Mineralocorticoid receptor antagonists in heart failure : exploring the gap between guideline-directed medical therapy and real-world practice

Abstract: Heart failure is the possible end-result of a variety of different diseases, where ischemic heart disease and hypertension are the most common causes in high income countries. In Sweden, heart failure has a prevalence of 2% in the adult population and rises to over 10% among people over 70 years of age. The 5-year all-cause mortality is about 50%. To put in context, the age-adjusted 5-year mortality, first hospitalization rate and premature life-year loss were shown to be similar to those of the most common forms of cancer combined. The triad of Angiotensin-Converting Enzyme Inhibitors (ACEIs) or Angiotensin II Receptor Blockers (ARBs), Beta-blockers (BBs), and Mineralocorticoid Receptor Antagonists (MRAs) are recommended in all patients with heart failure with reduced ejection fraction (HFrEF) to decrease mortality and morbidity rates. While most eligible patients get access to treatment with ACEIs/ARBs and BBs, national and international registry and observational studies have shown that MRA treatment is largely underused in patients with HFrEF. Treatment with MRAs has shown a 15-30% relative risk reduction of all-cause mortality inpatients with HFrEF at a follow-up time of 16 to 24 months, but not even half of all eligible patients receive this treatment. The aim of this theses was to explore the pattern of MRA use in a real-world heart failure population and the reasons for MRA underuse.With an observational retrospective study design, patients were included if they were diagnosed with heart failure at the Heart Centre or Department of Internal Medicine between January 2010 and January 2018. All patients were residents within the catchment area of the Umeå University Hospital, Sweden, and were identified by the hospital’s medical records. All data were collected from medical records. Index data were collected at the time of diagnosis, and follow-up data were collected by the journal entry closest to the end of the data collection period (2016-2018).From the medical record content analysis, we found that contraindications including renal dysfunction, hypotension and hyperkalemia were the most common reasons for not receiving treatment with MRAs. However, almost half of those patients did not meet the guideline-directed contraindications. After excluding patients with contraindications, the underutilization of MRAs was 10%. Patients without MRAs had been hospitalized for heart failure to a much lesser extent. It is possible that this group of patients were often overlooked, which is supported by the finding that nearly one-third of these patients never had a follow-up at the cardiology clinic. Overall, we estimated that about 60% of thepatients with HFrEF would tolerate MRA treatment in the long-term, but only about 45% of the patients with HFrEF in our population were prescribed and maintained on MRAs.Since renal dysfunction was the most common reason for not initiating MRA treatment, we wanted to evaluate how accurate eight different creatinine-based equations for estimated glomerular filtration rate (eGFR) were in heart failure patients. We showed that none of the exclusively creatinine-based equations for eGFR were accurate in predicting mGFR. All creatinine-based eGFR equations overestimated the renal function. Our findings suggests that more accurate methods are needed for determining eGFR in patients with heart failure since overestimation causes an unnecessary risk of serious adverse effects and may also lead to patients not receiving optimal guideline-directed medical therapy.We also found that half of all patients initiated on MRAs discontinued treatment. The most common reasons for discontinuation were renal dysfunction and elevated serum-potassium but again, a majority of those did not meet guideline-directed contraindications. Independent predictors of MRA discontinuation were lower eGFR, increased serum-potassium, lower blood pressure, higher comorbidity index and higher left ventricular ejection fraction. Patients who discontinued MRAs had a higher risk of all-cause mortality after adjusting forrelevant covariates. One-third of all patients with moderately impaired renalfunction developed worsening renal function (WRF) but use of MRAs did not impact the risk. Furthermore, use of MRAs did not increase the adjusted overallrisk of mortality even when experiencing WRF.In conclusion, there seems to be a substantial avoidable under-treatment with MRAs especially for elderly patients that are admitted to the hospital for reasons other than heart failure as well as in patients with moderately impaired renal dysfunction with mild hyperkalemia. We suggest that the risk of inadequate means of follow-up restrains optimal use of MRAs, especially in patients with moderately impaired renal function and or mild hyperkalemia that require frequent and regular laboratory monitoring to assure the safe use of MRAs. In addition, better methods are needed to accurately estimate renal function in heart failure patients. These findings contribute to the understanding of the underlying reasons behind the gap between the guideline-directed use of MRAs and real-world practice.