Cardiovascular Comorbidities in Patients with IPF
It is important to note that, in many patients, CVD is diagnosed before IPF [
46]. Comprehensive cardiovascular evaluation represents an opportunity for cardiologists to identify undiagnosed IPF in patients with CVD and refer them to a pulmonologist with expertise in ILD.
Patients with IPF demonstrate a high burden of CVD, with a number of studies reporting an increased risk of CVD in patients with IPF versus those without [
3‐
5,
47]. Although respiratory failure is the most frequent cause of death in patients with IPF, CVD is still responsible for up to 10% of deaths [
39,
48,
49]. The presence of cardiovascular comorbidities in patients with IPF and the effect on mortality have been investigated in several studies. For example, in a retrospective study of patients with pulmonary fibrosis treated at a single hospital in Finland, CVD remained associated with increased mortality in multivariate analyses adjusted for age, gender, smoking status, and percent predicted DLco [
46]. Similarly, in a study including data from 272 patients with IPF from an ILD tertiary referral center, atherosclerosis and ‘other’ cardiac diseases were associated with increased mortality [
50].
PH in Patients with IPF
PH is currently classified into five categories, which are differentiated by multiple factors including hemodynamic characteristics and pathological findings [
51]. Group 3 PH is associated with lung disease and is a common cardiovascular complication diagnosed in patients with IPF, with prevalence varying between 3% and 86% but most often found to be between 30% and 50% [
39,
52‐
57]. The presence of PH in patients with IPF is associated with a number of negative outcomes. For example, in a retrospective cohort study including data obtained from a US healthcare database on 6013 LTx candidates with IPF who were followed-up until death, LTx, or any other censoring event, ‘mild’ and ‘severe’ PH were significantly associated with mortality [
58].
The pathophysiologic mechanisms accounting for PH in patients with IPF are complex [
39]. Hypoxemic vasoconstriction and destruction of the pulmonary vascular bed by fibrosis, as well as aberrant angiogenesis and endothelial dysfunction, are likely to influence the development of PH [
39,
59,
60]. However, the biological processes underlying progressive fibrogenesis may also be contributing factors as profibrogenic cytokines are also vasoactive [
39,
59‐
62]. In addition, other common comorbidities in patients with IPF, such as emphysema, obstructive sleep apnea (OSA), thromboembolic disease, and HF are also likely to contribute to the development of PH [
39]. In particular, the fibrotic lung tissue from patients with IPF is reported to increase levels of coagulation factors and their downstream activators [
63,
64]. Venous thromboembolism has been used as a proxy for such a ‘procoagulant state’ and has been linked to interstitial idiopathic pneumonia (of which IPF is part; Fig.
1), especially amongst those never treated with anticoagulants [
65].
The symptoms of PH are non-specific and overlap with those of IPF, including dyspnea, exercise intolerance, and fatigue [
39,
66]. This means that many patients with IPF are not evaluated for PH [
39,
66]. The presence of PH should, however, be considered in every patient with IPF, especially when dyspnea or oxygen desaturation is disproportionate to the physiologic impairment demonstrated on pulmonary function testing or the findings on HRCT imaging [
39,
53]. Other indicators of PH may include percent predicted DLco < 30%, unexpected reductions in 6 min walk distance (6MWD) often with oxygen desaturation to below 85%, and impaired heart-rate recovery after exertion [
39,
53]. Although right-heart catheterization is considered the gold standard of diagnosis for Group 1 PH (pulmonary arterial hypertension), it is not systematically recommended in patients with IPF who exhibit the signs and symptoms of PH unless the patient is being considered for LTx, or if it is clinically indicated [
56,
66]. When PH is suspected, quantification of NT-proBNP levels in patients with IPF can provide confirmation of whether further investigation is necessary [
67]. A diagnosis of PH becomes very unlikely in patients with NT-proBNP < 95 ng/l [
67]. In patients with NT-proBNP ≥ 95 ng/l, a transthoracic echocardiogram can be used to look for signs of elevated right ventricular systolic pressure, such as dilation of the right atrium and/or ventricle, and right ventricular dysfunction [
39]. The echocardiographic probability of PH can be defined as low, intermediate, or high based on a combination of peak tricuspid regurgitation velocity and the presence or absence of signs of PH on echocardiogram [
56]. HRCT images of the chest may also assist with the identification of PH when showing a main pulmonary artery diameter > 29 mm or a pulmonary artery diameter greater than that of the aorta [
66].
There are a number of therapies available for Group 1 PH, including calcium channel blockers, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs [
56]. However, international treatment guidelines for IPF and PH do not recommend treating Group 3 PH in patients with IPF with the therapies available for Group 1 PH because of a lack of clinical evidence supporting the efficacy and safety of these treatments and the potential risk of impairing gas exchange through the inhibition of hypoxic vasoconstriction [
56,
68]. Nevertheless, the guidelines do recommend that patients with IPF and PH and who are hypoxemic should receive long-term oxygen therapy [
11,
56].
A number of randomized controlled trials have investigated therapies for Group 1 PH in patients with IPF and ILD with mixed and sometimes deleterious results (a comprehensive list is found in Table
4). For example, the RISE-IIP study of riociguat in patients with idiopathic interstitial pneumonia and PH was terminated early due to an increased risk of death or serious adverse events (AEs) in the active treatment group [
39,
69]. The STEP-IPF trial of sildenafil in patients with advanced IPF, defined as percent predicted DLco < 35%, was completed but did not show a significant treatment benefit for the primary endpoint of the proportion of patients with an increase in 6MWD ≥ 20% at week 12 [
70]. However, significant treatment benefits were observed for secondary endpoints versus placebo, including changes in arterial oxygenation, percent predicted DLco, dyspnea, and quality of life (QoL) after 12 weeks of treatment [
70]. The use of sildenafil in combination with antifibrotics has recently attracted attention based on two randomized placebo-controlled clinical trials of patients with IPF [
71,
72]. NCT02951429 is enrolling patients with IPF with more advanced disease (percent predicted DLco ≤ 40%) at risk of Group 3 PH, and will investigate the efficacy, safety, and tolerability of sildenafil added to pirfenidone over 52 weeks [
71,
73]. The primary outcome is the percentage of patients with disease progression, defined as the occurrence of ≥ 15% decline in 6MWD, respiratory-related non-elective hospitalization, or all-cause mortality. Another trial, INSTAGE (NCT02802345), enrolled patients with IPF and advanced lung-function impairment (percent predicted DLco ≤ 35%), and investigated the efficacy and safety of sildenafil added to nintedanib over 24 weeks [
72]. The primary outcome was the change from baseline at week 12 in St George’s Respiratory Questionnaire (SGRQ) total score. These results were recently reported and showed that the difference in change from baseline in the SGRQ total score between the nintedanib and sildenafil treatment arm and the nintedanib alone arm was not significant at weeks 12 or 24 [
74]. A large number of exploratory outcomes showed no benefit of adding sildenafil to treatment with nintedanib, with the exception that patients treated with nintedanib plus sildenafil had a lower risk of reaching a composite endpoint of absolute decline in percent predicted FVC of ≥ 5% or death than those treated with nintedanib alone [
74]. The absence of an increase in BNP level in the patients who received nintedanib plus sildenafil in the trial may indicate a reduction in right ventricular stress [
74].
Table 4
Randomized placebo-controlled clinical trials investigating Group 1 PH treatments in patients with ILD and Group 3 PH
| 40 patients with comorbid IPF and PH (100%) | Ambrisentan | Change from baseline in 6MWD at week 16 | Terminated early due to a lack of efficacy |
| 492 patients with IPF with (10%) and without comorbid PH | Ambrisentan | Time to IPF progression, defined as the first occurrence of death, respiratory-related hospitalization, or categorical decline in lung functiona | Terminated early due to an interim analysis indicating a low likelihood of efficacy, with a potential increase in the risk of disease progression and respiratory-related hospitalization |
| 147 patients with comorbid idiopathic interstitial pneumonia and PH (100%) | Riociguat | Change from baseline in 6MWD at week 26 | Terminated early due to an increased risk of death or serious adverse events in the active treatment arm |
| 60 patients with comorbid fibrotic interstitial pneumonia and PH (100%) | Bosentan | Percentage of patients with change from baseline in pulmonary vascular resistance index ≥ 20% over 16 weeks | Completed. No significant treatment effect versus placebo over 16 weeks on pulmonary hemodynamics, functional capacity, or symptoms |
| 180 patients with advanced IPF (percent predicted DLco < 35%) with or without comorbid PH (% not reported) | Sildenafil | Percentage of patients with increase from baseline in 6MWD ≥ 20% at week 12 | Completed. No significant treatment benefit versus placebo on the primary endpoint, although significant benefits were observed for arterial oxygenation, percent predicted DLco, dyspnea, and QoL |
| 119 patients with advanced IPF (percent predicted DLco < 35%) with (19%) or without right-sided ventricular systolic dysfunction | Sildenafil | Multivariate linear regression was performed to investigate the relationship between right ventricular abnormalities, sildenafil, and changes in 6MWD and QoL over 12 weeks | Completed. In patients with right-sided ventricular systolic dysfunction, sildenafil was associated with significantly less decline in 6MWD and significant improvements in QoL versus placebo over 12 weeks |
| Patients with IPF with more advanced disease at risk of Group 3 PH (planned sample size = 176) | Sildenafil + pirfenidone | Percentage of patients with disease progression, defined as ≥ 15% decline in 6MWD from baseline, respiratory-related non-elective hospitalization, or all-cause mortality over 52 weeks | Recruiting |
| 274 patients with IPF and percent predicted DLco ≤ 35% | Sildenafil + nintedanib | Change from baseline in SGRQ total score at week 12 | Completed |
Other Comorbidities in Patients with IPF
In addition to CVD and PH, other comorbidities, such as gastroesophageal reflux disease (GERD) and OSA, are frequently associated with IPF [
75]. The precise prevalence of GERD amongst patients with IPF is difficult to ascertain because of differences in diagnostic procedures, but it may affect over 80% of individuals [
76,
77]. It has been hypothesized that GERD may contribute to the progression of IPF in some patients and studies exploring the effect of anti-acid therapy have been performed. In an analysis of the placebo arms of three IPF Clinical Research Network randomized clinical trials, those patients taking anti-acid medication at baseline had a slower decline in percent predicted FVC over 30 weeks [
78]. A post hoc analysis of a separate clinical trial data set did not replicate this result and a more recent Phase II clinical trial of omeprazole in patients with IPF has yet to report (NCT02085018) [
79,
80].
OSA is a frequent comorbid condition in patients with IPF, with a reported prevalence between 58% and 88% [
53]. Despite this high reported prevalence, surprisingly few patients are evaluated for OSA [
53]. If left untreated, OSA can result in nocturnal hypoxemia, the presence of which was recently shown to predict worsened survival in patients with IPF [
81]. Moderate-to-severe OSA is generally treated with continuous positive airway pressure and this treatment has been shown to improve QoL measures in patients with IPF [
53].