Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
■ THERAPY REVIEW Sacubitril/valsartan for chronic heart failure: its future potential STEVE CHAPLIN NYHA Symptoms I No symptoms and no limitation in ordinary physical activity, eg shortness of breath when walking, climbing stairs, etc. II Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity III Marked limitation in activity due to symptoms, even during less-than-ordinary activity, eg walking short distances (20–100m) Comfortable only at rest IV Severe limitations in activity Experiencing symptoms even while at rest Mostly bedbound patients Table 1. New York Heart Association (NYHA) functional classification of heart failure Sacubitril/valsartan (Entresto), a combined neprilysin inhibitor/ angiotensin II-receptor antagonist for the treatment of chronic heart failure with reduced ejection fraction, was launched in the UK in January. The phase 3 clinical trial PARADIGM-HF established its efficacy in chronic heart failure but what is its future place in therapy, according to the latest guidelines and research? F ew new drugs enjoy the warm reception accorded to sacubitril/valsartan (Entresto) since publication of the international PARADIGM-HF trial (Prospective Comparison of ARNI [angiotensin receptor–neprilysin inhibitor] with ACEI [ACE inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) in 2014,1 and its subsequent launch in the UK in January 2016. Many analyses of PARADIGM-HF have been published since the original trial and new indications are being explored. So what is the potential of this novel combination of a neprilysin inhibitor and an angiotensin II-receptor antagonist? What makes sacubitril/valsartan special? In a word, PARADIGM. One of the largest trials of a treatment for heart failure ever conducted, it included 8442 patients with chronic symptomatic heart failure (mostly New York Heart Association (NYHA) class II or III – see Table 1) despite taking an ACE inhibitor and a beta-blocker, and with a reduced ejection fraction averaging about 30 per cent. The double-blind trial randomised patients to treatment with sacubitril/valsartan 97mg/103mg (200mg) twice daily or the ACE inhibitor enalapril 10mg twice daily (see Figure 1). Sacubitril/valsartan significantly reduced the risk of the primary endpoint (a composite of death from cardiovascular causes or first hospitalisation for worsening heart failure) by 20 per cent compared with enalapril after a median 27 months’ follow-up (see Table 2).1 The trial was terminated early because an interim analysis showed a significant benefit of sacubitril/valsartan over enalapril. Sacubitril/ valsartan also significantly decreased all-cause mortality, cardiovascular death and the risk of hospitalisation for heart failure, and improved the symptoms and physical limitations of heart failure compared with enalapril. It did not reduce the decline in renal function or the risk of atrial fibrillation. 26 ❚ Prescriber November 2016 prescriber.co.uk Sacubitril/valsartan Single-blind run-in period† (6 to 8 weeks) Median exposure: 15 days (n=10,513) Enalapril 10mg twice daily Double-blind period‡ (actual duration was event driven) Median exposure: 29 days (n=9419) Sacubitril/ valsartan 49/51mg (100mg) twice daily l THERAPY REVIEW ■ Sacubitril/valsartan 97/103mg (200mg) twice daily Sacubitril/valsartan 97/103mg (200mg) twice daily (n=4209) 1:1 randomisation Enalapril 10mg twice daily (n=4233) †All patients were on an ACE inhibitor or antiotensin II-receptor antagonist prior to the run-in period ‡Median follow-up duration was 27 months; patients were treated for up to 4.3 years Figure 1. PARADIGM-HF trial design What else did PARADIGM-HF show? The many analyses of the PARADIGM-HF data show that sacubitril/valsartan slows heart failure progression compared with enalapril. Its benefits are consistent despite regional differences in patient populations, there is equal benefit for stable patients and those recently hospitalised, when outpatient dose intensification is assessed and regardless of background therapy. It reduces re-admission for any cause within 30 days. Outcomes were worse after dose reduction during the trial, with worsening ejection fraction at baseline, higher baseline risk score and in patients with diabetes or prediabetes, but efficacy relative to enalapril was unchanged. Sacubitril/valsartan was superior for any cause of death, though differences in clinical outcomes between the treatment arms were not statistically significant in those aged 75 years and older (see Figure 2) and the incidence of symptomatic hypotension in this age group was higher with sacubitril/valsartan (18 vs 12 per cent with enalapril).2 It is estimated that sacubitril/valsartan confers one to two years of increased life expectancy and survival free from heart failure for patients like those in PARADIGM-HF. antagonist – formerly the next step8 – or that they should be intolerant of an ACE inhibitor. US guidance specifies a lower symptom severity but is more explicit, stating: “In patients with chronic symptomatic HFrEF [heart failure with reduced ejection fraction] NYHA class II or III who tolerate an ACE inhibitor or ARB [angiotensin II-receptor antagonist], replacement by an ARNI [angiotensin receptor– neprilysin inhibitor] is recommended to further reduce morbidity and mortality”.6 By contrast, the Scottish Intercollegiate Guidelines Network (SIGN) positions sacubitril/valsartan after the addition of an aldosterone antagonist and for patients with ejection fraction ≤40 per cent.4 An aldosterone antagonist is considered as effective as sacubitril/valsartan, though it is an addition to an ACE inhibitor rather than a substitute. A meta-analysis of eight trials involving almost 4000 patients showed that adding an aldosterone antagonist in this way reduces all-cause mortality (relative risk [RR] 0.79) and admission due to cardiac causes (RR 0.62).9 In PARADIGM-HF, about half of participants were taking an aldosterone antagonist but it made no difference to the efficacy of sacubitril/valsartan. Place in therapy Adoption despite qualms It is clear from the above that there is a lot of evidence for sacubitril/valsartan, all from one phase 3 trial. It is argued that the trial was so large and the results so consistent that the quality of evidence it provides is equivalent to four or five separate trials.3 This was an innovative treatment, and one that made a big difference to patients who were symptomatic despite standard therapy. Consequently, sacubitril/valsartan has already been incorporated into management guidelines – but at different steps.4-7 The guidance could hardly be more favourable. NICE recommends sacubitril/valsartan as an option for people with chronic heart failure and reduced ejection fraction (≤35 per cent) who have NYHA class II–IV symptoms, despite stable treatment with an ACE inhibitor or an angiotensin II-receptor antagonist.7 It does not state that patients must be taking an aldosterone NICE accommodated several reservations about the evidence when it recommended sacubitril/valsartan. It noted that in participants from western Europe, who were most representative of patients in the UK, the difference between the treatment arms in the primary endpoint was not statistically significant (hazard ratio [HR] 0.89; CI 95% 0.74–1.07). However, NICE decided this “would not factor in its decision-making”. Compared with UK practice, participants in PARADIGM-HF were younger (mean age 64 years), there were only 60 patients (0.7 per cent) with NYHA class IV symptoms, and fewer were women (22 per cent), had co-morbidities or used a cardiac device. Black people were under-represented (5 per cent), which is important because they are at higher risk of angioedema.10 The dose of valsartan used was higher than some patients tolerate and the ACE inhibitor comparator was enalapril, whereas prescriber.co.uk Prescriber November 2016 ❚ 27 ■ THERAPY REVIEW l Sacubitril/valsartan UK clinicians prefer ramipril (though everyone accepted a class effect was likely). Finally, the trial’s run-in phase included a period when all participants received sacubitril/valsartan, during which 6.4 per cent withdrew from the study due to adverse effects or abnormal lab results.1 Selecting patients for tolerability in this way may have reduced the incidence of angioedema in the trial. Whether these patient differences mean that outcomes in clinical practice differ from those in PARADIGM-HF remains to be seen. Uptake so far Statistics on NHS prescribing are not yet available (and will have been influenced by the wait for NICE guidance) but NICE estimates that the number of people taking sacubitril/ valsartan will grow to about 64,500 by 2020/21.11 There are about 411,000 people with heart failure in England, of whom 107,000 meet the NICE eligibility criteria for treatment with the new combination. Within five years it is expected that 60 per cent of eligible patients will be taking sacubitril/valsartan (see Figure 3), 34 per cent will have an ACE inhibitor and the remainder will take an angiotensin II-receptor antagonist. Prescribing costs will increase: a year’s treatment with an ACE inhibitor costs only £32 compared with £1194 for sacubitril/valsartan11 and the estimated cost per quality-adjusted life year (QALY) saved was “at the upper end of the range that would normally be considered a cost-effective use of NHS resources”.7 This will be offset by savings totalling £5.4 mil- lion per year through fewer hospital admissions, leaving a net impact of about £70 million annually by 2020/21. Uptake in Europe is reportedly higher than in the USA, where sales have been slower than forecast due to administrative obstacles imposed by medical insurance companies and concerns about cost and long-term safety.12-14 Neprilysin is one of many pathways for clearing amyloid beta and its inhibition raises the spectre of Alzheimer’s disease. There’s no evidence of an increased risk of Alzheimer’s disease so far, but a threeyear trial will begin shortly to compare measures of cognitive function in patients treated with sacubitril/valsartan or valsartan monotherapy.15 Other heart failure trials In a move widely interpreted as an attempt to bolster confidence in sacubitril/valsartan in the USA, Novartis has announced a new programme of clinical trials, some of which are already under way. FortiHFy will include 40 trials, generating data on “symptom reduction, efficacy, safety, quality of life benefits and real world evidence” in heart failure.16 Most of the success to date has been in patients with reduced ejection fraction but heart failure with preserved ejection fraction accounts for around half of cases and its prevalence appears to be growing.17 Treatment is less successful than when ejection fraction is reduced. Drug treatment focuses on symptom relief and has not been shown to reduce mortality, morbidity or improve exercise intolerance.5 PARAGON-HF is a trial comparing the effects of sacubitril/valsartan and valsartan monotherapy on Primary endpoint Sacubitril/valsartan (% patients) Enalapril (% patients) Hazard ratio (CI 95%) p value Death from cardiovascular causes or first hospitalisation for heart failure 21.8 26.5 0.80 (0.73–0.87) p<0.001 All-cause mortality 17.0 19.8 0.84 (0.76–0.93) p<0.001 Cardiovascular death 13.3 16.5 0.80 (0.71–0.89) p<0.001 First hospitalisation for heart failure 12.8 15.6 0.79 (0.71–0.89) p<0.001 Death from any cause 17.0 19.8 0.84 (0.76–0.93) p<0.001 Change in clinical summary score from baseline to 8 months* -2.99 ±0.36 -4.63 ±0.36 1.64 (0.63–2.65) p=0.001 New-onset atrial fibrillation 3.1 3.1 0.97 (0.72–1.31) p=0.83 Decline in renal function** 2.2 2.6 0.86 (0.65–1.13) p=0.28 Secondary endpoints *Kansas City Cardiomyopathy Questionnaire (KCCQ) score (on a scale from 0 to 100, with higher scores indicating fewer symptoms and physical limitations associated with heart failure); data are least-squares mean ± standard error of the between group difference **Defined as end-stage renal disease or as a decrease in the estimated glomerular filtration rate (eGFR) of ≥50 per cent or a decrease of >30ml/min/1.73m2 from randomisation to <60ml/min/1.73m2 Table 2. Primary and secondary outcomes in the PARADIGM-HF trial, comparing sacubitril/valsartan and enalapril in patients with symptoms of heart failure1 30 ❚ Prescriber November 2016 prescriber.co.uk Sacubitril/valsartan cardiovascular death and hospitalisation for heart failure when added to standard care (excluding ACE inhibitors and angiotensin II-receptor antagonists) in patients with preserved ejection fraction.18 Patients are ≥55 years of age with left ventricular ejection fraction ≥45 per cent who need treatment with a diuretic to relieve NYHA class II–IV symptoms. Follow-up will be four to five years and results are expected in 2019. A 12-week phase 2 trial in patients with preserved ejection fraction (PARAMOUNT, n=266) showed that, compared with valsartan monotherapy, sacubitril/valsartan reduced N-terminal pro B-type natriuretic peptide (NT-proBNP; the primary endpoint, a marker of left ventricular wall stress)19 and this was independent of the greater reduction in systolic blood pressure.20 PARADISE-MI is testing the hypothesis that sacubitril/ valsartan can reduce cardiovascular death, hospitalisation for heart failure and new-onset heart failure in patients at high risk of heart failure after a myocardial infarction.21 Ramipril is the comparator; completion is expected in 2020. A trial in Ireland is also looking at prevention by comparing the effects of sacubitril/valsartan with valsartan alone on left ventricular diastolic function in people with hypertension, diabetes or other risk factors for heart failure.22 Other trials in people with hear t failure include TRANSITION, which is comparing initiation of sacubitril/valsartan before or after discharge in patients admitted with acute decompensation;23 and PIONEER-HF, a comparison with enalapril of the effects of sacubitril/valsartan treatment on NT-proBNP in stable patients admitted for acute decompensated heart failure and reduced ejection fraction.24 Results for both are expected in 2018. Cardiovascular death Cardiovascular death or heart failure hospitalisation 18 18 12 10 8 6 4 2 sacubitril/valsartan 14 12 10 8 6 4 2 0 0 <55 55-6465-74 ≥75 Age (years) Heart failure hospitalisation 18 <55 55-6465-74 ≥75 Age (years) All-cause death 18 16 Rate per 100 patient years 16 Rate per 100 patient years enalapril 16 Rate per 100 patient years Rate per 100 patient years 16 14 l THERAPY REVIEW ■ 14 12 10 8 6 4 2 14 12 10 8 6 4 2 0 0 <55 55-6465-74 ≥75 Age (years) <55 55-6465-74 ≥75 Age (years) Figure 2. Clinical outcomes with sacubitril/valsartan vs enalapril in PARADIGM-HF according to age (rate per 100 patient-years of treatment; error bars are 95% confidence intervals). Reproduced from Jhund et al. 20152 prescriber.co.uk Prescriber November 2016 ❚ 31 ■ THERAPY REVIEW l Sacubitril/valsartan People with heart failure in England 410,783 295,764 Reduced ejection fraction Reduced ejection fraction and NYHA class II–IV symptoms 210,288 Reduced ejection fraction ≤35 per cent and NYHA class II–IV symptoms Reduced ejection fraction ≤35 per cent and NYHA class II–IV symptoms and taking an ACE inhibitor/ angiotensin II-receptor antagonist People taking sacubitril/valsartan from year five onwards 125,121 107,541 64,525 Figure 3. Number of people with heart failure in England, proportion eligible for treatment and predicted proportion treated with sacubitril/ valsartan in five years’ time11 Use in hypertension In PARADIGM-HF, sacubitril/valsartan was associated with a greater reduction in systolic blood pressure than enalapril (3.2mmHg) and symptomatic hypotension was significantly more common (14.0 vs 9.2 per cent respectively).1 Its therapeutic potential in hypertension has since been evaluated in many trials (see Clinicaltrials.gov for a full list), suggesting a greater blood pressure-lowering effect than valsartan alone or olmesartan and efficacy as add-on therapy when amlodipine has failed. A recent review assessing the efficacy and safety of sacubitril/valsartan in hypertension suggests that the effect on blood pressure is greater in Asian patients than Caucasian patients and treatment is well tolerated, though the risk of orthostatic hypotension requires further study.25 The authors of this review speculate that sacubitril/valsartan may offer greater efficacy and a similar safety profile compared with established anti hypertensive drugs. The results of the PARAMETER trial in elderly people with systolic hypertension were reported recently.26 Compared with the angiotensin II-receptor antagonist olmesartan, once-daily sacubitril/valsartan significantly reduced measures of aortic stiffness (including aortic systolic pressure and pulse pressure) at 12 weeks but not after 52 weeks. It is rumoured that Novartis will not pursue marketing authorisation for hypertension.27 Use in chronic kidney disease Inhibition of neprilysin causes natriuresis and reduces intra glomerular pressure and proteinuria. This, in combination with inhibition of the renin-angiotensin system, indicates obvious potential for sacubitril/valsartan in the treatment of chronic kidney disease (CKD).28 Supported by indirect evidence from clinical trials of other neprilysin inhibitors, the effect of sacubitril/ valsartan in CKD is now being evaluated in the UK Heart And Renal Protection III (UK HARP-III) trial (http://www.harp3trial. 32 ❚ Prescriber November 2016 org). This Oxford-based trial is comparing sacubitril/valsartan with the angiotensin II-receptor antagonist irbesartan as monotherapy in patients with proteinuric CKD. The primary endpoint is the change in glomerular filtration rate after 12 months. Recruitment is now complete (n=414). Other neprilysin inhibitors in development Several neprilysin inhibitors have been in development over the past 30 years but only sacubitril (in combination with valsartan) has successfully reached the market.29 Interest in this class of agents appears to have stalled in the early to mid-2000s and there is surprisingly little information in the public domain about forthcoming neprilysin inhibitors. Therevance Biopharma has TD-0714 and TD-1439 in phase 1 development for heart failure and CKD30, but otherwise Novartis appears to have the market to itself for the near future. Solvay Pharmaceuticals was developing daglutril, a dual inhibitor of neprilysin and endothelin-converting enzyme that has been shown to lower blood pressure in people with type 2 diabetes, nephropathy and hypertension,31 but no studies have been published more recently. Summary Sacubitril/valsartan is an innovative treatment for heart failure that improves symptoms and reduces the risk of death and hospital admission compared with ACE inhibitor therapy – the standard for many years. It has generated huge enthusiasm among specialists and has already found a place in management guidelines. There are differences between UK patients with heart failure and the participants in the clinical trial on which its reputation is built but it is not yet known if they are important. More clinical trials will refine its role, especially in patients with heart failure and preserved ejection fraction and in CKD, but a licence for hypertension looks unlikely in the near future. prescriber.co.uk Sacubitril/valsartan References 1. McMurray JJ, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. 2. Jhund PS, et al. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J 2015;36:2576–84. 3. Jhund PS, McMurray JJ. The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan. Heart 2016;102:1342–7. 4. Scottish Intercollegiate Guidelines Network. Management of chronic heart failure. SIGN 147. March 2016. http://www.sign.ac.uk/pdf/ SIGN147.pdf 5. Ponikowski P, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37(27):2129–2200. 6. Yancy CW, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: An update of the 2013 ACCF/ AHA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2016;68:1476–88. 7. NICE. Sacubitril valsartan for treating symptomatic chronic heart l THERAPY REVIEW ■ failure with reduced ejection fraction. TA388. April 2016. https://www. nice.org.uk/guidance/ta388 8. NICE. Chronic heart failure in adults: management. CG108. August 2010. https://www.nice.org.uk/guidance/cg108 9. Hu LJ, et al. Additional use of an aldosterone antagonist in patients with mild to moderate chronic heart failure: a systematic review and meta-analysis. Br J Clin Pharmacol 2013;75:1202–12. 10. Gibbs CR, et al. Angioedema due to ACE inhibitors: increased risk in patients of African origin. Br J Clin Pharmacol 1999;48:861–5. 11. NICE. Resource impact report: Sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction (TA388). April 2016. 12. Husten L. New cardio drugs off to very slow start. Cardiobrief 27 April 2016. http://cardiobrief.org/2016/04/27/new-cardio-drugs-offto-very-slow-start [accessed October 2016]. 13. Cardiomyopathy UK. Uptake of new heart failure drug slow, say makers. 6 November 2015 http://www.cardiomyopathy.org/news--media/ latest-news/post/126-uptake-of-new-heart-failure-drug-slow-say-makers [accessed October 2016]. 14. Ward A. Novartis chief warns of paradigm shift to slower US drug sales. Financial Times 21 April 2016 https://www.ft.com/content/ POEMs In patients with type 2 diabetes and cardiovascular disease, empagliflozin reduces cardiovascular and all-cause mortality Clinical question: In patients with type 2 diabetes and cardiovascular disease, does the addition of empagliflozin improve outcomes? Study design: Randomised controlled trial (double-blinded). Funding source: Industry. Allocation: Concealed. Setting: Outpatient (any). Bottom line: In patients with established cardiovascular disease and type 2 diabetes, the addition of empagliflozin to standard therapy reduces all-cause mortality and cardiovascular mortality. This is notable because empagliflozin is the only drug other than metformin to demonstrate a mortality benefit, albeit for a fairly narrow group of patients. A dose of 10mg appears to provide a similar benefit to the 25mg dose, but with half the risk of genital infections. It is not appropriate to extend these conclusions to all patients with type 2 diabetes, as they are at lower risk of bad outcomes and are unlikely to benefit to the same degree. (LOE = 1b) Synopsis: Empagliflozin decreases reabsorption of glucose in the kidneys, leading to greater urinary excretion. In this industry-sponsored trial, adults with type 2 diabetes and known cardiovascular disease were randomised to receive either empagliflozin 10mg, empagliflozin 25mg, or placebo. The 7028 patients were recruited from 590 sites in 42 countries. The mean age of participants was 63 years, 71 per cent were male, and 5 per cent were African-American. This was a very high-risk group: 75 per cent had coronary artery disease, 23 per cent had a previous stroke, 20 per cent had peripheral arterial disease and 25 per cent had a coronary artery bypass graft. The other diabetes medications used by patients included metformin (75 per cent), insulin (53 per cent) or a sulfonylurea (43 per cent). Analysis was by modified intention Reference: Zinman B, et al, for the EMPA-REG OUTCOME Investigators. N Engl J Med 2015;373(22):2117–28. prescriber.co.uk to treat for all patients who received at least one dose of the study drug. The primary outcome was a composite of myocardial infarction (MI), stroke or cardiovascular death. Patients were followed up for a median of 3.1 years. Results for the two empagliflozin doses were pooled and compared with placebo. The patients in the intervention groups had lower all-cause mortality (5.7 vs 8.3 per cent; p<0.001; number needed to treat [NNT] = 38 over 3.3 years), cardio vascular mortality (3.7 vs 5.9 per cent; p<0.001; NNT=45 over 3.3 years), and hospitalisation for heart failure (2.7 vs 4.1 per cent; p=0.002, NNT=71). There were no differences in other outcomes, including MI, stroke, coronary revascularisations or transient ischaemic attacks. The pooled dropout rate due to adverse events was 11.5 per cent for the study drug and 13.0 per cent for placebo. There were more episodes of urosepsis or pyelo nephritis in the empagliflozin groups (0.8 vs 0.5 per cent), and far more genital infections (5.0 vs 1.5 per cent in men; 10.0 vs 2.6 per cent in women). Prescriber November 2016 ❚ 33 ■ THERAPY REVIEW l Sacubitril/valsartan b2062788-07a8-11e6-9b51-0fb5e65703ce [accessed October 2016]. 15. Efficacy and Safety of LCZ696 Compared to Valsartan on Cognitive Function in Patients With Heart Failure and Preserved Ejection Fraction (PERSPECTIVE). ClinicalTrials.gov; identifier: NCT02884206. 16. Novartis. Novartis announces investment in FortiHFy clinical program of Entresto and heart failure. Press release 19 May 2016. https://www.novartis.com/news/media-releases/novartis-announcesinvestment-fortihfy-clinical-program-entrestor-and-heart [accessed October 2016]. 17. Andersson C, Vasan RS. Epidemiology of heart failure with preserved ejection fraction. Heart Fail Clin 2014;10:377–88. 18. Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF). ClinicalTrials.gov; identifier: NCT01920711. 19. Solomon SD, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 2012;380:1387–95. 20. Jhund PS, et al. Independence of the blood pressure lowering effect and efficacy of the angiotensin receptor neprilysin inhibitor, LCZ696, in patients with heart failure with preserved ejection fraction: an analysis of the PARAMOUNT trial. Eur J Heart Fail 2014;16:671–7. 21. Prospective ARNI vs ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI (PARADISE-MI). ClinicalTrials. gov; identifier: NCT02924727. 22. ARNI in Asymptomatic Patients With Elevated Natriuretic Peptide and Elevated Left Atrial Volume Index eLEvation (PARABLE). ClinicalTrials.gov; identifier: NCT02682719. 23. Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event (TRANSITION). ClinicalTrials.gov; identifier: NCT02661217. 24. comParIson Of Sacubitril/valsartaN Versus Enalapril on Effect on ntpRo-bnp in Patients Stabilized From an Acute Heart Failure Episode (PIONEER-HF). ClinicalTrials.gov; identifier: NCT02554890. 25. Bavishi C, et al. Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials. Eur Heart J 2015;36:1967–73. 26. Brauser D. PARAMETER: LCZ696 bests olmesartan in decreasing arterial stiffness in elderly. Medscape 1 September 2015. http://www. medscape.com/viewarticle/850291 [accessed October 2016]. 27. Peck P. ESC: Entresto for hypertension? Yes! Blockbuster heart failure drug may also lower systolic BP. Medpage Today 31 August 2015. http://www.medpagetoday.com/MeetingCoverage/ESC/53333 [accessed October 2016]. 28. Judge P, et al. Neprilysin inhibition in chronic kidney disease. Nephrol Dial Transplant 2015;30:738–43. 29. McMurray JJ. Neprilysin inhibition to treat heart failure: a tale of science, serendipity, and second chances. Eur J Heart Failure 2015;17:242–47. 30. Therevance Biopharma. TD0714. http://www.theravance.com/ cardiovascular [accessed October 2016]. 31. Parvanova A, et al. Effect on blood pressure of combined inhibition of endothelin-converting enzyme and neutral endopeptidase with daglutril in patients with type 2 diabetes who have albuminuria: a randomised, crossover, double-blind, placebo-controlled trial. Lancet Diabet Endocrinol 2013:1:19–27. Declaration of interests None to declare. Steve Chaplin is a pharmacist who specialises in writing on therapeutics 34 ❚ Prescriber November 2016 prescriber.co.uk