M34 Cardiovascular safety of nintedanib in subgroups by cardiovascular risk at baseline in the tomorrow and inpulsis trials

Abstract

Introduction and AimNintedanib is a tyrosine kinase inhibitor, a drug class that may be associated with increased risk of arterial thromboembolic events. The efficacy and safety of 52 weeks’ treatment with nintedanib versus placebo in patients with IPF were assessed in the TOMORROW and INPULSIS trials. Patients with myocardial infarction in the previous 6 months, unstable angina in the previous month, or stroke in the previous year were excluded. We assessed the effect of CV risk at baseline on the CV safety of nintedanib 150 mg bid.MethodsIncidence rates of major adverse CV events (MACE) in subgroups of patients with a history of atherosclerotic CV disease and/or≥1 CV risk factor at baseline (higher CV risk), and patients with no history of atherosclerotic CV disease and no CV risk factors at baseline (lower CV risk), were analysed using pooled data from the TOMORROW and INPULSIS trials. CV risk factors were defined as hypertension, dyslipidaemia, BMI ≥30 kg/m2, current/former smoking, and diabetes. MACE were based on fatal adverse events included in the system organ classes “cardiac disorders” and “vascular disorders” in MedDRA; events in the subordinate standardised MedDRA query (SMQ) “myocardial infarction”; stroke based on selected preferred terms from the subordinate SMQs “haemorrhagic cerebrovascular conditions” and “ischaemic cerebrovascular conditions”; and MedDRA preferred terms “sudden death”, “cardiac death” and “sudden cardiac death”.ResultsAt baseline, 1107 (89.9%) patients (656 nintedanib, 451 placebo) had higher CV risk and 124 (10.1%) patients (67 nintedanib, 57 placebo) had lower CV risk. In patients with higher CV risk, incidence rates (95% CI) of MACE were 3.88 (2.58, 5.84) and 3.49 (2.10, 5.79) per 100 patient–years in the nintedanib and placebo groups, respectively. In patients with lower CV risk, incidence rates (95% CI) of MACE were 4.78 (1.54, 14.82) and 5.37 (1.73, 16.65) per 100 patient–years in the nintedanib and placebo groups, respectively.ConclusionIn pooled data from the TOMORROW and INPULSIS trials, the incidence of MACE was similar between the nintedanib and placebo groups in patients with higher CV risk at baseline and in patients with lower CV risk at baseline.Please refer to page A262 for declarations of interest in relation to abstract M34.Abstract M34 Figure 1

Nintedanib in Idiopathic Pulmonary Fibrosis: Practical Management Recommendations for Potential Adverse Events

“…For major adverse cardiac events including stroke, there was no difference between the intervention and placebo groups, irrespective of baseline risk. The actual clinical significance of these findings is not clear and a notable limitation of this analysis was the size of the lower cardiovascular risk groups (nintedanib: n = 67, placebo: n = 57) in comparison to the higher cardiovascular risk groups (nintedanib: n = 656, placebo: n = 451) [32]. This was due to the fact that 90% of the trial participants had at least 1 risk factor and were classified as higher risk at baseline.…”

“…To address these findings in greater detail, a retrospective post hoc analysis was performed on the pooled data from the TOMORROW and INPULSIS trials. Data were stratified by intervention and the analysis looked at the incidence of cardiac AEs in those patients considered to be either at higher cardiovascular risk (those with a history of atherosclerotic heart disease or ≥1 cardiovascular risk factor) or at lower cardiovascular risk (no history of atherosclerotic heart disease with no cardiovascular risk factors) at baseline [32]. Here, the incidence of MI was slightly higher in the higher cardiovascular risk intervention group (3.03 per 100 patient years) when compared to the corresponding placebo group (1.16 per 100 patient years).…”

Repurposing Nintedanib for Pathological Cardiac Remodeling and Dysfunction

“…Since we observed a reduction in cardiac hypertrophy in NTB treated animals, we were interested in determining if NTB directly affects cardiomyocytes apart from its well- Noth et al investigated the cardiovascular safety of NTB in IPF patients. 23 They perormed an analysis using pooled data from the TOMORROW and INPULSIS trials and concluded that irrespective of cardiovascular risk at baseline, the incidence of major adverse cardiac events was similar between patients treated with NTB vs placebo.…”