Skip to main content

Main menu

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • ERS Guidelines
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • Peer reviewer login
  • Alerts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • ERS Guidelines
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • Peer reviewer login
  • Alerts
  • Subscriptions

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

Imre Noth, Marlies Wijsenbeek, Martin Kolb, Francesco Bonella, Lizette Moros, Daniel Wachtlin, Tamera J. Corte
European Respiratory Journal 2019 54: 1801797; DOI: 10.1183/13993003.01797-2018
Imre Noth
1Division of Pulmonary and Critical Care Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: IN2C@hscmail.mcc.virginia.edu
Marlies Wijsenbeek
2Dept of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Kolb
3Dept of Respiratory Medicine, Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Martin Kolb
Francesco Bonella
4Interstitial and Rare Lung Disease Unit, Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lizette Moros
5Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel Wachtlin
6Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tamera J. Corte
7Royal Prince Alfred Hospital, Camperdown, Australia
8University of Sydney, Sydney, Australia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Nintedanib is a tyrosine kinase inhibitor used to treat idiopathic pulmonary fibrosis (IPF). We investigated the cardiovascular safety of nintedanib using pooled data from the TOMORROW and INPULSIS trials.

Cardiovascular events were assessed post hoc in patients with a history of atherosclerotic cardiovascular disease (CVD) and/or one or more cardiovascular risk factors at baseline (“higher cardiovascular risk”) and patients with no history of atherosclerotic CVD and no cardiovascular risk factors at baseline (“lower cardiovascular risk”).

Incidence rates were calculated for 1231 patients (n=723 nintedanib and n=508 placebo), of whom 89.9% had higher cardiovascular risk. Incidence rates of major adverse cardiovascular events were similar in the nintedanib and placebo groups in patients with higher cardiovascular risk (3.88 (95% CI 2.58–5.84) and 3.49 (95% CI 2.10–5.79) per 100 patient-years, respectively) and lower cardiovascular risk (4.78 (95% CI 1.54–14.82) and 5.37 (95% CI 1.73–16.65) per 100 patient-years, respectively). Incidence rates of myocardial infarction in the nintedanib and placebo groups, respectively, were 3.03 (95% CI 1.91–4.81) and 1.16 (95% CI 0.48–2.79) per 100 patient-years in patients with higher cardiovascular risk and 1.59 (95% CI 0.22–11.29) and 1.78 (95% CI 0.25–12.64) per 100 patient-years in patients with lower cardiovascular risk. Incidence rates of other ischaemic heart disease in the nintedanib and placebo groups, respectively, were 1.85 (95% CI 1.02–3.34) and 3.28 (95% CI 1.94–5.54) per 100 patient-years in patients with higher cardiovascular risk and 0 and 1.80 (95% CI 0.25–12.78) per 100 patient-years in patients with lower cardiovascular risk.

These data help to establish the cardiovascular safety profile of nintedanib in IPF.

Abstract

In pooled data from the randomised TOMORROW and INPULSIS trials in patients with IPF, the incidence rates of major adverse cardiovascular events were similar in the nintedanib and placebo groups both in patients with higher and lower cardiovascular risk http://bit.ly/2KUY8IP

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease characterised by decline in lung function and worsening dyspnoea [1]. IPF occurs more frequently in males and in ex-smokers, and typically presents in the sixth or seventh decade of life [1].

Cardiovascular diseases (CVDs) represent common comorbidities in patients with IPF [2–6]. Cardiovascular conditions associated with IPF include ischaemic heart disease (IHD), cerebrovascular disease and systemic arterial hypertension [2, 4]. Cardiovascular risk is a continuum and is influenced by a number of risk factors. Guidelines for prevention of CVD issued by the European Society of Cardiology recommend an assessment of total cardiovascular risk in apparently healthy adults aged >40 years or those with relevant risk factors such as smoking, hypertension, cholesterol levels and diabetes [7].

Nintedanib is an approved treatment for IPF that reduces disease progression by reducing the rate of decline in forced vital capacity (FVC) [8]. In the latest international treatment guidelines for IPF, nintedanib received a conditional recommendation for use, indicating that it would be an appropriate choice for the majority of patients [4]. Nintedanib is an intracellular inhibitor of tyrosine kinases, including vascular endothelial growth factor, fibroblast growth factor and platelet-derived growth factor receptors [9, 10]. Other tyrosine kinase inhibitors with different inhibition profiles have been associated with cardiovascular adverse events including pulmonary hypertension, left ventricular dysfunction and arterial thromboembolic events [11]. In the phase III INPULSIS trials, when broad search terms for myocardial infarction or other IHD were used, a higher proportion of patients in the nintedanib group than in the placebo group were found to have myocardial infarction (2.7% (17 out of 638) versus 1.2% (five out of 423)), while a lower proportion had other IHD (1.7% (11 out of 638) versus 3.1% (13 out of 423)) [12]. When narrow search terms were used, which took into account only those cases that were highly likely to represent myocardial infarction or IHD, 1.7% (11 out of 638) of patients in the nintedanib group versus 0.5% (two out of 423) of patients in the placebo group had myocardial infarction and 1.6% (10 out of 638) of patients in the nintedanib group versus 3.1% (13 out of 423) of patients in the placebo group had other IHD (data on file). For two out of the 11 nintedanib-treated patients who had a myocardial infarction, this event was judged as drug related (data on file). The US and European Union prescribing information for nintedanib recommends caution when treating patients at higher cardiovascular risk, including those with coronary artery disease [13, 14].

We assessed the effect of cardiovascular risk at baseline on the cardiovascular safety profile of nintedanib in patients with IPF using pooled data from the randomised placebo-controlled phase II TOMORROW trial and phase III INPULSIS trials.

Methods

Data were pooled from the nintedanib 150 mg twice daily and placebo groups of the phase II TOMORROW trial and the phase III INPULSIS trials. The designs and results of these trials have been reported [8, 15]. Briefly, eligible patients were ≥40 years of age with a diagnosis of IPF, FVC ≥50% predicted and diffusing capacity of the lung for carbon monoxide 30−79% predicted. Patients with a recent history of myocardial infarction (previous 6 months), unstable angina (previous month) or stroke (previous year) were excluded. In each trial, patients were randomised to receive nintedanib or placebo for 52 weeks.

Post hoc subgroup analyses were conducted in patients with a history of atherosclerotic CVD and/or one or more cardiovascular risk factors at baseline (“higher cardiovascular risk”) and patients with no history of atherosclerotic CVD and no cardiovascular risk factors at baseline (“lower cardiovascular risk”). “History of atherosclerotic CVD” was assessed based on the comorbidities reported by the patient and provided in case report forms. These were coded according to preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA) version 16.1. For the purposes of this analysis, “atherosclerotic CVD” was identified based on the subordinate Standardised MedDRA Queries (SMQs) “myocardial infarction” and “other IHD” within the SMQ “IHD”, the subordinate SMQ “ischaemic cerebrovascular conditions” within the SMQ “cerebrovascular disorders”, and the MedDRA preferred terms “peripheral arterial occlusive disease”, “ischaemia” and “arteriosclerosis” (table 1). “Cardiovascular risk factors” were defined based on the SMQs “hypertension” (including metabolic syndrome, essential hypertension (primary/essential/idiopathic hypertension), hypertensive cardiomyopathy and hypertensive heart disease), “dyslipidaemia” (including hypercholesterolaemia, hypertriglyceridaemia, combined hyperlipidaemia and secondary dyslipidaemia), as well as body mass index (BMI) >30 kg·m−2, current/ex-smoker and diabetes at baseline (table 1). These criteria for identifying patients at higher and lower cardiovascular risk were chosen arbitrarily, but based on cardiovascular risk factors identified by professional associations [7]. It was not possible to use a published cardiovascular risk scoring system given the data that were collected on the patients who participated in the trials.

View this table:
  • View inline
  • View popup
TABLE 1

Definitions for atherosclerotic cardiovascular disease (CVD) and cardiovascular risk factors

Baseline cardiovascular therapies were classified according to World Health Organization Anatomical Therapeutic Chemical coding. Incidence rates (per 100 patient-years) of adverse events of myocardial infarction, other IHD and major adverse cardiovascular events (MACE) were analysed. Myocardial infarction and other IHD were based on one or more events in the subordinate SMQs “myocardial infarction” and “other IHD”, respectively. MACE was based on one or more events based on fatal adverse events included in the MedDRA system organ classes “cardiac disorders” and “vascular disorders”, fatal and nonfatal events in the subordinate SMQ “myocardial infarction”, stroke based on selected preferred terms from the subordinate SMQs “haemorrhagic cerebrovascular conditions” and “ischaemic cerebrovascular conditions”, and the MedDRA preferred terms “sudden death”, “cardiac death” and “sudden cardiac death”.

Adverse events with onset after the first dose and up to 14 days (in the TOMORROW trial) or 28 days (in the INPULSIS trials) after the last dose of study drug were included in the analyses. Analyses were descriptive and based on patients who received one or more doses of study drug.

Results

Cardiovascular risk at baseline

1231 patients were included in this analysis (723 treated with nintedanib 150 mg twice daily and 508 treated with placebo). At baseline, 1107 patients (89.9%) had higher cardiovascular risk and 124 patients (10.1%) had lower cardiovascular risk, according to the aforementioned definitions. The proportion of patients with higher cardiovascular risk was similar in the nintedanib and placebo groups (table 2). Patients at higher cardiovascular risk had higher weight and BMI, and a greater proportion were male (table 3). Baseline characteristics were generally similar in the nintedanib and placebo groups within each cardiovascular risk subgroup, although the proportion of Asians was higher in the nintedanib group. Of patients with higher cardiovascular risk at baseline, 22% had a history of atherosclerotic CVD. The most common form of atherosclerotic CVD was coronary artery disease (supplementary table S1). Of patients with higher cardiovascular risk, 65.5% had one or two cardiovascular risk factors (figure 1). Current/ex-smoker was the most common risk factor (79.7%), followed by hypertension (47.9%), dyslipidaemia (35.7%), BMI >30 kg·m−2 (30.6%) and diabetes (22.6%) (figure 2). The proportions of patients with each risk factor were similar in the nintedanib and placebo groups. Four patients (0.6%) in the nintedanib group and four patients (0.9%) in the placebo group had no cardiovascular risk factors (as defined in this analysis) but had a history of atherosclerotic CVD. In patients with higher cardiovascular risk, 66.2% were receiving a therapy for CVD, 36.4% were receiving a lipid-modifying agent (e.g. a statin) and 30.9% were receiving an antithrombotic agent (e.g. acetylsalicylic acid) (figure 3 and supplementary table S2). The proportions of patients receiving specific cardiovascular therapies were generally similar in the nintedanib and placebo groups.

View this table:
  • View inline
  • View popup
TABLE 2

Cardiovascular risk at baseline

View this table:
  • View inline
  • View popup
TABLE 3

Baseline characteristics by cardiovascular risk at baseline

FIGURE 1
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 1

Number of cardiovascular risk factors in patients with higher cardiovascular risk at baseline.

FIGURE 2
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 2

Frequency of cardiovascular risk factors in patients with higher cardiovascular risk at baseline.

FIGURE 3
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 3

Baseline cardiovascular therapy by cardiovascular risk at baseline. RAS: renin–angiotensin system.

Cardiovascular adverse events

In the whole pooled population, myocardial infarction, other IHD and MACE adverse events were reported in 2.0%, 2.1% and 3.6% of patients, respectively. In patients with higher cardiovascular risk at baseline, the incidence rate of myocardial infarction was 3.03 (95% CI 1.91–4.81) per 100 patient-years in the nintedanib group and 1.16 (95% CI 0.48–2.79) per 100 patient-years in the placebo group. The incidence rate of other IHD was 1.85 (95% CI 1.02–3.34) per 100 patient-years in the nintedanib group and 3.28 (95% CI 1.94–5.54) per 100 patient-years in the placebo group (figure 4). In patients with lower cardiovascular risk at baseline, the incidence rates of myocardial infarction and other IHD were similar in the nintedanib and placebo groups, but the number of patients and the number of events were very low (figure 4). The types of event reported are shown in supplementary table S3. The incidence rates of MACE were similar in the nintedanib and placebo groups, both in patients with higher cardiovascular risk at baseline (3.88 (95% CI 2.58–5.84) and 3.49 (95% CI 2.10–5.79) per 100 patient-years, respectively) and in patients with lower cardiovascular risk at baseline (4.78 (95% CI 1.54–14.82) and 5.37 (95% CI 1.73–16.65) per 100 patient-years, respectively) (figure 4). The types of event reported are shown in supplementary table S4.

FIGURE 4
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 4

Incidence rates of myocardial infarction, other ischaemic heart disease (IHD) and major adverse cardiovascular (CV) events (MACE) by CV risk at baseline. See main text for more details of MACE.

Discussion

We assessed the cardiovascular safety of nintedanib in subgroups by cardiovascular risk at baseline using pooled data from the TOMORROW and INPULSIS trials. Most patients (90%) in these trials were defined as having higher cardiovascular risk at baseline, of which 78% had one or more cardiovascular risk factors but no history of atherosclerotic CVD. For the purpose of our analyses, cardiovascular risk factors were defined as hypertension, dyslipidaemia, BMI >30 kg·m−2, current/ex-smoker and diabetes. Age and sex were not included as cardiovascular risk factors in our analyses, as IPF predominantly occurs in older males and this was reflected in the patient populations enrolled in these clinical trials. The majority of patients with higher cardiovascular risk at baseline were receiving a cardiovascular therapy, most commonly statins, and almost a third were receiving an antithrombotic agent.

Irrespective of cardiovascular risk at baseline, the incidence rate of MACE was low (<5 per 100 patient-years), and was similar in the nintedanib and placebo groups. In patients with higher cardiovascular risk at baseline, the incidence rate of myocardial infarction was higher in the nintedanib group than in the placebo group, whereas the incidence rate of other IHD was lower in the nintedanib group than in the placebo group. The clinical significance of these findings is unknown. In patients with lower cardiovascular risk, the incidence rates of myocardial infarction and other IHD were similar between treatment groups, but the number of patients and the number of events were very low. Our data are consistent with data from INPULSIS-ON, the open-label extension of the INPULSIS trials, which showed a similarly low incidence rate of MACE in patients treated with nintedanib in both trials (3.19 (95% CI 2.27–4.49) per 100 patient-years) after a mean±sd total exposure to nintedanib of 40.7±14.6 months [16]. The incidence rate of myocardial infarction in this analysis was 0.77 (95% CI 0.39–1.54) per 100 patient-years. Taken together, these data do not suggest cardiovascular safety concerns over the use of nintedanib in patients with IPF.

Patients with IPF treated with nintedanib in clinical practice appear to have cardiac adverse event profiles that are similar to those observed in clinical trials despite having more impaired lung function and more comorbidities [17–22]. However, such comparisons should be made with caution given the different methodologies used to collect the data. Data from post-marketing surveillance in the USA conducted for 1 year after the launch of nintedanib as a treatment for IPF showed incidence rates for MACE and myocardial infarction of 2.9 and 1.0 per 100 patient-years, respectively [20]. Scant data are available on rates of myocardial infarction in patients with IPF, but the incidence rate of myocardial infarction in patients treated with nintedanib in the TOMORROW and INPULSIS trials is similar to that reported in an analysis of US healthcare claims data from 9286 patients with IPF prior to the availability of antifibrotic therapy (2.2 per 100 patient-years) [2].

Our analyses have a number of limitations: patients were not randomised by cardiovascular risk at baseline, no data on cardiovascular therapy use prior to the trials were available, and analyses were conducted post hoc, with no formal statistical tests performed, and not based on risk calculations. The definition used for “high cardiovascular risk” was broad, including patients with even a single cardiovascular risk factor. A substantial proportion of patients in the “low cardiovascular risk” subgroup were males or aged >65 years, which are established risk factors for CVD. Patients with a recent history of myocardial infarction (previous 6 months), unstable angina (previous month) or stroke (previous year) were excluded from these trials. Caution should be exercised in the interpretation of these data given the uncertainty arising from sampling variability, especially for the small subgroup of patients with no cardiovascular risk factors at baseline, and the limitations in attributing observed differences in event rates to randomised treatment, use of cardiovascular medications or patient characteristics.

In conclusion, post hoc analyses of pooled data from the TOMORROW and INPULSIS trials suggest that the incidence of MACE was similar between patients treated with nintedanib and placebo irrespective of cardiovascular risk at baseline. The incidence of myocardial infarction was higher in the nintedanib group than in the placebo group among patients with higher cardiovascular risk, whereas the incidence rate of other IHD was lower in the nintedanib group than in the placebo group. Overall, the incidence of myocardial infarction was similar in nintedanib-treated patients in the TOMORROW and INPULSIS trials as in epidemiological data from patients with IPF not treated with nintedanib. These data help to establish the cardiovascular safety profile of nintedanib in patients with IPF. Observational and pharmacovigilance studies will continue to provide additional data on cardiovascular events in patients with IPF treated with nintedanib.

Supplementary material

Supplementary Material

Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

Supplementary material ERJ-01797-2018.SUPPLEMENT

Shareable PDF

Supplementary Material

This one-page PDF can be shared freely online.

Shareable PDF ERJ-01797-2018.Shareable

Acknowledgements

Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Julie Fleming and Wendy Morris (FleishmanHillard Fishburn, London, UK) during the preparation of this article. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version of the manuscript, which reflects the authors' interpretation and conclusions.

Footnotes

  • This article has supplementary material available from erj.ersjournals.com

  • Support statement: The TOMORROW and INPULSIS trials were funded by Boehringer Ingelheim. Funding information for this article has been deposited with the Crossref Funder Registry.

  • Conflict of interest: I. Noth reports personal fees for consultancy, lecturing, advisory board work and travel support from Boehringer Ingelheim and Roche/Genentech, personal fees for advisory board work from Sanofi and Global Blood Therapeutics, and personal fees for consultancy from Veracyte, outside the submitted work.

  • Conflict of interest: M. Wijsenbeek reports grants and other from Boehringer Ingelheim and Roche, and other from Galapagos, outside the submitted work.

  • Conflict of interest: M. Kolb reports grants from Canadian Pulmonary Fibrosis Foundation and Canadian Institute for Health Research, has acted as site principal investigator in industry-sponsored clinical trials for Roche, Sanofi and Boehringer Ingelheim, grants from and advisory board work for Pulmonary Fibrosis Foundation, personal fees for advisory board work from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Vertex, Genoa, Gilead, Prometic and Alkermes, and grants and personal fees for advisory board work from Roche Canada and Janssen, outside the submitted work.

  • Conflict of interest: F. Bonella reports personal fees for consultancy, lecturing and travel support from Boehringer Ingelheim and Roche, outside the submitted work.

  • Conflict of interest: L. Moros is an employee of Boehringer Ingelheim.

  • Conflict of interest: D. Wachtlin is an employee of Boehringer Ingelheim.

  • Conflict of interest: T.J. Corte reports grants and personal fees for travel, lecturing and advisory board compensation from Boehringer Ingelheim, grants and personal fees for travel, lecturing, steering committee work and advisory board compensation from Roche, grants from Gilead, Bayer, Intermune and BMS, and personal fees for advisory board compensation from AstraZeneca, during the conduct of the study.

  • Copyright ©ERS 2019
http://creativecommons.org/licenses/by-nc/4.0/

This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

References

  1. ↵
    1. Raghu G,
    2. Collard HR,
    3. Egan JJ, et al.
    An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183: 788–824.
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    1. Collard HR,
    2. Ward AJ,
    3. Lanes S, et al.
    Burden of illness in idiopathic pulmonary fibrosis. J Med Econ 2012; 15: 829–835.
    OpenUrlCrossRefPubMed
    1. Hyldgaard C,
    2. Hilberg O,
    3. Bendstrup E
    . How does comorbidity influence survival in idiopathic pulmonary fibrosis? Respir Med 2014; 108: 647–653.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Raghu G,
    2. Amatto VC,
    3. Behr J, et al.
    Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review. Eur Respir J 2015; 46: 1113–1130.
    OpenUrlAbstract/FREE Full Text
    1. Kreuter M,
    2. Ehlers-Tenenbaum S,
    3. Palmowski K, et al.
    Impact of comorbidities on mortality in patients with idiopathic pulmonary fibrosis. PLoS One 2016; 11: e0151425.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Kreuter M,
    2. Costabel U,
    3. Richeldi L, et al.
    Statin therapy and outcomes in trials of nintedanib in idiopathic pulmonary fibrosis. Respiration 2018; 95: 317–326.
    OpenUrl
  5. ↵
    1. Piepoli MF,
    2. Hoes AW,
    3. Agewall S, et al.
    2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016; 37: 2315–2381.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Richeldi L,
    2. du Bois RM,
    3. Raghu G, et al.
    Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2071–2082.
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Hilberg F,
    2. Roth GJ,
    3. Krssak M, et al.
    BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008; 68: 4774–4782.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Wollin L,
    2. Maillet I,
    3. Quesniaux V, et al.
    Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Med 2014; 349: 209–220.
    OpenUrl
  9. ↵
    1. Shah RR,
    2. Morganroth J
    . Update on cardiovascular safety of tyrosine kinase inhibitors: with a special focus on QT interval, left ventricular dysfunction and overall risk/benefit. Drug Saf 2015; 38: 693–710.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Corte T,
    2. Bonella F,
    3. Crestani B, et al.
    Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis. Respir Res 2015; 16: 116.
    OpenUrl
  11. ↵
    Boehringer Ingelheim Pharmaceuticals, Inc. OFEV (nintedanib). Prescribing information. 2018. https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Ofev/ofev.pdf Date last accessed: August 16, 2018.
  12. ↵
    Boehringer Ingelheim. OFEV (nintedanib). Summary of product characteristics. 2018. https://www.ema.europa.eu/en/documents/product-information/ofev-epar-product-information_en.pdf Date last accessed: August 16, 2018.
  13. ↵
    1. Richeldi L,
    2. Costabel U,
    3. Selman M, et al.
    Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011; 365: 1079–1087.
    OpenUrlCrossRefPubMedWeb of Science
  14. ↵
    1. Crestani B,
    2. Quaresma M,
    3. Kaye M, et al.
    Long-term nintedanib treatment in idiopathic pulmonary fibrosis (IPF): new data from INPULSIS-ON. Eur Respir J 2017; 50: OA3402.
    OpenUrl
  15. ↵
    1. Bonella F,
    2. Kreuter M,
    3. Hagmeyer L, et al.
    Insights from the German compassionate use program of nintedanib for the treatment of idiopathic pulmonary fibrosis. Respiration 2016; 92: 98–106.
    OpenUrlCrossRefPubMed
    1. Hughes G,
    2. Toellner H,
    3. Morris H, et al.
    Real world experiences: pirfenidone and nintedanib are effective and well tolerated treatments for idiopathic pulmonary fibrosis. J Clin Med 2016; 5: 78.
    OpenUrlCrossRefPubMed
    1. Galli JA,
    2. Pandya A,
    3. Vega-Olivo M, et al.
    Pirfenidone and nintedanib for pulmonary fibrosis in clinical practice: tolerability and adverse drug reactions. Respirology 2017; 22: 1171–1178.
    OpenUrl
  16. ↵
    1. Noth I,
    2. Oelberg D,
    3. Kaul M, et al.
    Safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis in the USA. Eur Respir J 2018; 52: 1702106.
    OpenUrlAbstract/FREE Full Text
    1. Toellner H,
    2. Hughes G,
    3. Beswick W, et al.
    Early clinical experiences with nintedanib in three UK tertiary interstitial lung disease centres. Clin Transl Med 2017; 6: 41.
    OpenUrl
  17. ↵
    1. Brunnemer E,
    2. Wälscher J,
    3. Tenenbaum S, et al.
    Real-world experience with nintedanib in patients with idiopathic pulmonary fibrosis. Respiration 2018; 95: 301–309.
    OpenUrl
PreviousNext
Back to top
View this article with LENS
Vol 54 Issue 3 Table of Contents
European Respiratory Journal: 54 (3)
  • Table of Contents
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Cardiovascular safety of nintedanib in subgroups by cardiovascular risk at baseline in the TOMORROW and INPULSIS trials
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Citation Tools
Cardiovascular safety of nintedanib in subgroups by cardiovascular risk at baseline in the TOMORROW and INPULSIS trials
Imre Noth, Marlies Wijsenbeek, Martin Kolb, Francesco Bonella, Lizette Moros, Daniel Wachtlin, Tamera J. Corte
European Respiratory Journal Sep 2019, 54 (3) 1801797; DOI: 10.1183/13993003.01797-2018

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Cardiovascular safety of nintedanib in subgroups by cardiovascular risk at baseline in the TOMORROW and INPULSIS trials
Imre Noth, Marlies Wijsenbeek, Martin Kolb, Francesco Bonella, Lizette Moros, Daniel Wachtlin, Tamera J. Corte
European Respiratory Journal Sep 2019, 54 (3) 1801797; DOI: 10.1183/13993003.01797-2018
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Abstract
    • Abstract
    • Introduction
    • Methods
    • Results
    • Discussion
    • Supplementary material
    • Shareable PDF
    • Acknowledgements
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Subjects

  • Interstitial and orphan lung disease
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

Original Articles

  • Systematic assessment of respiratory health in illness susceptible athletes
  • Identifying early PAH biomarkers in systemic sclerosis
  • Viable virus aerosol propagation by PAP circuit leak
Show more Original Articles

Interstitial lung disease

  • Use of statins and risk of ILD/IPF
  • Rituximab and mycophenolate mofetil in ILD
  • Incidence of interstitial lung abnormalities
Show more Interstitial lung disease

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About the ERJ

  • Journal information
  • Editorial board
  • Press
  • Permissions and reprints
  • Advertising

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Publication ethics and malpractice
  • Submit a manuscript

For readers

  • Alerts
  • Subjects
  • Podcasts
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Print ISSN:  0903-1936
Online ISSN: 1399-3003

Copyright © 2023 by the European Respiratory Society