Stage D Heart Failure With Preserved Ejection Fraction, Heart Transplantation, and Mechanical Circulatory Support

Definition of Stage D Heart Failure

The American College of Cardiology (ACC) and American Heart Association (AHA) guideline for the management of heart failure (HF) classifies disease progression into four stages. Stage A includes patients with risk factors for HF but without structural heart disease, stage B includes those with structural heart disease without HF symptoms, stage C represents symptomatic HF associated with underlying structural heart disease, and stage D reflects refractory symptoms despite guideline-directed medical therapy (GDMT). As opposed to the New York Heart Association (NYHA) functional classification system, whereby patients are grouped by symptom severity and can move from class to class regardless of structural heart disease, this classification emphasizes the natural progression of disease through clinical stages.

While discussion of stage D HF has traditionally been limited to those patients with advanced heart failure with reduced ejection fraction (HFrEF), recognition and understanding of heart failure with preserved ejection fraction (HFpEF) has evolved and with it the need to address the management of patients with stage D HFpEF.

Defining advanced HF, end-stage HF, or stage D HF in a clear manner is important for clinical and research purposes, but it is challenging to do so as the natural history of HF is diverse and its clinical course highly variable. Existing definitions of stage D HF address particular populations but are arguably too imprecise for assessment of individual patients. It is usually a cluster of findings that defines stage D HF rather than a single characteristic. A recent consensus document from the Heart Failure Society of America (HFSA) Guidelines Committee suggests that stage D HF be defined by the presence of progressive and/or persistent severe signs and symptoms of HF despite optimized medical, surgical, and device therapy. The definition further includes frequent hospitalizations, severely limited exertional tolerance, and poor quality of life, which are associated with high morbidity and mortality. Importantly, the progressive decline should be primarily driven by the HF syndrome.

HFpEF Phenotypes Resulting in Stage D HF

According to ACC/AHA guidelines, HFpEF is defined as the presence of the HF syndrome in an individual with a left ventricular (LV) ejection fraction (EF) of 50% or more. Regardless, HFpEF remains a challenging diagnosis for multiple reasons, including lack of universal definition that unites broad and heterogenic groups of patients. HFpEF is largely the diagnosis of exclusion in patients with clinical symptoms of HF and evidence of preserved or normal EF.

Patients suffering from HFpEF, where LV diastolic dysfunction (DD) predominates, usually also exhibit LV systolic dysfunction as evident by abnormalities of longitudinal strain, LV end-systolic (Ees) stiffness (elastance), ventricular-arterial coupling (Ea/Ees ratio), and vasculoventricular coupling (see Chapter 29 ). In addition, chronotropic incompetence, abnormal vasorelaxation, right heart dysfunction, and abnormalities in the periphery are also present in patients with HFpEF. Given this complexity and diverse etiology, HFpEF likely represents a group of several pathologies and diagnoses, which are caused by different etiologies but produce the same syndrome. A better understanding of this phenotypic heterogeneity, as well as efforts to identify a common denominator for HFpEF, is essential to identify potential therapeutic targets. An ideal HFpEF taxonomy system would cluster together pathophysiologically similar individuals who may respond in a more predictable way to treatment.

Exploring the pathophysiology of HFpEF is challenging, and the natural history of clinical progression from the preclinical cardiac dysfunction (stage B) to the final clinical stages of HFpEF (stages C and D) depends on the clinical phenotype. The traditional classification proposed by HFSA guidelines divided HFpEF into different groups based on the most likely cause of the disease ( Fig. 22.1 ). Of note, many of the diagnoses in this classification system can be treated, therefore suggesting that progression of HFpEF to stage D HF may be preventable.

Various other classification systems for HFpEF have been proposed. These stratify HFpEF based on clinical variables, physical characteristics, laboratory data, electrocardiogram (ECG) parameters, and/or echocardiographic parameters. A recent analysis of 397 patients with HFpEF utilizing phenomapping (unbiased cluster analysis of dense phenotypic data) identified three clinically relevant categories of patients with HFpEF with significantly different underlying etiology, pathophysiology, and clinical outcomes. However, despite the ability of this analytic approach to separate patients into clusters, there remained a substantial overlap in numerous patients’ clinical characteristics, demonstrating the heterogeneous nature of this disease.

Xanthopoulos and Starling ( Fig. 22.2 ) recently proposed a phenotypical classification of HFpEF composed of two groups based on the contribution of hypertension to development of the disease (hypertensive vs nonhypertensive). This hypertension-centric classification system is based on several observations. First, hypertension is the most common comorbidity in patients with HFpEF who otherwise have a single comorbidity, whereas other noncardiac comorbidities are rare in this population. Second, hypertension always preexists HFpEF, whereas virtually all the other noncardiac comorbidities may or may not. Third, comorbidities have minimal contribution to the development of nonhypertensive HFpEF (valvular, cardiomyopathic, and extramyocardial).

Epidemiology

HF is a major public health problem, which is projected to become an epidemic. HF is the most common cause of hospitalization among individuals age 65 years and older. Even though estimates of HFpEF prevalence vary depending on the study population and EF cutoff used, it is believed that half of patients with HF have preserved EF. Compared to patients with HFrEF, those with HFpEF are older and more likely to be female. The incidence and prevalence of HFpEF increases sharply with age. Analysis of age and sex adjusted incidence of HF from 2000 to 2010 in Olmsted County, Minnesota, by Gerber et al. showed the incidence of HF declined for both HFpEF (EF ≥50%) and HFrEF (EF <50%). However, the declines were greater for HFrEF (−45%) than for HFpEF (−28%). The proportion of incident cases of HFpEF increased from 47.8% in 2000–2003 to 52.3% in 2008–2010. In another study, Owan et al. found that the prevalence of HFpEF is increasing relative to HFrEF at a rate of 1% per year, suggesting that HFpEF may become the most common type of HF in the near future. Using the Get With The Guidelines dataset, Steinberg et al. found that the proportion of patients hospitalized with acute HF who had HFpEF increased from 33% in 2005 to 39% in 2010. At the same time the proportion of HF hospitalizations due to HFrEF decreased from 52% to 47% in the United States. These data suggest that the HF landscape is evolving, and it is projected that by the year 2020, 65% of patients hospitalized with HF will have a preserved EF.

The true prevalence of stage D HF, particularly in the HFpEF subgroup, is unknown. Estimates are controversial and based on limited data. Estimates of current theoretical patients with advanced HFpEF ranges between 110,500 and 325,000. Our approach to deriving these estimates are described next.

The current population of the United States is 326 million based on the latest United Nations estimates with 75% being 20 years old or older, thus yielding ∼245 million adults. The most recent AHA statistics indicate a HF prevalence of 6.5 million (years 2011–2014) in Americans 20 years of age and older, yielding an estimated HF prevalence of 2.7%.

In 2007 Ammar et al. published a community-based study evaluating the prevalence of HF stages from Olmsted County, Minnesota. Of patients who had HF, ∼17% were classified as having HF symptoms (stage C), 3% were further classified as advanced stage C, and ∼0.4% were classified as having severe HF (stage D). These estimates are from rural Minnesota, where the population is homogeneous and mostly white, and likely differ from heterogeneous inner-city urban areas that have a high prevalence of African Americans and Hispanics who tend to have higher rates of hypertension. These areas tend to have more individuals with stage D HF, with a prevalence of ∼5%.

Implantable Hemodynamic Monitoring in HFpEF

An important goal in HF management is decongestion: decreasing ventricular filling pressures without compromising cardiac output. Because physical examination findings of congestion are inconsistent, various implantable cardiac filling pressure monitoring devices have been developed in an effort to help clinicians guide HF therapy, prevent exacerbation, and alter natural history of the disease.

Early studies demonstrated the safety and feasibility of long-term right ventricular (RV) pressure monitoring, helping advance knowledge of the pathophysiology of HF, and suggesting that continuous RV pressure monitoring may reduce HF hospitalizations. These discoveries resulted in development of Chronicle (Medtronic, Minneapolis, Minnesota, USA), the first implantable hemodynamic monitor. Chronicle was an implantable RV outflow tract hemodynamic monitor that recorded RV systolic pressure (RVSP), RV diastolic pressure (RVDP), and estimated pulmonary artery pressure (PAP). COMPASS-HF, a randomized clinical trial testing the efficacy of Chronicle, enrolled 301 patients with NYHA Class III-IV symptoms regardless of LV EF, but failed to show any significant effect on hospitalizations as compared to the control group. Secondary analyses of the trial showed a 36% relative risk reduction for first HF readmission, suggesting potential clinical benefit of the implantable hemodynamic monitoring in patients with advanced HF.

Because HF decompensation is characterized by progressive increase in left atrial (LA) pressure, another target for hemodynamic monitoring was development of a permanent implantable direct LA pressure monitoring system. The first to be developed was the HeartPOD (Savacor, a subsidiary of St. Jude Medical, Minneapolis, Minnesota, USA), an implantable transseptal (right atrium to left atrium) sensor lead coupled with a subcutaneous antenna coil. The efficacy of this device was studied in the HOMEOSTASIS pilot study, a prospective uncontrolled cohort, which demonstrated improvements in hemodynamics, symptoms, and outcomes when treatment was guided by LA pressure monitoring. Based on these findings LAPTOP-HF, a large randomized trial designed to test the safety and effectiveness of LA pressure–guided HF therapy, was launched and planned to enroll 730 patients. However, LAPTOP-HF was terminated early by the study’s data and safety monitoring board after randomization of only 486 patients because of a high number of implant-related complications.

A further anatomic target for cardiac hemodynamic monitoring in chronic HF is the pulmonary artery (PA). CardioMEMS (St. Jude Medical, Minneapolis, Minnesota, USA) was the first catheter-delivered PAP sensor, implanted via right heart catheterization approach. The device consists of a wireless three-dimensional (3-D) coil and a pressure-sensitive capacitor covered with silicone. The pivotal trial of this device was the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial, a multicenter, single-blinded, randomized controlled trial of 550 patients with symptomatic HF. In this trial, HF medications were adjusted on the basis of hemodynamic data provided by the sensor. The CHAMPION trial found a 37% reduction in the primary end point of HF-related hospitalization compared to the control group (HR 0.63, 95% confidence interval [CI] 0.52–0.77; P <0.0001). These findings were consistent among those patients who had HFpEF (21% of the cohort), with the rate of HF hospitalization being 46% lower in the treatment group compared with control (incidence rate ratio, 0.54; 95% CI, 0.38–0.70; P <0.0001). Based on the results of the CHAMPION trial in 2014 the US Food and Drug Administration (FDA) approved use of the CardioMEMS sensor in both patients with HFpEF and HFrEF, who had symptomatic HF (NYHA Class III) and were on optimal medical therapy with a history of HF hospitalization within the last year. Follow-up studies to date, including both long-term follow-up of the CHAMPION cohort and postmarketing real-world populations, continue showing the benefit of PA pressure monitoring.

Currently ongoing is GUIDE-HF (ClinicalTrials.gov identifier NCT03387813), a randomized clinical trial intended to evaluate the utility of PA pressure monitoring with the CardioMEMS sensor in an expanded patient population, including HF patients outside of the present indication, but at risk for future HF events or mortality. The trial will enroll patients with either HFpEF or HFrEF, and NYHA Class II-IV symptoms who have an elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) and/or a prior HF hospitalization ( https://clinicaltrials.gov/ct2/show/NCT03387813 ). Estimated enrollment will be 3600 participants, with an estimated completion date of April 2023.

Interatrial Shunt Devices in Treatment of HFpEF

Creation of iatrogenic interatrial shunting has been suggested as a novel therapy for patients with HFpEF and ongoing symptoms despite medical therapy. The potential mechanism of benefit is reduction of LA pressure, particularly during exertion, which relieves pulmonary venous congestion. The preliminary hypothesis for this approach was generated in preclinical computer-based modeling of HFpEF hemodynamics. Currently two devices are available and are being evaluated in ongoing studies in patients with HFpEF. The V-Wave shunt device (V-Wave, Caesarea, Israel) consists of an hourglass-shaped, self-expanding nitinol stent frame, and the Interatrial Shunt Device (IASD II, Corvia Medical Inc., Tewksbury, Massachusetts, USA) is a self-expanding nitinol device ( Fig. 22.3 ).

In a phase I study, the IASD II device led to reduced LA pressures at 6 months and to improved symptoms, quality of life, and functionality as assessed by the 6-minute walk test. There were no device-related complications at 1 year. In the REDUCE LAP-HF I phase 2 trial, which enrolled patients with HFpEF and NYHA Class III-IV symptoms, the same device was successfully implanted in over 90% of patients, and no periprocedural complications were observed. At the 1-month follow-up, the IASD resulted in a greater reduction in pulmonary capillary wedge pressure (PCWP) compared with sham controls. Further studies and longer follow-up is necessary to understand if mechanistic effects of such devices will translate into meaningful clinical outcomes improvement.