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Mineralocorticoid receptor antagonists in heart failure: exploring the gap between guideline-directed medical therapy and real-world practice
Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.ORCID-id: 0000-0001-9319-0242
2021 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå Universitet , 2021. , s. 74
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2154
Nyckelord [en]
Heart failure, Mineralocorticoid receptor antagonists, estimated glomerular filtration rate, hyperkalemia, impaired renal function, worsening renal function, guideline-directed medical therapy
Nationell ämneskategori
Kardiologi
Forskningsämne
kardiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-189161ISBN: 978-91-7855-651-9 (digital)ISBN: 978-91-7855-650-2 (tryckt)OAI: oai:DiVA.org:umu-189161DiVA, id: diva2:1609066
Disputation
2021-12-03, Bergasalen / Zoom, Norrlands Universitetssjukhus, 901 85, Umeå, 09:00 (Svenska)
Opponent
Handledare
Anmärkning

Oregelbunden paginering

Tillgänglig från: 2021-11-12 Skapad: 2021-11-05 Senast uppdaterad: 2021-12-06Bibliografiskt granskad
Delarbeten
1. Obstacles to mineralocorticoid receptor antagonists in a community-based heart failure population
Öppna denna publikation i ny flik eller fönster >>Obstacles to mineralocorticoid receptor antagonists in a community-based heart failure population
2018 (Engelska)Ingår i: Cardiovascular therapeutics, ISSN 1755-5914, Vol. 36, nr 5, artikel-id e12459Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

AIM: Previous studies and national assessments indicate an undertreatment of mineralocorticoid receptor antagonists (MRA) in heart failure with reduced ejection fraction (HFrEF). This study aimed to investigate why MRA is not used to full extent.

METHODS: A complete community-based heart failure population was studied. Several variables were collected, and medical records were scrutinized to identify reasons for not prescribing MRA.

RESULTS: Of 2029 patients, 812 had EF ≤40%. Five hundred and fifty-three patients (68%) tried MRA at some point but 184 of these (33%) discontinued therapy. There were 259 patients that never tried MRA with 177 with a listed explanation or contraindication. Eighty-two patients, 10% of the total HFrEF population, had no clear contraindications. They were older and had less HF hospitalizations compared to patients on MRA (P < 0.05) and 32% did not have any follow-up at the cardiology clinic. Contraindications to MRA were renal dysfunction (93 patients), hypotension (28 patients), and hyperkalemia (25 patients). Only six patients had hyperkalemia without renal dysfunction. Of the patients with renal dysfunction, 66 (72%) had eGFR >30 mL/min.

CONCLUSIONS: The reasons why MRA are underutilized were mainly because of contraindications. However, the data suggest that physicians are overly cautious about moderately reduced kidney function. There seems to be a 10%-18% avoidable undertreatment with MRA, especially for elderly patients that are admitted to the hospital for other reasons than heart failure. This suggests that patients with heart failure would benefit from routine follow-up at a cardiology clinic.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2018
Nyckelord
heart failure, heart failure with reduced ejection fraction, mineralocorticoid receptor antagonist, undertreatment
Nationell ämneskategori
Kardiologi
Forskningsämne
medicin; kardiologi
Identifikatorer
urn:nbn:se:umu:diva-151506 (URN)10.1111/1755-5922.12459 (DOI)000444410000008 ()30019390 (PubMedID)2-s2.0-85052519095 (Scopus ID)
Tillgänglig från: 2018-09-06 Skapad: 2018-09-06 Senast uppdaterad: 2021-11-09Bibliografiskt granskad
2. Comparison of creatinine-based methods for estimating glomerular filtration rate in patients with heart failure
Öppna denna publikation i ny flik eller fönster >>Comparison of creatinine-based methods for estimating glomerular filtration rate in patients with heart failure
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2020 (Engelska)Ingår i: ESC Heart Failure, E-ISSN 2055-5822, Vol. 7, nr 3, s. 1150-1160Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Aims: Glomerular filtration rate is an important factor in management of heart failure (HF). Our objective was to validate eight creatinine-based equations for estimating glomerular filtration rate (eGFR) in an HF population against measured glomerular filtration rate.

Methods and results: One hundred forty-six HF patients (mean age 68 +/- 13 years, mean left ventricular ejection fraction 45% +/- 15) within a single-centre hospital that underwent Cr-51-EDTA clearance between 2010 and 2018 were included in this retrospective study. eGFR was estimated by means of Cockcroft-Gault ideal and actual weight, the Modification of Diet in Renal Disease Study (MDRD), simplified MDRD with isotope dilution mass spectroscopy traceable calibration, the Chronic Kidney Disease Epidemiology Collaboration, revised Lund-Malmo, full age spectrum, and the Berlin Initiative Study 1. Mean measured glomerular filtration rate was 42 mL/min/1.73 m(2). Pearson's correlation coefficient (r) had the highest precision for MDRD (r = 0.9), followed by revised Lund-Malmo (r = 0.88). All equations except MDRD (mean difference -4.8%) resulted in an overestimation of the renal function. The accuracy was below 75% for all equations except MDRD.

Conclusions: None of the exclusively creatinine-based methods was accurate in predicting eGFR in HF patients. Our findings suggest that more accurate methods are needed for determining eGFR in patients with HF.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2020
Nyckelord
Heart failure, Renal function, Estimated glomerular filtration rate, Creatinine
Nationell ämneskategori
Kardiologi
Identifikatorer
urn:nbn:se:umu:diva-168959 (URN)10.1002/ehf2.12643 (DOI)000513015500001 ()32052932 (PubMedID)2-s2.0-85079448295 (Scopus ID)
Forskningsfinansiär
Cancerforskningsfonden i Norrland
Tillgänglig från: 2020-04-01 Skapad: 2020-04-01 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
3. Motives, predictors, and outcomes of MRA discontinuation in a real-world heart failure population
Öppna denna publikation i ny flik eller fönster >>Motives, predictors, and outcomes of MRA discontinuation in a real-world heart failure population
Visa övriga...
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Kardiologi
Forskningsämne
kardiologi
Identifikatorer
urn:nbn:se:umu:diva-189142 (URN)
Tillgänglig från: 2021-11-04 Skapad: 2021-11-04 Senast uppdaterad: 2021-11-09
4. Mineralocorticoid receptor antagonists use in patients with heart failure and impaired renal function
Öppna denna publikation i ny flik eller fönster >>Mineralocorticoid receptor antagonists use in patients with heart failure and impaired renal function
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2021 (Engelska)Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 16, nr 10, artikel-id e0258949Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Aims: Impaired renal function is a major contributor to the low proportion of mineralocorticoidreceptor antagonist (MRA) treatment in patients with heart failure with reduced ejection fraction(HFrEF). Our aims were to investigate the impact of MRA treatment on all-cause mortalityand worsening renal function (WRF) in patients with HFrEF and moderately impairedrenal function.

Methods: Retrospective data between 2010–2018 on HFrEF patients from a single-centre hospitalwith estimated glomerular renal function (eGFR) < 60 ml/min/1.73 m2 were analysed. WRF was defined as a decline of by eGFR > 20%.

Results: 416 patients were included, 131 patients on MRA and 285 without MRA, mean age was 77years (SD ± 9) and 82 years (SD ± 9), respectively. Median follow-up was 2 years. 128patients (32%) experienced WRF, 25% in the MRA group and 30% in patients without MRA(p = 0.293). In multivariable analysis, hospitalization for heart failure and systolic blood pressurewere associated with WRF (p = 0.015 and p = <0.001), but not use of MRA (p = 0.421).MRA treatment had no impact on the risk of adjusted all-cause mortality (HR 0.93; 95% CI,0.66–1.32 p = 0.685). WRF was associated with increased adjusted risk of all-cause mortality(HR 1.43; 95% CI, 1.07–1.89 p = 0.014). Use of MRA did not increase the adjusted overallrisk of mortality even when experiencing WRF (HR 1.15; 95% CI, 0.81–1.63 p = 0.422).

Conclusion: In this cohort of elderly HFrEF patients with moderately impaired renal function, MRA didnot increase risk for WRF or all-cause mortality.

Ort, förlag, år, upplaga, sidor
Public Library of Science, 2021
Nyckelord
Heart failure, Mineralocorticoid receptor antagonists, chronic kidney disease, worsening renal function, elderly; mortality
Nationell ämneskategori
Kardiologi
Forskningsämne
kardiologi
Identifikatorer
urn:nbn:se:umu:diva-189136 (URN)10.1371/journal.pone.0258949 (DOI)000755563200050 ()34710128 (PubMedID)2-s2.0-85118245832 (Scopus ID)
Tillgänglig från: 2021-11-04 Skapad: 2021-11-04 Senast uppdaterad: 2023-09-05Bibliografiskt granskad

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