Methods
swelling, edema, anemia, angioedema, hyperkalemia, hypotension, hypersensitivity, renal dysfunction
ADVERSE EVENTS, EDEMA, ANEMIA, ANGIOEDEMA, CARDIOVASCULAR DISEASES, HEART, HYPERSENSITIVITY
This study was designed as an open label non-randomized clinical trial being conducted in the Adult Cardiology Department of National Institute of Cardiovascular Diseases (NICVD), Karachi, Pakistan during January 2021 to June 2021. The sample for this study was calculated to be n = 121, keeping the confidence level at 95% and a 7% margin of error with anticipated treatment success of 81.1% [In clinical trial was performed in accordance with the Declaration of Helsinki, study was started after obtaining approval from ethical review committee of NICVD (ERC-05/2020) and written informed consent was obtained from all the patients regarding their participation in the study and publication of data while maintaining confidentiality and anonymity. This clinical trial was registered at ClinicalTrial.gov with NCT05387967. The required number of consecutive patients meeting the inclusion criteria were recruited for this study. After obtaining written informed consent, patient’s demographic and baseline clinical characteristics were obtained. Inclusion criteria for the study are either gender, between 18 and 80 years of age, diagnosed with HFrEF with New York Heart Association (NYHA) class II-IV, and left ventricular ejection fraction (LVEF) ≤ 40%. Pre-inclusion safety parameter were patients who were stable on any dose of beta blockers, ACEI or ARB prior to enrolment in the study. Patients who refused to participate in the study or patients with hyperkalemia (baseline potassium > 5.2 mmol/L), hypotension (baseline systolic blood pressure (SBP) < 90 mmHg), renal dysfunction (baseline estimated glomerular filtration rate (eGFR) < 30 mL/min), anemia (hemoglobin level: < 13.5 g/dL in men and < 12.0 g/dL in women), and history of hypersensitivity to the active substances, Sacubitril/Valsartan, or to any of the excipients or drugs of similar chemical classes were excluded from the study (Fig. Study flow chart. All the recruited patients were prescribed with Sacubitril/Valsartan at a starting dose of 50 (24/26) mg BID which was up-titrated, over the period of initial 6 weeks, to the maximum tolerated dose up to 200 (97/103) mg BID and further followed for a total of 12 weeks. A weekly telephonic follow-up was made to assess the patient’s medication adherence level and any adverse events. All the patients were kept under a close follow-up for the period of 12 weeks, the safety and tolerability outcomes were assessed.Safety parameters included incidence of any of the following during 12 weeks of follow-up period; hypotension (SBP < 90 mmHg), renal dysfunction (eGFR < 30 mL/min), hyperkalemia (potassium > 5.2 mmol/L), and angioedema (rapid edema, or swelling, of the area beneath the skin or mucosa). Tolerability was defined as the dose tolerated by the patients which did not require down titration or discontinuation of prescribed dose during follow-up with the frequency of follow-up after 1st week, 2nd week, 4th week, 8th week, and 12th week. Functional status of all the patients was also assessed as NYHA functional class on every follow-up week. Echocardiography was performed, at baseline as well as at 12th week follow-up, and improvement in left ventricular ejection fraction, systolic, and diastolic dimension were evaluated.All the collected information was recorded using a predefined structural proforma. Collected data were analyzed using SPSS version-21 (IBM Corp). Mean ± standard deviation (SD) were computed for the quantitative (continuous) variables, such as hemodynamic parameters, laboratory parameters, and echocardiographic parameters, and paired samples t-test was conducted to compare baseline with 12th week assessments. NYHA classification before and at the end of 12-weeks therapy was compared with the help of Chi-square test. Frequency and percentages were calculated for categorical variables such as tolerability and safety measures and Chi-square test/ Fisher's exact test were applied for the compare the results for various baseline characteristics of the patients.