Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study

Ouwerkerk, Wouter; Voors, A.A.; Anker, SD; Cleland, JG; Dickstein, Kenneth; Filippatos, Gerasimos; Harst, Pim van der; Hillege, H. L.; Lang, Chim C.; Maaten, JM ter; Ng, Leong L.; Ponikowski, Piotr; Samani, NJ; Veldhuisen, DJ van; Zannad, Faı̈ez; Metra, Marco; Zwinderman, A. H.

doi:10.1093/eurheartj/ehx026

Cited by 337 publications

(381 citation statements)

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“…5 In particular, combination therapy with renin-angiotensinaldosterone system inhibitor (RAASi) and/or mineralocorticoid receptor antagonist (MRA) agents, while recommended to reduce the incidence of hospitalization, 5 may further increase the risk of hyperkalaemia in this already-vulnerable population. [8][9][10] At present, the clinical burden of hypokalaemia and hyperkalaemia among European HF patients, and relationships between serum potassium and adverse clinical outcomes in this population, is not well characterized. [8][9][10] At present, the clinical burden of hypokalaemia and hyperkalaemia among European HF patients, and relationships between serum potassium and adverse clinical outcomes in this population, is not well characterized.…”

Section: Introductionmentioning

confidence: 99%

Serum potassium and clinical outcomes in heart failure patients: results of risk calculations in 21 334 patients in the UK

et al. 2019

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Aims At present, the clinical burden of hypokalaemia and hyperkalaemia among European heart failure patients, and relationships between serum potassium and adverse clinical outcomes in this population, is not well characterized. The aim of this study was to investigate associations between mortality, major adverse cardiac events, and renin–angiotensin–aldosterone system inhibitor (RAASi) discontinuation across serum potassium levels, in a UK cohort of incident heart failure patients. Methods and results This was a retrospective observational cohort study of newly diagnosed heart failure patients listed in the Clinical Practice Research Datalink, with a first record of heart failure (index date) between 2006 and 2015. Hypokalaemia and hyperkalaemia episodes were defined as the number of serum potassium measurements exceeding each threshold (<3.5, ≥5.0, ≥5.5, and ≥6.0 mmol/L), without such a measurement in the preceding 7 days. Risk equations developed using Poisson generalized estimating equations were utilized to estimate adjusted incident rate ratios (IRRs) relating serum potassium and clinical outcomes (death, major adverse cardiac event, and RAASi discontinuation). Among 21,334 eligible heart failure patients, 1969 (9.2%), 7648 (35.9%), 2725 (12.8%), and 763 (3.6%) experienced episodes of serum potassium <3.5, ≥5.0, ≥5.5, and ≥6.0 mmol/L, respectively. The adjusted IRRs for mortality exhibited a U‐shaped association pattern with serum potassium. Relative to the reference category (4.5 to <5.0 mmol/L), adjusted IRRs for mortality were estimated as 1.98 (95% confidence interval: 1.69–2.33), 1.23 (1.12–1.36), 1.35 (1.14–1.60), and 3.02 (2.28–4.02), for patients with serum potassium <3.5, ≥5.0 to <5.5, ≥5.5 to <6.0, and ≥6.0 mmol/L, respectively. The adjusted IRRs for major adverse cardiac events demonstrated a non‐statistically significant relationship with serum potassium. Discontinuation of RAASi therapy exhibited a J‐shaped trend in association with serum potassium. Compared with the reference category (4.5 to <5.0 mmol/L), adjusted IRRs were estimated as 1.07 (0.89–1.28) in patients with serum potassium <3.5 mmol/L, increasing to 1.32 (1.14–1.53) and 2.19 (1.63–2.95) among those with serum potassium ≥5.5 to <6.0 and ≥6.0 mmol/L, respectively. Conclusions In UK patients with new onset heart failure, both hypokalaemia and hyperkalaemia were associated with increased mortality risk, and hyperkalaemia was associated with increased likelihood of RAASi discontinuation. Our results demonstrate the potential importance of serum potassium monitoring for heart failure outcomes and management.

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Section: Introductionmentioning

confidence: 99%

Serum potassium and clinical outcomes in heart failure patients: results of risk calculations in 21 334 patients in the UK

et al. 2019

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“…β-blockers and AngII receptor inhibitors have become widely used and effective cardiovascular medicines (Liao et al, 2004; Ouwerkerk et al, 2017). In the present study, we found that LPA 3 deficiency led to reduced cardiac function and increased infarct size after MI.…”

Section: Discussionmentioning

confidence: 99%

Protective Role for LPA3 in Cardiac Hypertrophy Induced by Myocardial Infarction but Not by Isoproterenol

et al. 2017

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Background: We previously reported that lysophosphatidic acid (LPA) promoted cardiomyocyte hypertrophy in vitro via one of its G protein-coupled receptor subtypes, LPA3. In this study, we examined the role of LPA3 in cardiac hypertrophy induced by isoproterenol (ISO) and myocardial infarction.Methods: In vitro, neonatal rat cardiomyocytes (NRCMs) were subjected to LPA3 knocked-down, or pretreated with a β-adrenergic receptor (β-AR) antagonist (propranolol) before LPA/ISO treatment. Cardiomyocyte size and hypertrophic gene (ANP, BNP) mRNA levels were determined. In vivo, LPA3-/- and wild-type mice were implanted subcutaneously with an osmotic mini-pump containing ISO or vehicle for 2 weeks; echocardiography was performed to determine the heart weight/body weight ratio, cardiomyocyte cross-sectional area, and level of ANP mRNA expression. LPA3-/- and wild-type mice were subjected to permanent coronary artery ligation or sham surgery for 4 weeks; cardiac function, including the degree of hypertrophy and infarction size, was determined.Results: In vitro, we found that knocked-down LPA3 in NRCMs did not attenuate ISO-induced hypertrophy, and propranolol was unable to abolish LPA-induced hypertrophy. In vivo, chronic ISO infusion caused cardiac hypertrophy in wild-type mice, while hypertrophic responses to ISO infusion were not attenuated in LPA3-/- mice. However, in a myocardial infarction (MI) model, LPA3-/- mice exhibited reduced cardiac hypertrophy compared to wild-type mice at 4 weeks post-MI, which was associated with reduced cardiac function and increased infarct size.Conclusions: Our data show that LPA3 appears to play a protective role in myocardial hypertrophy post-MI, but does not appear to be involved in the hypertrophy that occurs in response to β-AR stimulation in vivo and in vitro. These results implicate LPA-LPA3 lipid signaling in cardiac hypertrophy occurring after pathological insults like MI, which presents a new variable in β-AR-independent hypertrophy. Thus, modulation of LPA3 signaling might represent a new strategy for preventing the stressed myocardium from ischemia injury.

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“…14 In BIOSTAT-CHF, patients receiving >50 % of recommended doses of ACEIs and BBs had better outcomes than those taking lower doses. 14 Similarly, in the Austrian Heart Failure Registry, improved guideline adherence related to dose escalation towards optimal levels was associated with reduced long-term mortality in ambulatory HFrEF patients surviving 1 year after registration. 15 …”

Section: Clinical Practicementioning

confidence: 91%

Quality of Physician Adherence to Guideline Recommendations for Life-saving Treatment in Heart Failure: an International Survey

Cowie¹,

Komajda²

2017

Cardiac Failure Review

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Access at: www.CFRjournal.com Advances in diagnosis and treatment have improved the outlook for the estimated 26 million patients with heart failure (HF) worldwide, 1 but there remains a continuing need for further reduction in mortality and hospitalisation and the associated social and financial consequences of the disease. In a European study of outcomes after HF hospitalisation, 17 % of patients died within 12 months and 44 % were rehospitalised, 2 and the most recent data from the British National Heart Failure Audit showed in-hospital mortality of 8.9 % and mortality at 1 year of 26.7 % in those surviving to leave hospital. 3 Patients are at greatest risk in the first 30 days after hospitalisation, 4 though there is some evidence that good adherence to HF treatment guidelines may improve clinical outcomes. 5 The latest HF guidelines from the European Society of Cardiology (ESC) recommend key pharmacological therapies for patients with HF with reduced ejection fraction (HFrEF) in order to reduce mortality and hospitalisation. 6 These include angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) if ACEIs are not tolerated, beta blockers (BBs), mineralocorticoid receptor antagonists (MRAs), ivabradine for patients in sinus rhythm with a heart rate ≥70 bpm, and sacubitril/valsartan as a replacement for ACEIs in ambulatory patients with HFrEF who remain symptomatic despite optimal ACEI, BB and MRA treatment (Figure 1). 6 Yet, even when prescription levels of guidelines-based HF treatment are high, patients may fail to reach target doses of potentially lifesaving medicines, 7 and there is some evidence that suboptimal dosing may adversely influence outcomes. 8,9 QUALIFY (QUality of Adherence to guideline recommendations for LIFe-saving treatment in heart failure surveY) was initiated to improve understanding of the impact of physicians' adherence to guideline Physicians' adherence scores and follow-up data have been reported for 6,669 patients with chronic heart failure and left ventricular ejection fraction ≤40 % who had been hospitalised for worsening HF in the previous 1-15 months. 12 Patients were treated at 547 centres in 36 countries in Africa, Asia, Australia, Europe, the Middle East and North, Central and South America (Figure 2). 10,12 Measuring Physicians' AdherenceThe focus of QUALIFY was on physicians' adherence to HF guidelines and did not include patient adherence to prescribed treatment. The adherence score used in QUALIFY was the ratio of the treatment actually prescribed to the treatment that should theoretically have been prescribed. The latter took account of eligibility criteria, guidelines-based contraindications to drugs or treatments and use in ≥50 % of recommended dosages. Target doses were defined by ESC guidelines when available 11 and, in the case of ivabradine, according Abstract QUALIFY (QUality of Adherence to guideline recommendations for LIFe-saving treatment in heart failure surveY) showed that good physician adherence to guideline recommendations ...

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Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study

Abstract: Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%.

Cited by 337 publications

References 52 publications

Serum potassium and clinical outcomes in heart failure patients: results of risk calculations in 21 334 patients in the UK

Serum potassium and clinical outcomes in heart failure patients: results of risk calculations in 21 334 patients in the UK

Protective Role for LPA3 in Cardiac Hypertrophy Induced by Myocardial Infarction but Not by Isoproterenol

Quality of Physician Adherence to Guideline Recommendations for Life-saving Treatment in Heart Failure: an International Survey

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