PARAGON: A multicenter, randomized, double-blind, parallel group, active-controlled study to evaluate the efficacy and safety of LCZ696 compared to valsartan, on morbidity and mortality in heart failure patients (NYHA Class II-IV) with preserved ejection fraction

Project Description

Cardiovascular (CV) disease is the leading cause of death in the western world. Heart failure (HF) incidence approaches 10 per 1000 population after 65 years of age in the United States (US) (Roger et al 2012) with HF prevalence between 2 and 3% in Europe and between 10 and 20% in European elderly (McMurray et al 2012). It affects nearly 6.6 million people over the age of 18 in the US with an additional 3 million new cases expected by 2030; a 25% increase from 2010 (Roger et al 2012).

In recent years, HF has been shown to occur with normal systolic function. HF with normal or “near-normal” ejection fraction (EF) has been designated HF with preserved ejection fraction (HFpEF). Studies have typically defined preserved EF with a cut-off of 40-50%, with 45% being the most common EF cut-off utilized in clinical trials. HFpEF accounts for approximately half of HF cases, and is associated with substantial morbidity and mortality (Lam et al 2011). Moreover, the prevalence of HFpEF, as well as its relative prevalence compared with HF with reduced ejection fraction (HFrEF), has been increasing in recent years (Owan et al 2006, Borlaug and Paulus 2011). Compared with HFrEF, patients with HFpEF are older, predominantly female, more likely to have hypertension (HTN) and atrial fibrillation (AF), and less likely to have coronary artery disease (Lenzen et al 2004, MAGGIC 2012). Mechanisms implicated in HFpEF include abnormal diastolic function with resultant increase in ventricular filling pressures, increased vascular stiffness, and abnormal systolic function despite preserved EF (Tartière-Kesri et al 2012, Tan et al 2009). Recently, these individuals have also been shown to have an impaired natriuretic and renal endocrine response to acute volume expansion early in the development of this syndrome (McKie et al 2011).

HF hospitalization is the single most common cause of admission in patients with HFpEF, representing an important marker of disease progression and, thus, an important indicator of poor subsequent outcomes, including death. Hospitalization for HF also adversely affects quality of life (QoL) and, in addition, because these events are frequently recurrent, HF hospitalization places a huge economic burden on health-care systems. This problem is a growing one in patients with HFpEF, as HF hospitalization is becoming relatively more common in patients with HFpEF compared to those with HFrEF (Lewis et al 2007, Hoekstra et al 2011). Recurrent HF hospitalizations are frequent in HFpEF with rates similar to HFrEF (Lenzen et al 2004, Fonarow et al 2007, Ahmed et al 2008, Solomon et al 2007, Steinberg et al 2012).

Unlike HFrEF, no pharmacologic therapies have shown benefit in HFpEF. Current guidelines focus on treating co-morbid conditions, such as diabetes mellitus (DM), HTN, renal insufficiency, AF and coronary artery disease, which are common in HFpEF patients (Hunt et al 2005, McMurray et al 2012). Thus, there is no evidence-based therapy specific for HFpEF and a substantial need exists for clinical trials investigating therapeutic options for patients with HFpEF. Three recent outcomes trials (PEP-CHF, perindopril; CHARM-Preserved, candesartan; I-PRESERVE, irbesartan) have failed to show a clinical benefit in HFpEF (Cleland et al 2006, Yusuf et al 2003, Massie et al 2008). In TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), a recent outcomes study in HFpEF, spironolactone did not significantly reduce the incidence of the primary composite outcome of death from CV causes, aborted cardiac arrest, or hospitalization for the management of HF (Pitt et al 2014).