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  • Cardiovascular risk in chronic kidney disease
    (2024) Ha, Jeffrey
    Thesis
    Background A high burden of cardiovascular disease in chronic kidney disease (CKD) confers an increased risk of adverse cardiovascular events and mortality. However, compared with atherosclerotic cardiovascular disease, elevated risk of nonatherosclerotic cardiovascular events such as atrial fibrillation (AF) and heart failure is underappreciated and understudied in CKD. Optimal strategies for recognising and mitigating these risks in CKD are limited. This requires systematic evaluation of risk profiles and therapeutic interventions to manage cardiovascular risk across the spectrum of CKD. Aims The overarching aim of this thesis is to generate high-quality evidence to guide risk stratification and management of cardiovascular disease in CKD by: 1. improved delineation of markers for CKD (albuminuria and estimated glomerular filtration rate [eGFR]) as independent risk factors for incident AF and heart failure; and, 2. systematic evaluation of the cardiovascular risk-benefit profiles of newer therapeutic interventions across the range of kidney function, including kidney failure requiring dialysis. Methods The research program was divided into two themes: 1. Cardiovascular risk evaluation through: i. a systematic review to investigate the association of eGFR and urine albumin-to-creatinine ratio (UACR) with risk of incident AF (38 studies, 28,470,249 participants with 530,041 incident AF cases); and, ii. an observational study to analyse the independent association and interaction of albuminuria and kidney function with risk of hospitalisation for heart failure (HHF) or cardiovascular death, in a post hoc analysis of participant-level data pooled from randomised controlled trials (RCTs) involving 14,434 participants with type 2 diabetes (T2D) 2. Evaluation of treatments through: i. a systematic review and meta-analysis of RCTs assessing the benefits and risks of oral anticoagulants in CKD, including dialysis-dependent kidney failure (45 trials, 34,082 participants); and, ii. a binational population-based study assessing safety (risk of bleeding) and effectiveness (risk of all-cause death or stroke) of rivaroxaban versus warfarin across a broad range of kidney function in 55,568 adults with AF; and, iii. a systematic review and meta-analysis of RCTs assessing cardiovascular safety of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) compared with ESA (erythropoiesis stimulating agent) or placebo in patients with dialysis-dependent and non-dialysis CKD (25 trials, 26,478 participants). Results This thesis has demonstrated an exposure-dependent association between the markers of CKD and increased risk of incident AF, and in T2D, increased risk of HHF or cardiovascular death. It has systematically defined the progressive increase in risk of incident AF with lower eGFR and higher albuminuria, independent of established cardiovascular risk factors. Patients with a combination of both lower eGFR and higher albuminuria were also at a multi-fold greater risk of HHF or cardiovascular death. Direct oral anticoagulants (DOACs) demonstrated a benefit–risk profile superior to vitamin K antagonists (VKAs) in early-stage CKD. For advanced CKD or end-stage kidney disease (ESKD), there was limited trial evidence to establish benefits or harms of either VKAs or DOACs. Instead, observational data showed that the safety and effectiveness of the DOAC rivaroxaban compared with warfarin was consistent across a broad range of kidney function in adults with AF. Long-term cardiovascular safety of HIF-PHIs and ESAs was comparable in adults with dialysis-dependent and non-dialysis CKD. Effective strategies to reduce cardiovascular risk in advanced CKD and ESKD are limited, identifying a critical evidence gap that should be the focus of further research. Conclusions Our findings support the utility of markers for CKD to identify individuals at high risk of incident AF, and in patients with T2D, increased risk of HHF or cardiovascular death. This research shows that eGFR and UACR should be routinely included in cardiovascular risk assessment. Certainty of evidence for interventions to manage cardiovascular risk varies according to CKD severity. Our findings suggest that DOACs should be the treatment of choice for patients with AF and non-dialysis CKD, with low-certainty evidence that DOACs may have an acceptable risk-benefit profile in patients with dialysis-dependent ESKD. HIF-PHIs are an acceptable alternative to ESAs in patients with dialysis-dependent ESKD for the treatment of anaemia, and in non-dialysis CKD they are also a reasonable treatment option. Thus, this thesis has generated high-quality evidence to guide cardiovascular risk management in CKD and support future trials.