patients with diastolic heart failure. Cardiovascular Drugs (more...)

NOTE: A major limitation of the Zi study was the very small sample size (N=74) compared to the Cleland study (N=850).

5.2.1.4. Health Economic Methodological introduction

The 2003 Guideline22 concluded that the treatment of patients with heart failure and LVSD with ACE inhibitors is cost effective, largely due to the costs saved from the reduced risk of hospitalisation. Treatment was cost saving and had very favourable cost effectiveness ratios even when conservative assumptions were employed.

No relevant economic analysis was identified from our review assessing the cost-effectiveness of ACEI in patients with heart failure and preserved LVEF.

5.2.1.5. Health economic evidence statements

Clinical evidence showed that ACEI therapy did not improve mortality but it significantly reduced hospital admissions in patients with heart failure and preserved LVEF. Given that ACEI treatment is relatively cheap; the use of this therapy in patients with HFPEF is likely to be cost-effective.

5.2.1.6. From evidence to recommendations

Relative value placed on the outcomes considered

In the two appraised trials54;53 compared to placebo, ACEI had no effect on all cause mortality at 6–12 months or on the rate of adverse events at 6–18 months. In the small study by Zi et al, there was no impact on quality of life at 6 months or on the rate of improvement of patients with NYHA Class III to II at 6 months. In PEP-CHF trial54, treatment with ACEI resulted in significant (35%) reduction in the rate of heart failure hospitalisation at 1 year, while it had no impact on cardiovascular mortality at 1 year.

There was no difference between those given placebo and those given ACEI in terms of the side effects, quality of life or the New York Heart Association functional class.

However, at completion of the PEP-CHF study by Cleland et al54, there was an insignificant trend towards reduced hospitalisation at 5 years. The significant reduction in heart failure hospitalisation at 1 year in PEP-CHF was derived from a post-hoc analysis. The GDG felt both trials were underpowered with wide confidence intervals around the results. Therefore, the GDG believed that there was insufficient evidence of effectiveness of ACEI in HFPEF to recommend their general use in patients with HFPEF.

Quality of evidence

The evidence reported on all the parameters alluded to above from the two trials was of moderate quality.

Trade-off between clinical benefits and harms

While the GDG did not consider that a post hoc finding of a reduction in heart failure hospitalisation at one year was sufficient to recommend the widespread use of ACEI in HFPEF in the absence of any other significant benefit, it was noted that there was no evidence of significant harm either, with adverse event rates similar in active treatment and placebo arms of the two trials.

Trade-off between net health benefits and resource use

No relevant economic analysis was identified from our review assessing the cost-effectiveness of ACEI in patients with heart failure and preserved LVEF. From clinical trials, net resource use would be likely to be low given that hospital admissions might be reduced, and ACEI therapy is of relatively low cost. However, the GDG noted that the pre-specified hospitalisation endpoint was non-significant and the GDG therefore did not attach weight to the reduction of hospitalisation at one year.

Use of ACEI in left ventricular systolic dysfunction

The evidence base for use of ACEI in left ventricular systolic dysfunction was not formally reviewed. The GDG noted the 2003 recommendations. The GDG endorsed that ACEI doses should be up-titrated slowly up to the target doses used in randomised controlled trials (RCTs). The safety of treatment with ACEI is best achieved by adhering to the protocols used in the clinical trials and proposed in the 2003 guidelines as practical recommendations, as well as the recommendations of the NICE chronic kidney disease guideline. It is particularly important to measure the serum urea, electrolytes, creatinine and eGFR before the initiation of ACEI, following each dose increment, and then at regular intervals.

5.2.1.7. Recommendations

The GDG decided the evidence was inadequate to support the use of ACEI in HFPEF. With regard to the use of ACEI in left ventricular systolic dysfunction, the 2003 practical recommendations were endorsed:

Start ACE inhibitor therapy at a low dose and titrate upwards at short intervals (for example, every 2 weeks) until the optimal tolerated or target dose is achieved. [2010]

Measure serum urea, creatinine, electrolytes and eGFR at initiation of an ACE inhibitor and after each dose increment.7,8 [2010]

5.2.2. Beta Blockers

Clinical question:

What is the efficacy and safety of beta blockers in comparison to placebo, optimal medical management or other beta blockers in people with chronic heart failure?

5.2.2.1. Clinical introduction

The 2003 guidance appraised the evidence on the use of beta-blockers in heart failure due to left ventricular systolic dysfunction (HF with LVSD). The findings and most of the recommendations in the document remain valid. Patients who have HF with LVSD who do not have reversible chronic obstructive pulmonary disease should be considered for the introduction of beta-blockers at low doses. These should be up-titrated slowly. The introduction of beta-blockers in these patients reduces morbidity, hospitalisation, and mortality. The latter includes a reduction of sudden cardiac death.

Reasons for Review

Since the 2003 guidelines, randomised clinical trials have been published looking at comparing selective and non-selective beta-blockers in the treatment of heart failure, at the order of therapeutic strategies (ACEI/BB), and at the use of other beta-blockers in elderly patients with heart failure. There may also be some indirect evidence of the use of these agents in patients with heart failure with preserved left ventricular ejection fraction (HFPEF).

5.2.2.2. Clinical Methodological introduction

  1. BB: What is the safety and efficacy of BB vs placebo in older adults with chronic heart failure?
  2. What is the safety and efficacy of selective vs non-selective BBs in chronic heart failure?
  3. What is the safety and efficacy of BBs in patients with non LVSD chronic heart failure?
  4. What is the safety and efficacy of BB then ACEI vs ACEI then BB for chronic heart failure?
a. Beta blockers versus placebo in older adults with chronic heart failure

Five papers were identified comparing beta-blockers with placebo in older adults with chronic heart failure 55; 56; 57; 58; 59. Two of these papers were in a sub-population derived from RCTs carried out on all patients with chronic heart failure 55; 56. Table 5.1 below summarises the patient population and intervention for each study. Patients with COPD were excluded in all studies except one study 58.

Table 5.1

Patient population and intervention: beta blockers in older adults with heart failure.

b. Evidence profile: Beta blockers versus placebo for patients with LVEF > 35%

One paper pre-specified subanalysis analysis from SENIORS exploring the efficacy of beta-blockers in patients with LVEF > 35%.

Table 5.2

Population and intervention: efficacy of beta blockers in patients with LVEF >35%.

NOTE: The study reported the following statistically significant differences between patients with reduced LVEF and those with preserved LVEF at baseline:

  • Proportion of women: LVEF ≤ 35% 29.8%; LVEF > 35% 49.9%
  • NYHA functional class II: LVEF ≤ 35% 52.8%; LVEF > 35% 62.5%
  • NYHA functional class III: LVEF ≤ 35% 42.5%; LVEF > 35% 32.2%
  • Sitting systolic blood pressure (mm Hg): LVEF ≤ 35% 135.5; LVEF > 35% 145.4
  • Sitting diastolic blood pressure (mm Hg): LVEF ≤ 35% 79.2; LVEF > 35% 82.9
  • Proportion on diuretic: LVEF ≤ 35% 87.9%; LVEF > 35% 83.1%
  • Proportion on Angiotensin converting enzyme inhibitor: LVEF ≤ 35% 80.5%; LVEF > 35% 85.9%
  • Proportion on Angiotensin II antagonist: LVEF ≤ 35% 9.9%; LVEF > 35% 5.6%
  • Proportion of Aldosterone antagonist: LVEF ≤ 35% 32.1%; LVEF > 35% 5.6%
c. Selective vs non-selective beta blockers in chronic heart failure in reduced LVEF?

Three papers were identified comparing selective with non-selective β blockers for chronic heart failure60;61;62. One of the papers61 reported on additional data from the main study60. Both studies excluded patients with COPD. Table 5.3 below summarises the patient population and interventions by study.

Table 5.3

Patient population and interventions: selective vs non-selective beta blockers.

d. Beta blockers then ACEI compared with ACEI then beta blockers in reduced LVEF

One study was identified comparing beta-blockers then ACEI with ACEI then beta-blockers 63. Patients with COPD were excluded. Table 5.4 below summarises the patient population and intervention for each study.

Table 5.4

Patient population and intervention: BB then ACEI vs ACEI then BB.

5.2.2.3. Clinical evidence statements

a. Beta blockers versus placebo in older adults with chronic heart failure

Compared with placebo, beta-blockers had a significant reduction on

  • Mortality – all cause up to 27 months [low quality]
  • Sudden death – up to 24 months [low quality]

Compared with placebo, beta-blockers were associated with no significant differences for:

  • All cause hospitalisation – up to 27 months [moderate quality]
  • Quality of life – Minnesota Living with Heart Failure at 40 weeks [low quality]
  • Adverse events – no. of patients at 40 weeks [low quality]
  • Adverse events – no. of patients (leading to withdrawal of study medication) at 12 months [low quality]

The evidence profile below summarises the quality of evidence and outcome data from five papers55,56,57,58,59 comparing beta-blockers with placebo in older adults with chronic heart failure.

Evidence profile

Comparison of beta-blockers with placebo in older adults. Bibliography: Deedwania PC, Gottlieb S, Ghali JK et al. Efficacy, safety and tolerability of beta-adrenergic blockade with metoprolol CR/XL in elderly patients with heart failure. European Heart (more...)

b. Beta blockers versus placebo for patients with preserved LVEF (LVEF > 35%)

For patients with LVEF > 35%, there was no significant difference between beta-blockers and placebo for:

  • All cause hospitalisation or CV hospitalisation (no of patients) at 21 mths [moderate quality]
  • All cause mortality (no of patients) at 21 mths [moderate quality]
  • All cause mortality –at 21 mths [moderate quality]
  • All cause hospitalisation - (no of patients) at 21 mths [moderate quality]

The evidence profile below summarises the quality of evidence and outcome data from the one paper comparing beta-blockers with placebo for chronic heart failure and preserved LVEF

Evidence profile

Comparison of beta-blockers with placebo for chronic heart failure and preserved LVEF (LVEF > 35%). Question: Should Beta blockers be used for Chronic heart failure - older adults? Bibliography: van Veldhuisen DJ, Cohen SA, Bohm M et al. Beta-blockade (more...)

c. Selective vs non-selective beta blockers in chronic heart failure?

Compared to non-selective beta blockers, selective beta-blockers were associated with a significant increase in:

  • Mortality – all cause mean follow-up 58 months [moderate quality]
  • Sudden death - mean follow-up 58 months [moderate quality]

Compared to non-selective beta blockers, selective beta-blockers were associated with no significant differences for:

  • Mortality and hospitalisation – all cause mean follow-up 58 months [high quality]
  • Quality of life – Minnesota Living with Heart Failure follow-up 12 weeks [moderate quality]
  • Adverse events – no. of patients experiencing mean follow-up 58 months [high quality]

The evidence profile below summarises the quality of evidence and outcome data from three papers comparing selective with non-selective beta blockers for chronic heart failure 60; 61; 62.

Evidence profile

Comparison of selective vs non-selective beta blockers. Question: Should Selective BB vs non-selective BB be used for chronic heart failure? Bibliography: Bibliography: Poole-Wilson PA SK. Comparison of carvedilol and metoprolol on clinical outcomes in (more...)

d. Evidence profile: Beta blockers then ACEI compared with ACEI then beta blockers

Compared to ACEI then beta blockers, beta blockers then ACEI were associated with no significant differences for:

  • Mortality and hospitalisation – all cause mean follow-up 1.22 years [high quality]
  • Mortality – all cause mean follow-up 1.22 years [moderate quality]
  • Hospitalisation – all cause mean follow-up 1.22 years [high quality]
  • Sudden death - mean follow-up 1.22 years [moderate quality]
  • Adverse events – no. of patients experiencing mean follow-up 58 months [high quality]

The evidence profile below summarises the quality of evidence and outcome data from one study comparing beta blockers then ACEI with ACEI then beta blockers 63.

Evidence profile

Comparison of BB then ACEI vs ACEI then BB. Bibliography: Willenheimer R, van Veldhuisen DJ, Silke B et al. Effect on survival and hospitalisation of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with (more...)

5.2.2.4. Health Economic Methodological introduction

From the 2003 Guideline22, economic evidence on beta-blockers consistently showed beta-blockers to be cost effective, largely through costs saved from the reduced risk of hospitalisation. In the UK, only carvedilol and bisoprolol were licensed for the treatment of heart failure at the time of issue of the 2003 Guideline. No study had made a direct comparison between carvedilol and bisoprolol, and there was no evidence on their relative cost-effectiveness.

From our review, one UK cost-effectiveness analysis assessing a beta-blocker in patients with chronic heart failure was identified and presented to the GDG.

Yao et al. (2008)64 presented a cost-utility analysis based on the SENIORS trial, reporting cost per QALY gained. They constructed an individual patient-simulation model within a Markov framework, from a UK NHS perspective, and with a lifetime horizon. The compared interventions were nebivolol + standard care versus placebo + standard care (82.1% of patients were taking ACEI, 6.6% ARB, 27.6% aldosterone antagonist, 39.3% glycosides, 42.2% aspirin, and 82.1% diuretics). The SENIORS trial was conducted on a population of elderly patients with heart failure (≥ 70 years; mean age of 76.1). Nebivolol was up titrated during a 16-week period (target of 10mg once daily). The maximum dosage maintained during SENIORS was 1.25 mg/day in 7.2% of patients, 2.5 mg/day in 7.6%, 5 mg/day in 13.3%, and 10 mg/day in 71.9%. The probabilities used in the model were mainly taken from SENIORS (hospitalisation for cardio-vascular event, cardiac death, sudden death). Probability of death due to other causes was derived from mortality rates in the UK general population (age- and sex-specific, excluding cardiac-related deaths). It was assumed that every patient was 70 years old at the beginning of the study. Health-utility scores for each NYHA class were derived from the CARE-HF trial 65. When a patient was hospitalised, a disutility score of −0.1 was applied. The cost components used in the analysis were: drug cost, GP visit cost, outpatient specialist visit cost, and cardiovascular hospitalisation cost. It was assumed that patients in the nebivolol group attended a GP visit each month for 3 months, and then once every 3 months. Once every 3 months was assumed for the standard-care group. It was also assumed that every cardiovascular hospitalisation was followed by two outpatient attendances. Future costs and benefits were discounted at 3.5% per annum. The sensitivity analysis varied the age of patients at the beginning of the analysis, the discount rate, and the number of outpatient visits. Table 5.5 presents the quality and applicability assessment of this economic analysis.

Table 5.5

Economic study assessment.

5.2.2.5. Health economic evidence statements

Results of the Yao et al. (2008) analysis 64 are presented in Table 5.6. These results showed that adding nebivolol to standard care is cost-effective in the UK for elderly patients with heart failure. The main limitation of this analysis was that potentially important resource use measures were not collected in SENIORS and assumptions were necessary for numbers of GP and outpatient attendances. The GDG felt that the assumption used in the analysis of one GP visit each month for the first three months in the nebivolol cohort does not reflect current clinical practice as more visits are necessary after initiating nebivolol.

Table 5.6

Results – Yao 2008 economic analysis.

5.2.2.6. From evidence to recommendations

Relative value placed on the outcomes considered

The GDG noted that the new evidence concerned the use of beta-blockers in older people with heart failure, the relative effectiveness of the non-selective beta-blocker Carvedilol compared with the selective beta-blocker Metoprolol tartrate, and the sequencing of therapy: ACEI followed by beta-blockers compared with beta-blockers followed by ACEI.

Quality of evidence

The GDG noted the evidence for the use of Nebivolol in older people with heart failure in the SENIORS study 58. The GDG reviewed the post-hoc analyses of two randomised controlled studies of the older adult population using Bisoprolol or Metoprolol CR/XL 55,56. The consistency of the results of the post-hoc analyses in the elderly sub-groups (reduction in all cause mortality and sudden death) with the randomised controlled trial that had specifically looked at this population was noted.

Trade-off between clinical benefits and harms

The GDG noted that there were no studies that specifically looked at the use of beta-blockers in the treatment of HFPEF. One third of the population recruited into the SENIORS study of Nebivolol in heart failure in older adults 58 were patients with a left ventricular ejection fraction >40%. While the size of effect in the sub-group with an ejection fraction >35% was of similar magnitude to that seen in patients with LVSD, the effect in the subgroup with higher ejection fraction was non-significant. 59 The GDG considered that there was insufficient evidence to recommend using beta-beta-blockers in the treatment of HFPEF and that further research was required.

The GDG reviewed the COMET trial 60 comparing the impact of the non-selective beta-blocker Carvedilol to the selective beta-blocker Metoprolol tartarate in the treatment of heart failure. Although the study suggested that Carvedilol was superior at reducing all cause mortality and sudden death, the GDG were not convinced that this difference between Carvedilol and the short acting Metoprolol tartrate was necessarily applicable to other beta-blockers. The GDG noted that the MERIT-HF trial used the long-acting Metoprolol Succinate, and CIBIS II trial used Bisoprolol. Both Metoprolol Succinate and Bisoprolol are selective beta-blockers with outcomes in heart failure not dis-similar to those achieved in the trials that used Carvedilol. The GDG concluded that the implication is that the best results can be achieved by using the beta-blocking agents of proven efficacy in heart failure, namely: Carvedilol, Metoprolol Succinate, Bisoprolol, and Nebivolol.

The GDG considered the CIBIS III trial63, and noted that heart failure patients derived similar outcome of therapy with ACEI followed by beta-blockers, to those treated with beta-blockers followed by ACEI. The GDG accepted that both agents should be given in the absence of contra-indications irrespective of the sequence they are given. The GDG agreed that either agent (or both) could be commenced first (see Section 5.2.1 on ACEI). The clinical decision to use one of these two agents before the other, or to commence both of them simultaneously depends on the clinical status of the patient. Several factors could affect the choice, including the patient s blood pressure, heart rate, the presence of symptomatic ischaemia, arrhythmias and other co-morbidity.

The GDG expressed concern that certain subgroups of patients with heart failure continue to be under-treated with beta-blockers. These include patients with chronic obstructive pulmonary disease (COPD), peripheral vascular disease, diabetes mellitus, erectile dysfunction and older adults. Patients with asthma and reversible airway obstruction were excluded from the trials of beta blockers in heart failure. The remaining patients with COPD should be able to tolerate beta blockers, and are likely to benefit significantly from their use. These patients are undertreated when they develop heart failure, and their outcomes are worse than the average heart failure patient. There is no evidence that selective beta-blockers will worsen these patients pulmonary function. (Salpeter 2005)66. Beta-blockers are often avoided in patients with peripheral vascular disease for fear of exacerbating intermittent claudication, but this concern is unfounded (Radack 1991)67. Although patients with recently unstable diabetes mellitus were excluded from some trials of beta-blockers in heart failure, significant numbers of diabetic patients have been included in beta-blocker trials such as COMET with no evidence that diabetes adversely influenced the effectiveness of the beta-blocker 68; 69(COMET, MERIT-HF). Erectile dysfunction can be caused by some beta-blockers, but there are many causes including other medications and vascular disease. Discussion of these factors with the patient and explanation of the symptomatic and prognostic impact of beta-blockers in heart failure will better inform the decisions made by the patient and the health professional regarding these agents.

There is now sufficient evidence to justify the use of beta-blockers licensed for heart failure in patients in these groups, with the exception of patients who have COPD with reversible obstructive pulmonary disease. This group was excluded from the trials using selective beta-blockers such as bisoprolol (CIBIS II) 56 and Metoprolol CR/XL (MERIT-HF)55. The GDG noted that beta-blockers can be used in irreversible COPD. Moreover, in a meta-analysis of the trials on cardio-selective beta-blockers used in mild to moderate reversible COPD, no clinically significant adverse respiratory effects were demonstrated. (Salpeter 2005)66.

The GDG suggested that if practitioners have particular concerns about side effects in patients with heart failure who also have irreversible COPD or peripheral vascular disease, then a selective beta-blocker licensed for heart failure could be considered.

The GDG considered the issue of managing patients who develop heart failure while on a beta-blocker not licensed for heart failure for another indication such as angina, hypertension, or arrhythmia. Contrary to the 2003 guidance, the GDG felt that it would be appropriate to switch to an agent licensed for use in heart failure, given the demonstrated significant impact these agents have on morbidity and mortality.

The GDG endorsed the 2003 practical recommendations. It is important, during the uptitration of beta-blockers, to monitor the patient s pulse rate, blood pressure and the clinical status, to avoid side effects such as symptomatic bradycardia and symptomatic hypotension. The uptitration should be undertaken gradually and slowly to achieve the target doses used in the clinical trials, if tolerated. The patient needs to be informed that transient pulmonary congestion could occur at times during uptitration of beta-blockers.

Trade-off between net health benefits and resource use

From the 2003 Guideline22, economic evidence on beta-blockers consistently showed beta-blockers to be cost effective. Our review added a study64 that addressed the use of beta blockers in older adults with heart failure. This study64 demonstrated that these agents are also cost-effective for this specific population.

5.2.2.7. Recommendations

Offer both angiotensin-converting enzyme (ACE) inhibitors and beta-blockers licensed for heart failure to all patients with heart failure due to left ventricular systolic dysfunction. Use clinical judgement when deciding which drug to start first. [new 2010]

Offer beta-blockers licensed for heart failure to all patients with heart failure due to left ventricular systolic dysfunction, including:

  • older adults and
  • patients with:

    peripheral vascular disease

    erectile dysfunction

    diabetes mellitus

    interstitial pulmonary disease and

    chronic obstructive pulmonary disease (COPD) without reversibility. [new 2010]

Introduce beta-blockers in a start low, go slow manner, and assess heart rate, blood pressure, and clinical status after each titration. [2010]

Switch stable patients who are already taking a beta-blocker for a comorbidity (for example, angina or hypertension), and who develop heart failure due to left ventricular systolic dysfunction, to a beta-blocker licensed for heart failure. [new 2010]

5.2.3. Aldosterone antagonists

Clinical Question:

What is the efficacy and safety of using an aldosterone antagonist in addition to optimal medical management compared to placebo plus optimal medical management in adults with chronic heart failure?

5.2.3.1. Clinical introduction

There is evidence of enhanced activity of the renin-angiotensin-aldosterone system in patients with heart failure. The modulation of this system started by the introduction of angiotensin-converting-enzyme inhibitors (ACEI), and followed by the introduction of the angiotensin receptor blockers in the treatment of heart failure. Spironolactone, an aldosterone antagonist, was contra-indicated in combination with ACEI, until the publication of the RALES study in 1999. This was reviewed in the 2003 guidance. The latter document confirmed that moderately to severely symptomatic patients with heart failure (NYHA Class III–IV) despite optimal medical therapy would attain lower hospitalisation rates and higher survival rates with the addition of spironolactone. Further evidence on the use of aldosterone antagonists in heart failure was expected in 2003.

Reason for review

Since the publication of the 2003 guideline, new evidence for the use of Aldosterone Antagonists in heart failure has been published. NICE guidance on the management of patients with myocardial infarction includes advice on the use of aldosterone antagonists in patients with heart failure following acute myocardial infarction 70.

In patients on ACEI and beta-blockers who remain symptomatic, aldosterone antagonists as well as other options may be indicated.

5.2.3.2. Clinical Methodological introduction

Aldosterone antagonist + optimal medical management vs. placebo + optimal medical management

Three papers from the EPHESUS trial programme were identified comparing aldosterone antagonists plus optimal medical management with placebo plus optimal medical management in patients with heart failure post-MI 71,72;73

PITT 2003 compared eplerenone with placebo in patients 3–14 days after acute myocardial infarction (MI) with left ventricular dysfunction. PITT 2005 was a post-hoc analysis reporting further outcomes at 30 days and PITT 2006 reported results for the subgroup of patients included in the EPHESUS trial with severe left ventricular impairment (LVEF ≤30%).

Two studies were identified comparing aldosterone antagonists plus optimal medical management with placebo plus optimal medical management in patients with heart failure due to severe left ventricular systolic dysfunction (LVEF <35%) 74,75.

PITT 1999 was a part of the RALES study comparing spironolactone with placebo in patients with heart failure and severe LVSD (LVEF <35%). Patients were included with a history of NYHA class II through IV, a left ventricular ejection fraction ≤ 35%, and a history of NYHA class III or IV within the prior six months of enrolment. ANON 1996 75 was performed by the RALES investigators, this trial was intended as a dose finding trial for spironolactone in patients with HF due to severe LVSD (LVEF <35%).

The results from the EPHESUS severe heart failure subgroup were not meta-analysed with these results due to severe heterogeneity for the outcome heart failure hospitalisation, which may have been caused by the different populations (heart failure vs. heart failure post-MI), the different type of aldosterone antagonist used (spironolactone vs. eplerenone) or the difference in outcome (nonfatal HF hospitalisation vs. HF hospitalisation).

Three studies were identified comparing aldosterone antagonists plus optimal medical management with placebo plus optimal medical management in patients with chronic heart failure 76–78.

Barr (1995) 78 compared spironolactone with placebo in a population with chronic heart failure (CHF) secondary to coronary heart disease. Macdonald (2004) 77 compared spironolactone with placebo in a population with mild heart failure, defined as patients who at diagnosis their CHF had been at least NYHA class II, but optimising their treatment had improved the patients condition substantially into a stable and less symptomatic one. Agostoni (2005) 76 compared spironolactone with placebo in a population with CHF and reduced lung diffusion.

5.2.3.3. Clinical evidence statements

a. Aldosterone antagonists plus optimal medical management vs. placebo plus optimal medical management in patients with heart failure post-MI

Compared with placebo, aldosterone antagonists resulted in a significant reduction of:

  • Mortality all cause at 30 days [moderate quality]
  • Mortality all cause at 16 months [high quality]
  • Mortality all cause at 16 months – subgroup: severe LVSD / LVEF <35% [moderate quality]
  • Sudden death at 16 months [moderate quality]
  • Sudden death at 16 months – subgroup: severe LVSD / LVEF <35% [moderate quality]

Compared with placebo, aldosterone antagonists significantly increased:

  • Hyperkalaemia at 16 months [high quality]

Compared with placebo, aldosterone antagonists had a non-significant effect on:

  • Sudden death at 30 days [high quality]
  • HF hospitalisation at 30 days [moderate quality]
  • Nonfatal HF hospitalisation at 16 months – subgroup: severe LVSD / LVEF <35% [moderate quality]
  • All hospitalisation at 16 months [high quality]

The evidence profile below summarises the quality of the evidence and outcome data from 3 studies 71–73 comparing aldosterone antagonists plus optimal medical management with placebo plus optimal medical management in patients with heart failure post-MI.

Evidence profile

Aldosterone antagonists plus optimal medical management vs. placebo plus optimal medical management in patients with heart failure post-MI. Question: Should aldosterone antagonist vs placebo be used for chronic heart failure post-MI? Bibliography: Pitt (more...)

a. Aldosterone antagonists plus optimal medical management vs. placebo plus optimal medical management in patients with heart failure due to severe LVSD (LVEF <35%)9

Compared with placebo, aldosterone antagonists had a significant reduction on:

  • Mortality all cause at 24 months [moderate quality]
  • HF hospitalisation at 24 months [moderate quality]

Compared with placebo, aldosterone antagonists had a significant increase on:

  • Gynecomastia in men at 24 months [high quality]

Compared with placebo, aldosterone antagonists a non-significant increase on:

  • Hyperkalaemia at 3 to 24 months [low quality]

The evidence profile below summarises the quality of the evidence and outcome data from 2 studies 74,75 comparing aldosterone antagonists plus optimal medical management with placebo plus optimal medical management in patients with heart failure due to severe LVSD (LVEF <35%).

Evidence profile

Aldosterone antagonists plus optimal medical management vs. placebo plus optimal medical management in patients with heart failure due to severe LVSD (LVEF <35%). Question: Should aldosterone antagonist vs placebo be used for heart failure due (more...)

b. Aldosterone antagonists plus optimal medical management with placebo plus optimal medical management in patients with chronic heart failure

Compared with placebo, aldosterone antagonists non-significantly increased:

  • Hyperkalaemia >5.5 mmol/l at two months [low quality]
  • Raised creatinine >300 umol/l at 8 weeks [low quality]

Compared with placebo, aldosterone antagonists non-significantly worsened:

  • Quality of life- Minnesota Living with Heart Failure Questionnaire (MLWHFQ) score at 6 months [low quality]

Compared with placebo, aldosterone antagonists had a non-significant reduction on:

  • Creatinine mean change at 6 months [low quality]

The evidence profile below summarises the quality of the evidence and outcome data from 3 studies 76–78 comparing aldosterone antagonists plus optimal medical management with placebo plus optimal medical management in patients with chronic heart failure.

Evidence profile

Aldosterone antagonists plus optimal medical management vs. placebo plus optimal medical management in patients with chronic heart failure. Question: Should aldosterone antagonist vs placebo be used for all chronic heart failure? Bibliography: Agostoni (more...)

5.2.3.4. Health Economic Methodological introduction

From the 2003 Guideline22, no relevant economic evidence relating to aldosterone antagonists in heart failure was identified. From our review, two cost-effectiveness analyses assessing the addition of an aldosterone antagonist to optimal medical treatment in patients with chronic heart failure were identified and presented to the GDG. The first one was a UK study assessing eplerenone in patients with heart failure and left ventricular systolic dysfunction post acute myocardial infarction, and the other was an Irish study assessing spironolactone in patients with severe chronic heart failure and left ventricular systolic dysfunction. We believe the healthcare system in Ireland is reasonably comparable to the UK’s NHS.

UK study assessing eplerenone

Duerden et al. (2008)79 presented a cost-effectiveness analysis conducted from a UK NHS perspective with a 3-year time horizon (reporting cost per life-year gained). This analysis was based on the EPHESUS trial and assessed the addition of eplerenone to optimal medical treatment in patients with heart failure and left ventricular systolic dysfunction post acute myocardial infarction. For the placebo cohort, resource use estimates were calculated using data from the Office of National Statistics, data from the England and Scotland NHS, and probabilities published by the NICE clinical guideline on secondary prevention of myocardial infarction70. In addition for the placebo cohort, survival estimates were derived from an 18-month epidemiological study assessing patients with all-cause heart failure and carried out in West London (Cowie 2000)9). Survival estimates from this study were extrapolated to 3 years (predicting a 48% survival). For the eplerenone cohort, additional resource use and additional survival were taken from EPHESUS (16-month follow-up) and extrapolated to 3 years. Costs considered in this assessment were the hospitalisation cost and the cost of eplerenone (additional drug cost for the treatment cohort). A 100% adherence and compliance to eplerenone was assumed. Future costs and benefits were discounted at 3.5% per annum. The sensitivity analysis varied mortality rates (increasing by 10%, 15%, and 20%). Table 5.7 presents the quality and applicability assessment of this economic analysis.

Table 5.7

Economic study assessment.

Irish study assessing spironolactone

Tilson et al. (2003)80 conducted a cost-effectiveness analysis reporting cost per life-year gained and was based on the RALES trial. The analysis was developed from an Irish perspective and for a 10-year time horizon. The assessed population were patients with severe chronic heart failure (NYHA class III & IV) and left ventricular systolic dysfunction with a mean age of 65 years. Adding spironolactone to optimal medical management was compared to optimal medical treatment only (might include diuretics, ACEI, digoxin, BB, or a combination of these). Probabilities of death and hospitalisation for the placebo cohort were taken from a cohort of patients followed over 12 months in an Irish teaching hospital. The differences in probabilities of death and hospitalisation for the treatment cohort were taken from RALES. It was assumed that no difference in death and hospitalisation rates occurred between the cohorts after the 2-year mean duration of follow-up for RALES. Costs incorporated in the analysis were spironolactone treatment cost, hospitalisation cost for severe heart failure, and outpatient visit cost. A two-way sensitivity analysis varied probabilities of death and hospitalisation, and one-way sensitivity analyses varied the hospitalisation cost and added outpatient visits to the spironolactone cohort. Future costs and outcomes were discounted at 5% and 1.5% respectively. Table 5.7 presents the quality and applicability assessment of this economic analysis.

5.2.3.5. Health economic evidence statements

UK study assessing eplerenone

Results of the Duerden et al. (2008) cost-effectiveness analysis79 are presented in Table 5.8. These results showed that adding eplerenone to optimal medical treatment in patients with heart failure and left ventricular systolic dysfunction post acute myocardial infarction is cost-effective in the UK. Limitations of this study were that the analysis used a short time horizon (3 years) to assess a long-term treatment for a chronic disease, the analysis did not estimate QALYs, and the sensitivity analysis did not vary resource use estimates.

Table 5.8

Results - Duerden 2008 economic analysis.

Irish study assessing spironolactone

Results of the cost-effectiveness analysis by Tilson et al. (2003)80 are presented in Table 5.9. Considering a cost-effectiveness threshold of £13,000 per life-year gained, we concluded that adding spironolactone to optimal medical treatment is highly cost-effective in Ireland. Limitations of the study were that it did not incorporate quality of life, and the mean age of the population of patients in the RALES study was lower than in the Irish population of patient with chronic heart failure (65 vs 76 years).

Table 5.9

Results - Tilson 2003 economic analysis.

5.2.3.6. From evidence to recommendations

Relative value placed on the outcomes considered

The GDG reviewed the evidence of using aldosterone antagonists in the treatment of chronic heart failure. Two agents were assessed: Spironolactone and Eplerenone. The GDG noted that there was no direct comparison made between the two agents in the treatment of heart failure.

In the RALES study aldosterone antagonist spironolactone was added to loop diuretics and an ACEI in patients with moderate to severe chronic heart failure (NYHA Class III–IV) who remained symptomatic. The GDG noted the significant 30% reduction of both all cause mortality and heart failure hospitalisation at 24 months of therapy with spironolactone. This treatment also resulted in a significant rise in the incidence of gynaecomastia in males, with no significant rise in the risk of hyperkalaemia. However, subsequent observational evidence suggests that the rise in use of spironolactone following the publication of the RALES study was associated with a significant rise in the number of hospitalisations and mortality related to hyperkalaemia and renal failure in patients with chronic heart failure over the age of 66 years treated with ACEI and spironolactone. (Juurlink 2004)82. The GDG took this to highlight the importance of strict monitoring in such patients and of strict adherence to the inclusion and exclusion criteria used in the clinical trial.

In the EPHESUS study, use of the aldosterone antagonist eplerenone was tested in the treatment of symptomatic heart failure (LVEF<40%) after myocardial infarction, or in asymptomatic heart failure caused by left ventricular systolic dysfunction (LVEF<40%) after myocardial infarction in diabetic patients. Eplerenone was used in addition to conventional medical therapy (loop diuretics, ACEI/ARB, beta-blockers). The GDG debated whether the cohort of patients with heart failure after myocardial infarction could be considered as relevant to recommendations on the treatment of chronic heart failure. While the heart failure in this cohort had resulted from acute myocardial infarction, patients continued to display evidence of left ventricular systolic dysfunction (LVEF<40%, with symptoms unless diabetic) some 3–14 days after myocardial infarction and management continued beyond the acute phase of the infarction. Therefore, the GDG decided that the evidence from this group of trials was relevant. Eplerenone therapy resulted in 14%, and 20% reductions of all cause mortality and sudden death, respectively, at 16 months. The GDG noted the evidence from subgroup analysis of the same trial suggesting better outcomes when the agent is started in the first 7 days following the acute event (Adamopoulos 2009)83. Not surprisingly, the impact of therapy was larger in the subgroup of patients with the more severe left ventricular systolic dysfunction (LVEF<30%). There was also a significant reduction of non-fatal heart failure hospitalisations at 16 months, for this group in a post-hoc analysis.

Quality of evidence

The GDG noted the greater weight to be given to results of pre-specified analyses of randomised controlled trials as opposed to post-hoc analyses of randomised controlled trials. The GDG felt it was not appropriate to combine the post-hoc analysis of the outcomes in the sub-group of patients with LVEF<30% treated with eplerenone 72, with the study of patients with LVEF<35% treated with spironolactone74 in a meta-analysis since the two cohorts received different medical therapies and had different backgrounds.

The GDG looked at the small trials that assessed the impact of adding these agents in heart failure patients on quality of life, hyperkalaemia and renal failure. These results are superseded by the larger studies.

Trade-off between clinical benefits and harms

The general side effects of this class of drug are hyperkalaemia and renal impairment.

Since the initiation of aldosterone antagonists is a decision to be made by a specialist, and the decision whether to stop or reduce dose of aldosterone antagonists in the light of rises in serum creatinine and potassium or decline of eGFR is also to be made by a specialist, it is not appropriate to give detailed recommendations on how frequently to monitor renal function or when to stop these agents. The GDG recognised the value of the practical recommendations in the previous guideline, and were happy to support these, recognising that they would have a useful role in implementation of the guidance. In addition, the GDG accepts the NICE guidance on the diagnosis and management of Chronic Kidney Disease, recommending the addition of estimating GFR to the routine assessment and monitoring of renal function. Thus urea, electrolytes, creatinine and eGFR should be checked at 1 week, and at 1, 2, 3, and 6 months and 6 monthly thereafter. They also recommended that the aldosterone antagonist dose should be halved if the potassium rises to 5-5-5.9 mmol/l and stopped if the potassium rises above 6 mmol/l or the creatinine above 220 μmol/l. The latter is based on the evidence from the clinical trials of aldosterone antagonists in heart failure.

There are other side-effects that are pertinent to the non-selective aldosterone antagonist spironolactone, namely gynaecomstia and mastodynia

Trade-off between net health benefits and resource use

The GDG considered the health economic analysis79 assessing eplerenone based on the EPHESUS trial73. On a three-year time horizon, the incremental cost-effectiveness ratio (ICER) was less than £7000 per life-year gained, making the use of eplerenone in heart failure after myocardial infarction already treated with beta-blockers and ACEI, a cost-effective therapy.

In the cost-effectiveness study by Tilson et al, conducted from an Irish perspective and based on the RALES study80, the use of spironolactone was also cost effective (ICER of £291 per life-year gained).

There is no comparative study between the two aldosterone antagonists. The GDG felt that the two agents are probably comparable. From a health economic point of view, the substantially lower cost of spironolactone compared to eplerenone was noted. The current evidence reviewed suggests that spironolactone should be used in severe chronic heart failure (NYHA Class III–IV), and eplerenone should be used in the patients with heart failure following myocardial infarction. The latter is in keeping with the guidance of NICE on the management of myocardial infarction complicated by heart failure.

The GDG are aware of two other trials: the EMPHASIS trial assessing the use of Eplerenone in mild heart failure (NYHA Class II), and the TOPCAT trial looking at the use of smaller doses of spironolactone in patients with heart failure and preserved left ventricular ejection fraction. The EMPHASIS trial was expected to complete recruitment in October 2011, however early termination in May 2010 is said by the sponsors to be due to superiority of eplerenone compared to placebo. The GDG did not have access to the data to analyse.

Another potential use of eplerenone might be where side effects specific to spironolactone (painful gynaecomastia) preclude the continuation of therapy.

The GDG agreed with the 2003 recommendation that a specialist should initiate spironolactone. The same applies to eplerenone.

The GDG suggested as a research recommendation a study investigating the best third agent in the treatment of heart failure, comparing AA vs. ARB in the treatment of heart failure patients who remain symptomatic after optimal therapy with ACEI and BB.

5.2.3.7. Recommendations

The GDG drafted recommendations on the use of aldosterone antagonists as second-line treatment after considering evidence for angiotensin II receptor antagonists and hydralazine in combination with nitrates. See Recommendations R28 and R29.

In patients with heart failure due to left ventricular systolic dysfunction who are taking aldosterone antagonists, closely monitor potassium and creatinine levels, and eGFR. Seek specialist advice if the patient develops hyperkalaemia or renal function deteriorates11. [new 2010]

For patients who have had an acute MI and who have symptoms and/or signs of heart failure and left ventricular systolic dysfunction, treatment with an aldosterone antagonist licensed for post-MI treatment should be initiated within 3–14 days of the MI, preferably after ACE inhibitor therapy. (This recommendation is from ‘MI: secondary prevention’ NICE clinical guideline 48.) [2007]

Patients who have recently had an acute MI and have clinical heart failure and left ventricular systolic dysfunction, but who are already being treated with an aldosterone antagonist for a concomitant condition (for example, chronic heart failure), should continue with the aldosterone antagonist or an alternative, licensed for early post-MI treatment. (This recommendation is from ‘MI: secondary prevention’, NICE clinical guideline 48.) [2007]

5.2.4. Isosorbide Dinitrate/Hydralazine combination

Clinical Question:

What is the efficacy and safety of isosorbide dinitrate/hydralazine combination in comparison to a) Placebo, b) ACEI c) placebo + optimal medical treatment in the medical management of adults with heart failure?

5.2.4.1. Clinical introduction

The veno-dilator isosorbide dinitrate and the arterial dilator hydralazine were used in combination in 1986 in the VHeFT I trial to address the increased pre-load and the increased afterload in heart failure due to severe left ventricular systolic dysfunction. This was the first trial showing that pharmacological therapy could reduce mortality in heart failure. This was followed by the first trial of angiotensin converting enzyme inhibitors (ACEI) in heart failure in 1987. A comparison between the two interventions in 1991 (VHeFT-II trial) showed superiority of ACEI in terms of mortality reduction compared to the hydralazine and nitrate combination. The use of the combined vasodilators Hydralazine and Isosorbide Dinitrate was limited to the cohort of patients with heart failure and severe chronic kidney disease who are not on renal replacement therapy (without direct evidence advising this use). Due to the limited experience in using these agents at the time, it was appropriate for the 2003 guideline to limit their use to cases chosen by the specialist. The guideline raised concerns at the time about using them in combination with other therapeutics.

Reason for review

Since the publication of the guideline in 2003 new evidence in relation to ethnicity has emerged.

5.2.4.2. Clinical Methodological introduction

a. Isosorbide dinitrate/ hydralazine vs. placebo in addition to optimal medical management in the black population

Four studies (2 RCTs) were identified comparing isosorbide and hydralazine combination versus placebo in addition to optimal medical management in the black population with heart failure84–87. In one RCT the patients self-identified as black (defined as of African descent)85 and in one RCT the patients were defined as ‘black’ but no further details of ethnic origin were provided. Two of the studies reported on different outcomes from the main RCT study86;84. The studies by Carson 87 and Taylor 84 are analysed separately to reflect the differences in the background medications the patients were receiving. Table 5.10 below presents a summary of the patient population, background medications and interventions for each study.

Table 5.10

Population and interventions for studies.

b. Isosorbide dinitrate plus hydralazine vs. ACE I in the black population

One RCT was identified comparing isosorbide dinitrate + hydralazine vs ACEI in the black population 87.

c. Isosorbide dinitrate plus hydralazine vs. placebo in different age groups

One post hoc sub-group analysis of an RCT was identified comparing isosorbide dinitrate + hydralazine versus placebo in addition to optimal medical management in different age groups88. Table 5.11 below summarises the patient population and intervention for this study.

Table 5.11

Population and interventions for RCT (Cohn et al.).

d. Isosorbide dinitrate plus hydralazine vs. ACE I in different age groups

One post hoc sub-group analysis of an RCT was identified comparing isosorbide dinitrate + hydralazine versus ACE I in different age groups89. Table 5.12 below summarises the patient population and intervention for this study.

Table 5.12

Population and intervention RCT (Johnson et al.).

5.2.4.3. Clinical evidence statements

a. Isosorbide + hydralazine vs. placebo + optimal medical management in the black population
TAYLOR 84

Compared with placebo (+optimal medical therapy), the combined isosorbide dinitrate plus hydralazine (+optimal medical therapy) has a significant reduction in:

  • All cause mortality 0 to 18 months [moderate quality]
  • Hospitalisation for heart failure mean 12.8 months [moderate quality]
  • Cardiovascular death mean 10 months [moderate quality]

Compared with placebo (+optimal medical therapy), the combined isosorbide dinitrate plus hydralazine (+optimal medical therapy) has a significant improvement in:

  • Composite score follow-up range 0 to 18 months [high quality]
  • Quality of life [moderate quality]

Compared with placebo (+optimal medical therapy), the combined isosorbide dinitrate plus hydralazine (+optimal medical therapy) was associated with a:

  • significant increase in headache [high quality] and dizziness [high quality]

Compared with placebo (+optimal medical therapy), the combined isosorbide dinitrate plus hydralazine (+optimal medical therapy) had no significant effect on:

  • The number of unplanned emergency room admissions or unscheduled office visits [moderate quality]

The evidence profile below summarises the quality of the evidence and outcome data from 4 studies (2 RCTs) 84–87 comparing isosorbide dinitrate + hydralazine versus placebo in addition to optimal medical management in the black population (patients self-identified as black: defined as of African descent). Two of the studies reported on different outcomes

Evidence profile

Isosorbide dinitrate + hydralazine (+ optimal medical management) versus placebo (+ optimal medical management) in the black population. Question: Should isosorbide dintrate and hydralazine (vs. placebo) be used in addition to optimal medical therapy (more...)

CARSON 87

Compared with placebo, the combined isosorbide dinitrate plus hydralazine had no significant effect on:

  • All cause mortality up to 66 months (5.5 yrs) [moderate quality]
  • Hospitalisation for heart failure 66 months [moderate quality]

The evidence profile below summarises the quality of the evidence and outcome data from the one RCT87 comparing isosorbide dinitrate + hydralazine versus placebo in the black population (patients self-identified as black: defined as of African descent).

Evidence profile

Question: Should Isosorbide + hydralazine be used vs placebo? Bibliography: Carson P, Ziesche S, Johnson G et al. Racial differences in response to therapy for heart failure: Analysis of the Vasodilator-Heart Failure Trials. Journal of Cardiac Failure. (more...)

b. Isosorbide dinitrate plus hydralazine vs. ACE I in the black population

Compared with ACEI, isosorbide dinitrate plus hydralazine had no significant effect on:

  • All cause mortality follow-up 0 to 66 months [moderate quality]
  • Hospitalisations for chronic heart failure follow-up 0 to 66 months [moderate quality]

The evidence profile below summarises the quality of the evidence and outcome data from 1 RCT 87 comparing isosorbide + hydralazine versus ACE I in the black population.

Evidence profile

isosorbide dinitrate + hydralazine versus ACE I in the black population. Question: Should isosorbide dinitrate + hydralazine vs ACE I be used for chronic heart failure in black population? Bibliography: Carson P, Ziesche S, Johnson G et al. Racial differences (more...)

c. Isosorbide dinitrate plus hydralazine vs. placebo in different age groups

Compared with placebo, the post-hoc sub group analysis did not detect a significant difference for isosorbide plus hydralazine compared with placebo in the > 60 yrs or < 60 yrs for:

  • all cause mortality [low quality]

The evidence profile below summarises the quality of the evidence and outcome data from 1 RCT (post-hoc sub group analysis) 88 comparing isosorbide dinitrate + hydralazine versus placebo in different age groups. The table below summarises the patient population and intervention for this study.

Evidence profile

Isosorbide dinitrate + hydralazine versus placebo in different age groups. Question: Should isosorbide dinitrate + hydralazine vs placebo be used for chronic heart failure in different age groups? Bibliography: Cohn JN, Archibald DG, Francis GS. Veterans (more...)

d. Isosorbide plus hydralazine vs. ACE I in different age groups

The evidence profile below summarises the quality of the evidence and outcome data from 1 RCT (post-hoc subgroup analysis) 89 comparing isosorbide dinitrate + hydralazine versus ACE I in different age groups. The table below summarises the patient population and intervention for this study.

Evidence profile

Comparing isosorbide dinitrate + hydralazine versus ACE I in different age groups. Author(s): Date: 2009-03-11

Compared with ACEI, the post-hoc sub group analysis did not detect a significant difference for isosorbide dinitrate plus hydralazine compared with ACEI in the over 60 yrs or < 60 yrs for:

  • all cause mortality at 2 yrs [low quality]

5.2.4.4. Health Economic methodological introduction

From the 2003 Guideline22, one US study considered the cost effectiveness of isosorbide dinitrate and hydralazine combination in comparison to standard therapy with digoxin and diuretics, using data from the V-HeFT I trial. This was found to be a cost-effective therapy in the US context, but the generalisability of this result to the UK is questionable.

From our review, one cost-effectiveness analysis assessing the isosorbide dinitrate +hydralazine (ISDN+HYD) combination in patients with chronic heart failure was identified and presented to the GDG.

Angus et al. (2005)86 developed a cost-effectiveness analysis based on the African-American Heart Failure Trial (A-HeFT), reporting cost per life-year gained. A US Medicare perspective was taken, and an 18-month time horizon (A-HeFT follow-up) and a lifetime horizon were considered. The assessed population was black people with moderate to severe heart failure (94.9% with class III NYHA heart failure). Compared interventions were (1) standard therapy (beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, aldosterone antagonist, digoxin and diuretics); and (2) standard therapy + (ISDN+HYD) combination therapy (20mg/37.5mg), starting with one tablet three times daily and titrating to two tablets three times daily as tolerated. Survival estimates for the 18-month analysis were taken from the A-HeFT study. Resource use estimates were also taken from the A-HeFT study. To extrapolate survival for a lifetime horizon, the authors used survival estimates reported by Bardy et al.90 (NYHA class III patients) and assumed no additional survival benefits of ISDN+HYD therapy beyond the duration of the trial. In addition, it was assumed that there would be no additional benefits of ISDN+HYD therapy in terms of resource use after 18 months (the ISDN+HYD therapy cost was the only additional cost for the treatment arm after 18 months). A secondary analysis on a lifetime horizon was conducted considering one additional year of effect of ISDN+HYD therapy beyond the duration of the trial. Cost components considered were hospitalisation (including physician cost), emergency room visits, unscheduled physician visits, scheduled physician visits, ISDN+HYD therapy, concomitant medication and other cares. Table 5.13 presents the quality and applicability assessment of this economic analysis.

Table 5.13

Economic study assessment.

5.2.4.5. Health economic evidence statements

Results of the Angus et al. (2005) analysis86 are presented in Table 5.14. Bootstrapping was used to estimate confidence around the within trial cost-effectiveness results (18 months). Results show that ISDN/HYD therapy is cost-effective in black people with advanced heart failure in the US. According to the A-HeFT trial, the ISDN+HYD combination therapy improves survival, and leads to fewer hospitalisations, shorter hospitalisations, and consequently lower healthcare costs. Combining cost and health outcomes, ISDN+HYD is a dominant therapy (more effective and less costly) at least over a short time horizon. We can also conclude that this therapy is associated with a favourable cost-effectiveness profile in a long-time horizon. However, the generalisation of these results in a UK context is questionable as this study was conducted from a US perspective, a health-care system not directly comparable to the UK NHS.

Table 5.14

Results - Angus 2005 economic analysis.

5.2.4.6. From evidence to recommendations

Relative value placed on the outcomes considered

The GDG reviewed the statement from the 2003 guidelines concerning the use of the combination of Hydralazine and Isosorbide Dinitrate in heart failure, and felt that the 2003 conclusions were valid, even though they were based on a trial when the baseline therapy in 1986 was diuretics and digoxin only. The GDG noted that the main studies related to this subject, since the publication of the 2003 guidelines, were on the use of the combination in the black population, who were found to be less responsive than non-blacks to treatment with Angiotensin Converting Enzyme Inhibitors (ACEI).85,84,86,87 Subsequent evidence of benefit for the combination of hydralazine and nitrates was found from subgroup analyses of prospective studies using the combination either against placebo or in comparison to ACEI. Evidence for the impact of the combination in black patients with moderate to severe heart failure (mainly NYHA III) came from the AHEFT study where the combination of hydralazine and nitrates was given in addition to optimal therapy that included ACEI/ARB, BB and Aldosterone antagonists. The GDG noted that adding the combination to optimal therapy (ACEI, BB and AA) in such patients reduced morbidity and mortality.

The response was related to the treatment with the combination rather than with one of the two drugs. It was felt that patients should be simultaneously commenced on both drugs, and that the doses should be increased gradually according to tolerance, aiming to achieve the target doses used in the clinical trials.

The GDG considered the use of the term ‘black’ as used in these studies. Black patients of African and Carribean descent have been found to derive less benefit than non-blacks from ACEI in both heart failure and hypertension trials, and it is this group in the UK to which this evidence is applicable.

Quality of evidence

The RCT evidence on the treatment of black people with heart failure with hydralazine and nitrate vs. placebo and vs ACEI was of moderate to high quality. The evidence for the age groups analysis was of low quality due to the inclusion of post-hoc subgroup analysis from RCT data 88,89.

Trade-off between clinical benefits and harms

In a post-hoc analysis in blacks, the treatment of black people with heart failure with hydralazine and nitrate vs. placebo resulted in reduced morbidity and mortality, better quality of life but with more headache and dizziness. The comparison with ACEI was associated with wide confidence intervals. The GDG noted that the patients included in the AHEFT trial 85 were already treated with ACEI, beta-blockers (BB), and aldosterone antagonists suggesting that earlier concerns about the safety of the combination in the presence of treatment with ACEI and BB could be allayed.

The GDG noted that the effect of the combination is not limited to an age group. The GDG also noted that side-effects could limit some patients’ tolerance of the treatment with the combination.

The GDG discussed the potential use of the combination in heart failure patients with renal dysfunction, in whom ACEI and ARB could not be used. The GDG noted the publication of the Chronic Kidney Disease Guideline No. 73 (2008) that gives recommendations on the management of patients with impaired renal function who may be on ACEI, ARB and/or aldosterone antagonists91.

There is no evidence on the use of this combination in non-black patients who remain symptomatic after treatment with ACEI and beta-blockers. In the absence of such evidence, one could consider adding these agents on the pathophysiological basis of the helpful vasodilatation offered by these agents in such patients. In addition to the lack of evidence in this regard, and to the potential for intolerance related to side-effects, the introduction of these agents requires the patient’s blood pressure to be adequate or raised. It may be that non-black hypertensive patients with heart failure who remain symptomatic after treatment with ACEI and beta-blockers and who could not have ARB or aldosterone antagonists could benefit from the introduction of this combination. The GDG noted that international guidelines (ESC/ACC/AHA) made such a recommendation but felt that, in the absence of firm evidence to support this, a research recommendation was more appropriate.

The addition of this combination should be initiated by a specialist.

Trade-off between net health benefits and resource use

The GDG noted that the health economic review suggested that the addition of this combination in black patients, who remain symptomatic of heart failure while on ACEI and beta-blockers, is cost saving over 18 months. It is likely to be cost-effective over the lifetime as long as the effects observed in trials continue for some months beyond the 18 month trial follow-up. The GDG noted that the cost-effectiveness analysis86 was developed from a US perspective, so may be of limited applicability to the UK NHS. The GDG felt that the short time horizon was not a significant limitation given that life expectancy is short in patients who remain at NYHA class III (94% of the cohort) despite treatment with ACEI and beta-blockers.

5.2.4.7. Recommendations

Seek specialist advice and consider hydralazine in combination with nitrate for patients with heart failure due to left ventricular systolic dysfunction who are intolerant of ACE inhibitors and ARBs. [2010]

The GDG also drafted a recommendation on the use of hydralazine in combination with nitrate as second-line treatment, after considering evidence for aldosterone antagonists and ARBs. See Recommendations R28 and R29.

5.2.5. Angiotensin-II receptor antagonists vs placebo

Clinical question:

What is the efficacy and safety of angiotensin-II receptor antagonists (ARB) in comparison to placebo in the medical management of adults with heart failure?

5.2.5.1. Clinical introduction

The modulation of the renin-angiotensin-aldosterone axis as an integral pathway for the therapy of heart failure is well established. This is achieved through the addition of ACEI and aldosterone antagonists. In addition, angiotensin receptor blockers (Antagonists of type I receptor of Angiotensin II) are proven as anti-hypertensive agents, working to modulate the renin-angiotensin-aldosterone axis. Unlike ACEI they do not cause dry cough, one of the most common causes of stopping ACEI therapy. When patients are intolerant of ACEI, the introduction of angiotensin receptor blockers (ARB) is frequently proposed as an alternative. This was the position in 2003 when the existing guidelines were published. However no firm recommendation was possible at that stage.

Reasons for Review

New randomised clinical trials have reported on the use of ARBs in the treatment of heart failure due to left ventricular systolic dysfunction as an add-on to ACEI, in the treatment of heart failure due to left ventricular systolic dysfunction where ACEI are not tolerated, in heart failure with preserved left ventricular ejection fraction and in heart failure due to left ventricular systolic dysfunction caused by myocardial infarction. Some of the trials looking at similar populations produced different results. Thus, there is a need for a review and appraisal of the evidence.

Traditionally, when ACEI are not tolerated due to side effects (such as cough), an ARB is used. However, the question arises as to whether ARBs exert the same effect as ACEI. In addition, another question is whether all ARBs exert the same effect. Clarification is needed on the potential risks from combining ACEI, ARB and beta-blockers. Another issue is whether patients who remain symptomatic despite therapy with ACEI and beta blockers should be additionally treated with ARBs, aldosterone antagonists or the combination of hydralazine and nitrates.

5.2.5.2. Clinical Methodological introduction

Angiotensin-II receptor antagonists (ARBS) vs. placebo
a. In patients with heart failure and LVSD

Five studies were identified comparing ARBs vs. placebo in heart failure with left ventricular systolic dysfunction (LVSD)92–96.

In all the studies the use of background angiotensin-converting enzyme inhibitors (ACE-I) was not permitted during the trial period.

Populations
  • NYHA class II–IV and LVEF ≤40% (CHARM-alternative, Val-HeFT-post-hoc analysis)
  • NYHA class II–III and LVEF ≤45% (STRETCH, ARCH-J)
  • NYHA class II–IV, mean pulmonary capillary wedge pressure ≥15 mmHg (Mazayev)
Intervention
  • Candesartan- CHARM-alternative (up to 32 mg/day), STRETCH (up to 16mg/day), ARCH-J (up to 8mg/day)
  • Valsartan -Val-HeFT-post-hoc analysis (up to 160mg ×2/day) Mazayev (40, 80 or 160mg ×2 day)
Note
  • Hypotension was reported as either an adverse event or a cause for discontinuation. In the post hoc subgroup, hypotension was reported as a persistent standing systolic BP < 80 mm Hg or symptoms of hypotension and a cause of treatment discontinuation.
b. In patients with HFPEF

In I-PRESERVE 97 treatment with an angiotensin-converting enzyme inhibitor (ACEI) was only permitted when such therapy was considered essential, 25% of included patients were subsequently on a background of ACE inhibitor at baseline. In CHARM-preserved 98 initially ACE inhibitors were not allowed as concomitant therapy, however with the publication of new trials, their use was permitted in appropriate patients; 20% of included patients were subsequently on a background of ACE inhibitor at baseline.

Populations
  • NYHA class II–IV, LVEF >40% (CHARM-preserved)
  • NYHA class II–IV, LVEF ≥45% (I-PRESERVE)
Intervention
Note

Hypotension was reported as either a serious adverse events or a cause for discontinuation

5.2.5.3. Clinical evidence statements

a. ARBs vs. placebo in heart failure with left ventricular systolic dysfunction (LVSD)

Compared with placebo, angiotensin-II receptor antagonists had a significant reduction on:

  • HF hospitalisation [moderate quality]
  • Composite score (CV mortality and HF hospitalisation) [moderate quality]

Compared with placebo, angiotensin-II receptor antagonists significantly increased:

  • Hyperkalaemia [moderate quality]
  • Raised creatinine [moderate quality]
  • Hypotension [moderate quality]

Compared with placebo, angiotensin-II receptor antagonists significantly improved:

Compared with placebo, angiotensin-II receptor had a non-significant affect on:

  • All cause mortality [high quality]
  • All cause mortality post-hoc subgroup [low quality]
  • Hypotension post-hoc subgroup [low quality]
  • Mean increase in creatinine post-hoc subgroup [moderate quality]

Change in NYHA class was reported in one study 95:

  • Improved: placebo: 28/201 (14%); 4mg: 39/203 (19%); 8mg 41/202 (20%); 16mg: 34/201 (17%); Total on Candesartan: 114/606 (24%)
  • No change: placebo: 170/201(85%); 4mg: 162/203 (80%); 8mg: 161/202 (80%); 16mg: 165/201 (82%); Total on Candesartan: 488/606 (81%)
  • Deterioration: placebo: 3/210 (1%); 4mg: 2/203 (1%); 8mg: 0/202 (0%); 16mg: 2/201 (1%); Total on Candesartan: 4/606 (0.7%)

The evidence profile below summarises the quality of the evidence and outcome data from 5 studies 92–96 comparing ARBs vs. placebo in heart failure with left ventricular systolic dysfunction (LVSD)

Evidence profile

ARBs vs. placebo in heart failure with left ventricular systolic dysfunction (LVSD). Question: Should angiotensin II receptor blockers (ARBs) vs. placebo be used for chronic heart failure? Bibliography: Matsumori A. Efficacy and safety of oral candesartan (more...)

b. ARBs vs. placebo in heart failure with preserved ejection fraction (HFPEF)

Compared with placebo, angiotensin-II receptor antagonists significantly increased:

  • Hyperkalaemia [moderate quality]
  • Raised creatinine [moderate quality]

Compared with placebo, angiotensin-II receptor antagonists had a non-significant effect on:

  • All cause mortality [high quality]
  • CV mortality [high quality]
  • Hypotension [low quality] - however there was serious heterogeneity (I2 82%) seen when meta-analysing the results from I-PRESERVE and CHARM-preserved for this outcome. A possible cause for the inconsistency of results could be due to the use of the stronger drug candersartan in CHARM-preserved compared to irbesartan in I-PRESERVE.
  • HF hospitalisation [high quality]
  • Composite score (CV mortality and HF hospitalisation) [high quality]

Compared with placebo, angiotensin-II receptor antagonists made no difference to:

  • Mean increase in creatinine [high quality]

The evidence profile below summarises the quality of the evidence and outcome data from 2 studies 97,98 comparing ARBs vs. placebo in heart failure with preserved ejection fraction (HFPEF).

Evidence profile

ARBs vs. placebo in heart failure with preserved ejection fraction. Question: Should angiotensin II receptor blockers (ARBs) vs. Placebo be used for HFPEF? Bibliography: Massie BM, Carson PE, McMurray JJ et al. Irbesartan in patients with heart failure (more...)

5.2.5.4. Health Economic methodological introduction

From the 2003 Guideline22, there was no UK-based economic evaluation of the use of angiotensin-II receptor antagonists in the treatment of heart failure. One cost-effectiveness analysis from the United States was found comparing losartan with the ACE inhibitor captopril99. This analysis showed little difference between the cost-effectiveness ratio of these two drugs when used for symptomatic heart failure in older people.

From our review, one economic analysis developed from the UK perspective assessing an angiotensin-II receptor antagonist (ARB) in patients with chronic heart failure was identified and presented to the GDG.

McMurray et al. (2006)100 developed an economic analysis based on the ‘Assessment of Reduction in Mortality and morbidity’ (CHARM) programme assessing the addition of candesartan to optimal medical treatment. Cost-effectiveness analyses reporting cost per life-year gained were conducted on the basis of CHARM-Added and CHARM-Alternative trials. These cost-effectiveness analyses were developed from three perspectives (UK, France, and Germany) and considered within-trial time horizons (median follow-up of 41 months for CHARM-Added and of 34 months for CHARM-Alternative). The health benefit considered was all-cause mortality. Costs considered were drug treatment (including 4 GP visits and 4 biochemistry tests for drug initiation and up-titration in the candesartan arm), hospital admission (all-cause admissions), and cardiovascular procedures. The sensitivity analysis increased the length of non-cardiovascular admission by 30% in the candesartan group (potential additional cost of certain adverse events [renal impairment]), added the cost of one GP visit for candesartan-related adverse events not leading to admission (renal impairment and hypotension), varied the length of hospital stay ± 20%, and used 3.5% as discount rate for UK analyses (base-case analyses used 3%). Table 5.15 presents the quality and applicability assessment of this economic analysis.

Table 5.15

Economic study assessment.

5.2.5.5. Health economic evidence statements

Table 5.16 presents UK results of the cost-effectiveness analyses developed by McMurray et al. (2006)100. These results considered all-cause mortality, all-cause hospital admissions, and costs related to cardiovascular procedures and drug treatments. These cost-effectiveness results show that adding candesartan to optimal medical treatment was cost-saving in CHARM-Added and cost-effective in CHARM-Alternative. The cost-effectiveness result of CHARM-Alternative has a very broad confidence interval. The breadth of the confidence interval reflects the uncertainty around the mortality reduction. An interval was not reported for the CHARM-Added result.

Table 5.16

Cost-effectiveness results - McMurray 2006 economic analysis.

The GDG expressed concerns about these results considering that the resource use was underestimated in the candesartan arm. They discussed the four GP visits and biochemistry tests for candesartan initiation and up-titration, and suggested that the number of visits and tests under-estimate the usual UK practice. In addition, the GDG noted that additional GP visits for candesartan-related complications (hypotension and renal impairment) are usual practice. Additional GP visits were calculated for candesartan-related complications in the sensitivity analysis, and this did not affect the conclusions. The variation in the sensitivity analysis that affected the results most was when increasing the length of stay for non-cardiovascular admissions by 30% in the candesartan group to account for potential additional cost related to certain adverse events (renal impairment). The effect of this was that the treatment was no longer cost-saving in CHARM-Added (results not presented).

No cost-effectiveness analysis was developed on CHARM-preserved. For this trial, the effect of the treatment was non-significant on all-cause mortality and on all-cause hospitalisations (Table 5.17). In addition, the length of stay per hospitalised patient was longer (non-significant) for the treatment arm100.

Table 5.17

Outcomes from CHARM-Preserved.

It should be noted that the McMurray et al. (2006) study100 used a short time horizon, and did not consider quality of life.

5.2.5.6. From evidence to recommendations

Relative value placed on the outcomes considered

Compared to placebo, ARB did not reduce all cause mortality. However, treatment with ARB led to significant reduction in the rate of heart failure hospitalisation (CHARM-Alternative and the ARCH-J trials)92,96. There was also a significant reduction of the composite end-point of cardiovascular mortality and heart failure hospitalisation (CHARM-alternative trial) 92.

Only one trial (Val-HeFT post-hoc analysis) 77 showed an improved quality of life score, and another trial (STRETCH) 95 showed an increased number of patients with improved NYHA functional class when treated with ARB.

Treatment with ARB resulted in significant increase in hyperkalaemia, hypotension and raised creatinine level.

The GDG were aware of two trials (ELITE II and OPTIMAAL) that provided direct comparison of ARB with ACEI in heart failure due to left ventricular systolic dysfunction102,103. ELITE-II compared Losartan to Captopril in patients > 60 years with LVEF < 40% and found similar morbidity and mortality associated with treatment with either agent. OPTIMAAL compared Losartan to Captopril in patients with significant left ventricular systolic dysfunction following Q wave myocardial infarction and found a trend for reduced mortality in the captopril arm, and no difference in morbidity. All the placebo-controlled ACEI trials except CONSENSUS-II (which was in a unique early AMI phase using intravenous ACEI), have consistently shown reduction of morbidity and mortality in heart failure due to left ventricular systolic dysfunction, in contrast with the results of the placebo-controlled ARB trials. However, such indirect comparison can be misleading. The ARB trials were performed in a different era in heart failure patients with better prognosis as a result of treatment with other effective agents such as beta-blockers. Therefore, it will have been more difficult to demonstrate survival benefit in these studies. The more recent HEAAL study104, which was published after the cut off date for the literature searches for this guideline, did find reduced mortality and heart failure hospitalisation in people on high dose (150 mg/day) losartan as compared to low dose (50 mg/day) losartan in the treatment of heart failure due to LVSD in patients intolerant of ACEI (85% due to cough). However, the higher dose was associated with increased renal complications and hyperkalaemia.

The GDG explored the current practice of readily switching patients with heart failure with LVSD from ACEI to ARB whenever side-effects are encountered. Intractable dry cough is the only side-effect that remains unique to ACEI and is readily relieved by switching treatment to ARB. The GDG felt that in light of the the stronger evidence base (and lower cost) of ACEI, treatment should only be switched when ACEI are not tolerated.

Angio-oedema reflects true intolerance to ACEI. It can, however, occur with ARB, albeit much less frequently. The occurrence of renal impairment, hypotension or hyperkalaemia while on ACEI should initially call for reduction (when significant) of the dose of ACEI rather than an immediate switch to ARB (see Appendix J on practical recommendations). The GDG advises that every attempt is made not to stop ACEI in the presence of side-effects, and that education is provided for patient and carers. The GDG noted that some of the patients recruited into the CHARM-Alternative trial had hypotension, hyperkalaemia or renal impairment as the reason for stopping ACEI, and that many were able to tolerate the ARB candesartan. However, candesartan itself led to significantly more patients than placebo discontinuing the study medication due to hypotension, hyperkalaemia and renal impairment.

The GDG considered the impact of treatment of heart failure associated with preserved left ventricular ejection fraction, with ARB.

Two large randomised controlled trials were reviewed.97,98 CHARM-Preserved and I-PRESERVE. ARB had no impact in this group of patients on all cause mortality, cardiovascular mortality, heart failure hospitalisation and the composite score of cardiovascular mortality and heart failure hospitalisation. These agents did not significantly cause hypotension resulting in symptoms or in withdrawal from the trial. However, they significantly increased the incidence of hyperkalaemia and the number of patients with raised serum creatinine (though not the mean creatinine level between the placebo and the ARB treated groups). Taken alone, CHARM-Preserved trial showed a reduction of hospitalisation, but not when combined with I-PRESERVE in meta-analysis.

Quality of evidence

In trials looking at the impact of ARB therapy on patients with heart failure and reduced left ventricular ejection fraction, the evidence of lack of effect on all cause mortality was of high quality in all the trials, except the Val-HeFT-post-hoc analysis93, where the evidence on the effect of all cause mortality was of low quality.

Moderate quality evidence was observed for the significant reduction in heart failure hospitalisation and in the composite score of cardiovascular mortality and heart failure hospitalisation.

Moderate quality of evidence from single trials showed that ARB therapy in these patients leads to improved quality of life scores, and increased number of patients with improved NYHA functional class. Similarly, moderate quality of evidence was observed for ARB therapy increasing the rates of hyperkalaemia, hypotension and raised creatinine level.

The appraisal of trials looking at the impact of ARB on patients with heart failure and preserved left ventricular ejection fraction produced high-quality evidence that these agents have no impact on: all cause mortality, cardiovascular mortality, composite score of cardiovascular mortality and heart failure hospitalisation or on the mean increase in serum creatinine. However, moderate quality evidence was observed for the ARB therapy resulting in a significant rise in the number of patients with raised creatinine, and in the significant increase in the incidence of hyperkalaemia.

Trade-off between clinical benefits and harms

The use of ARB is not justifiable in patients with heart failure and preserved left ventricular ejection fraction as there is no evidence of benefit, with evidence of potential harmful side effects (hyperkalaemia and raised creatinine level).

An ARB could be prescribed to patients with heart failure and preserved left ventricular ejection fraction if there is another indication to prescribe them, such as systemic hypertension or diabetes mellitus.

In patients with heart failure and left ventricular systolic dysfunction, the use of ARB is helpful in reducing hospitalisation, improving quality of life and improving heart failure functional class. There is also evidence from some trials of a reduction in the combined endpoint of mortality and hospitalisation. However, treatment with these agents requires frequent monitoring of serum urea, electrolytes, creatinine and eGFR to guard against the potential side effects of the drugs.

Trade-off between net health benefits and resource use

The use of ARB in patients with heart failure and left ventricular systolic dysfunction was found to be cost effective, however the GDG noted the broad confidence interval of the results of the cost-effectiveness analysis of the CHARM-Alternative trial 100. The breadth of the confidence interval reflects the uncertainty around the mortality reduction.

For the cost-effectiveness of ARBs in patients with heart failure and preserved ejection fraction, the GDG agreed that the evidence is not clear or conclusive in this population.

5.2.5.7. Recommendations

Consider an ARB licensed for heart failure as an alternative to an ACE inhibitor for patients with heart failure due to left ventricular systolic dysfunction who have intolerable side effects with ACE inhibitors. [new 2010]

Monitor serum urea, electrolytes, creatinine and eGFR for signs of renal impairment or hyperkalaemia in patients with heart failure who are taking an ARB12,13. [new 2010]

5.2.6. Angiotensin-II receptor antagonists +other vs placebo + other

Clinical Question:

What is the efficacy and safety of a) angiotensin-II receptor antagonists (ARBs) plus an Angiotensin Converting Enzyme Inhibitors ( ACEIs) in comparison to ACE I plus placebo b) ARBs + ACEI + BB vs placebo + ACEI + BB in the medical management of adults with heart failure?

5.2.6.1. Clinical introduction

See Clinical Introduction for ARB1 (Section 5.2.5.1) above

5.2.6.2. Clinical Methodological introduction

a. Angiotensin-II receptor antagonists (ARBs) plus Angiotensin Converting Enzyme Inhibitors (ACEI) in comparison to ACEI plus placebo

Two studies were identified comparing ARB plus ACEI with Placebo plus ACEI (Houghton et al; Krum et al)

Population - percentage of patients on background ACEI and BB
  • Houghton et al: ACEI 100% BB 0%
  • Val-Heft subgroup (Krum et al): ACEI 100%, BB 0%
Intervention
  • Valsartan up to 320mg (160mg bd) (Val-Heft subgroup analysis – Krum et al)
  • Losartan up to 50mg/day (Houghton et al)
Comparison
b. ARBs + ACEI + betablockers (BB) vs placebo + ACEI + BB in the medical management of adults with chronic heart failure?
Population - percentage of patients on background ACEI and BB
  • CHARM-added (McMurray et al): ACEI 100%, BB 55%
  • Val-HeFT (Cohn et al): ACEI 92%, BB 35%
  • Cocco et al: ACEI 100%, BB 100%
Intervention
  • Candesartan up to 32 mg/day (CHARM-added – McMurray et al)
  • Valsartan up to 320 mg/day (160mg bd) (Val-HeFT – Cohn et al.)
  • Valsartan up to 160 mg/day (Cocco et al.)
c. ARBs + ACEI + betablockers (BB) vs placebo + ACEI + BB in the medical management of adults with heart failure post myocardial infarction

The VALIANT trial 105 was designed differently to the trials used in patients with chronic heart failure (see above). Patients were not on a background of ACEI but were randomised to ARB + ACEI vs ACEI vs ARB, and most patients were on a background of beta blockers.

Population - percentage of patients on background ACEI and BB
  • VALIANT BB 70%
Intervention
  • Valsartan (up to 160mg bd) vs Valsartan (up to 80mg bd) plus captopril (up to 150 mg/day) vs captopril (up to 150 mg/day)

5.2.6.3. Clinical evidence statements

a. Angiotensin-II receptor antagonists (ARBS) plus Angiotensin Converting Enzyme Inhibitors (ACEI) in comparison to ACEI plus placebo in chronic heart failure

Compared with ACEI + placebo, ARBs + ACEI significantly reduced:

  • First hospitalisation [low quality]

Compared with ACEI + placebo, ARBs + ACEI significantly improved:

  • QoL (MLHQ) [moderate]

Compared with ACEI + placebo, ARBs + ACEI significantly increased:

  • Hyperkalaemia [high quality]

Compared with ACEI + placebo, ARBs + ACEI had no difference on:

  • Mortality [moderate quality]
  • Increased serum creatinine (μmol/L) [low quality]

The evidence profile below summarises the quality of the evidence and outcome data from 2 studies106,107. Krum 2004 was a subgroup analysis of the Val-HeFT RCT. Both studies compared ARBs + ACEI vs. ACEI + placebo in heart failure with left ventricular systolic dysfunction (LVSD). Patients in both arms in both studies were not on a background of BB.

Evidence Profile

ARBs + ACEI vs. ACEI + placebo in heart failure with left ventricular systolic dysfunction (LVSD). Question: Should ARB + ACEI (no BB) vs Placebo + ACEI (no BB) be used for CHF? Bibliography: H. Krum, P. Carson, C. Farsang, A. P. Maggioni, R. D. Glazer, (more...)

b. ARB + ACEI + BB vs placebo + ACEI + BB in patients with chronic heart failure

Compared with placebo + ACEI + BB, ARB + ACEI + BB had a significant reduction on:

  • HF hospitalisation [moderate quality]
  • Composite score (CV mortality and HF hospitalisation) [high quality]

Compared with placebo + ACEI + BB, ARB + ACEI + BB had a significantly fewer number of cases with:

  • Worsened NYHA class [low quality]

Compared with placebo + ACEI + BB, ARB + ACEI + BB had no significant effect on:

  • All cause mortality [moderate quality]
  • Improved NYHA class [low quality]
  • Unchanged NYHA class [low quality]

Compared with placebo + ACEI + BB, ARB + ACEI + BB were significantly worse for:

  • Hypotension [moderate quality]
  • Hyperkalaemia [high quality]
  • Increased serum creatinine (number of patients) [high quality]

NYHA class

The results of one study that could not be incorporated into the meta-analysis showed108:

  • Patient NYHA class II
  • Candesartan 13.8% got worse vs 23.8% improved
  • Placebo 20.8 got worse vs 18.7% improved
  • NYHA III–IV
  • Candsartan 4.2% got worse vs 45.7% improved
  • Placebo 5.5% got worse vs 45.8% improved

The evidence profile below summarises the quality of the evidence and outcome data from three studies 101,109,110 comparing ARBs + ACEI + BB vs. placebo + ACEI + BB in heart failure with reduced left ventricular ejection fraction (LVEF).

Evidence profile

Question: Should ARB + ACEI + BB vs Placebo + ACEI + BB be used for CHF? Bibliography: McMurray et al Effects of candesartan in patients with chronic heart failure and reduced left ventricular systolic function taking angiotensin-converting-enzyme inhibitors: (more...)

Evidence Profile: ARBs + ACEI + BB vs. placebo + ACEI + BB in heart failure with left ventricular systolic dysfunction (LVSD)

c. ARB + ACEI + BB vs placebo + ACEI + BB in chronic heart failure post myocardial infacrtion

The evidence profile below summarises the quality of the evidence and outcome data from one study 105 comparing ARBs + ACEI + BB vs. placebo + ACEI + BB in post-MI patients with heart failure with reduced left ventricular ejection fraction (LVEF).

Evidence profile

Question: Should ARB + ACEI + BB vs Placebo + ACEI + BB be used for post-MI and CHF? Bibliography:. M. A. Pfeffer, J. J. McMurray, E. J. Velazquez, J. L. Rouleau, L. Kober, A. P. Maggioni, S. D. Solomon, K. Swedberg, Werf F. Van de, H. White, J. D. Leimberger, (more...)

Compared with placebo + ACEI + BB, ARB + ACEI + BB had a significant reduction on:

  • HF hospitalisation [high quality]

Compared with placebo + ACEI + BB, ARB + ACEI + BB had no difference on:

  • All cause mortality [high quality]
  • Hyperkalaemia [moderate quality]

Compared with placebo + ACEI + BB, ARB + ACEI + BB were significantly worse for:

  • Hypotension [high quality]

5.2.6.4. Health Economic methodological introduction

McMurray et al. (2006)100 developed an economic analysis based on the CHARM programme. This analysis was presented in Section 5.2.1.5.

5.2.6.5. From evidence to recommendations

Relative value placed on the outcomes considered

The question was considered in two stages: adding ARB to the combination of ACEI and beta- blockers and combining ARB with ACEI.

For the first part, there were four appraised studies. Three of the studies were of similar design adding candesartan101 (CHARM-Added study), or Valsartan109,110 (Val-HeFT, Cocco et al) to treatment with an ACEI that was given to 92–100% of participants. In addition, beta-blockers were given to 100% of the patients in the Cocco et al study, 55% in CHARM-Added and 35% in the Val-HeFT study. The fourth study105 (VALIANT) was in patients with heart failure due to LVSD following myocardial infarction. The design was more complex in that there were three arms in the study: ACEI, Valsartan or ACEI + Valsartan. In the VALIANT study 77% of the patients were on beta-blockers.

The addition of ARB to the combined ACEI and BB in patients with heart failure and LVSD did not affect all cause mortality but did significantly reduce heart failure hospitalisation, and the combined score of heart failure hospitalisation and mortality.

This intervention led to significantly less chance of worsening NYHA functional class. Adding ARB to this combination significantly increased the incidence of hyperkalaemia, hypotension and raised serum creatinine.

There was some concern raised after the publication of the Val-HeFT study 110 about the safety of combining ARB with beta- blockers in patients with heart failure. This led to a safety warning in the 2003 NICE guidelines on heart failure. However, given the results of the other studies that used both Candesartan 101 (CHARM-Added) and Valsartan 105 (VALIANT), the GDG concluded this combination could be used safely.

The second part of the question addressed combining ARB with ACEI. Two studies were appraised: Krum et al (sub-study of Val-HeFT trial)106, and Houghton et al107. These used Valsartan and Losartan, respectively.

Compared to placebo, the addition of Valsartan to ACEI in the Krum et al trial106 did not impact on all cause mortality, but it significantly reduced the rate of first hospitalisation. This addition also resulted in significant improvement in the quality of life. There was no significant impact of adding Losartan in the Houghton et al study107 on the incidence of hyperkalaemia or increased serum creatinine.

Quality of evidence

There is high-quality evidence that adding ARB to the combination of ACEI and beta-blockers results in significantly reduced combined score of cardiovascular mortality and heart failure hospitalisation; and for increased risk of hyperkalaemia.

With regards to the impact of this addition on all cause mortality, heart failure hospitalisation, hypotension, and the number of patients with raised serum creatinine, the evidence is of moderate quality.

The evidence supporting the remainder of the statements was of low quality. The evidence behind the statements derived from the Houghton et al study107 of the addition of ARB to ACEI was of moderate quality. The main statements derived from the results of the Krum study106 were based on low quality evidence. The latter is particularly related to the fact that this study was a post-hoc analysis.

Trade-off between clinical benefits and harms

The addition of ARB to other drugs for heart failure with LVSD did not reduce all cause mortality, but the trials were not powered to detect such an effect. However, another analysis (Young et al) from the CHARM programme combined the results of CHARM-Added and CHARM-Alternative. This was powered to look at the impact of ARB on mortality in heart failure patients with reduced left ventricular ejection fraction. It showed a statistically significant reduction of all cause mortality and cardiovascular mortality. This was in addition to the significant reduction of heart failure hospitalisation.

ARBs reduce the combined score of cardiovascular mortality and heart failure hospitalisation, as well as reducing the rate of hospitalisation and improving quality of life score. Against these benefits are the potential risks of hyperkalaemia, hypotension and raised serum creatinine. The latter three potential harms call for frequent checks to be made on the renal profile and the electrolyte balance when patients are given these agents. These harms have also to be considered when prescribing these agents to heart failure patients with significant renal dysfunction or borderline low systolic blood pressure. Further details regarding the issue of monitoring and adjusting the doses of ARB are in Appendix J. The GDG considered whether some patients with heart failure and LVSD might be prescribed ACEI, beta-blockers, ARB and an aldosterone antagonist. Although some patients in the CHARM-Added trial were on quadruple therapy, these were the minority. The GDG does not believe there is sufficient evidence to support the widespread use of quadruple therapy. Similarly, even in the absence of beta-blockers the GDG does not recommend using triple therapy of ACEI with ARB and aldosterone antagonists for safety concerns (risks of hyperkalaemia and renal impairment). A similar view was adopted by the Chronic Kidney Disease NICE guidance where such combination of ACEI/ACEI and AA was discouraged.

Trade-off between net health benefits and resource use

The use of ARB in patients with heart failure and left ventricular systolic dysfunction added to ACEI and beta-blockers was found to be cost-saving in the reviewed cost-effectiveness analysis based on CHARM-Added100.

A confidence interval was not reported with this result. The all-cause mortality reduction in the CHARM-Added trial, although not statistically significant, was larger than that recorded in our meta-analysis when the study was combined with other trials (RR=0.91 vs RR=0.98) (Section 5.2.5.4). Had the meta-analysis been used ARBs might not appear cost-effective.

5.2.6.6. Recommendation

The GDG drafted a recommendation on the use of angiotensin II receptor antagonists as second-line treatment after considering evidence for Aldosterone antagonists and hydralazine in combination with nitrates. See Recommendations R28 and R29.

Drugs not within scope of partial update

There were agents that were outside the scope of the partial update. These included Aspirin and HMG-CoA reductase inhibitors (statins). For more information refer to Appendix M, the 2003 Guideline22:

For the statins, the reader is referred to

  • Lipid Modification: Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease (NICE Clinical Guideline No.67 (2008)). Available from www.nice.org.uk/CG67.
  • Statins for the prevention of cardiovascular events (NICE Technology Appraisal No.94 (2006) Available from www.nice.org.uk/TA094.

The GDG was aware of two large randomized controlled trials of statins in patients with heart failure that were published recently. These were: Effect of rosuvastatin in patients with chronic heart failure (GISSI-HF trial group)111, and the CORONA study: 104. These trials randomized 4574 patients with heart failure and 5011 patients over the age of 60 years with systolic heart failure of ischaemic origin, respectively, to have 10 mg rosuvastatin or placebo. The statin did not have an impact on any of the trials’ outcomes other than reducing hospitalisation in the CORONA study. Therefore, it is unlikely that statins would be beneficial in heart failure. The GDG felt that in the light of this evidence, the recommendation on statin use from the 2003 guideline should be deleted.

The GDG, when discussing the GISSI-HF trial of rosuvastatin in heart failure, also noted the other part of the trial that looked at the effects of n-3 polyunsaturated free fatty acid ethyl esters (PUFA) in patients with chronic heart failure111. This trial randomized 6975 patients with heart failure to receive either 1 g n-3 PUFA or placebo. This treatment resulted in reduction of both mortality and hospitalisation. The GDG had not formally reviewed the evidence on this topic, n-3 PUFA is not licensed for use in heart failure at this stage and the topic remains outside the scope. Therefore the GDG did not make a recommendation.

Recommendations

5.2.7. All recommendations for the pharmacological treatment of heart failure

Medicines adherence

For more information refer to NICE guideline:

  • Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. NICE clinical guideline 76 (2009). Available from www.nice.org.uk/guidance/CG76.
R26.

Dosing regimens should be kept as simple as possible, and the healthcare professional should ensure that the patient and carer are fully informed about their medication. [2003]

Heart failure due to left ventricular systolic dysfunction

First-line treatment

See also recommendations R30 – R34 on the use of ACE inhibitors and beta-blockers for first-line treatment. See recommendations R39 – R40 for alternative first-line treatments for patients who are intolerant of ACE inhibitors. See recommendation R38 for alternative first-line treatments for patients who are intolerant of ACE inhibitors and ARBs.

R27.

Offer both angiotensin-converting enzyme (ACE) inhibitors and beta-blockers licensed for heart failure to all patients with heart failure due to left ventricular systolic dysfunction. Use clinical judgement when deciding which drug to start first. [new 2010] KPI

Second-line treatment

See also recommendations R35 – R37 and R40 on second-line treatments.

R28.

Seek specialist advice before offering second-line treatment to patients with heart failure due to left ventricular systolic dysfunction. [new 2010]

R29.

Seek specialist advice and consider adding one of the following if a patient remains symptomatic despite optimal therapy with an ACE inhibitor and a beta-blocker:

  • an aldosterone antagonist licensed for heart failure (especially if the patient has moderate to severe heart failure [NYHA14 class III–IV], or has had an MI within the past month) or
  • an angiotensin II receptor antagonist (ARB) licensed for heart failure15 (especially if the patient has mild to moderate heart failure [NYHA class II–III]) or
  • hydralazine in combination with nitrate (especially if the patient is of African or Caribbean origin16 and has moderate to severe heart failure [NYHA class III–IV]). [new 2010] KPI

ACE inhibitors (first-line treatment)

See also recommendation R27.

R30.

Start ACE inhibitor therapy at a low dose and titrate upwards at short intervals (for example, every 2 weeks) until the optimal tolerated or target dose is achieved. [2010]

R31.

Measure serum urea, creatinine, electrolytes and eGFR at initiation of an ACE inhibitor and after each dose increment.1718 [2010]

Beta-blockers (first-line treatment)

See also recommendation R27.

R32.

Offer beta-blockers licensed for heart failure to all patients with heart failure due to left ventricular systolic dysfunction, including:

  • older adults and
  • patients with:

    peripheral vascular disease

    erectile dysfunction

    diabetes mellitus

    interstitial pulmonary disease and

    chronic obstructive pulmonary disease (COPD) without reversibility. [new 2010] KPI

R33.

Introduce beta-blockers in a ‘start low, go slow’ manner, and assess heart rate, blood pressure, and clinical status after each titration. [2010]

R34.

Switch stable patients who are already taking a beta-blocker for a comorbidity (for example, angina or hypertension), and who develop heart failure due to left ventricular systolic dysfunction, to a beta-blocker licensed for heart failure. [new 2010]

Aldosterone antagonists (second-line treatment)

See also recommendations R28 and R29.

R35.

In patients with heart failure due to left ventricular systolic dysfunction who are taking aldosterone antagonists, closely monitor potassium and creatinine levels and eGFR. Seek specialist advice if the patient develops hyperkalaemia or renal function deteriorates19. [new 2010]

R36.

For patients who have had an acute MI and who have symptoms and/or signs of heart failure and left ventricular systolic dysfunction, treatment with an aldosterone antagonist licensed for post-MI treatment should be initiated within 3–14 days of the MI, preferably after ACE inhibitor therapy. (This recommendation is from ‘MI: secondary prevention’ NICE clinical guideline 48.) [2007]

R37.

Patients who have recently had an acute MI and have clinical heart failure and left ventricular systolic dysfunction, but who are already being treated with an aldosterone antagonist for a concomitant condition (for example, chronic heart failure), should continue with the aldosterone antagonist or an alternative, licensed for early post-MI treatment. (This recommendation is from ‘MI: secondary prevention’, NICE clinical guideline 48.)

Hydralazine in combination with nitrate (alternative first-line treatment)

See also recommendations R28 and R29 for the use of hydralazine in combination with nitrate as second-line treatment.

R38.

Seek specialist advice and consider hydralazine in combination with nitrate for patients with heart failure due to left ventricular systolic dysfunction who are intolerant of ACE inhibitors and ARBs. [new 2010]

Angiotensin II receptor antagonists (second-line or alternative first-line treatment)

See also recommendations R28 and R29 for the use of ARBs as second-line treatment.

R39.

Consider an ARB licensed for heart failure as an alternative to an ACE inhibitor for patients with heart failure due to left ventricular systolic dysfunction who have intolerable side effects with ACE inhibitors. [new 2010]

R40.

Monitor serum urea, electrolytes, creatinine and eGFR for signs of renal impairment or hyperkalaemia in patients with heart failure who are taking an ARB20,21. [new 2010]

Digoxin

R41.

Digoxin is recommended for:

  • worsening or severe heart failure due to left ventricular systolic dysfunction despite first- and second-line treatment for heart failure.22 [2003, amended 2010]

All types of heart failure

Diuretics
R42.

Diuretics should be routinely used for the relief of congestive symptoms and fluid retention in patients with heart failure, and titrated (up and down) according to need following the initiation of subsequent heart failure therapies. [2003]

R43.

The diagnosis and treatment of heart failure with preserved ejection fraction should be made by a specialist, and other conditions that present in a similar way may need to be considered. Patients in whom this diagnosis has been made should usually be treated with a low to medium dose of loop diuretics (for example, less than 80 mg furosemide per day). Patients who do not respond to this treatment will require further specialist advice. [2003]

Calcium channel blockers
R44.

Amlodipine should be considered for the treatment of comorbid hypertension and/or angina in patients with heart failure, but verapamil, diltiazem or short-acting dihydropyridine agents should be avoided. [2003]

Amiodarone
R45.

The decision to prescribe amiodarone should be made in consultation with a specialist. [2003]

R46.

The need to continue the amiodarone prescription should be reviewed regularly. [2003]

R47.

Patients taking amiodarone should have a routine 6-monthly clinical review, including liver and thyroid function test, and including a review of side effects. [2003]

Anticoagulants23
R48.

In patients with heart failure in sinus rhythm, anticoagulation should be considered for those with a history of thromboembolism, left ventricular aneurysm, or intracardiac thrombus. [2003]

Aspirin
R49.

Aspirin (75–150 mg once daily) should be prescribed for patients with the combination of heart failure and atherosclerotic arterial disease (including coronary heart disease). [2003]

Inotropic agents
R50.

Intravenous inotropic agents (such as dobutamine, milrinone or enoximone) should only be considered for the short-term treatment of acute decompensation of chronic heart failure. This will require specialist advice. [2003]

Heart failure due to valve disease
R51.

Patients with heart failure due to valve disease should be referred for specialist assessment and advice regarding follow-up. [2003]

R52.

ACE inhibitor therapy should not be initiated in a patient with a clinical suspicion of haemodynamically significant valve disease, until the valve disease has been assessed by a specialist. [2003]

General

Age
R53.

The management of heart failure should be determined by clinical criteria, irrespective of the age of the patient. [2003]

R54.

Tolerance of drugs may be lower and side effects require closer and more frequent monitoring in older patients. [2003]

Gender
R55.

The principles of pharmacological management of heart failure should be the same for men and women. [2003]

R56.

In women of reproductive age who have heart failure, contraception and pregnancy should be discussed. If pregnancy is being considered or occurs, specialist advice should be sought. Subsequently, specialist care should be shared between the cardiologist and obstetrician. [2003]

R57.

The potential teratogenic effects of drugs should be considered. [2003]

Comorbidities
R58.

Manage co morbidities according to:

  • ‘Hypertension’, NICE clinical guideline 34
  • MI: secondary prevention’, NICE clinical guideline 48
  • ‘Type 2 diabetes’, NICE clinical guideline 87

and other relevant NICE guidance. This is particularly important in heart failure with preserved ejection fraction. [new 2010]

5.3. Invasive procedures

5.3.1. Introduction

Although drug therapy is the mainstay of treatment of heart failure, some patients will also benefit from diagnostic or interventional invasive procedures. These procedures are organised by the specialist. This guideline can only give general advice, and specialist advice is strongly recommended where such procedures might be considered.

Procedures within the scope of the update

5.3.2. Cardiac resynchronisation therapy

Cardiac resynchronisation therapy (CRT) is one of the major new advances in the management of heart failure, resulting in reduced morbidity and increased survival of heart failure patients with dys-synchrony. The GDG were aware of new advances in the evidence-base for CRT, widening the indications for these devices to involve patients with less severe heart failure. This is the basis of a pending review for the existing guidance in 2010. For more information refer to:

Please refer to the NICE website for updates on the review status of this appraisal.

5.3.3. Implantable cardioverter-defibrillators (ICDs)

The 2003 guideline included recommendations from NICE Technology Appraisal No 11 (Guidance on the use of implantable cardioverter defibrillators for arrhythmias). These have been superseded by Technology Appraisal No 95 (2006). However, that guidance did not cover the patients with non-ischaemic dilated cardiomyopathy. For more information refer to:

NICE will consult on review plans for this guidance in August 2010. Please refer to the NICE website for updates on the review status of this appraisal.

Procedures outside the scope of the update

Other interventional procedures considered in the 2003 guideline were outside the scope of the partial update (2010). For more information please refer to the following sections of Appendix M, the 2003 Guideline 22.

  • Coronary revascularisation (7.4.1)
  • Cardiac transplantation (7.4.2)
  • Ventricular assist devices (7.4.3)
  • Mitral valve surgery and cardiomyoplasty (7.4.6)

Recommendations

5.3.4. Recommendations for invasive procedures

Coronary revascularisation

R59.

Coronary revascularisation should not be routinely considered in patients with heart failure due to systolic left ventricular impairment, unless they have refractory angina. [2003]

Cardiac transplantation

R60.

Specialist referral for transplantation should be considered in patients with severe refractory symptoms or refractory cardiogenic shock. [2003]

Cardiac resynchronisation therapy

Refer to ‘Cardiac resynchronisation therapy for the treatment of heart failure’ (NICE technology appraisal guidance120 [2007]). Please refer to the NICE website for updates on the review status of this appraisal.

Implantable cardioverter-defibrillators (ICDs)

Refer to the ‘Implantable cardioverter defibrillators for arrhythmias’ (NICE technology appraisal guidance 95 [2006]). Please refer to the NICE website for updates on the review status of this appraisal.

5.4. Treatment algorithm

Treating heart failure

Footnotes

22

See ‘Atrial fibrillation’ (NICE clinical guideline 36) for recommendations on the use of digoxin in patients with atrial fibrillation.

7

For practical recommendations on treatment with ACE inhibitors see ‘Chronic kidney disease’ (NICE clinical guideline 73).

8

For more information see Appendix J.

9

Patients were included with a history of NYHA class II through IV, a left ventricular ejection fraction ≤ 35%, and a history of NYHA class III or IV within the prior six months of enrolment

10

Patients were included with a history of NYHA class II through IV, a left ventricular ejection fraction ≤ 35%, and a history of NYHA class III or IV within the prior six months of enrolment

11

For more information see Appendix J.

12

For practical information on treatment with ARBs see ‘Chronic kidney disease’ (NICE clinical guideline 73).

13

For more information see Appendix J.

14

The New York Heart Association classification of heart failure.

15

Not all ARBs are licensed for use in heart failure in combination with ACE inhibitors

16

This does not include mixed race.

17

For practical recommendations on treatment with ACE inhibitors see ‘Chronic kidney disease’ (NICE clinical guideline 73).

18

For more information see Appendix J.

19

For more information see Appendix J.

20

For practical recommendations on treatment with ARBs see ‘Chronic kidney disease’ (NICE clinical guideline 73).

21

For more information see Appendix J.

23

See also ‘Atrial fibrillation’ (NICE clinical guideline 36) for recommendations on the use of anticoagulants in patients with atrial fibrillation

Copyright © 2010, National Clinical Guideline Centre.

Apart from any fair dealing for the purposes of research or private study, criticism or review, as permitted under the Copyright, Designs and Patents Act, 1988, no part of this publication may be reproduced, stored or transmitted in any form or by any means, without the prior written permission of the publisher or, in the case of reprographic reproduction, in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK. Enquiries concerning reproduction outside the terms stated here should be sent to the publisher at the UK address printed on this page.

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