Addressing a Prominent Health Burden Using Real World Evidence: Management of Heart Failure with Preserved Ejection Fraction

Heart Failure: Common, Debilitating and Growing Public Health Issue

Heart failure (HF) is a complex, debilitating syndrome affecting an estimated 63 million people worldwide (GBD 2016). Its impact on patients and health systems continues to increase in tandem with rising rates of obesity, hypertension, and diabetes in an aging population.

HF is comprised of several types, distinguished by distinct symptom profiles and functional status or ejection fraction (EF). Diastolic heart failure (DHF), also called heart failure with preserved ejection fraction (HFpEF), is a syndrome that presents as congestive heart failure and includes diminished diastolic function and a normal or near-normal left ventricular ejection fraction of 50% or higher. Some estimates suggest that 30% to 75% of HF cases are actually due to HFpEF.

Established treatments for HF with reduced ejection fraction (HFrEF), another type of HF, have shown no efficacy in clinical trials for HFpEF. As such, there currently are no treatment options for HFpEF other than those used for management of symptoms and comorbidities. Two drug classes with indications for other medical conditions have been under investigation in clinical trial programs for HFpEF. For a combination angiotensin receptor-neprilysin inhibitor (ARNI), results from a late-phase trial showed evidence of a heterogeneous response, with potential benefit in certain subgroups (escardio.org). For sodium-glucose co-transporter-2 (SGLT2) inhibitors, completion of phase 3 trials evaluating long-term morbidity and mortality in HFpEF patients are scheduled for completion in 4Q 2020 and 2Q 2021.

Real-World Data Sourced to Identify Treatment Opportunities with Greatest Potential Impact

To explore how real-world observations may provide insight into the challenges of and opportunities for managing DHF, a preliminary analysis of de-identified data from ambulatory patients was performed using an electronic health record (EHR) platform offered by Veradigm (see textbox).

 

Research Goal: To better describe patient populations with and without comorbidities to identify where new treatments for HFpEF could have the most potential impact for improving health outcomes.

 


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The analysis objectives were to characterize HFpEF patients according to key demographics and comorbidities and to evaluate use of SGLT2 inhibitors and ARNI in the management of these patients over a 24 month period.

Eligible patients were evaluated as a group (symptomatic HFpEF) and were also stratified according to whether they had a comorbid diagnosis of diabetes mellitus (DM) (type 1 or type 2) or hypertension (HTN), yeilding the following four subgroups:


  1. Symptomatic HFpEF wtih DM
  2. Symptomatic HFpEF without DM
  3. Symptomatic HFpEF with HTN
  4. Symptomatic HFpEF without HTN

Real World Evidence: Retrospective Data Review of HFpEF Patient Subgroups

Of the 91,757 patients with HFpEF, 30,161 (32.9%) met additional symptom and age eligibility criteria. Among these eligible patients, 9,158 (30.4%) were diagnosed with comorbid DM and 13,168 (43.7%) were diagnosed with comorbid HTN during the 24 months prior to selection.

Other commonly occurring comorbidities were hyperlipidemia (29.8%), atrial fibrillation/other arrhythmias (25.6%), and obesity (16.0%). In RCTs, hypertension has been shown to be the most common comorbidity among HFpEF patients. The full white paper provides descriptive statistics of patient demographics.

Further analysis of the EHR dataset offers insight into how comorbidities differ in patients with and without DM, and with and without HTN.

 

A higher percentage of symptomatic HFpEF patients with DM had a diagnosis of HTN than HFpEF patients without DM (59.6% vs 36.7%). These real-world findings closely align with findings from large-scale RCTs, in which patients with HFpEF  and comorbid DM were reported to have higher BMIs and generally higher rates or prevalence of HTN than patients without comorbid DM (MacDonald et al, 2008; Aguilar et al, 2010; Lindman et al, 2014; Kristensen et al, 2017).

Mean BMI values for all symptomatic HFpEF subgroups exceeded the threshold for Class 1 obesity, and the highest mean BMI was reported for the subgroup with comorbid DM. Multiple comorbidities appeared to occur more frequently in the patients with DM than in the patients without DM.

Medication use was explored. Beyond the study entry requirement of documented use of diuretic medications, one-half of patients had prescriptions for ACE-inhibitors (25.9%) and ARBs (26.5%), while 65.7% had prescriptions for beta-blockers. Just under 2% had prescriptions or documented use of SGLT2 inhibitors, two-thirds of which had a DM diagnosis. Slightly more (2.4%) had evidence of ARNI use. Interestingly, most patients with prescriptions for or documented use of ARNI did not have comorbid HTN.

Diagnosis of HFpEF minimally requires careful evaluation of clinical signs and symptoms of heart failure, evidence of structural abnormalities or diastolic dysfunction, and documentation of ejection fraction (LVEF >50%). In Veradigm’s retrospective study, selection of patients was based on International Classification of Disease (ICD) codes encompassing probable HFpEF (e.g., diastolic, acute on chronic diastolic, combined systolic and diastolic) and symptomatic evidence, specifically, written prescriptions for or documented use of diuretics. These diagnoses and prescription data are available in the structured fields of de-identified patient records. Evolving natural language processing (NLP) capability increasingly enables efficient data capture and transformation of patient information in ambulatory EHRs such as presenting symptoms and EF, often stored as free text within semi-structured or unstructured data fields.

Actionable and Meaningful RWE

This retrospective analysis demonstrates how de-identified ambulatory patient data from an EHR platform from Veradigm may be used to generate actionable and meaningful RWE. The analysis, as described in the full white paper, offers insight into the nature of the unmet need, and provides further insights into patient subgroups (such as those with DM and HT and/or hyperlipidemia), where the most potential impact could be derived from new interventions.



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References

Aguilar D, Deswai A, Ramasubbu K, et al. Comparison of patients with heart failure and preserved left ventricular ejection fraction among those with versus without diabetes mellitus. Am J Cardiol 2010;105(3):373-377.

[Escardio.org. 2019] PARAGON-HF misses endpoint in preserved heart failure, but benefit noted in some patients. European Society of Cardiology; Press Release. 2019 September. https://www.escardio.org/The-ESC/Press-Office/Press-releases/paragon-hf-misses-endpoint-in-preserved-heart-failure-but-benefit-noted-in-some-patients

[GBD 2016] Disease and Injury Incidence and Prevalence Collaborators . Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017; 390:1211–1259.

Kristensen SL, Mogensen UM, Jhund PS, et al. Clinical and echocardiographic characteristics and cardiovascular outcomes according to diabetes status in patients with heart failure and preserved ejection fraction: a report from the I-Preserve trial (Irbesartan in Heart Failure with Preserved Ejection Fraction). Circulation 2017;135(8):724-735.

Lam CSP, Chandramouli C, Ahooja V, Verma S.  SGLT‐2 Inhibitors in Heart Failure: Current Management, Unmet Needs, and Therapeutic Prospects. Journal of the American Heart Association. 2019;8:e013389. https://www.ahajournals.org/doi/10.1161/JAHA.119.013389

Lindman BR, Davila-Roman VG, Mann DL, et al. Cardiovascular phenotype in HFpEF patients with or without diabetes: a RELAX trial ancillary study. J Am Coll Cardiol 2014;64:541-549.

MacDonald MR, Petrie MC, Varyani F, et al. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM). Eur Heart J 2008;29(11): 1377-1385.

Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016; 37:2129–2200.