Novartis announces new data that shows Entresto™▼(sacubitril/valsartan) can be initiated both pre- or post-discharge with comparable safety and tolerability in patients with heart failure
Dec 03, 2018
TRANSITION study shows sacubitril/valsartan can be initiated with a comparable safety and tolerability profile following an acute decompensation episode of heart failure in a wide range of stabilised patients, both prior to discharge or in an out-patient setting1
During TRANSITION, within a few days of pre-discharge initiation of sacubitril/valsartan, NT-proBNP levels in the pre-discharge group decreased significantly, compared with standard of care heart failure medical treatment in the post-discharge group. Incidence of adverse events (AEs) and sacubitril/valsartan discontinuations due to AEs was similar in pre-discharge and post-discharge initiation groups1,2
83% of patients are hospitalised at least once for an acute heart failure episode during the course of their condition3
These results are supportive of the safety data from the landmark PARADIGM-HF study, where sacubitril/valsartan was proven to be superior to enalapril in reducing cardiovascular mortality, heart failure hospitalisation and 30-day hospital readmission in heart failure patients with reduced ejection fraction4,5
London, 03 December 2018 – Novartis presented new data from the TRANSITION study at The British Society of Heart Failure (BSH) 21st Annual Autumn Meeting (29-30 November) in London. This data, presented for the first time in the UK, showed that Entresto™ (sacubitril/valsartan) was well tolerated in heart failure patients with reduced ejection fraction (HFrEF), who have been stabilised after hospitalisation due to an acute decompensation heart failure episode (ADHF). The results from TRANSITION are supportive of the safety and tolerability data from the PARADIGM-HF study, which demonstrated sacubitril/valsartan has important clinical benefits for heart failure patients1,4,5.
Heart failure is a serious progressive disease with 83% of patients hospitalised at least once for an ADHF during the course of their condition2. Hospitalisation provides an opportunity for physicians to optimise heart failure treatment according to guidelines to reduce the likelihood of hospital readmission and death, reduce the burden of hospitalisations, and improve patient outcomes6.
In TRANSITION, the safety and tolerability of sacubitril/valsartan were assessed in HFrEF patients after they had been stabilised following an ADHF. Patients were randomised to initiate sacubitril/valsartan therapy either in the hospital (pre-discharge) or shortly after leaving the hospital (post-discharge)1,2. At 10 weeks, more than 86% of patients were receiving sacubitril/valsartan for two weeks or longer without interruption. About half of the patients also achieved the primary endpoint which was a target dose of 97 mg/103 mg of sacubitril/valsartan twice daily within 10 weeks in both groups1,2. The license recommended starting dose of sacubitril/valsartan is one tablet of 49 mg/51 mg twice daily7.
Dr Klaus Witte, Senior Lecturer and Consultant Cardiologist, University of Leeds and Leeds Teaching Hospitals NHS Trust, who presented the data said, “These results are important. They provide confidence that sacubitril/valsartan is well tolerated shortly after stabilisation following an episode of ADHF. We already know that time is of the essence in patients with heart failure: getting patients onto the right tablets as soon as possible can save lives. It is therefore critical that we act with urgency and focus, with the aim of reducing the long-term risk of hospitalisation and cardiovascular death. Whether it is before or after the discharge of stable patients, physicians now have added confidence to prescribe sacubitril/valsartan at the earliest opportunity.”
These results support data from PARADIGM-HF, the largest clinical study ever conducted in heart failure comparing sacubitril/valsartan to enalapril, the standard of care at the time. PARADIGM-HF showed that sacubitril/valsartan significantly reduced the risk of death by 20% and hospitalisation by 21% in patients with heart failure versus enalapril2. These results in numbers show that treating 1,000 patients with sacubitril/valsartan instead of enalapril over a median treatment period of 27 months avoided 32 cardiovascular deaths, 111 hospitalisations (for any reason) and 53 hospitalisations specifically for heart failure1,2.
Simon Williams, Consultant Cardiologist at Wythenshawe Hospital and Chair-Elect of the BSH, said, "In PARADIGM-HF, we saw a significant reduction in deaths and re-hospitalisation of heart failure patients who were ambulatory. The fact that TRANSITION shows that sacubitril/valsartan can also be initiated when a patient is stabilised post-ADHF is highly reassuring. These two trials provide consistent evidence and should provide clinicians with further confidence to use sacubitril/valsartan in line with NICE recommendations.”
In addition, Novartis presented data from other trials such as PIONEER-HF, conducted in the U.S, at the 21st BSH Annual Autumn Meeting. Similar to the ARIADNE study results that were shown at the ESC Congress 2018 and TRANSITION, PIONEER-HF also demonstrated comparable safety data, with short-term exploratory endpoints suggesting a clinical benefit when sacubitril/valsartan was introduced to stable HFrEF patients pre-discharge compared with enalapril, which is often regarded as the current standard of care8.
TRANSITION is a randomised, phase IV, multicentre, open-label, parallel-group study, which assessed the safety and tolerability of sacubitril/valsartan in 1,002 reduced ejection fraction (HFrEF) patients, from 156 hospitals worldwide, after stabilisation following hospitalisation for acute heart failure, when treatment was started in hospital (pre-discharge) or shortly after leaving hospital (post-discharge)1,2. Patients were grouped based on their pre-admission treatment status: those who were receiving an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB), or those with no prior experience with an ACEI/ARB. Following screening and randomisation to sacubitril/valsartan, the study comprised a 10-week treatment period followed by a 16-week follow-up phase1,2. The primary and secondary endpoints were the number of patients achieving the target dose of sacubitril/valsartan of 97 mg/103 mg twice daily (bid) at week 10 (regardless of previous dose interruption or down-titration), and number of patients maintaining 49 mg/51 mg or 97 mg/103 mg bid for at least two weeks leading to week 10 after randomisation, respectively. The license recommended starting dose of sacubitril/valsartan is one tablet of 49 mg/51 mg twice daily. The dose should be doubled at 2-4 weeks to the target dose of one tablet of 97 mg/103 mg twice daily, as tolerated by the patient.7 The study protocol took into account the needs of the practicing cardiologists, and enabled investigators to select the appropriate starting dose of sacubitril/valsartan and dose adjustments due to clinical circumstances, allowing for differences between international hospitals and healthcare settings1,2.
About PIONEER-HF PIONEER-HF is a prospective, multicentre, double-blind, randomised, controlled trial designed to assess the safety, tolerability, and efficacy of in-hospital initiation of sacubitril/valsartan compared with enalapril in appropriate, stable HFrEF patients who have been admitted for acute decompensation8,10. For more information please visit: https://clinicaltrials.gov/ct2/show/NCT02554890
ARIADNE is an observational, European, non-interventional study designed to describe the profile of HFrEF patients initiated on sacubitril/valsartan and patients continued on standard of care in the outpatient sector in terms of demographics, medical history, heart failure status and comorbidity burden.
About Entresto™ (sacubitril/valsartan) Sacubitril/valsartan is a twice-a-day medicine that reduces the strain on the failing heart. It does this by enhancing the protective neurohormonal systems (natriuretic peptide system) while simultaneously inhibiting the harmful effects of the overactive renin-angiotensin-aldosterone system (RAAS). Other common heart failure medicines, called angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), only block the harmful effects of the overactive RAAS. Sacubitril/valsartan contains the neprilysin inhibitor sacubitril and the angiotensin receptor blocker (ARB) valsartan.
In the United Kingdom, sacubitril/valsartan is indicated in adult patients for the treatment of symptomatic chronic heart failure with reduced ejection fraction. Sacubitril/valsartan is also indicated for the treatment of heart failure (New York Heart Association class II-IV) in patients with systolic dysfunction. It has been shown to reduce the rate of cardiovascular death, heart failure hospitalisation4 and 30-day hospital readmission compared to enalapril5, to reduce the rate of all-cause mortality compared to enalapril7, and to improve aspects of health-related quality of life (including physical and social activities) compared to enalapril11. Sacubitril/valsartan is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other angiotensin receptor blocker (ARB). Approved indications may vary depending upon the individual country.
About Heart Failure and Hospitalisation
Heart failure (HF) is a serious progressive disease with debilitating symptoms. HF patients are at risk of a sudden worsening of the disease that requires urgent care in hospital and it accounts for 5% of all hospital admissions in people over the age of 659,12. Heart failure accounts for a total of one million inpatient bed-days in the NHS which is equivalent to 2% of all inpatient bed-days in the NHS9. Every year, there over 67,000 hospitalisations due to HF in England and Wales,12 and on average, a HF patient remains in hospital for five to 10 days13. Due to this, heart failure presents a major and growing health-economic burden that currently costs the NHS £2.3 billion every year, which is equivalent to 2% of the entire NHS budget14 the majority of this is attributable to the costs of people being hospitalised because of HF15.
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2017, the Group achieved net sales of USD 49.1 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 125,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit www.novartis.com.
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Wachter R. et al., Initiation of sacubitril/valsartan in hospitalized patients with heart failure with reduced ejection fraction after hemodynamic stabilization: Primary results of the TRANSITION study. Data presented at: ESC 2018, Aug 25-29; Munich, Germany.
Pascual-Figal D. et al., Short-term effect on cardiac biomarkers of initiation of sacubitril/valsartan in hospitalized patients with heart failure and reduced ejection fraction: Results of the TRANSITION study. Poster Su2183 presented at: AHA congress 2018, Nov 10–12; Chicago, Illinois.
Yancy CW. et al., 2013 ACCF/AHA Guideline for the Management of Heart Failure, J Am Coll Cardiol. 2013; 62(16):e147-e239.
McMurray JJV., et al., Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med 2014; 371:993-1004.
Desai, AS., et al., Influence of Sacubitril/Valsartan (LCZ696) on 30-Day Readmission After Heart Failure Hospitalization. JACC 2016;68(3):241-248.
Maggioni, AP., et al., Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail. 2013 Oct;15(10):1173-84.
Velazquez E, et al., Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2018. doi: 10.1056/NEJMoa1812851.
NICE. Chronic Heart Failure. National Cinical Guidelines for Diagnosis and Management in Primary and Secondary Care. August 2010. Available at: www.ncbi.nlm.nih.gov/books/NBK65340/ [Last accessed: November 2018].
Velazquez EJ, et al., Rationale and design of the comparison of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial. Am Heart J. 2018 Apr;198:145-151.
Chandra A, et al., Effects of Sacubitril/Valsartan on Physical and Social Activity Limitations in Patients With Heart FailureA Secondary Analysis of the PARADIGM-HF Trial. JAMA Cardiol. 2018;3(6):498-505. doi:10.1001/jamacardio.2018.0398. [Last accessed: November 2018].