OPTImal PHARMacological therapy for patients with heart failure: Rationale and design of the OPTIPHARM-HF registry

Introduction

Heart failure (HF) represents a global health issue affecting more than 60 million people worldwide and leads the cause of hospitalization in both the United States and Europe.¹ Despite the improvement in cardiovascular (CV) outcomes, patients with HF are yet exposed to an excess risk of hospitalization for HF and CV death.^{1, 2}

Beta-blockers (BB), mineralocorticoid receptor antagonists (MRAs), angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan, and sodium–glucose cotransporter 2 (SGLT2) inhibitors, dapagliflozin and empagliflozin, have been shown to improve survival and outcomes in patients with HF with reduced and mildly reduced ejection fraction (HFrEF and HFmrEF, respectively). Combination of these four drugs is recommended by international guidelines^{3, 4} for HFrEF and may be considered for patients with HFmrEF (class IIb for BB, MRA, and ARNI). SGLT2 inhibitors have also shown to improve HF outcomes in HF with preserved ejection fraction (HFpEF).^{5, 6} All four drug classes are now approved by international Medicines Agencies, representing the standard of care of patients with HF. Recently, vericiguat has been shown to reduce the risk of CV death or hospitalization for HF in patients with HF with maximally tolerated guideline-directed medical therapy (GDMT).⁷ Although scientific societies strongly recommend treatment optimization, in practice patients remain often undertreated for multiple reasons, including treatment inertia, cost/access limitations, absolute or relative contraindications, and real or perceived intolerance.^{8, 9} Prior registries and administrative databases have largely characterized medication use patterns prior to the introduction of the most recent GDMT, SGLT2 inhibitors, prior to latest guideline updates^10-13 and mostly included HFrEF patients. There is a need to describe the prevalence of GDMT at a national level in a contemporary large ‘real-world’ HF population and to assess the extent to which current recommendations for drug combination therapy are adopted in clinical practice.

These insights can facilitate a better understanding of barriers and disparities in HF medical treatment to eventually improve efforts to translate new knowledge into clinical practice and guarantee better patient care. The OPTIimal PHARMacological therapy for patients with Heart Failure (OPTIPHARM-HF; NCT06192524) registry is designed to (i) evaluate medical care and outcomes of patients with HF, (ii) understand reasons for lack of implementation of evidence-based treatment and the impact of comorbidities on treatment tolerance and titration; (iii) assess the impact of adherence to treatment on clinical outcomes in patients with HF across the spectrum of ejection fraction; and (iv) assess management strategy differences between naïve versus chronic HF patients.

Study design

The OPTIPHARM-HF registry is a prospective, observational, national study of adult patients with HF in Italy (Figure 1). Both outpatients and inpatients with chronic and acute decompensated HF will be consecutively recruited per protocol intention. Centres will enrol patients during the course of an outpatient visit or during a hospitalization for HF. Patients will be followed for a maximum duration of 24 months or until death or study withdrawal. Because this is a prospective observational non-interventional cohort study, there will be no attempt to influence clinical practice. The study will enrol patients from approximately 35 Italian HF care centres (community, specialized and advanced care centres). Investigators' sites include facilities specialized in the management of adults with HF. Inpatient and outpatient HF practices are identified to ensure broad representation and affiliation with academic institutions. The research protocol has been approved by the ethics committee of the University Hospital of Brescia under the number NP5441 and complies with the Declaration of Helsinki. When the investigator has decided to include a patient in the registry, a signed informed consent form will be obtained from each patient, once the purposes and objectives of the registry have been illustrated. Patients may withdraw their consent at any time.

Discussion

In recent years there has been a relevant breakthrough in the medical therapy management of patients with HF across the left ventricular ejection fraction (LVEF) spectrum. Along with traditional conventional medical therapies, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB), MRAs and BB, sacubitril/valsartan and SGLT2 inhibitors have shown additional significant reduction of hard clinical endpoints on top of conventional medical therapy.^{2, 5, 18} Compared with conventional therapy, HFrEF quadruple pharmacological therapy was estimated to afford up to eight additional years free from CV death or HF hospitalization and to confer up to 73% relative risk reduction in all-cause mortality.^{2, 19, 20} Based on the results of PARAGON-HF and PARAGLIDE-HF, ARNI may be considered in patients with a LVEF up to 60% or, according to the guideline classifications, with HFmrEF and HFpEF.²¹ On the other hand, based on landmark trials and meta-analyses¹⁸ SGLT2 inhibitors are effective irrespective of LVEF and are recommended also in patients with HFpEF.^{3, 4} Recent evidence supports also treatment of iron deficiency and the use of vericiguat. A recent metanalysis showed a 25% relative risk reduction of CV death or HF hospitalization conferred by intravenous iron therapy among patients with HF with evidence of iron deficiency.²² Lastly, vericiguat showed a 10% risk reduction of CV death or HF hospitalization among worsening HFrEF on top of conventional medical therapy and is recommended in class IIb.²³

Despite the profound benefits deriving by the combination of foundational HF medical therapies, yet there are unmet clinical needs related to the low prescription rate and the clinical challenge in the patterns of drug introduction, limiting a wide and consistent optimal background medical therapy. The CHAMP-HF registry showed a 27%, 33% and 67% of eligible HFrEF patients who were not prescribed ACEi/ARB/ARNI, BB and MRAs, respectively.¹¹ Also, among patients with prescribed medications, the doses were generally low. Similar results come from other European and Asian registries, showing a substantial underutilization of GDMT, particularly with respect to achieving target doses.^{24, 25}

There is an urgent need to understand the barriers for reaching a full drug pattern prescription, titration to target doses and persistence of GDMT. Indeed, most studies on medication use in HF show the unmet need of guideline implementation, but do not explain why this is the case. Also, available data mostly derive from studies conducted prior to the recent evidence of the efficacy of SGLT2 inhibitors, iron replacement and vericiguat. In addition, epidemiological data are mostly confined to HFrEF patients or, worse, based on administrative databases lacking details regarding mandatory characteristics of the patients enrolled such as their LVEF. In contrast, OPTIPHARM-HF is one of the first registries describing contemporary practice of management of HF with full details regarding patient characteristics.

OPTIPHARM-HF will provide important information on medication prescription and adherence in a real-world setting with broad inclusion criteria reproducing real-world clinical practice as compared to clinical trials. The registry will provide a comprehensive understanding of the contemporary management of patients with HF across the ejection fraction spectrum and across different clinical stages and phenotypes, such as those with worsening HF, advanced HF and HFimpEF. The registry will also assess medication changes, including the initiation and up-titration of new HF therapies in patients with de novo HF and after a hospitalization for acute HF. Yet, there is a lack of evidence from real-world data regarding the sequence initiation of GDMT in these patients.^26-28 Compared to previous international guidelines which advocated a sequential step-by-step initiation by starting the drug classes in chronological order of entry into the guideline, new recommendations suggest a rapid initiation and up-titration of pillars drugs without delay.^{3, 4} Although different sequencing approaches have been proposed, no validated data are yet available. Recently, the STRONG-HF trial provided direct evidence that intensive, simultaneous and rapid sequence initiation and titration of GDMT up to 100% of the recommended doses within 2 weeks of discharge for acute HF is safe, well-tolerated, and effective for reducing death and HF hospitalization.²⁹ However, its applicability and adoption in clinical practice, beyond the context of a clinical trial, is less known. Finally, the OPTIPHARM-HF will assess implementation of comprehensive HF management including treatment of comorbidities, such as iron deficiency, valvular heart disease, kidney dysfunction and electrolyte abnormalities, including hyperkalaemia and the use of potassium binders in optimization of GDMT.

The OPTIPHARM-HF is a national registry, potentially limiting the external generalizability of our findings, although barriers encountered on HF care are most likely exchangeable across different regions. Patients will be enrolled in HF centres with different levels of quality of care. Nevertheless, as compared to rural hospitals or general practice there will be an expected more consistent and stringent GDMT and dose up-titration. This may limit the ability to reflect real-world data across different geographic areas. Potential clinical confounding that could affect treatment implementation, response or prognosis could not be captured by available case report forms, such as socioeconomic status, lifestyle factors and quality of life.

Although data will be consecutively collected, the study population will be limited to patients providing informed consent and completing study visits. This may introduce a potential selection bias, although this limitation is common to other previous prospective registries¹¹ and clinical trials in general. Additionally, due to the nature of this study, clinical endpoints will be reported by the investigator and not centrally adjudicated.

Conclusion

The OPTIPHARM-HF will collect essential information on the HF medical therapy guideline implementation, uptake of GDMT and new drugs, and quality of care for patients with HF in a national context. The study will assess in a real-world context the prevalence of medication treatment prescription and titration as well as the cause of underuse, in a broad HF population across the whole ejection fraction spectrum and among different clinical phenotypes. These data will have important implications for improving patient care and adoption of new evidence into clinical practice.