Introduction
Idiopathic pulmonary fibrosis (IPF) is an irreversible, progressive, unpredictable, and fatal fibrotic lung disease that occurs predominantly in older adults. The prognosis of IPF is poor, with an estimated median survival of 2–5 years from the time of diagnosis and survival rates lower than those reported for many common cancers [
1‐
4]. Until recently, no treatments were available for IPF. In 2014, two drugs, pirfenidone and nintedanib, were approved in the USA to treat IPF. Pirfenidone is an oral small molecule with antifibrotic and antiinflammatory properties that slow fibrosis in various in vivo models [
5,
6]. Nintedanib is an oral small molecule that inhibits multiple receptor tyrosine kinases, including platelet-derived growth factor receptor α and β, fibroblast growth factor receptors 1–3, and vascular endothelial growth factor receptors 1–3, which have been implicated in IPF pathogenesis [
7].
Cardiovascular (CV) diseases and risk factors constitute an important group of comorbid conditions in patients with IPF, and medications are often used to treat patients with CV risk factors [
8‐
12]. The profile of patients with IPF (> 60 years of age, mostly male, and frequently current or former smokers) is similar to the general profile of patients at higher risk for CV disease. A recent review described a high prevalence of CV disease and CV risk factors, including arrhythmia, atrial fibrillation, ischemic heart disease, cerebrovascular disease, diabetes, hypercholesterolemia, hyperlipidemia, and weight disorders, in patients with IPF [
12]. In a claims database analysis, patients with IPF were reported to have a significantly higher prevalence of coronary artery disease, heart failure, atrial fibrillation, and myocardial infarction than matched controls [
13]. Patients with IPF have also been reported to be significantly more likely than the general population to have a history of hypertension and diabetes and to have received several CV medications, even prior to IPF diagnosis [
8,
11]. A higher prevalence of coronary artery disease has also been reported in patients with IPF compared with matched patients who had chronic obstructive pulmonary disease [
9].
A recent study of the impact of comorbidities on mortality in patients with IPF showed a significant negative impact of coronary artery disease, arteriosclerosis, and other CV diseases (mainly valvular heart disease, cardiac arrhythmias, and dilated cardiomyopathy) on survival [
14]. Of note, the use of statins in patients with IPF was recently reported to be associated with better clinical outcomes, including lower risks of death, all-cause hospitalization, respiratory-related hospitalization, and IPF-related mortality [
15]. On the other hand, warfarin as a primary therapy for IPF was shown to be associated with an increased risk for all-cause mortality and combined all-cause mortality (i.e., non-elective, non-bleeding hospitalization, and mortality) in a clinical trial, which was stopped early because of these deleterious outcomes [
16]. Furthermore, a post hoc analysis of patients with IPF who were randomized to placebo in the pirfenidone phase III trials suggested that baseline use of anticoagulants (90.6% warfarin) for medical indications (primarily atrial fibrillation, prophylaxis of venous thromboembolism, and deep vein thrombosis) was an independent risk factor for IPF-related mortality [
17]. In addition, a retrospective cohort study of patients with IPF suggested worse survival and shorter time to disease progression in patients receiving anticoagulants [
18]. There is a general uncertainty about the safety of warfarin in patients with IPF with secondary indications for anticoagulation, such as atrial fibrillation and venous thromboembolic disease [
17,
19].
Due to the increased CV risk in the IPF patient population and its correlation with mortality, understanding the impact of IPF treatment on CV and bleeding events in patients with IPF is critical. This analysis examined whether pirfenidone treatment impacted the CV [major adverse cardiac events–plus (MACE-plus)] and bleeding risks in patients with IPF enrolled in the three phase III trials of pirfenidone. In addition, the analysis also assessed whether concomitant CV medication use affected the treatment outcome of pirfenidone. The prevalence of CV risk factors, CV comorbidities, and related concomitant medication use in these three trials is provided. These findings will provide an additional consideration when implementing treatment for IPF, especially in patients with CV risk factors.
Discussion
Given the older age and high reported prevalence of CV-related comorbidities in patients with IPF, the purpose of this analysis was to describe the frequency of baseline CV risk factors, CV comorbidities, and related concomitant medication use and to assess CV and bleeding events in patients with IPF from the pirfenidone phase III clinical trials. The impact of specific CV medication use concomitant with pirfenidone on clinical outcomes was also examined. Consistent with previous reports and with findings in real-world observational registries, CV risk factors and comorbidities were highly prevalent in patients with IPF enrolled in the pirfenidone phase III trial population [
8‐
10,
27‐
29]. Current or former smoking, hypertension, obesity, hypercholesterolemia, and hyperlipidemia were the most common risk factors, reported in 65%, 52%, 44%, 23%, and 23% of patients, respectively. The percentages of patients with CV risk factors in the pirfenidone phase III trials were consistent with data from prospective real-world registries, including PASSPORT (patients using pirfenidone) and INSIGHTS-IPF and IPF-PRO (patients with IPF), although actual rates varied, and the low number of patients in IPF-PRO limits comparisons (S1 Fig) [
27‐
29]. In PASSPORT, hypertension and coronary artery disease were reported in 42% and 11% of patients at baseline, respectively. In INSIGHTS-IPF, coronary artery disease was reported in 25% of patients at baseline; in IPF-PRO, sleep apnea and coronary artery disease were reported in 29% and 31% of patients at baseline, respectively.
In this IPF clinical trial population, the use of concomitant CV and antithrombotic medications was frequent, with approximately half of all patients receiving statins (50.4%) and/or antiplatelet agents (48.9%). The percentage of patients who experienced CV or bleeding events was similar between groups receiving pirfenidone 2403 mg/day or placebo.
The beneficial effect of pirfenidone on the month 12 outcomes of death, respiratory-related hospitalization, and composites (including ≥ 10% absolute decline in % predicted FVC) was generally apparent in both users and non-users of CV and antithrombotic medications. The overall benefit of pirfenidone on these outcomes among patients receiving warfarin is encouraging considering current international guidelines, which strongly recommend against the use of warfarin in patients with IPF [
33]. This recommendation is based on the results of the ACE-IPF study, which evaluated warfarin as a primary therapy for IPF [
16]. Not only did warfarin fail to exhibit efficacy in ACE-IPF, but patients with IPF receiving warfarin had increased mortality [
16]. In a previous analysis, patients in the phase III trials who were randomized to placebo and received anticoagulants had an increased risk of IPF-related mortality vs non-users of anticoagulants, supporting the results in the ACE-IPF study [
17,
18]. In contrast, our findings suggest that warfarin can be safely administered with pirfenidone and retain the beneficial effect of pirfenidone without detriment to the patient. Importantly, most patients receiving warfarin did so for the entire study period. However, because of the small number of patients treated with both pirfenidone and warfarin during the first year (
n = 28; S1 Table), these findings must be interpreted with caution. No apparent difference was observed in outcomes between pirfenidone and placebo among heparin users; this finding should also be interpreted with caution due to small sample size (
n = 25 for pirfenidone;
n = 40 for placebo; S1 Table) and limited duration of use during the study period (most patients received heparin for ≤ 30 days). To examine the effects of pirfenidone on clinical efficacy outcomes, larger real-world studies of patients receiving anticoagulants for treatment of medical indications will need to be analyzed.
Among users of statins, treatment with pirfenidone was associated with a beneficial effect at month 12 on death, respiratory-related hospitalizations, and the composite endpoints, including ≥ 10% absolute decline in % predicted FVC. Statin use in patients with IPF has shown potential clinical benefits. A post hoc analysis of the use of statins in patients in the placebo arms of the pirfenidone phase III trials found that statin use was associated with improved disease-related outcomes, including IPF-related mortality and all-cause and respiratory-related hospitalization [
15].
Previous integrated analyses of the clinical trials of pirfenidone demonstrated its favorable long-term safety [
34,
35]. Given the older age and high reported prevalence of CV risk factors and comorbidities in patients with IPF, it is important to understand the impact of IPF treatment specifically on CV and bleeding risks. MACE-plus and bleeding events occurred in 2.3% and 4.0% of the clinical trial population, respectively, over a median duration of exposure to study drug of approximately 12 months. The incidences of MACE-plus and bleeding events were similar between the pirfenidone and placebo groups, suggesting that pirfenidone did not increase the risk of CV or bleeding events compared with placebo.
Although many factors such as lifestyle and convenience contribute to the choice of treatment in IPF, given the potential to affect comorbid conditions and interact with concomitant medications, a drug’s mechanism of action is also an important consideration. Although the exact mechanism of action of pirfenidone is unclear, this analysis suggests that pirfenidone treatment does not affect CV or bleeding risk in patients with IPF, many of whom have increased numbers of CV risk factors and comorbidities. Interestingly, in a rat model of cardiac fibrosis, pirfenidone demonstrated a protective effect, which may be partially controlled by a feedback loop of the angiotensin II type 1 receptor/p38 mitogen-activated kinase/renin-angiotensin system axis via liver X receptor-α activation [
36]. Furthermore, the use of several concomitant CV medications, including warfarin, did not appear to adversely impact the benefit of pirfenidone on efficacy outcomes. Considering the high prevalence of patients with CV risk factors in the IPF population as confirmed in this analysis, in addition to the recent study showing the association of CV disease with increased mortality in patients with IPF, the findings here provide an additional consideration when implementing treatment for IPF, especially in patients with CV risk factors [
14]. Of note, use of nintedanib, presumably because of one of its mechanisms of action (inhibition of vascular endothelial growth factor receptor), is associated with bleeding events and arterial thromboembolic events, which are listed among the warnings and precautions in the prescribing information [
37].
Study Limitations
This analysis is limited to a carefully selected IPF clinical trial population; patients with unstable or deteriorating cardiac disease within the previous 6 months were excluded from the pirfenidone clinical trials. Despite this limitation, CV comorbidities and CV medication use were common, and CV events were found to be relatively infrequent over the limited duration of the studies. The occurrence of CV events might be higher in broader groups of patients with IPF. This reasoning underscores the importance of comorbidity awareness in patients with IPF by all providers because pulmonologists typically rely on close collaboration with primary care providers in the comprehensive management of these complicated cases. In addition, this was a post hoc analysis of studies in which MACE-plus and bleeding events were included as reported by the investigator. Concomitant use of some CV medications of interest (e.g., anticoagulants such as warfarin and heparin) was limited in this cohort; therefore, these findings need to be interpreted with caution.
Conclusions
Awareness of CV risk factors, CV comorbidities, and use of concomitant medications is an important consideration in the management and treatment of patients with IPF. In this large, controlled study of patients with IPF, our findings confirm that CV risk factors and comorbidities are highly prevalent in patients with IPF and suggest that pirfenidone does not increase the risk of MACE-plus or bleeding events in these patients. The benefit of pirfenidone on clinical outcomes did not appear to be adversely impacted by use of several concomitant CV medication classes, including warfarin, antiplatelet agents, and statins. Compared with non-users of statins, patients receiving statins displayed a greater benefit of pirfenidone compared with placebo on the outcomes of death and respiratory-related hospitalization. No deleterious effects of treatment with pirfenidone on mortality or other clinical endpoints were observed in patients receiving warfarin; however, because of the small number of patients treated, no firm conclusions can be drawn. Larger studies are needed to investigate the effect of pirfenidone treatment on clinically important outcomes in patients receiving warfarin.
Acknowledgements
We thank the participants in our study. Portions of these data were presented at the 2016 American Thoracic Society Annual Meeting. The authors thank Karina Raimundo, Bann-Mo Day, and Connie Lew for their contributions to this study.