Health Status After Switching Angiotensin-converting Enzyme Inhibitors or Angiotensin Receptor Blockers to Sacubitril-valsartan in Patients With Heart Failure With Reduced Ejection Fraction From Rural Tanzania: An Interventional Study

Background Non-communicable diseases (NCDs) cause more than 40 million deaths globally each year, and more than three quarters of them occur in low- and middle-income countries. The majority of deaths are caused by cardiovascular diseases, such as heart failure and stroke. Mortality from heart failure has been reported to be highest in Africa, with a one-year mortality rate of 34% compared to 16.5% in other low- and middle-income countries. Arterial hypertension is the most common underlying risk factor for heart failure in sub-Saharan Africa, also in rural areas. Patients mostly present in advanced stages of heart failure, and are not under regular treatment. International guidelines recommend diuretics, angiotensin- converting enzyme (ACE) inhibitors or angiotensin-neprilysin inhibitors (ARNI), angiotensin 2 receptor blockers (ARB), if ACE-inhibitors are not tolerated, beta-blockers, mineralocorticoid receptor antagonists, and sodium glucose co- transporter 2 (SGLT-2) inhibitors for treatment of chronic heart failure with reduced ejection fraction. An intensive treatment strategy with rapid up-titration of guideline-directed chronic heart failure therapy after acute heart failure reduces symptoms, improves quality of life, reduces the risk for all cause death, and is well tolerated. The PARADIGM trial showed that, if enalapril 10mg twice daily for at least 2 weeks was switched to sacubitril/valsartan in symptomatic patients with a left ventricular ejection fraction (LVEF) of ≤40% who had been under a stable heart failure therapy for at least 4 weeks, the combined endpoint of death and hospitalization for heart failure was significantly reduced from 26.5% to 21.8% compared to if the ACE inhibitor was continued. In the CHAMP-HF, a multicenter observational study of American outpatients with heart failure with reduced ejection fraction (HFrEF), 35.8% patients initiated on ARNI had a large (10 to <20 points) or very large (20 points and more out of 100) improvement in their health status expressed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score measured by the KCCQ-12 short version over a median (IQR) of 10.7 (6.7 -11.7) months of follow up, vs 27.5% of patients not initiated on ARNI. Among patients with HFrEF who were hospitalized for acute decompensated heart failure, the initiation of sacubitril/valsartan therapy led to a greater reduction in the N-terminal pro brain natriuretic peptide (NT-proBNP) blood concentration than enalapril therapy. One study could not detect any racial and ethnic differences in reduction of NT-proBNP, improvement in health status, and reverse remodeling in patients with systolic heart failure treated with sacubitril/valsartan. In patients with salt-sensitive hypertension, sacubitril/valsartan was superior to valsartan in office- and ambulatory blood pressure control, and was associated with an increased natriuresis and diuresis. Moreover, sacubitril-valsartan had a positive effect on glycemic control of heart failure patients with diabetes mellitus. It had similar effect on kidney function and albuminuria in patients with chronic renal failure compared to irbesartan.

In the PARADIGM trial, participants were recruited also in South Africa. However, none of the other studies were done in Africa, and the efficacy and safety of sacubitril/valsartan has never been studied in African patients outside South Africa. Sacubitril/valsartan is registered in Tanzania under the product name Uperio®.

The investigators hypothesize that the switch from a well-dosed ACE inhibitor or ARB to sacubitril/valsartan leads to an improvement of the health status, to an increase in the 6-minute walking distance, and to a reduction of the brain natriuretic peptide (BNP) blood concentration, in symptomatic patients with heart failure with reduced ejection fraction (HFrEF) from sub-Saharan Africa who are under a stable chronic heart failure therapy.

Setting The study will be conducted at the St Francis Regional Referral Hospital, Ifakara. This hospital is a referral center for a population of about 1 million people living in the Kilombero valley in rural Tanzania. Since 2021, a Heart and Lung Clinic has been annually serving 5000 patients with heart - or lung diseases. Comprehensive echocardiography, electrocardiography, lung ultrasound, and laboratory tests are done on a routine basis by a trained team. A patients cohort including more than 800 patients has been established. Sacubitril/valsartan is not prescribed yet for patients attending the clinic. The laboratory of the hospital offers chemistry including the measurement of serum-BNP routinely. There is an oxygen plant, an emergency department managing 90'000 patients per year, and a high dependency unit caring for 500 patients per year in this hospital.

Sample size Sample size calculation is based on findings from Thomas et al. (10) which reported that 35.8% of patients receiving ARNI experienced a large (≥10-points) or very large (≥20-points) improvement in the KCCQ summary score, compared to 27.5% of patients not initiated on ARNI therapy. Given the assumption of a null-hypothesis proportion of 0.275 and a Type I error rate of 0.05, and assuming a true proportion of 0.358, a sample size of 238 participants is required to achieve 80% power for a onesample z-test for a single proportion. In order to account for an estimated 25% rate of mortality and loss to follow-up, a maximum of 60 additional participants will beincluded for a total of 298 in order to reach the sample size of 238 evaluable participants.