High Intensity Care vs. GDMT Titration: Which Rapidly Improves Health Status in Patients With Heart Failure?

Patient-reported health status, an important measure of cardiovascular health, encompasses symptom burden, functional status, and health-related quality of life (HRQoL).¹ To patients with symptomatic heart failure (HF), improvement in fatigue, dyspnea, and depression have been shown to be of greater importance than achieving longer survival.² Moreover, patient-reported health status is an independent predictor of cardiovascular events, hospitalization, mortality, and costs of care.¹ As the goals of the majority of drug and device therapies in HF are to alleviate symptoms and improve functional capacity and HRQoL, it stands to reason that patient-reported health status should be assessed using reliable, reproducible, and responsive patient-reported outcome measures alongside any new therapeutic intervention in HF. While pivotal cardiovascular outcomes trials of individual pillars of contemporary guideline directed medical therapy (GDMT) have increasingly included measures of health status as key endpoints, little is known about how the implementation and optimization of GDMT impacts the health status of patients with HF.

In this issue of Circulation: Heart Failure, Čelutkienė et al³ aim to address this knowledge gap through a subanalysis of the STRONG-HF (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies) trial. The STRONG-HF trial was a multinational, open-label, randomized, parallel-group trial that tested a high-intensity care strategy of GDMT up-titration versus usual care and demonstrated a 34% reduction in the relative risk of the primary endpoint of all-cause mortality or HF readmission at 180 days in the high-intensity care arm.⁴ Prespecified exploratory endpoints included change in HRQoL from baseline, assessed prior to hospital discharge and before randomization, to day 90 using the EQ-5D. The EQ-5D is a standardized, global, generic measure of health status composed of two systems, the descriptive system (EQ-5D-5L) and the EQ visual analogue scale (EQ-VAS). The EQ-5D-5L assesses five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Within each dimension, patients indicate their health state by selecting the most appropriate description from five levels: no, slight, moderate, severe, or extreme problems. The EQ-VAS asks patients to rate their health on a vertical visual analogue scale where 0 is “the worst health you can imagine” and 100 is “the best health you can imagine”, providing a quantitative self-assessment of overall health.⁵ The primary STRONG-HF analysis reported a significantly greater increase in the EQ-VAS from baseline to day 90 in the high-intensity care group compared with the usual care group.⁴ In the current study, Čelutkienė et al provide further details about the components of EQ-5D that were assessed.

Overall, the authors found that the EQ-VAS increased (mean change 8.8 [SD 16.8]) points) in both the high-intensity (n=461) and usual care groups (n=454), but patients assigned to high-intensity care experienced a significantly greater improvement (adjusted treatment effect 3.49 [95% CI 1.74–5.24], p<0.0001). Randomization to high-intensity care, younger age (p<0.001), absence of HF hospitalization in the prior year (p<0.001), absence of chronic obstructive pulmonary disease/asthma (p=0.027), lower New York Heart Association class (p<0.001), and lower jugular venous pressure (p=0.023) were independent predictors of improvement in the EQ-VAS at 90 days. In addition, the improvement in all five dimensions of the EQ-5D-5L was greater for patients in the high-intensity group compared with usual care (p<0.05 for all). As the authors acknowledge, the presence and degree of EQ-5D change was subject to bias in this open label trial as patients may have reported greater improvements by nature of being in the high-intensity care group. With this key limitation in mind, this study nevertheless identifies several notable considerations for the assessment of health status in patients hospitalized with HF.

Contemporary cardiovascular outcomes trials that enrolled patients with acute HF help contextualize expected health status impairments in hospitalized patients. As an example, in a participant-level pooled analysis from the DAPA-HF and DELIVER trials, health status, as measured by the Kansas City Cardiomyopathy Questionnaire-Total Symptom Score, declined on average approximately 10 points prior to HF hospitalization.⁶ This suggests that patients who are hospitalized for HF are enrolled at their worst health status, and, as a corollary, patients may regress to their “baseline” state, a better health status, in ambulatory care. As was done in STRONG-HF, both EQ-5D-5L and EQ-VAS record self-rated patient health status on the day of assessment, which is distinct from other HF-specific patient-related outcome measures which include a 2–4 week recall period. In this analysis, though health status improved for patients in both groups by 90 days, a significantly higher proportion of patients in the high-intensity care group achieved a change in EQ-VAS of >3 points (67.2% vs. 57.1%, p<0.001) and a change in EQ-5D-5L utility index score of >0.080 (47.8% vs. 37.9%, p<0.001), considered by the authors to be the minimally important difference for both measures. This prompts us to examine the totality of the interventions deployed in this post-discharge period. Also of note, Čelutkienė et al show that “anxiety/depression” was the most improved EQ-5D-5L dimension in the high-intensity versus usual care group (Mann-Whitney odds 1.26; p<0.001). Though HF-specific instruments would better isolate the effect of HF symptoms on health status, generic instruments like EQ-5D can provide a broader assessment of the impacts of acute HF, HF hospitalization, and post-discharge management on other key health status domains.

It may be tempting to attribute the health status gains seen in this study to achievement of target dose GDMT, but prior randomized trials of foundational HF therapies have not demonstrated similar improvements in EQ-5D scores.^7,8 Notably, in this study, improvements in health status were observed across multiple domains of the EQ-5D including pain/discomfort and anxiety/depression, which may be caused by comorbid conditions and less sensitive or responsive to HF therapies. Taken together, as core elements of GDMT have individually been shown to lead to only modest general health status improvements based on disease-agnostic tools such as EQ-5D, it seems less likely that rapid titration of even combination GDMT was the predominant reason for the health status gains observed in STRONG-HF. Moreover, the delayed integration of contemporary foundational GDMT and add-on therapies including sacubitril/valsartan, sodium-glucose-co-transporter-2 inhibitors, and intravenous iron supplementation into the STRONG-HF protocol further underscores that GDMT may not solely account for the magnitude of health status improvement in the high-intensity group.

Ultimately, we must separate the impact of the high-intensity implementation strategy from the rapid titration of the therapies themselves. During the first 90 days of the trial, patients in the high-intensity care arm had a mean of 4.8 visits versus 1.0 visits for the usual care group. More frequent clinical encounters in the vulnerable post-discharge period may have facilitated access to other “co-interventions” such as visiting nurses, referrals to cardiac rehabilitation, and physical and occupational therapy. Furthermore, frequent in-person visits might have allowed early identification and more optimal management of non-HF comorbidities that may impair dimensions of global health status. Participants in the high-intensity care group may have rated their health status higher in part due to the perception of being monitored more closely and feeling better supported with the care transition in the high-intensity arm. Indeed, in the PACT-HF trial, another randomized trial of frequent and high-touch post-discharge care versus usual care for patients recently hospitalized with HF, the EQ-5D-5L score was significantly higher in the intervention group at hospital discharge and at six weeks post-discharge.⁹

Finally, it is critical to highlight that in this study, patients with lower baseline EQ-VAS were more likely to be women, self-reported Black, and non-European (p<0.001). This is consistent with multiple observational studies and randomized trials in HF that have shown similar HRQoL disparities in minoritized sex/gender and racial/ethnic populations. Women with HF are older, have less caregiver support, report more psychological and physical limitations, and are less likely to receive guideline-recommended therapies¹⁰ — all potential contributions to poor disease-specific and generic health status scores. Less is known about the drivers of health status trajectories in Black and non-European individuals with HF, but socioeconomic determinants of health, structural racism, income inequality, and lack of access to modern HF treatments are all posited to contribute. These findings from STRONG-HF again highlight the urgency to rigorously investigate and address these patient-centered priorities in global and diverse clinical environments.

The contemporary era of GDMT has undoubtedly afforded patients the largest benefits in HF-related morbidity and mortality. With this foundational evidence base established, it is now time to incorporate patient-centered approaches to further improve outcomes. STRONG-HF provides an evidence-based framework to improve patient-reported health status through the high-risk period after hospitalization for acute HF; however, real-world implementation of this high-intensity care model remains as the enduring challenge. Ensuring five clinical encounters within 90 days for all patients after HF hospitalization is nearly impossible in contemporary HF care models. Perhaps the greatest lessons from STRONG-HF are both the imperative to achieve target dose GDMT and to invest in the care paradigms shown to improve mortality and deliver rapid and clinically relevant improvements in health status. As these key lessons are adapted worldwide, it will be imperative to ensure that potentially less resource-intensive and lower touch interventions maintain this emphasis on equitably improving health status for all.