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‘4-drug regimen essential for treating heart failure’
by Son, Hyung Min Nov 20, 2025 06:15am
Heart failure remains one of the most dangerous cardiovascular diseases. Rather than simply causing fatigue or shortness of breath, it is a systemic disorder in which structural and functional impairment of the heart leads to reduced blood flow and multi-organ decline. In rapidly aging countries like Korea, prevalence is rising at an even faster pace. The prevalence of heart failure in Korea has increased by approximately 4.5-fold over the past 20 years, exceeding 26% among those aged 80 and older. More notably, the 5-year survival rate for heart failure is lower than that for major cancers like breast or prostate cancer. This demonstrates that it is no longer merely a chronic condition but a severe disease directly linked to survival. Amidst this shift towards heart failure becoming a severe disease, DailyPharm met with Professor Michael Böhm, Chair of the ESC Scientific Program Committee and Professor of Internal Medicine at Saarland University Hospital, and Professor Byung-Su Yoo, President of of the Korean Heart Failure Society and Professor of Cardiology at Yonsei University Wonju College Hospital to discuss the the current state of heart failure and the challenges in the Korean treatment environment. (from the left) Prof Michael Boehm, Prof Byung-Su YooBoth experts highlighted the particularly rapid disease progression and high readmission risk associated with heart failure with reduced ejection fraction (HFrEF), emphasizing that “early treatment determines survival.” Among heart failure types, HFrEF is known for its rapid worsening, with more than 20% of patients readmitted within one year after discharge. Rehospitalization not only signifies worsening prognosis but also directly leads to increased mortality. Consequently, global guidelines explicitly state that ‘the success of HFrEF treatment hinges on the initial treatment strategy.’ This means that the only evidence-based strategy to improve survival rates is to promptly initiate the four pillars of heart failure therapy (ACE inhibitors or angiotensin receptor neprilysin inhibitors, beta-blockers, mineralocorticoid antagonists, and SGLT-2 inhibitors) upon diagnosis and uptitrated to target doses as quickly as possible. Among these, Entresto (sacubitril/valsartan), a representative ARNI therapy, is the most crucial pillar in HFrEF treatment. In the landmark PARADIGM-HF study, Entresto reduced cardiovascular death and heart failure hospitalization by 20% compared to the conventional ACE inhibitor enalapril, completely shifting the HFrEF treatment paradigm. Consistent results showing reduced risks of sudden death and emergency room visits provided the rationale for transitioning from the RAAS monotherapy era to a new standard of care centered on ARNIs. Germany is a prime example of a country where this shift was swiftly implemented in clinical practice. Standard therapy, including Entresto, is applied early on to most HFrEF patients, and a standardized heart failure care pathway, prioritizing achieving target doses, is already firmly established in the country. By contrast, Korea continues to face criticism for a low four-drug application rate and inadequate dose titration. Experts emphasize that such gaps ultimately translate into survival disparities, stressing the need for early treatment optimization. Q. What is the proportion of HFrEF patients, and what are the key clinical characteristics of the disease? eb Prof Byung-Su YooProf. Yoo: While data varies, the Korean Heart Failure III Registry, which focuses on tertiary hospital patients, shows approximately 55% or more cases are HFrEF. This reflects the patient population characteristics of tertiary hospitals, which treat a high proportion of severe cases. In actual clinical practice, with preserved ejection fraction (HFpEF) or mildly reduced ejection fraction (HFmrEF) would be more common. This distribution is becoming more pronounced due to the recent increase in elderly and obese patients. HFrEF is characterized by significantly impaired systolic function, faster progression, and more severe symptoms such as dyspnea, edema, and fatigue. Prof. Michael: In Europe, HFrEF is also estimated at around 50%, but the actual proportion may be higher. Women with hypertension, atrial fibrillation, stroke, or diabetes were often classified as HFpEF in the past. Under the latest criteria, they may now be reclassified as HFrEF or HFmrEF. This shift suggests that heart failure classification based on ejection fraction may be revised in the future. Q. What is the evidence supporting the establishment of the four-drug regimen as the standard treatment for heart failure? Prof. Yoo: The standard treatment for heart failure is a therapeutic strategy established based on decades of accumulated clinical research. The effects of existing medications—beta-blockers, ACE inhibitors, ARBs, and MRAs—in reducing mortality and rehospitalization have been consistently demonstrated through large trials. The addition of SGLT2 inhibitors completed the four foundational pillars, and RAAS inhibitors are now shifting toward ARNI class drugs. Crucially, evidence shows that applying all four drugs together can reduce the risk of death or hospitalization by over 70%. Therefore, unless there are specific contraindications, actively using this regimen from the outset is key to improving prognosis. It is established as standard therapy that must be adhered to unless there are specific reasons not to, due to its clear efficacy in improving major events (hard outcomes). The standard therapy mentioned has already been proven effective in numerous studies. Specifically, using these four standard drugs can reduce mortality and hospitalization rates by approximately 70% or more, with this benefit observed in one out of every four patients. Prof. Michael: Heart failure pharmacotherapy has long evolved toward regulating the neuroendocrine axis. ACE inhibitors and MRAs were developed first, and major large-scale clinical trials established the current treatment foundation. As these studies accumulated, mortality rates in heart failure patients gradually decreased. Indeed, meta-analyses show that mortality and hospitalization rates decrease by approximately 65% when initiating all four agents together. Q. Why is Entresto preferred over other RAAS inhibitors? Prof. Yoo:The rationale for prioritizing Entresto (ARNI) is clearly demonstrated in the PARADIGM-HF study. In this study, Entresto reduced major hard outcomes, including death and hospitalization, by approximately 20% compared to the existing ACE inhibitor enalapril. This study is particularly significant because it demonstrated superiority not against a placebo, but directly against the then-standard of care, an ACE inhibitor. Mechanistically, the ARB (valsartan) is combined with a novel mechanism—a neprilysin inhibitor (sacubitril)—which synergistically enhances sodium excretion, vasodilation, and myocardial protection. These biological effects translated into actual clinical outcomes, establishing ARNI as the new standard that replaces existing RAAS inhibitors. Prof Michael Boehm#Prof. Michael: PARADIGM-HF can be regarded as a study that changed the treatment paradigm for heart failure. It presented a new mechanism capable of replacing ACE inhibitors, the existing standard therapy, and as a large-scale randomized study, it secured long-term data, demonstrating high stability and reliability. Recruiting a control group of this scale again would be practically difficult, making it unlikely that a comparable study could be replicated. Entresto demonstrated significant improvements not only in the primary endpoint but also in patients' quality of life (QoL). Survey-based assessments showed substantial relief in patients' overall well-being and symptom burden, carrying profound clinical significance for heart failure patients, particularly those with HFrEF. Furthermore, it demonstrated superior renal function preservation compared to ACE inhibitors and even confirmed the long-term benefit of reducing the risk of developing diabetes. These additional benefits can be seen as a result of the complementary properties of the sacubitril and valsartan combination, holding great significance in that it can provide patients with a better clinical experience across the entire spectrum of heart failure treatment. Why must all four therapies as standard therapy be initiated “as early as possible”? Prof. Yoo: HFrEF is a disease with a particularly poor prognosis at diagnosis, with many patients experiencing a rapid deterioration within the first 3 months. Since this is the period with the highest risk of death and rehospitalization, the four-drug standard therapy regimen must be introduced as quickly as possible. The effect of these medications is not merely symptom relief; they rapidly reduce mortality and hospitalization rates. Delaying treatment means immediately forfeiting these benefits. Numerous studies have accumulated showing that the earlier these medications are applied in HFrEF patients, the greater the improvement in prognosis. Consequently, both domestic and international guidelines emphasize early intervention. Prof. Michael: The reason early intensive therapy is crucial is that there exists a clinical golden time for heart failure. From the moment of initial diagnosis, myocardial stress in HFrEF patients increases rapidly, and structural and functional damage progress quickly during this process. Therefore, the four drugs must be initiated as soon as possible before the benefits of treatment accumulate. Furthermore, a sequential, delayed introduction of medications can result in leaving the patient's clinical risk unaddressed. Large-scale patient data also consistently show that rapid initiation of combination therapy improves survival rates and reduces hospitalization risk compared to monotherapy or delayed initiation. For these reasons, Europe also operates treatment strategies aiming for early completion of the four-drug regimen whenever possible. Q. South Korea still has a low initial adoption rate for the four-drug regimen. What tasks are necessary for improvement? Professor Yoo: The reasons for suboptimal initial treatment optimization in Korea involve a complex interplay of factors: time and environmental constraints on healthcare providers, patient concerns about polypharmacy, and staffing burdens in clinical settings. However, given the substantial clinical benefits of the four-drug regimen, establishing it as the common clinical pathway is necessary. Strengthening the role of heart failure centers and specialized clinics, establishing integrated treatment algorithms applicable from the initial visit stage, and creating structures that facilitate active dose titration in clinical practice are crucial. This should be accompanied by patient education to improve medication adherence and policy support to ensure consistent treatment standards across regional healthcare institutions. In terms of clinical inertia, a particularly unique situation in Korea is that healthcare providers have very limited time when seeing outpatients and must manage a large volume of patients. This makes it extremely difficult to carry out standard treatment or personalized therapy for patients. To summarize, the target level for standard treatment in Korea has significantly improved. However, it can be said that there is still room for improvement for many practitioners, excluding specialists who specifically treat heart failure patients. Prof. Michael: As seen in Germany, a ‘standardized clinical pathway’ is key to increasing early treatment initiation rates. We need a system that allows any doctor to design treatment based on the same criteria, rather than relying on the experience and skill level of individual clinicians. Furthermore, in the process of managing patients to reach the maximum tolerated dose of medication, it is crucial to establish time flexibility and a continuous monitoring system in the clinical setting. Indeed, the standard four-drug regimen that includes Entresto achieves optimal efficacy only when doses are sufficiently titrated. Therefore, expanding outpatient, nursing, and educational systems for this purpose is absolutely essential. A national-level management model would ultimately narrow Korea’s treatment gap and improve outcomes for many patients.

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