Predictors of incident heart failure in a cohort of patients with ischemic heart disease

Introduction heart failure (HF) is a major complication following ischemic heart disease (IHD) and it adversely affects the outcome. The objective of this study was to identify predictors of HF in patients with IHD. Methods this is a 24-month longitudinal retrospective study of all consecutive patients diagnosed with IHD. Endpoints were incident HF and time to incident HF. Patients with a previous history of HF were excluded. Results a total of 306 patients with IHD were included in the analysis. The 6-month, 12-month and 18-month cumulative risk of developing incident HF were 18.8%, 28.4%, and 53.5% respectively. Increasing age, female gender, diabetes mellitus (DM), lower hemoglobin, and dilated left atrium were strong predictors of incident HF. Predictors of shorter time to incident HF were coexisting DM and hypertension, and the presence of dilated left atrium in patients with left ventricular ejection fraction < 40%. The strongest predictor of incident HF in patients with DM was a higher level of LDL cholesterol. Conclusion patients with IHD have a higher risk of incident HF. Strong predictors of incident HF in these patients were increasing age, female gender, DM, lower hemoglobin and dilated left atrium. Such patients need close follow-up and more intensive treatment.


Introduction
Ischemic heart disease (IHD) is one of the major underlying causes of heart failure (HF) [1][2][3]. In sub-Saharan Africa, IHD was formerly considered rare, but reports from 2008 indicate that it ranks 8th among the adult leading causes of death in the region. IHD in Ethiopia has also dramatically increased over the last 30 years, from 88 to 960 per 100,000 patients with cardiovascular disease [4][5][6][7]. IHD increases the risk of HF by about 8 times, with a population attributable risk of 65% in men and 48% in women [8]. HF is a clinical syndrome characterized by symptoms of breathlessness, ankle swelling, and fatigue that may be accompanied by signs such as elevated jugular venous pressure, pulmonary crackles and peripheral edema [9].
Although the growing use of coronary artery revascularization procedures and better medical treatment have largely improved the outcome of an acute coronary syndrome, heart failure as a complication of IHD still remains a problem because of a scarcity of resources for proper intervention, particularly in resource-limited settings. Even in settings with coronary revascularization, IHD still remains one of the leading causes of clinical HF onset. The possible mechanisms include loss of functioning myocytes, fibrosis of myocardium, and subsequent remodeling of left ventricular (LV) that adversely affects LV function [10]. Furthermore, the risk of HF may increase from chronic myocardial dysfunction resulting from hypoperfusion/hibernation [11,12]. A clear knowledge of the risk factors or predictors of HF after IHD could guide therapeutic decisions and monitoring by identifying high-risk patients and pursuing more strict treatment and close follow-up in certain subsets. This study aimed to identify predictors of incident HF in a cohort of patients with IHD.

Methods
Study design and clinical setting: this retrospective cohort study was designed to assess all consecutive patients with a diagnosis of IHD coming to Black Lion Specialized and tertiary referral Hospital in Addis Ababa, Ethiopia. The study population was consecutively recruited and enrolled starting from November 30, 2015. A total of 306 adults (age of 18 years and above) IHD patients were included in the cohort and they were followed to measure the outcomes. Each study participant was followed up for 24 months or until the diagnosis of HF was made. Patients with IHD or HF were identified based on the treating Physician's final diagnosis that was made based on symptoms suggestive of IHD or HF. The study was approved by the institutional review board of the College of Health Sciences, Black Lion Hospital, and permission to use de-identified personal healthcare information for all included subjects was obtained. the hazard ratios for predictors of HF. In cases of missing data, the "Exclude cases pair wise" option was used during analysis. A 5% significance level was adopted for all tests and all tests were 2-sided.
Statistical analyses were performed using SPSS 23.0 (IBM).

Results
Baseline characteristics: out of 306 IHD patients without prior HF before November 2015, 64.1% (n= 196) developed HF during the study period, with a follow up of 24 months. Patients who developed HF were older, more often female, diabetic, had lower hemoglobin and bigger left atrium. The proportion of patients taking calcium channel blockers and antidiabetic medications was higher in those who developed HF during follow up compared to those who did not develop HF (Table 1). Comorbidities and risk factors such as hypertension, dyslipidemia, smoking, cerebrovascular accidents, and peripheral arterial diseases were similar between the two groups.
There was no significant difference in baseline left ventricular dimensions, nephropathy and blood pressure parameters between those who developed HF and those who did not develop HF. Although it did not reach statistical significance, patients with IHD who developed HF appear to have a lower level of baseline left ventricular ejection fraction (LVEF) than those who did not develop HF (Figure   1 A). In both patient groups, LVEF appears to be higher in older patients. The 6-month, 12-month and 18-month cumulative risk of developing HF were 18.8%, 28.4%, and 53.5% respectively (Figure

B).
Incident HF and its predictors: increasing age, female gender, DM, lower baseline hemoglobin, LVEF less than 40% and bigger LAD increased the risk of incident HF on bivariate analysis (Table 2). After adjustment, age 66 years and above, female gender, DM, and bigger LAD were associated with an increased risk of incident HF. Age 66 years and above, and DM increased the risk of incident HF by about four-fold.

Predictors of incident HF by DM status: patients with DM who
developed HF were predominantly male and had a significantly higher proportion of advanced HF symptoms (functional class 3-4) and dislipidemia on bivariate analysis when compared to patients with incident HF but no DM. The time to incident HF was also significantly shorter in diabetic patients (Table 3). After adjustment, DM was associated with advanced HF symptoms and dyslipidemia. DM   following IHD [15][16][17]. We also identified female gender and lower hemoglobin as parameters associated with the future risk of incident HF. These have also been shown in other studies. Anemia is clearly associated with increased adverse events including short-term mortality following IHD [13, 18,19]. Furthermore, anemia is common in HF patients due to inflammation, iron deficiency, kidney disease, and use of ACE inhibitors [20]. LVEF less than 40% is also the other predictor for incident HF, similar to the other studies [21]. The other strong predictor of incident HF identified in this study was bigger LA.

Limitations and strengths: This study has some limitations.
Unmeasured confounders or details about a physician or patient decision-making that are not captured by the registry may have accounted for differences in treatments and outcomes. As in any observational study, we cannot rule out the effect of residual confounding due to unmeasured variables. Additionally, preceding HF was identified on a clinical basis but was different from the definition used for the primary endpoint defined appropriately by Framingham criteria. Even though Framingham criteria were not explicitly used by Doctors to determine preceding HF, it is the primary classification employed in our daily practice for the diagnosis of HF. As such, we do not believe that this difference is likely to affect our study results or conclusions. This study has strengths. We examined the role of multiple risk factors including left atrial size and lipid parameters on post-IHD prognosis including subgroups of DM and LVEF.

Conclusion
Many clinical co-morbidities determine the risk for development of HF following IHD. Importantly, older age, gender, DM, left atrial size and LVEF were predictors of incident HF in patients with IHD. In patients with DM, the strongest predictors of incident HF were coexistent HTN and higher LDL cholesterol. While in patients with LVEF < 40%, the presence of dilated LA was a predictor of short time to incident HF.
These findings are vital in assisting the clinician and researcher to identify patients at risk of developing HF. It is also an input for further studies and policy decision making. Patients with risk factors, if identified, may benefit from a close follow-up, more intensive medical treatment and additional interventions including effective intervention strategies such as percutaneous coronary intervention, and coronary artery bypass graft.
What is known about this topic  Heart failure remains a frequent complication of ischemic heart disease despite the use of revascularization in patients with acute coronary syndrome;  Patients with diabetes have a two-to fourfold higher risk of HF than people without diabetes;  The link between diabetes and the development of HF in patients with ischemic heart disease is not fully known.

What this study adds
 The incidence of HF in Ethiopian patients with ischemic heart disease is larger than reports from the other studies;

Competing interests
The author declares no competing interests.

Acknowledgments
This study would not have been possible without the support of the staff Cardiology Division, Black Lion Hospital who participated in data collection. Medical Education Partnership Initiative, Addis Ababa University also deserves gratitude for the modest financial support for the data collection process.