A comment from primary care

Br J Cardiol 2016;23(suppl 1):S1–S16doi:10.5837/bjc.2016.s01 Leave a comment
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Sponsorship Statement: This sponsored supplement was initiated and funded by Novartis. Editorial control, however, was retained by the authors and editors but Novartis reviewed the supplement for technical accuracy only before publication.

ENT16-CO51; May 2016
Entresto™ (sacubitril/valsartan) prescribing information is available here

Much of the work in reducing the mortality and morbidity from heart failure will be carried out in primary care. Treatment of these patients with optimal therapy will bring significant benefits. As the armamentarium of agents to treat this condition grows, this article considers why many patients are inappropriately treated in primary care and which patients will most benefit from the new angiotensin-receptor–neprilysin inhibitor (ARNI) class of drugs.


Heart failure, if left untreated, has a worse prognosis than the majority of cancers. Yet with the best possible treatment − most of which can and possibly should be delivered in primary care − the one-year mortality can be as low as 10%.

Earlier articles in this supplement have described how beta blockers, angiotensin-converting enzyme (ACE) inhibitors and mineralocorticoid receptor antagonists (MRAs) offer significant incremental survival benefits to patients with heart failure and reduced ejection fraction (HFREF) that can be further augmented by device therapy. Consider:

  • an implantable cardioverter defibrillator (ICD) in patients with severe left ventricular systolic dysfunction (LVSD), i.e. left ventricular ejection fraction ≤35%
  • cardiac resynchronisation therapy (CRT), with or without a defibrillator, in patients with co-existing left bundle branch block.

The benefits of ensuring patients with HFREF are on the appropriate combination of drugs at appropriate doses are likely to increase survival and reduce the short-term risk of hospitalisation compared with untreated heart failure patients. It is, therefore, unfortunate that many patients with LVSD remain poorly treated in primary care and are often left on suboptimal doses or, inappropriately, exception reported for treatment (i.e. those patients who are not included when determining Quality and Outcome Framework [QOF] achievement).

A common (inappropriate) rationale given for exclusion of beta blockade is chronic obstructive pulmonary disease (COPD). Up to a third of COPD patients are thought to have significant underlying LVSD (often undiagnosed) and residual breathlessness in these patients is often solely attributed to underlying obstructive airways disease. Measurement of serum natriuretic peptides (e.g. brain natriuretic peptide [BNP] or N-terminal proBNP [NTproBNP]) in such patients is a useful screening test for possible co-existing heart failure. If clinicians are anxious about beta blockade in patients with obstructive airways disease, spirometry to rule out significant reversibility should provide reassurance.

Unmet need

The size of the unmet need in heart failure in England can be demonstrated by primary care QOF figures. The most recent data (March 2015)1 relate to heart failure care; these showed a Read-coded ‘heart failure’ prevalence of 0.73% and a Read-coded ‘LVSD’ prevalence of 0.21%. This is likely to represent significant underdetection/miscoding as the true UK prevalence of heart failure is likely to be 1–2%. Of the patients that are coded as LVSD in primary care, 86% are on an ACE inhibitor or angiotensin-receptor blocker (ARB) but only 65% are on both an ACE inhibitor/ARB and beta blocker. Across Clinical Commissioning Groups in England, exception reporting rates for beta blockers vary more than four-fold.

QOF data give no indication of whether patients are on optimised doses but there is anecdotal evidence that dosing is often suboptimal. Patients tend to be initiated on low doses of ACE inhibitors and beta blockers in hospital at the time of diagnosis, then often not subsequently up-titrated appropriately in primary care. Part of the explanation is that QOF does not incentivise optimisation. There are also likely to be capacity and educational gaps that contribute to the problem.

Effective use of community heart failure nurses can help address the unmet clinical and educational need within primary care. This precious resource can facilitate the optimisation process as well as provide advice and mentorship to clinicians to improve confidence in managing complex patients in primary care.

Case history

The case

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  • A 76-year-old patient with long-standing COPD presents with gradually worsening breathlessness on exertion over the previous six months despite good COPD treatment
  • He has a significant smoking history: an ex-smoker with a 30 pack year history
  • He also has longstanding hypertension but no specific cardiac history
  • Recent spirometry confirms moderate/severe COPD: FEV1/FVC 0.6; FEV1 48% expected


Always consider the possibility of co-existing heart failure in a patient with COPD and residual dyspnoea despite optimal COPD treatment.

Patients with COPD commonly have co-existing left ventricular systolic failure or HFREF due to common risk factors, such as smoking. This patient also has long-standing hypertension, which is the second commonest cause of HFREF after ischaemic heart disease. BNP or N-terminal proBNP (NTproBNP) testing would be useful to determine the requirement of echocardiography to assess ventricular function.

COPD can also lead to right-sided heart failure secondary to pulmonary hypertension – look for raised jugular venous pressure and peripheral oedema. Significant tricuspid regurgitation and elevated right ventricular systolic pressure on echocardiography are suggestive of significant pulmonary hypertension.

Patients suitable for ARNIs

The angiotensin-receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan is the first in a new class of drug therapy that may help address the challenge of improving outcomes in HFREF. As we have seen in earlier articles, PARADIGM-HF2 demonstrated a benefit for sacubitril/valsartan over enalapril 10 mg twice daily in symptomatic patients with a left ventricular ejection fraction ≤40%.

NICE recommendation

As with any new agent, we need to work out which patients are likely to derive the most benefit. Recent National Institute of Health and Care Excellence (NICE) guidance in the technology appraisal guidance (TAG)2 for sacubitril/valsartan has recommended the drug as an innovative and cost-effective option for treating symptomatic chronic HFREF, in people:

  • with New York Heart Association (NYHA) class II to IV symptoms and
  • with a left ventricular ejection fraction of ≤35% or less
  • who are already taking a stable dose of ACE inhibitors or ARBs.

NICE recommends that treatment with sacubitril/valsartan should be started by a heart failure specialist with access to a multi-disciplinary heart failure team. Dose titration and monitoring should be performed by the most appropriate team member as defined in previous NICE guidance on the management of chronic heart failure in adults.3

Switching patients

Key considerations for primary care will be how to switch patients and then up-titrate the new drug. The previous article by John McMurray (see pages S11–S13) describes how to use sacubitril/valsartan and its contraindications including the concomitant use of ACE inhibitors due to the risk of angioedema necessitating a washout period of 36 hours before starting treatment.

The NICE TAG (TA388)2 recommends:

  • a starting dose of sacubitril/valsartan of 49/51 mg (100 mg) twice daily
  • or a starting dose of 24/26 mg (50 mg) twice daily for people not currently taking (or on low doses of) an ACE inhibitor or an ARB
  • the dose should be doubled every two to four weeks to the target of 97/103 mg (200 mg) twice daily, as tolerated by the patient.


In future, in view of the potential mortality and hospitalisation benefit, there may be a compelling case for using sacubitril/valsartan as an upstream therapy with the tantalising possibility that this could significantly reduce downstream hospitalisation costs and also the need for costly device therapy.

Key messages

  • HFREF has a very poor prognosis and is significantly underdiagnosed and undertreated with many diagnosed patients not on appropriate beta-blocker therapy
  • Mortality and hospitalisation can be improved by medical therapy overseen in primary care
  • Sacubitril/valsartan should be considered in patients with severe HFREF (EF ≤35%) who remain symptomatic despite otherwise optimal medical therapy.


1. Health and Social Care Information Centre. Quality and Outcomes Framework (QOF) 2014−15. Available from: http://www.hscic.gov.uk [accessed April 5th 2015].

2. National Institute for Health and Care Excellence. Technology appraisal guidance (TA388). Sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction. London: NICE, 27 April 2016. Available from: http://www.nice.org.uk/guidance/ta388 [accessed 26 May 2016].

3. National Institute for Health and Care Excellence. Chronic heart failure in adults: management (CG108). London: NICE, August 2010. Available from: https://www.nice.org.uk/guidance/cg108 [accessed 5 April 2016].

Dosing of sacubitril/valsartan: Throughout this supplement, the dosing of sacubitril/ valsartan (Entresto™, Novartis Pharmaceuticals) has been split to show the constituent doses.

In clinical trials, sacubitril/ valsartan – initially known as the investigational agent LCZ696 – was used in 100 mg and 200 mg doses. These translate to the licensed doses of 49 mg sacubitril/51 mg valsartan and 97 mg sacubitril/103 mg of valsartan, respectively.

A smaller 50 mg dose, which equates to 24 mg sacubitril/26 mg valsartan, is also available.

Disclaimer: Medinews Cardiology Limited advises healthcare professionals to consult up-to-date Prescribing Information and the full Summary of Product Characteristics available from the manufacturers before prescribing any product. Medinews Cardiology Limited cannot accept responsibility for any errors in prescribing which may occur.