Efficacy of Low Molecular Weight Heparin in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease Receiving Ventilatory Support

Abstract

Introduction: Severe and acute exacerbation of chronic obstructive pulmonary disease (COPD) is associated with a high mortality. Since COPD is an airway inflammatory disease, and heparin has shown anti-inflammatory effects in previous studies, we evaluated the clinical effect of low molecular weight heparin (LMWH; nadroparin) in COPD patients admitted into the hospital due to acute exacerbations. Methods: Sixty-six patients admitted to the intensive care unit (ICU) were randomly divided into control group (n = 33) and LMWH group (n = 33). The control group received conventional treatment, including oxygen therapy (non-invasive or conventional mechanical ventilation), anti-infection, atomization expectorant, spasmolysis, anti-asthmatics, and nutritional support. The LMWH group received the same treatment plus LMWH for 1 week. The levels of plasma C-reactive protein, interleukin-6, and fibrinogen were measured. The main outcomes were duration of mechanical ventilation, length of ICU stay, and hospital stay. Results: There were no significant differences between the groups with respect to demographics, severity of illness, and gas exchange variables. The levels of plasma C-reactive protein, interleukin-6, and fibrinogen were significantly decreased in the LMWH group. LMWH significantly reduced the mean duration of mechanical ventilation (6.6 days vs. 3.8 days; p < 0.01), the length of ICU stay (8.5 days vs. 5.6 days; p < 0.01) and hospital stay (14.3 days vs. 11.3 days; p < 0.01). Conclusions: The addition of LMWH to standard therapy benefits COPD patients with acute exacerbation.

Keywords :

• low-molecular-weight heparin
• inflammation
• chronic obstructive pulmonary disease
• acute exacerbation

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by minimally reversible airflow obstruction and progressive incapacity, and is the 4th leading cause of death worldwide (1). The prevalence of COPD is slowly rising in recent years; an epidemiologic study estimated a two-fold increase in deaths in the next 20 years (2). Acute exacerbation is the first leading cause of decompensation, hospital admission, and death in patients with COPD (3–5).

Heparin is a member of the glycosaminoglycans family, and one of the most often used anticoagulant drugs (6). Heparin is currently used to prevent and treat venous thrombosis and pulmonary embolism, arterial thrombosis in patients presenting with acute myocardial infarction. It prevents re-thrombosis after thrombolysis, and prevents thrombosis in extracorporeal circuits and hemodialysis (7). Although heparin is primarily used as an ­anticoagulant, it has shown anti-inflammatory activities in experimental and clinical studies (8,9).

Heparin may serve as an endogenous anti-inflammatory molecule involved in the control and resolution of inflammatory responses (10). Several clinical trials in various inflammatory diseases support the anti-inflammatory effect of heparin (11–13). Heparin and related compounds have shown clinical benefit to patients with bronchial asthma, ulcerative colitis, and burns (14).

Given that COPD is an airway inflammatory disease, we hypothesized that heparin may have some therapeutic benefit in patients with acute exacerbation of COPD. The aim of the present study was to evaluate the effects of low molecular weight heparin (LWMH; nadroparin (5000 U per day × 1 week, subcutaneously)) in COPD patients with acute exacerbation.

Methods

Subjects

Sixty-six patients with acute exacerbation of COPD were enrolled in this study. The eligible subjects should be older than 50 years, with at least 10 pack-years smoking history, a FEV₁ < 60% predicted at the time of inclusion or an inability to perform spirometry due to dyspnea, and an admitting diagnosis of acute exacerbation of COPD (defined as an acute increase in dyspnea, sputum volume, and/or sputum purulence without other attributable cause). Patients were excluded if they had acute heart failure, abnormal coagulation function, severe immune dysfunction, liver or kidney failure.

The study was approved by the Medical Ethics Committee for Clinical Trials at Shanghai First People's Hospital of Shanghai Jiaotong University, which complied with the ethical guidelines of the 1975 Declaration of Helsinki. Informed consent was obtained from each patient before the study.

Study design and protocol

Sixty-six patients were randomized into the standard therapy group (control group) or LMWH plus standard therapy group (LMWH group) with equal number. At the time of admission, all subjects received the standardized therapy, including non-invasive ventilation, albuterol and ipratropium bromide, nutritional support, and antibiotics (15).

Patients were then randomized using blocks of two randomization protocol into control group receiving standardized therapy and the LMWH group receiving standardized therapy plus nadroparin (5000 U daily × 1 week subcutaneously, the prophylactic dose). Each eligible patient was sequentially assigned to either treatment group according to a randomization table generated in advance by our in-house statisticians. The study design was open-labeled, and the treatment assignment was not blind to the investigators, attending physicians, nurses, or patients.

Patients who were treated with non-invasive mechanical ventilation were considered to need tracheal intubation if they met any of the following criteria: pH < 7.20; pH = 7.20–7.25 on 2 separate measures 1 hour apart; hypercapnic coma (Glasgow Coma Scale = 8 and a PaCO₂ = 60 mm Hg); a PaO₅₀₀ < 45 mm Hg despite a maximum tolerated fraction of inspired oxygen; and/or cardiac arrest (16).

Patients with conventional mechanical ventilation were screened each morning to assess recovery from respiratory failure and to determine whether or not they should be weaned from mechanical ventilation. In patients with non-invasive mechanical ventilation, weaning was considered successful if after at least 3 hours of breathing without ventilator assistance the following criteria were met: an arterial oxygen saturation ≥ 90% with a fraction of inspired oxygen ≤ 40%; a pH ≥ 7.35; and a respiratory rate ≤ 35 breaths/min.

C-reactive protein was measured using an automated clinical analyzer (Abbott Architect ci8200; Abbott Laboratories, Abbott Park, IL, USA) with the minimum detectable concentration of 5 mg/L. IL-6 levels were measured using the Quantikine High-sensitivity ELISA Commercial Kit (R&D Systems, Minneapolis, MN, USA) with the minimum detectable concentration of 0.039 pg/mL. Fibrinogen was assessed using a coagulation analyzer (Sysmex CA-7000; Dade-Behring) according to the Clauss method and calculated from ethylenediamine tetra-acetic acid to citrate plasma values with the minimum detectable concentration of 0.3 g/L.

Statistical analysis

Continuous variables were expressed as the mean ± standard deviation and compared between groups using the Student's t-test, and variables with a non-normal distribution were compared with the Mann–Whitney test. Categorical variables were compared with X² test or Fisher's exact test. All statistical analyses were performed using statistical software (SPSS 14.0; SPSS, Inc., Chicago, IL, USA). Statistical significance was defined as p < 0.05.

Results

COPD is associated with cigarette smoking and old age (17); therefore, all recruited patients were older than 50 years with 10 years of smoking history. The patient demographics and baseline characteristics are summarized in Table 1. There was no significant difference in the baseline values between the two treatment groups, including age, gender, weight, height, smoking history, baseline PaO₂, baseline PaCO₂, and SAPS II score. All of the patients in LMWH group completed the 1-week treatment, and no death occurred during this period.

Table 1  Baseline characteristics of the 66 patients  according to treatment assignment

Characteristics	Control	LMWH
	(n = 33)	(n = 33)	p-Value
Age, years	66.3 ± 6.3	65.5 ± 4.5	0.56
Sex, male/female	19/14	18/15	0.80
Weight, Kg	60.3 ± 8.7	58.9 ± 5.4	0.43
Height, cm	167.0 ± 8.4	164.5 ± 6.5	0.18
Smokers, current/former	22/11	16/17	0.14
Baseline PaO2, mmHg	62.5 ± 7.4	64.2 ± 7.7	0.35
Baseline PaCO2, mmHg	91.0 ± 11.3	90.5 ± 12.9	0.85
SAPS II	36.2 ± 5.2	34.7 ± 4.7	0.22

Data are presented as mean ± SD; PaO₂, oxygen tension in arterial blood; PaCO₂, carbon dioxide tension in arterial blood.

The plasma C-reactive protein levels decreased over time in the LMWH group and were significantly lower than the control group on days 3 (p < 0.01) and 6 (p < 0.01). The IL-6 levels were significantly lower in the LMWH group on days 3 (p = 0.00) and 6 (p = 0.00) compared to the control group. The fibrinogen levels were significantly lower in the LMWH group on days 3 (p = 0.02) and 6 (p < 0.01) compared to the control group. The white blood cell count was significantly lower in the LMWH group on day 3 (p < 0.01) compared to the control group (Figure 1).

Figure 1. Mean levels of C-reactive protein (CRP) (A), Interleukin-6 (IL-6) (B), Fibrinogen (C) and white blood cell count (WBC) (D) at selected time points after treatment. The error bars indicates standard errors. (*p < 0.05, and **p < 0.01, for comparison with control group).

The clinical outcomes were summarized in Table 2. Compared to the standard therapy (control group), treatment with LMWH plus standard therapy (LMWH group) significantly reduced the mean duration of mechanical ventilation (6.6 days vs. 3.8 days; p < 0.01), the length of ICU stay (8.5 days vs. 5.6 days; p < 0.01) and hospital stays (14.3 days vs. 11.3 days; p < 0.01). Failure of non-invasive mechanical ventilation was not significantly reduced in LMWH group (13% vs. 22%; p = 0.39). In-ICU mortality was similar in the LMWH and control groups (9% vs. 12%; relative risk, 1.37; 95% CI, 0.15–3.52; p = 0.69). There was no difference in the incidence of adverse effects between these two groups. No thromboenblic or major bleeding events occurred in either group, but clinically significant non-major bleeding events were found in 1 patient (3.0%) in the LWMH group and in 2 (6.1%) in the control group (95% CI, 0.04–5.61; p = 0.55). All non-major bleeding events were hematomas at the injection site.

Table 2.  Outcome measures 

Outcome	Control	LMWH	p-Value
	(n = 33)	(n = 33)
Duration of mechanical ventilation, d	6.6 ± 3.7	3.8 ± 2.2	0.001
NIMV	4.9 ± 1.8 (n = 22)	3.0 ± 0.9 (n = 23)	0.000
CMV	9.7 ± 4.3 (n = 11)	5.7 ± 3.1 (n = 10)	0.026
Length of ICU stay, d	8.5 ± 3.0	5.6 ± 1.8	0.000
NIMV	7.2 ± 1.8 (n = 22)	4.8 ± 0.7 (n = 23)	0.000
CMV	11.4 ± 3.1 (n = 11)	7.4 ± 2.3 (n = 10)	0.004
Length of hospital stay, d	14.3 ± 3.8	11.3 ± 2.0	0.000
NIMV	13.0 ± 3.4 (n = 22)	10.6 ± 1.7 (n = 23)	0.004
CMV	16.8 ± 3.1 (n = 22)	13.1 ± 1.7 (n = 10)	0.003
In-ICU mortality, No. (%)	4/33	3/33	0.689
NIMV	1/22 (n = 22)	1/23 (n = 23)	0.974
CMV	3/11 (n = 11)	2/10 (n = 10)	0.696
Failure of NIMV, No. (%)	5/22	3/23	0.396

Data are presented as mean ± SD unless specified otherwise. CMV, Convention mechanical ventilation; NIMV, noninvasive mechanical ventilation; ICU, intensive care unit.

In LMWH group, 23 patients (22/23) were treated with non-invasive mechanical ventilation (NIMV) and 10 patients (10/23) with conventional mechanical ventilation (CMV), compared to 22 patients (22/33) with NIMV and 11 patients (11/33) with CMV in control group. The clinical outcomes in each subgroup were summarized in Table 2. Either in NIMV or CMV subgroup, the mean duration of mechanical ventilation, the length of ICU stay, and hospital stays were significantly reduced in LMWH group compared to the control group.

Discussion

This study evaluated the effects of LMWH in addition to the standard treatment in COPD patients with acute exacerbations. The results demonstrated that 1 week of LMWH treatment had a positive anti-inflammatory effect, as evidenced by decreased CRP, IL-6, and fibrinogen levels. The length of ICU and hospital stays were also reduced. Airway and systemic inflammation occurs in patients with COPD (18). Stable COPD is associated with low-grade systemic inflammation manifested by an increase in blood leukocyte count, acute-phase proteins (CRP and fibrinogen), and inflammatory cytokines (19–21).

IL-6 and acute-phase proteins levels further increase during acute exacerbations of COPD and decline again during the recovery (20, 22). Clinical studies and ­animal experiments found an increase in the expression of neutrophil adhesion molecules and changes in neutrophil functions (23–25). Heparin modulates some of the pathophysiologic effects of endotoxin and TNF-α, such as neutrophil migration, edema formation, pulmonary hypertension, and hypoxemia (26). In addition, heparin has been shown to suppress specific neutrophil functions, such as superoxide generation and chemotaxis in vitro, and eosinophil migration (27). One of the proposed mechanisms underneath the anti-inflammatory actions of heparin is the binding of glycosaminoglycan to adhesion molecules on the surface of activated ECs (endocytes) and/or leukocytes (26).

Heparin influences immunologic responses and inhibits L- and P-selectin-mediated adhesion and TNF-α production by macrophages (26, 28). Several recent studies have demonstrated the anti-inflammatory activity of heparin (29, 30). In animal models, heparin disaccharide inhibits TNF-α production by macrophages and decreases the immune inflammation (29–31). The anti-inflammatory activity of heparin has been confirmed by small clinical trials involving patients with a range of inflammatory diseases, including rheumatoid arthritis, bronchial asthma and inflammatory bowel disease (32–35).

A hypercoagulable state exists in COPD patients; therefore heparin's anti-coagulant effect may add more benefit to COPD patients (36). Thus, heparin may have both anti-inflammatory and anticoagulant effects. In 2006, Brown et al. (37) reported that subcutaneously administrated LMWH (enoxaparin) once daily for 12 weeks in combination with conventional therapy provide additional clinical benefit, such as blood gas tension, dyspnea, and supplemental salbutamol use, to COPD patients (37).

Most recently, Shi et al. (38) reported that addition of LMWH to the conventional therapy (oxygen inhalation, spasmolysis, asthma relief, cough relief and sputum reduction) significantly improves the pulmonary functions in COPD patients with acute exacerbation. Our study showed that 1 week administration of heparin in combination with conventional therapy reduced the inflammatory molecules levels and the hospital and ICU stay of COPD patients with acute exacerbation, further supporting the clinical benefit of heparin in COPD.

This study is the first effort to evaluate the efficacy of a LMWH (nadroparin) in COPD patients with acute exacerbations in combination with standard therapy. Our observations suggest that further investigation is warranted to evaluate the use of heparin and related drugs in the treatment of COPD patients with acute exacerbations.

Declaration of Interest Statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Acknowledgment

Thanks to the Shanghai Young Physician Training Fund sponsored by Shanghai Medicine and Health Development Foundation for sponsorship to Y.Q.