Up-titration of Guideline Directed Medical Therapy (GDMT) and the occurrence of side effects in Heart Failure with reduced Ejection Fraction (HFrEF)

Abstract Background The ESC Guidelines recommend early, full-dose use of heart failure (HF) medications to enhance survival, but real-world application often faces delays and inconsistencies. Clinicians often fear side effects during up-titration to the recommended target dose (TD), i.e. hypotension, bradycardia, renal impairment, and hyperkalemia (HK). The dependency of side effects during dose escalation from the severity of HF remains unclear. Purpose This study aimed to evaluate the relationship between the occurrence of side effects during up-titration of HF medication and HF severity reflected by N-terminal pro B-type natriuretic peptide (NT-proBNP). Methods 425 patients with HFrEF and a complete data set of patient characteristics, medications and laboratory values at baseline (BL), 2 months (2M), and 6 months (6M) were included from our outpatient HF unit's prospective registry. Significant side effects were defined as: systolic blood pressure (SBP) <90mmHg, heart rate (HR) <50 beats per minute (bpm), potassium (K) >5.0mmol/l or K >5,5mmol/l and estimated glomerular filtration rate (eGFR) <30ml/min/1.73m2. Patients were categorized into three risk groups based on their NT-proBNP levels, i.e. low-risk with NT-proBNP <1000pg/ml, medium-risk with NT-proBNP 1000-2000pg/ml or high-risk with NT-proBNP >2000pg/ml. The occurrence of side effects was recorded and the development compared among the HF risk groups. Results Figure 1 shows up-titration of HF medication. Mean daily dosages of betablockers (BB), mineralocorticoid receptor antagonists (MRA) and renin-angiotensin-system inhibitors (RASi) increased significantly during follow-up (BL vs 2M and BL vs 6M, p<0.001 for all). The majority of patients received ≥50% of the recommended TDs at 6M (89% for BB, 83% for MRA, 88% for RASi and 91% for total mean TDs ≥50%), and the achieved daily dosages at 6M were largely comparable across the HF risk groups at 6M, except for RASi (p=0.030). Figure 2 depicts the side effects. Side effects developed almost exclusively at short-term within 2M except for lower SBP (Figure 2A). Newly developed side effects occurring after up-titration (2B) were even more rare and predominantly occurred within the highest NT-proBNP group. The occurrence of hypotension and bradycardia was infrequent and comparable within the HF risk groups. Renal dysfunction (at 6M p=0,041) and HK occurred predominantly in higher risk patients (HK at 2M p=0,001 and at 6M p<0,001). Conclusions Up-titration of HF medications is highly feasible, particularly in low- and medium-risk patients. Despite rare side effects such as hyperkalemia and renal impairment, up-titration remains unimpeded, especially in patients with NT-proBNP levels below 2000pg/ml. These findings emphasize the safety of up-titration in HF.