Benazepril

Study objectives: To assess the clinical relevance of angiotensin-converting enzyme inhibitors (ACEI) and 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) in the context of idiopathic pulmonary fibrosis (IPF).

Background: IPF is a progressive interstitial lung disease for which there is no effective treatment. ACEI and statins have been shown to possess antifibrotic properties in experimental models in vitro and in vivo.

Design, setting, and patients: Retrospective review of the effects of ACEI and statins on survival of 478 patients with IPF seen at Mayo Clinic Rochester from 1994 through 1996. Fifty-two patients (11%) were receiving ACEI, 35 patients (7%) were receiving statins, and 5 patients (1%) patients were receiving both at their initial visit.

Results: For subjects receiving ACEI, the median survival from the index visit was 2.2 years, compared to 2.9 years for subjects not receiving ACEI (p = 0.088). The median survival was 2.9 years if patients were receiving statins or not (p = 0.573). There was also no significant difference in survival between patients with IPF receiving either ACEI or statins vs those receiving neither at the index visit (2.5 years vs 3 years, respectively; p = 0.066). After adjusting for age, gender, recommended IPF treatment, smoking status, prior oxygen use, FVC, diffusion capacity for carbon monoxide, coronary artery disease, congestive heart failure, diabetes mellitus, and hypertension, there were no differences in survival between those subjects receiving either ACEI, statins, or both vs neither.

Conclusions: These data do not suggest a beneficial effect of ACEI and/or statins on survival in patients with IPF.

Key words: angiotensin-converting enzyme inhibitors; idiopathic pulmonary fibrosis; statins; treatment

Abbreviations: ACEI = angiotensin-converting enzyme inhibitors; CAD = coronary artery disease; CHF = congestive heart failure; DLCO = diffusing capacity of the lung for carbon monoxide; DM = diabetes mellitus; IPF = idiopathic pulmonary fibrosis; TGF = transforming growth factor; UIP = usual interstitial pneumonia

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Idiopathic pulmonary fibrosis (IPF) is a chronic, diffuse, parenchymal lung disease of unknown etiology. (1-3) IPF is a distinct type of idiopathic interstitial pneumonia, whose histopathologic hallmark is usual interstitial pneumonia (UIP). (1-4) Optimal therapy for IPF/UIP remains controversial. No agent has been rigorously shown to improve survival or quality of life for patients with IPF/UIP. (1) Consequently, IPF generally progresses relentlessly and carries the poorest prognosis of the chronic idiopathic interstitial pneumonias, with a median survived of < 3 years. (5) The clinical ineffectiveness of corticosteroids and immunosuppressives/cytotoxics, clarification of the unique histopathologic features of UIP, and a greater understanding of the injury/repair microenvironment of the lung have led to the proposal that IPF results from sequential lung injury and subsequent aberrant wound healing without significant inflammation, (3,6,7) thus generating interest in agents that specifically alter fibropoliferative mechanisms.

Angiotensin-converting enzyme inhibitors (ACEI) are widely used in the management of cardiovascular diseases and systemic hypertension. (8,9) 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) are the most commonly prescribed lipid-lowering agents and have proven benefit in primary (10) and secondary (11) prevention of coronary heart disease. There is increasing awareness that the broader pharmacologic properties of ACEI and statins encompass the abilities to modulate local fibroproliferative pathways in a variety of organ systems. In the lung, angiotensin II is emerging as a potentially important profibrotic mediator via induction of alveolar cell apoptosis (summarized by Uhal (12)) and as a fibroblast mitogen, (13) ACEI can block experimental models of lung fibrosis. (14-17) Lovastatin has been shown to induce apoptosis in normal and fibrotic lung fibroblasts in vitro, as well as reduce granulation tissue in association with ultrastructural evidence for fibroblast apoptosis in rive using a guinea pig wound chamber model. (18) We sought to extend these experimental findings by comparing survival in a group of patients with IPF at our institution who received ACEI for primary cardiovascular indications and/or statins for dyslipidemia with that of a large simultaneous cohort of patients with IPF/UIP not receiving these drugs.

MATERIALS AND METHODS

The Mayo Institution Review Board approved this study. Systematic search of the computerized patient database of our institution revealed 487 patients who satisfied diagnostic criteria for IPF seen at Mayo Clinic Rochester during the period of January 1, 1994, to December 31, 1996. The. clinical, radiologic, and histopathologic diagnostic criteria used to establish cases of IPF have been previously described. (19) Briefly, IPF was diagnosed if the patients presented with compatible clinical characteristics plus either consistent high-resolution chest CT findings or histopathologic evidence for idiopathic UIP. (19) Patients with known causes of diffuse pulmonary fibrosis were excluded from this analysis, including those with connective tissue diseases, pneumoconioses, radiation therapy to the thorax, history of use of drugs with the potential to cause lung fibrosis, neurofibromatosis, aspiration pneumonia, hypersensitivity pneumonitis, or biopsy evidence for another type of diffuse parenchymal lung disease.

The following data from the initial evaluation at our restitution were abstracted from the medical records: date of the initial visit during which the diagnosis of IPF was established within the study window (index visit date), age, gender, medications (via review of the physicians' documentation cross-checked by review of a patient-completed intake form for the initial consultation), smoking history, physical examination findings, laboratory results, pulmonary function data, high-resolution CT results, branches copy and lung biopsy (either extramurally or intramurally obtained) results (if available), and the presence of the following comorbidities: coronary artery disease (CAD), congestive heart failure (CHF), diabetes mellitus (DM), and hypertension. Treatments for IPF prior to and after the index visit date, including oxygen therapy, were also documented. Pulmonary function tests were performed using equipment (models 1070 and 1085; Medical Graphics; St. Paul, MN) calibrated daily according to American Thoracic Society specifications as previously described. (19) The baseline pulmonary function test was defined as the test performed at Mayo Clinic closest to the index visit, limited to tests within 90 prior or 14 days billowing the index visit date.

Patients were contacted during 1998 to assess vital status through questionnaires, phone calls, public record review, and subsequent patient visits. In addition, patients were contacted in 2000 via phone interview and medical record review to obtain 2-year follow-up data on all subjects.

Statistical Methods

Data are summarized using mean [+ or -] SD, median, and range for continuous variables, and frequency and percentage for categorical variables. Patient demographics were compared between those patients receiving ACEI and/or statins vs those not, using the two-sample, rank-sum test for continuous variables and a [chi square] test for categorical variables. For survival analysis, time zero is defined as the index visit, which was the date the patient was first seen at Mayo Clinic Rochester during the study period (January 1, 1994, to December 31, 1996). Cumulative survival probabilities were estimated using the Kaplan-Meier method. (20) The log-rank test (21) was used to compare survival among drug groups (ACEI vs no ACEI; statins vs no statins; ACEI or statins vs neither). In addition, a Cox proportional hazards regression model (22) was used to compare survival between drug groups adjusting for CAD, CHF, DM, and hypertension. A subsequent Cox proportional hazards regression model was used to compare survival between drug groups adjusting for CAD, CHF, DM, hypertension, age, gender, recommended treatment, smoking status, prior oxygen use to index Mayo clinic visit, percentage of predicted FE[V.sub.1], and percentage of predicted diffusing capacity of the lung for carbon monoxide (DLCO). In all cases, two-tailed p values [less than or equal to] 0.05 were considered statistically significant.

RESULTS

Demographics

During the 3-year period under study, IPF was diagnosed in 487 patients. Eight international (non-US/non-Canadian) persons were excluded from analysis because follow-up data could not be obtained, and one subject was excluded because on chart review for ACEI and statin use the patient was found to have had IPF incorrectly diagnosed previously. Baseline characteristics for the 478 patients analyzed for this study are summarized in Table 1. The most common recommended treatment for IPF was colchicine (235 patients; 49%), either singularly (166 patients; 35%) or in combination with prednisone (69 patients; 14%). This reflects the prevailing treatment philosophy of our group at that time. In the ACEI group, diagnosis was made by open-lung biopsy in eight patients (15%) receiving drug, vs 89 patients (21%) of those not receiving drug (p = 0.465). In the statins group, diagnosis was made by open-lung biopsy in 9 patients (26%) receiving drug, vs 88 patients (20%) of patients not receiving drug (p = 0.390).

Fifty-two patients (11%) were receiving ACEI for primary cardiovascular indications, and the specific agents were as follows: enalapril (n = 19), lisinopril (n = 16), captopril (n = 12), ramipril (n = 2), benazepril (n = 2), and quinapril (n = 1). Demographics of the IPF-ACEI group are displayed in Table 2. The only significant difference was that patients receiving ACEI were older than patients not receiving ACEI (p = 0.003). Thirty-five patients (7%) were receiving statins for lipid-lowering purposes, and the specific agents included the following: lovastatin (n = 18), simvastatin (n = 9), pravastatin (n = 6), and fluvastatin (n = 2). Patients receiving statins were younger (p = 0.007) and more likely to have previously smoked (p = 0.015) than their counterparts who did not receive statins (Table 3). Five patients were receiving both ACEI and statins; overall, 82 patients (17%) were receiving ACEI and/or statins. In the ACEI group, patients receiving drug were more likely than those not receiving drug to have CAD (29 patients [56%] vs 97 patients [23%], p < 0.001), CHF (14 patients [27%] vs 21 patients [5%], p < 0.001), DM (12 patients [23%] vs 51 patients [12%], p = 0.048), and hypertension (33 patients [63%] vs 122 patients [29%], p < 0.001).

In the statins group, CAD (20 patients [57%] vs 106 patients [24%], p < 0.001) was more common in patients receiving statins than those not, but there were no differences with respect to CHF (2 patients [6%] vs 33 patients [7%], p = 1.00), DM (7 patients [20%] vs 56 patients [13%], p = 0.205), or hypertension (12 patients [34%] vs 143 patients [32%], p = 0.852).

Survival

There were no differences in median survival between patients with IPF receiving ACEI or statins vs those not (Figs 1-3). For those subjects receiving ACEI, the median survival was 2.2 years, vs 2.9 years in subjects not prescribed ACEI (hazard ratio, 1.33; 95% confidence interval, 0.96 to 1.85; p = 0.088) [Fig 1]. The median survival was equivalent at 2.9 years if patients were receiving statins or not (hazard ratio, 1.13; 95% confidence interval, 0.73 to 1.75; p = 0.573) [Fig 2]. When comparing survival for those patients receiving statins or ACEI vs those receiving neither, no difference was found: median survival, 2.5 years for patients receiving ACEI or statins, vs 3 years for those not receiving either drug (hazard ratio, 1.30; 95% confidence interval, 0.98 to 1.73; p = 0.066) [Fig 3]. A subsequent analysis for ACEI, statins, and ACEI or statins was performed adjusting for CAD, CHF, DM, and hypertension; the findings did not change after adjusting for the presence of these comorbidities: ACEI use (hazard ratio, 1.05; 95% confidence interval, 0.73 to 1.52; p = 0.776), statin use (hazard ratio, 0.97; 95% confidence interval, 0.62 to 1.52; p = 0.895), and use of statins or ACEI (hazard ratio, 1.04; 95% confidence interval, 0.76 to 1.41; p = 0.819). A final analysis was performed adjusting for CAD, CHF, DM, hypertension, age gender, recommended treatment, smoking status, prior oxygen use, FVC, and DLCO with similar findings as above for each drug group.

[FIGURES 1-3 OMITTED]

DISCUSSION

The attention in IPF/UIP pathogenesis has shifted from chronic inflammation to aberrant wound/repair mechanisms with increased emphasis on the interplay of fibroblasts and alveolar epithelial cells. Consequently, the search for therapies has turned from traditional anti-inflammatory agents to those that may modify the cellular and cytokine constituents of fibroproliferative processes, as exemplified by the clinical trials involving pirfenidone (23) and interferon [gamma]. (24) However, results have been disappointing, and the search continues search for effective agents. ACEI and statins have demonstrated in vitro and in vivo capabilities to alter the components involved in extracellular matrix deposition.

Apoptosis of alveolar epithelial cells may be an important component of the aberrant wound-healing/ fibrotic process. (12) Increased alveolar epithelial cell death may disrupt control of the adjacent fibrotic process by reducing production of lung fibroblast proliferation inhibitors such as prostaglandin [E.sub.2] and altering production of interstitial collagen degraders such as matrix metalloproteinases. (12) Alveolar epithelial apoptosis via intratracheal installation of an antibody that activates the Fas receptor (25) (Fas antigen is a cell surface protein that medicates apoptosis) or bleomycin (which upregulates Fas) (26) is sufficient to initiate a fibrotic lung reaction in mice. Alveolar epithelial cell apoptosis is demonstrable in IPF, (27-29) and appears to occur in proximity to fibroblastic foci. (29)

Observations suggest a significant role for alveolar epithelial cell apoptosis in the pathogenesis of lung fibrosis, a role that appears related to local angiotensin mechanisms and is accordingly modifiable by ACEI in experimental systems. Fibroblasts from human fibrotic lung are capable of producing angiotensin peptides that kill alveolar epithelial cells in vitro. (30,31) Furthermore, autocrine production of angiotensin II in response to Fas activation (32) and TNF-[alpha]. (33) is associated with alveolar epithelial cell apoptosis. Finally, ACEI can block bleomycin-induced, (14) monocrotaline-induced, (15) [gamma] irradiation-induced, (16) and amiodarone-induced (17) experimental lung fibrosis.

Transforming growth factor (TGF)-[beta] has an integral role in the extracellular matrix composition in many organ systems, (34) and local expression of TGF-[beta] also appears to be linked to the local angiotensin system. In the kidney, fibrosis and chronic organ impairment result from exuberant expression of TGF-[beta], angiotensin II increases TGF-[beta] levels, and angiotensin II blockade decreases TGF-[beta] expression and matrix accumulation and helps preserve organ function (reviewed by Border and Noble (35,36)). Angiotensin II can induce TGF-[beta] expression cells throughout the cardiovascular system, including smooth-muscle cells, (37) and cardiac fibroblasts or myocytes. (38-41) ACEI administered shortly after myocardial infarction improves survival rate, (42) which may be due, in part, to mitigation of ventricular remodeling. In a rat model of nontransmural myocardial infarction, animals treated with ACEI had lower TGF-[beta] messenger RNA expression and collagen volume fractions in noninfarcted septal tissue vs untreated control animals after myocardial infarction. (43) An angiotensin/TGF-[beta] link has now been suggested in the lung. Angiotensin II is mitogenic for human fetal and adult lung fibroblasts in vitro, and this response is attenuated by anti-TCF-[beta] antibodies, suggesting the mitogenic effect is mediated by autocrine production of TGF-[beta]. (13)

Statins may lead to changes relevant to fibrogenesis beyond their lowering of serum cholesterol. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase decreases intracellular isoprenoids, especially geranylgeranylpyrophosphate and farensylpyrophosphate, which are critically important posttranslational modifiers for GTPases of the Ras and Rho family. (44) Ras and Rho are integral to cellular homeostatic functions. (45) Lovastatin induces dose- and time-dependent apoptosis in fibroblasts from normal and fibrotic lung in association with inhibition of Ras processing, implicating a Ras-dependent mechanism. (18) Using a human renal fibroblast cell line treated with statins, Eberlein et al (46) demonstrated reductions in basal as well as lysophosphatidic acid-induced and TGF-[beta]-induced expression of connective tissue growth factor a protein important in fibrogenesis, which was reversible by geranylgeranylpyrophosphate. The authors postulated that this statin effect was mediated through a Rho-dependent pathway. (46) Statins have been shown to inhibit vascular smooth-muscle synthesis of thrombospondin-1, which is an activator of TGF-[beta]. (47) These and other observations from renal and vascular tissues support a fibromodulating role for statins, but applicability to the lung is unclear.

It was within this context of an ever-increasing body of literature regarding the impacts of ACEI and statins on fibrogenesis that we sought to determine whether our patients with IPF receiving either ACEI and/or statins for traditional indications fared better than patients not receiving these medications. In our cohort of 478 patients, no retrospective differences in survival were noted between the 82 patients receiving ACEI and/or statins vs those receiving neither agent. The groups (control subjects, patients receiving ACEI, and patients receiving statins) were similar across gender, pulmonary function, and recommended IPF treatments. Median survival for all groups was slightly < 3 years, a finding consistent with a careful survival analysis of surgical lung biopsy-proven UIP cases. (5)

We recognize the methodologic limitations of tiffs retrospective analysis, including lack of blinded randomization to ACEI and/or statins use, variations in the specific types and doses of ACEI and statins prescribed, varying concurrent therapies for IPF, reliance on clinicoradiologic parameters for case definition in most patients, and incomplete information on duration of ACEI and statins use before establishment of the diagnosis of IPF. Nevertheless, the retrospective review method afforded a practical opportunity to analyze an extensive clinical experience to determine if the biological plausibility of ACEI and statins modulation of fibroproliferative processes translated into a demonstrable clinical benefit for patients with IPF. Properly designed, randomized trials are difficult to perform in this disorder, which is relatively rare, (48) clinically heterogenous early in its course, and usually fatal. (1) The retrospective review technique was recently used to reveal decreased rates of acute and chronic allograft rejection in lung transplant recipients receiving statins for lipid-lowering purposes vs a simultaneous transplant cohort not receiving statins. (49) This exciting development, which may have important implications in transplant management, speaks to the broad immunomodulating properties of statins that we hoped might have resulted in a survival benefit in our cohort.

In addition to aforementioned methodologic challenges, another potential explanation for the results may be that despite the large number of patients analyzed, our study was statistically underpowered to reliably detect a survival benefit of either ACEI or statins. It has been estimated that > 700 patients would be required to detect a 20% survival difference in a trial evaluating an agent for UIP/IPF. (50) In our cohort of 478 patients, 82 patients (17%) were receiving ACEI and/or statins. Compounding the limitations of these relatively small numbers is that patients were receiving many different ACEI and statins and, at least with statins, there may be differences in the fibromodulating properties of specific agents. (46) It does not appear that certain comorbidities masked the benefits of ACEI and statins. When adjusting for CAD, CHF, DM, and hypertension, no survival differences were noted.

In conclusion, we were not able to demonstrate survival differences between the groups receiving ACEI and/or statins vs neither. We conclude that ACEI and/or statins are not associated with improved survival in IPF, but acknowledge that the limitations of the data set do not definitively preclude an eventual beneficial role for these agents in this enigmatic disorder.

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* From the Divisions of Pulmonary and Critical Care Medicine (Drs. Nardrous, Olson, Douglas, and Ryu) and Biostatistics (Mr. Decker), Mayo Clinic, Rochester, MN.

Funding was provided by Mayo institutional funds.

Manuscript received October 15, 2003; revision accepted March 25, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chesnet.org).

Correspondence to: Eric J. Olson, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905: e-mail: olson.eric@mayo.edu

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