Heart failure and anemia in Sub-Saharan Africa: etiology, characterization, prognosis and the role of oral iron – experiences from Tanzania

Abstract: Background: Heart failure remains unexplored in sub-Saharan Africa. Comorbidities such as anemia and iron deficiency are common and associated with increased mortality. Oral iron supplementation may be feasible in heart failure in countries with limited health care resources. Objectives: 1. To describe the contemporary etiology, clinical characteristics, prognosis and prognostic predictors in patients with heart failure in Tanzania. 2. To determine the prevalence, correlates and prognostic implications of anemia and iron deficiency in patients with heart failure in Tanzania. 3. To compare patients with heart failure in Tanzania and Sweden, with regard to (1) clinical characteristics and utilization of heart failure therapy and (2) prognosis and its predictors. 4. To determine if 90 days of a fixed-dose oral iron sulphate supplementation on top of standard therapy in patients with heart failure and iron deficiency results in an improvement in serum ferritin and other hematological and cardiovascular parameters. Study I: Etiology, clinical characteristics and prognosis in Tanzanian heart failure patients The Tanzania heart failure (TaHeF) study was a prospective observational study conducted at Jakaya Kikwete Cardiac Centre of the Muhimbili National Hospital in Dar es Salaam, Tanzania. Patients ≥18 years of age with heart failure defined by the Framingham criteria were included and the main outcome measure was all-cause mortality. The study comprised 427 patients of whom 217 (51%) were females and the mean (standard deviation) age was 55 (17) years. Heart failure etiologies included hypertension (45%), cardiomyopathy (28%), rheumatic heart disease (12%) and ischemic heart disease (9%). The mortality rate, 22.4/100 person-years of observation over a median follow-up of 7 months, was independently associated with presence of atrial fibrillation, hazard ratio (HR) 3.4 (95% confidence interval [CI] 1.6-7.0); in-patient status, HR 3.2 (95% CI 1.5-6.8); anemia, HR 2.3 (95% CI 1.2-4.5); pulmonary hypertension, HR 2.1 (95% CI 1.1-4.2); creatinine clearance, HR 0.98 (95% CI 0.97-1.00); and lack of formal education, HR 2.3 (95% CI 1.3-4.2). Study II: Prevalence and prognostic implications of iron deficiency and anemia in heart failure in Tanzania The design and patient material were the same as in study I. The main outcome measure was a composite of time to hospitalization for heart failure or death. The prevalence of anemia was 57%. The overall prevalence of iron deficiency was 49% distributed as 69% vs. 21% in subjects with and without anemia (p<0.001). The one-year survival free from a composite of hospitalization for heart failure or death was 70%. The presence of iron deficiency anemia increased the likelihood for outcome measure (HR 2.67, 95% CI 1.4-5.1). Anemia without iron deficiency did not influence the risk. Study III: Characteristics and prognosis of patients with heart failure in Tanzania and Sweden This was a prospective study in which the patients from the TaHeF study (Study I) were compared with patients from the Swedish heart failure registry (SwedeHF). Patients from TaHeF (n=427) and SwedeHF (n=51,060) were initially compared in unmatched cohorts. Another comparison was made after matching 1:3 by gender and age ±5 years (TaHeF n=411 vs. SwedeHF n=1232). The primary outcome was time to all-cause mortality. In the unmatched cohorts the TaHeF patients were younger (age [interquartile range; IQR] 55 [40- 68] vs. 77 [64-84] years; p<0.001) and more commonly women (51 vs. 40%; p<0.001). The three-year survival was 61% in both cohorts. In the matched cohorts, TaHeF patients had more hypertension (47 vs. 37%; p<0.001) and more anemia (57 vs. 9%; p<0.001). Their left ventricular ejection fraction (LVEF) was more frequently preserved and heart failure more advanced and of longer duration. Beta-blockers were less frequently used in Tanzania. The crude mortality was worse in TaHeF (HR 2.25, 95% CI 1.78-2.85; p<0.001) with a three-year survival of 61 vs. 83%. However, following multivariable adjustment, the risk was similar (HR 1.07, 95% CI 0.69-1.66; p=0.760). In both cohorts, preserved LVEF was associated with higher mortality than reduced LVEF in the crude but not in the adjusted analyses. Study IV: Oral iron improves serum ferritin in patients with heart failure and iron deficiency: A single-arm clinical trial within the Tanzania heart failure study This was a prospective, single-arm clinical trial which included patients aged ≥18 years with stable symptomatic (NYHA II-IV) heart failure, hemoglobin 8-15g/dl, and iron deficiency, defined as serum ferritin level <100 ng/mL or 100-299 ng/mL with concurrent transferrin saturation <20%. Oral ferrous sulphate was administered at dose of 200 mg three times per day during 90 days. A total of 237 patients were screened of whom 102 met inclusion criteria (54% males; mean age ± SD 58 ± 16 years). In 97 patients who completed follow-up, the mean (± SD) ferritin level improved from 123±70 ng/mL at baseline to 255±143 ng/mL after 90 days of treatment (+107%; p<0.001), hemoglobin from 11.7±2 to 12.3±2g/dL (+5%; p<0.001), 6MWT distance from 543±148 to 574±166 meters (+6%; p<0.001), LVEF from 37.8±12.2 to 44.5±10.7% (+17%; p<0.001) and NT-proBNP from 986±774 to 582±503 ng/L (-41%; p<0.001). Conclusions: Patients with heart failure in Tanzania were younger than their counterparts from the developed world. Hypertension was the leading cause of heart failure in Tanzania, unlike in Sweden and other developed countries where ischemic heart disease is predominant. This calls for the need for early detection and treatment of hypertension. Even after age and gender matching, patients in Tanzania had more severe heart failure and worse crude but similar adjusted prognosis. Independent and modifiable predictors of mortality were anemia, atrial fibrillation and lack of education. Iron deficiency anemia, common in Tanzanian heart failure patients, was independently associated with a poor prognosis. Oral iron supplementation was sufficiently absorbed to replenish serum ferritin in Sub-Saharan patients with heart failure. It was associated with improved hemoglobin, 6MWT distance, LVEF and NT-proBNP.