Optimization of Target Dose Medical Therapy in Patients with Systolic Heart Failure: A Combined Retrospective and Prospective Observational Study

Heart failure is a complex clinical syndrome characterized by the inability of the heart to maintain adequate circulation due to structural and/or functional (systolic or diastolic) abnormalities.[1] It may result from any cardiac disorder that impairs ventricular filling or ejection of blood and remains primarily a clinical diagnosis supported by investigations such as chest radiography, electrocardiography, and echocardiography.[2] HF arises from structural and functional myocardial defects that compromise ventricular performance.[3] Although reduced left ventricular systolic function is the most common cause, abnormalities of the pericardium, myocardium, endocardium, heart valves, or great vessels may also contribute.[1] Pathogenic mechanisms include hemodynamic overload, ischemia-related dysfunction, ventricular remodelling, excessive neurohormonal activation, altered calcium handling, extracellular matrix changes, apoptosis, and genetic factors.[2]

HF may be classified as left, right, or biventricular, and as acute or chronic. Clinically, it is categorized into HFpEF (Heart Failure with preserved Ejection Fraction) and HFrEF (Heart Failure with reduced Ejection Fraction). HFpEF, commonly seen in elderly females, is characterized by an ejection fraction >50%, normal ventricular cavity size, and increased wall stiffness.[3]

HF is associated with significant morbidity, mortality, and reduced quality of life, imposing a substantial burden on healthcare systems.[3] One-year mortality following hospitalization ranges from 10% to 30%,[4] and median survival after diagnosis is less than four years.[5] Patients typically present with dyspnea, orthopnea, paroxysmal nocturnal dyspnea, fatigue, and peripheral edema.[6,7]

Therapeutic advances have demonstrated that ACE (Angiotensin-Converting Enzyme) inhibitors, beta-blockers, and MRAs (Mineralocorticoid Receptor Antagonists) improve clinical outcomes when titrated to guideline-recommended doses.[8] However, in routine practice, many patients fail to achieve target doses, and prognosis remains poor.[9] Moreover, real-world populations often differ from clinical trial cohorts, raising concerns about treatment optimization, particularly in HFpEF. In such settings, well-designed observational studies may provide valuable insights into therapeutic effectiveness.[10]

AIMS AND OBJECTIVES

The study aims to evaluate the effect of target-dose medical therapy using a combination of beta-blockers and RAAS inhibitor drugs (MRA + ACEI/ARB/ARNI) in patients with systolic heart failure. The primary objective was to determine the percentage of patients receiving each quartile of the target dose (<25%, 25–<50%, 50–<75%, and >75%) of BB and RAAS inhibitor therapy. The secondary objectives were to compare heart failure admission plus mortality, HF admissions alone, and mortality alone among patients receiving different quartiles of the target dose in order to assess the impact of dose optimization on clinical outcomes.

Table 1 illustrates that the majority of patients were elderly males with ischemic cardiomyopathy. Most patients were in NYHA Class II–III and had a high prevalence of diabetes and hypertension.

Table 2 shows significant improvement in dose optimization over 12 months, with a reduction in the low-dose group and a marked increase in patients achieving >50% of the target dose.

Table 3 demonstrates a significant reduction in Group A (low dose) and an increase in Group B1 after systematic uptitration.

Table 4 shows a statistically significant shift from low-dose Group A to high beta-blocker dose Group B2 over time.

Table 5 illustrates a gradual increase in patients achieving high doses of both BB and RAAS inhibitors (Group C), though numbers remained relatively small.

Table 6 shows significantly lower mortality in Group B2 (high BB dose) compared to Group B3 (moderate doses of both drugs).

Table 7 indicates that, except for NYHA class, no other baseline variables differed significantly between B2 and B3 groups, suggesting the mortality benefit in B2 was likely related to the higher beta-blockers dose.

This retrospective cohort study of 324 patients with systolic heart failure examined the proportion of patients receiving each quartile of the target dose for beta blockers and RAAS inhibitors (ACEI/ARB/ARNI + MRA) between January 2016 and December 2018. The cohort was predominantly male with ischaemic HFrEF (85.7%), approximately 70% were diabetic, and 95% were in NYHA Class II–III.

Dose Distribution and Up-titration

At baseline, most patients received sub-target doses: 13% were in the 0–15% group, 37% in the 15–30% group, and 35.2% in the 31–50% group; only 4.6% and 9.8% achieved 51–75% and 76–100% of the target dose, respectively. A further 12.3% were not on either drug class at enrolment. At 12-month follow-up, meaningful up-titration was evident: the proportion at ≥76% of target dose more than doubled (9.8% → 24.3%), while those in the lowest tier fell from 13% to 5%. Among patients initially below 15% of the target dose, 40% successfully stepped up by one year. Pair wise intergroup comparisons confirmed statistically significant increases in GDMT dosing at 3, 6, and 12 months, consistent with findings reported by Joseph et al.^[12]

Comparison with Published Data

Joseph et al.,^[12] in a retrospective study from a tertiary care centre in southern India, categorized HF patients into four dose-range arms for each drug class separately. For beta blockers, 55% were in the 0–25% group at baseline, improving to 21% in the ≥76% group at one year. For ACEI/ARBs, 44% reached the ≥76% tier at follow-up. Our data are broadly concordant; however, unlike that study, we assessed combined target dose across drug classes and correlated dose groups with mortality outcomes.

Landmark randomized trials achieved high individual target dose rates under controlled conditions - 42% in CIBIS-II,^[13] 80% in the U.S. Carvedilol HF Study,^[14] and 64% in MERIT-HF^[15]- yet real-world registries show a stark contrast. OPTIMIZE-HF^[16] found mean beta-blocker doses below 50% of the target, with fewer than 10% achieving the target dose at discharge. COHERE^[17] reported only 41% reaching the carvedilol 25 mg twice-daily dose. Contemporary trials show similar underachievement: approximately 50%, 30%, and 25% of patients reached beta-blocker targets in HF-ACTION, SHIFT,^[18] and CIBIS-ELD,^[19] respectively. These data consistently demonstrate a gap between efficacy trial results and routine clinical practice.

The CHAMP-HF Registry^[20] found that among patients eligible for all three drug classes, only 22.1% were simultaneously prescribed any dose of ACEI/ARB/ARNI, beta blocker, and MRA - and a mere 1.1% received target doses of all three. This underscores the case for trials that evaluate combined rather than individual target dose strategies.

Target Dose versus Target Heart Rate

Beta-blocker–mediated heart rate reduction decreases myocardial oxygen demand and improves mechanical efficiency-benefits abolished when HR is held constant by atrial pacing.^[21] Pacing at 80 versus 60 beats/min attenuated the beneficial effects of beta-blockade on left ventricular volume and systolic function.^[22] Notably, a meta-analysis demonstrated that achieving a low target HR-regardless of dose prescribed - was an independent determinant of survival in HFrEF patients in sinus rhythm.^[23] Eriksen-Volnes et al.,^[24] analyzing 2,689 patients from the Norwegian Heart Failure Registry, confirmed that HR ≥70 bpm was associated with worse outcomes, suggesting HR may be a more clinically meaningful target than absolute drug dose. Heart rate was not recorded at follow-up in the present study, and this question could therefore not be addressed.

Mortality Benefit with Combined Target Dose Therapy

Twelve-month mortality was compared across all five dose groups using the chi-square test. The primary mortality finding was a significant difference between Group B2 (beta blocker ≥50% target + RAAS inhibitor <50% target; mortality 11.5%) and Group B3 (both drugs at 15–50% target; mortality 27.4%) (p = 0.019). This indicates that prioritizing beta blocker dose over RAAS inhibitor dose confers a clinically meaningful survival advantage. Mortality in Group B1 (RAAS inhibitor ≥50% + Beta Blocker <50%) was 20%, not significantly different from Group B2, likely due to small group size. Group C (high dose of both agents) was expected to show the greatest benefit, but insufficient numbers precluded statistical analysis.

To assess whether the B2–B3 mortality difference was confounded by baseline characteristics, risk factors were compared (Table 1). Of the variables examined - etiology, rhythm, QRS duration, NYHA class, creatinine, and ejection fraction - only NYHA class differed significantly (p <0.001): Group B2 contained more NYHA Class III patients (61.3% vs. 20.8%), yet still demonstrated lower mortality, consistent with a dominant protective effect of higher beta blocker dosing even in more symptomatic patients. The RAAS inhibitor dose appeared to be a limiting factor for beta blocker up-titration, possibly due to haemodynamic effects. Taken together, these findings suggest that in GDMT for HFrEF, mortality is predominantly influenced by Beta Blocker dose achievement.

Context from Landmark Trials

Several pivotal trials demonstrated mortality benefit with individual agents without reporting combined target dose achievement. PARADIGM-HF^[25] showed that LCZ696 reduced mortality vs. enalapril (13.3% vs. 16.5%) in patients of whom 93.1% were on a stable beta blocker dose, though the degree of target dose achievement was not specified. COPERNICUS^[26] demonstrated a 35% reduction in mortality with carvedilol added to standard therapy including RAAS inhibitors. HEAAL^[27] showed that high-dose losartan (150 mg) reduced the composite of death or HF admission versus low-dose (50 mg), without reporting concurrent Beta Blocker dose achievement. The absence of combined dose data in all these trials represents a methodological gap that limits real-world application. Additionally, since ICD candidacy per MADIT-2 criteria^[28] requires optimization of medical therapy first, our finding that most patients remain on sub-target combined GDMT has direct implications for device referral timing.

LIMITATIONS

This study has important limitations: single-centre retrospective design, small non-consecutive sample, short 12-month follow-up, under-representation of NYHA Class I and IV patients, and insufficient numbers in Group C for statistical analysis. Heart rate was not recorded at follow-up, precluding evaluation of the target HR question. Large prospective multicentre trials are needed to evaluate combined beta blocker and RAAS inhibitor target dose strategies and their long-term impact on outcomes.

Stratifying patients with systolic heart failure according to percentage target doses of beta blockers and RAAS inhibitor therapy facilitates systematic uptitration and improves achievement of guideline-directed medical therapy. With structured follow-up, most patients can be titrated to 15–50% of the target dose, nearly one-quarter achieve >50% of either beta blocker or ACE-I/ARB/ARNI, and only a small minority reach >50% of both drug classes. Dose optimization is largely achievable within the first three months, with further incremental gains during continued follow-up. Importantly, achieving beta blocker doses of 50–100% of the target was associated with reduced mortality irrespective of RAAS inhibitor dose, underscoring the critical role of adequate beta blockade and its implications for timing advanced therapies such as ICD or CRT after optimal medical management.