Background: Renin-angiotensin-aldosterone system inhibitors (RAASi) are known to have cardio-renal protective benefits for chronic heart failure (HF) patients. Previous studies have characterised patterns in adverse clinical outcomes associated with sub-optimal RAASi dosing, such as mortality and hospitalisation.
Purpose: To characterise the relationship between RAASi dosing and mortality and major adverse cardiovascular event (MACE) risk in HF patients.
Methods: Primary care data from the UK Clinical Practice Research Datalink (CPRD) were used to identify patients with a HF diagnosis from Jan 2006 to Dec 2015. Patients with a history of HF or chronic kidney disease stage 3+ prior to this period were excluded. RAASi therapies included angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs). Patient-time spent on RAASi therapies was divided into 90-day intervals and mean dose in each interval was calculated across RAASi therapies, expressed as a percentage of the total European Society of Cardiology (ESC) guideline-recommended maintenance dose. Clinical outcomes of interest included all-cause mortality and MACE, a composite of arrhythmia, heart failure, myocardial infarction, and stroke. Generalized Estimating Equations were used to estimate adjusted odds ratios (ORs) relating RAASi dosage to mortality and MACE, respectively, whilst controlling for confounders, including patient demographics, clinical measurements (e.g. estimated glomerular filtration rate), and concomitant medications.
Results: Data were available for 13,113 patients with mean age of 72.5 years (SD =13.10), of whom 59.6% were male, 16.2% had diabetes, 11.8% with history of myocardial infarction, and 6.6% with history of stroke. Over the study follow-up period (mean 5.1 years), 9,293 (70.9%), 2,344 (17.9%) and 4,179 (31.9%) patients were in receipt of ACEi, ARBs and/or MRAs, respectively. A total of 2,807 deaths and 14,402 MACE events were recorded giving a crude mortality rate of 8.1 per 100 patient-years and a crude MACE rate of 41.4 per 100 patient-years. After adjusting for potential confounding factors, the OR was 4.70 (p<0.0001) for mortality comparing patients on <50% with those on ≥50% of the ESC-recommended RAASi dose; the adjusted OR for MACE was 1.75 (p<0.0001) for patients prescribed <50% of the ESC-recommended RAASi dose compared to those prescribed ≥50%.
Conclusion: This real-world analysis of HF patients on ESC guideline-recommended RAASi therapies suggests associations between sub-optimal RAASi dose and increased risk of mortality and MACE. These results highlight the potentially negative impact of sub-optimal RAASi dosing, and the need for therapies that allow HF patients to be maintained on optimised guideline-recommended RAASi treatments.