Cardiovascular safety of nintedanib in subgroups by cardiovascular risk at baseline in the TOMORROW and INPULSIS trials

Rationale:

Nintedanib (NIN) is an intracellular inhibitor of tyrosine kinases (TKI). The TKI class may be associated with an increased risk of arterial thromboembolic events. Efficacy and safety of 52 weeks' treatment with NIN versus placebo (PLC) in patients with idiopathic pulmonary fibrosis were assessed in Phase II TOMORROW trial and two Phase III 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 from these trials. We assessed the effect of CV risk at baseline on the CV safety of NIN 150 mg twice daily.

Methods:

Incidence rates of major adverse CV events (MACE) in subgroups of patients with a history of atherosclerotic CV disease (CVD) and/or ≥1 CV risk factor at baseline (higher CV risk) and patients with no history of atherosclerotic CVD and no CV risk factors at baseline (lower CV risk) were analyzed using pooled data from TOMORROW and INPULSIS trials. CV risk factors were defined as hypertension, dyslipidemia, body mass index > 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 the Medical Dictionary for Regulatory Activities (MedDRA); events in the subordinate standardized MedDRA query (SMQ) “myocardial infarction”; stroke based on selected preferred terms from the subordinate SMQs “hemorrhagic cerebrovascular conditions” and “ischemic cerebrovascular conditions”; and the MedDRA preferred terms “sudden death”, “cardiac death” and “sudden cardiac death”.

Results:

At baseline, 1107 (89.9%) patients (656 NIN, 451 PLC) had higher CV risk and 124 (10.1%) patients (67 NIN, 57 PLC) 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 NIN and PLC groups, respectively (Figure). 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 NIN and PLC groups, respectively (Figure).

Fig. 1

Conclusion:

In pooled data from the TOMORROW and INPULSIS trials, incidence of MACE was similar between NIN and PLC groups both in patients with higher CV risk (who comprised 90% of the patients in these trials) and lower CV risk at baseline.