Impact case study database

Heart failure (HF) is a condition when the heart cannot meet the body’s demands, with devastating consequences. HF patients have a survival rate of five years post-diagnosis, reduced quality of life and die prematurely. HF is also a substantial burden on health services; it is the leading cause of hospitalisations for adults over 65 years, costing the NHS over GBP2 billion (2010) and the US Medicare system, USD17 billion.

Around 50% of HF patients suffer from HF with reduced ejection fraction (HFrEF). Prior to the PARADIGM study, HFrEF was treated by ACE inhibitors, the gold standard of treatment for over 25 years. However, ACE inhibitors only partially improve HF, highlighting the need for new and improved drugs to treat HFrEF. PARADIGM-HF showed that sacubitril/valsartan considerably outperforms ACE inhibitors for treating HFrEF, making it the new gold standard of treatment. With approximately 20 million HF patients in Europe and the US alone, this discovery addresses a substantial, international public health burden.

PARADIGM-HF supports sacubitril/valsartan as a new HFrEF treatment

In 2014, based on preliminary results from the PARADIGM-HF trial, sacubitril/valsartan underwent a fast-track review by the FDA and European Medical Agency (EMA); indeed, it was the first CV drug to receive an EMA-accelerated review. Prof McMurray attended meetings with, and led responses to, questions posed by Health Authorities [5.A]. In 2015, Novartis gained regulatory approval for sacubitril/valsartan (trade name, Entresto) in the USA (FDA, July 2015) under the Accelerated Approval Programme; it was the first non-cancer drug ever to do so, reflecting the importance of this first-in-class (ARNi) drug. Approvals followed in Europe (EMA, Nov 2015), and, as of 2018, the drug has been approved in 112 countries and launched in over 90, each underpinned by the PARADIGM-HF findings [5.A, 5.B].

Impact on international and national guidelines

Based on key evidence from the PARADIGM-HF trial and UofG studies, the world’s most influential cardiovascular societies have given sacubitril/valsartan their highest-level recommendation, including the European Society of Cardiology (ESC), American College of Cardiology Foundation (ACCF), American Heart Association (AHA), and Heart Failure Society of America (HFSA) [‘international guidelines’, 5.C]. For example:

• ESC (2016) guidelines on heart failure recommend that ambulatory HFrEF patients with left ventricular ejection fraction (LVEF) of <35%, who remain symptomatic (class I,B recommendation), are treated with sacubitril/valsartan in place of an ACE inhibitor [5.C]

• ACC, AHA, and HFSA issued a Class 1 recommendation to switch HFrEF patients with LVEF <45%, from ACEi or an ARB to sacubitril/valsartan, as did the Canadian Cardiovascular Society (CCS) and the National Heart Foundation of Australia and Cardiac Society of Australia & New Zealand (NHFA/CSANZ) guidelines [5.C]

• The ESC (2019) Guidelines on Diabetes, Pre-Diabetes and Cardiovascular Diseases, developed in collaboration with the EASD (European Associations for the Study of Diabetes) recommend sacubitril/valsartan instead of ACEIs to reduce the risk of HF hospitalization and death in patients with HFrEF and type-2 diabetes who remain symptomatic, despite treatment with ACEIs (class 1,B) [5.C]

Furthermore, in March 2016, the UK guidelines—National Institute for Health and Care Excellence (NICE) and the Scottish Intercollegiate Guidelines Network (SIGN)—on HF management, recommended the use of sacubitril/valsartan in adult patients [5.D]. The NICE Technology Assessment and Scottish Medicines Consortium review [5.E], which both approved the drug for reimbursement, are framed entirely around the PARADIGM-HF study, with further support drawn from a UofG cost-effectiveness study [3.6]. The NICE expert review panel also highlighted [5.E] as particularly relevant to the UK the UofG findings that showed sacubitril/valsartan prevented hospitalisation across all ages, including older patients [3.3].

Changes in prescribing trends for HFrEF

Since the PARADIGM-HF study, McMurray and Jhund have continued advising Novartis, to support the clinical marketing of sacubitril/valsartan, sitting on advisory boards and delivering lectures, both promotional and non-promotional. Novartis said, ‘ Professor McMurray has been a critical medical expert for our global medical education activities to cardiologists during international scientific conferences…[His] advice as a participant in several advisory board meetings was crucial to inform our understanding of heart failure and best course of action to bring and innovative treatment to patients [5.A].

The ACC/AHA/HFSA and ESC’s class I recommendations—to prescribe sacubitril/valsartan to HFrEF patients—widely supported the subsequent upturn in this drug’s prescription, and commercial returns from the drug in the US and EU [5.F]. Currently, 25–30% of HFrEF patients in Europe are treated with sacubitril/valsartan, constituting over 1 million people in 2018. In the USA, 5.7 million people have heart failure, of whom 48% have a LVEF of <40%. Allowing for exclusions and other contraindications, around 2.6 million patients stand to benefit from sacubitril/ valsartan. By 2018, in the USA, a significant contributor to increase in prescriptions has been through inclusion in Medicare plans—currently 100% of these plans cover sacubitril/valsartan with an eligible Medicare population of ~1.86 million [5.G]. In November 2019, China added the drug to their National Drug Reimbursement Plan, which also increases the volume of patients benefitting.

Improved patient health and quality of life

The treatment of HF patients with sacubitril/valsartan reduced the risk of dying from a cardiovascular cause by 20%, HF hospitalizations by 21%, and the risk of dying from any cause by 16%, relative to enalapril, the previous gold standard treatment. The magnitude of benefit has been observed subsequently in real world studies across international settings [5.H]. The optimal implementation of sacubitril/valsartan therapy has been empirically estimated to prevent 28,484 deaths per year in the USA [5.I] and, based on a 20% reduction in deaths, equates to 5,700 deaths prevented in the UK. A UofG-led cost-effectiveness study suggested an additional 0.91 years of life with treatment on average per patient [3.6], which in this patient group for some means a 50–100% increase in life span, and 1.27 million life years saved in the 1.4 million people prescribed to date.

Economic benefits to health services and industry

In the five years following its launch in July 2015, sacubitril/valsartan (Entresto) has made USD 4.2 billion in sales for Novartis to July 2020 [5.A]. Sacubitril/valsartan has been found to be cost-effective in the USA, UK and in other developed health care systems. A US cost-effectiveness study (co-authored by McMurray [5.J]) estimated that 220 fewer hospital admissions will occur per 1000 HF patients treated with sacubitril/valsartan, compared to enalapril-treated patients, over 30 years; this equates to ~19,000 fewer hospitalisations per year among the 2.6 million US individuals eligible for sacubitril/valsartan treatment. Based on real data, it also reduces hospital re-admissions by 38% after first admission [5.K]. A report using real-world data showed a reduction in all-cause healthcare costs averaging 28% in the US (~USD1,275 per month per patient) compared with the previous gold standard ACE inhibitors [5.L].