Inhaled nebulised unfractionated heparin improves lung function in moderate to very severe COPD: A pilot study

Janis K. Shute, Luigino Calzetta, Vittorio Cardaci, Stefania di Toro, Clive P. Page, Mario Cazzola

Research output: Contribution to journalArticle

Abstract

Background COPD is an inflammatory airway disease characterised by progressive airflow limitation and air trapping, leading to lung hyperinflation and exercise limitation. Acute worsening of symptoms, including dyspnea, cough and sputum production, occurs during exacerbations which are associated with significantly reduced health related quality of life, and increased morbidity and mortality. Chronic bronchial mucus production and productive cough are risk factors for exacerbations. Medicines targeting bronchoconstriction and airway inflammation are the current mainstays of COPD therapy. However, there is growing concern with an increased risk of pneumonia in patients with COPD receiving regular inhaled corticosteroids and there is therefore a need to find safer alternative treatments. Previous studies have indicated that inhalation of unfractionated heparin (UFH) treats local inflammation, mucus hypersecretion and lung injury, without systemic anticoagulation, and is safe. Therefore, our primary objective was to demonstrate that inhaled UFH significantly improves lung function (FEV1) over 21 days of treatment in patients with COPD receiving pulmonary rehabilitation and that UFH provides a novel, safe and effective way of treating this complex disease. Methods Forty patients with moderate to very severe COPD admitted to the IRCCS San Raffaele Pisana Hospital for 21 days pulmonary rehabilitation were randomised to receive nebulised inhaled UFH (75,000 or 150,000 IU BID) or placebo for 21 days. All patients also received nebulised salbutamol (1 mg) and beclomethasone dipropionate (400 μg) BID over the same period. Lung function was measured at day 0, 7, 14 and 21 of treatment and at a follow-up visit 7 days post-treatment. Exercise capacity (6MWT) and dyspnoea (Borg score) were measured before and after treatment. In pre-clinical studies, the ability of basic proteins found in COPD sputum to neutralise the anticoagulant activity of heparin was determined using the AMAX heparin assay kit. Main results At both doses, UFH significantly increased FVC following 7 days of treatment and 150,000 IU BID significantly increased FEV1 (+249 ± 69 ml compared with placebo) at this time, an effect maintained to the 28 day follow-up. Clinically significant improvement in exercise capacity and dyspnoea were seen after 21 days of treatment with both doses of UFH. There were no serious adverse events or effects on systemic coagulation. Pre-clinical studies demonstrated that the basic proteins lactoferrin, platelet factor-4 (PF-4), IL-8 and polyarginine, as a model of the eosinophil cationic protein (ECP), found in COPD sputum neutralise the anticoagulant activity of heparin. Conclusion Inhaled nebulised UFH is safe and provides additional clinical benefit for patients with moderate to very severe COPD through effects that are independent of its anticoagulant activity.

Original languageEnglish
Number of pages9
JournalPulmonary Pharmacology and Therapeutics
DOIs
Publication statusAccepted/In press - Oct 3 2017

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Chronic Obstructive Pulmonary Disease
Heparin
Lung
Sputum
Dyspnea
Anticoagulants
Exercise
Mucus
Therapeutics
Cough
Patient rehabilitation
Rehabilitation
Placebos
Eosinophil Cationic Protein
Inflammation
Platelet Factor 4
Beclomethasone
Lactoferrin
Bronchoconstriction
Albuterol

Keywords

  • Anticoagulant activity
  • Clinical trial
  • COPD
  • Inhaled
  • Lung function
  • Unfractionated heparin

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Biochemistry, medical
  • Pharmacology (medical)

Cite this

Inhaled nebulised unfractionated heparin improves lung function in moderate to very severe COPD : A pilot study. / Shute, Janis K.; Calzetta, Luigino; Cardaci, Vittorio; di Toro, Stefania; Page, Clive P.; Cazzola, Mario.

In: Pulmonary Pharmacology and Therapeutics, 03.10.2017.

Research output: Contribution to journalArticle

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abstract = "Background COPD is an inflammatory airway disease characterised by progressive airflow limitation and air trapping, leading to lung hyperinflation and exercise limitation. Acute worsening of symptoms, including dyspnea, cough and sputum production, occurs during exacerbations which are associated with significantly reduced health related quality of life, and increased morbidity and mortality. Chronic bronchial mucus production and productive cough are risk factors for exacerbations. Medicines targeting bronchoconstriction and airway inflammation are the current mainstays of COPD therapy. However, there is growing concern with an increased risk of pneumonia in patients with COPD receiving regular inhaled corticosteroids and there is therefore a need to find safer alternative treatments. Previous studies have indicated that inhalation of unfractionated heparin (UFH) treats local inflammation, mucus hypersecretion and lung injury, without systemic anticoagulation, and is safe. Therefore, our primary objective was to demonstrate that inhaled UFH significantly improves lung function (FEV1) over 21 days of treatment in patients with COPD receiving pulmonary rehabilitation and that UFH provides a novel, safe and effective way of treating this complex disease. Methods Forty patients with moderate to very severe COPD admitted to the IRCCS San Raffaele Pisana Hospital for 21 days pulmonary rehabilitation were randomised to receive nebulised inhaled UFH (75,000 or 150,000 IU BID) or placebo for 21 days. All patients also received nebulised salbutamol (1 mg) and beclomethasone dipropionate (400 μg) BID over the same period. Lung function was measured at day 0, 7, 14 and 21 of treatment and at a follow-up visit 7 days post-treatment. Exercise capacity (6MWT) and dyspnoea (Borg score) were measured before and after treatment. In pre-clinical studies, the ability of basic proteins found in COPD sputum to neutralise the anticoagulant activity of heparin was determined using the AMAX heparin assay kit. Main results At both doses, UFH significantly increased FVC following 7 days of treatment and 150,000 IU BID significantly increased FEV1 (+249 ± 69 ml compared with placebo) at this time, an effect maintained to the 28 day follow-up. Clinically significant improvement in exercise capacity and dyspnoea were seen after 21 days of treatment with both doses of UFH. There were no serious adverse events or effects on systemic coagulation. Pre-clinical studies demonstrated that the basic proteins lactoferrin, platelet factor-4 (PF-4), IL-8 and polyarginine, as a model of the eosinophil cationic protein (ECP), found in COPD sputum neutralise the anticoagulant activity of heparin. Conclusion Inhaled nebulised UFH is safe and provides additional clinical benefit for patients with moderate to very severe COPD through effects that are independent of its anticoagulant activity.",
keywords = "Anticoagulant activity, Clinical trial, COPD, Inhaled, Lung function, Unfractionated heparin",
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AU - Shute, Janis K.

AU - Calzetta, Luigino

AU - Cardaci, Vittorio

AU - di Toro, Stefania

AU - Page, Clive P.

AU - Cazzola, Mario

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N2 - Background COPD is an inflammatory airway disease characterised by progressive airflow limitation and air trapping, leading to lung hyperinflation and exercise limitation. Acute worsening of symptoms, including dyspnea, cough and sputum production, occurs during exacerbations which are associated with significantly reduced health related quality of life, and increased morbidity and mortality. Chronic bronchial mucus production and productive cough are risk factors for exacerbations. Medicines targeting bronchoconstriction and airway inflammation are the current mainstays of COPD therapy. However, there is growing concern with an increased risk of pneumonia in patients with COPD receiving regular inhaled corticosteroids and there is therefore a need to find safer alternative treatments. Previous studies have indicated that inhalation of unfractionated heparin (UFH) treats local inflammation, mucus hypersecretion and lung injury, without systemic anticoagulation, and is safe. Therefore, our primary objective was to demonstrate that inhaled UFH significantly improves lung function (FEV1) over 21 days of treatment in patients with COPD receiving pulmonary rehabilitation and that UFH provides a novel, safe and effective way of treating this complex disease. Methods Forty patients with moderate to very severe COPD admitted to the IRCCS San Raffaele Pisana Hospital for 21 days pulmonary rehabilitation were randomised to receive nebulised inhaled UFH (75,000 or 150,000 IU BID) or placebo for 21 days. All patients also received nebulised salbutamol (1 mg) and beclomethasone dipropionate (400 μg) BID over the same period. Lung function was measured at day 0, 7, 14 and 21 of treatment and at a follow-up visit 7 days post-treatment. Exercise capacity (6MWT) and dyspnoea (Borg score) were measured before and after treatment. In pre-clinical studies, the ability of basic proteins found in COPD sputum to neutralise the anticoagulant activity of heparin was determined using the AMAX heparin assay kit. Main results At both doses, UFH significantly increased FVC following 7 days of treatment and 150,000 IU BID significantly increased FEV1 (+249 ± 69 ml compared with placebo) at this time, an effect maintained to the 28 day follow-up. Clinically significant improvement in exercise capacity and dyspnoea were seen after 21 days of treatment with both doses of UFH. There were no serious adverse events or effects on systemic coagulation. Pre-clinical studies demonstrated that the basic proteins lactoferrin, platelet factor-4 (PF-4), IL-8 and polyarginine, as a model of the eosinophil cationic protein (ECP), found in COPD sputum neutralise the anticoagulant activity of heparin. Conclusion Inhaled nebulised UFH is safe and provides additional clinical benefit for patients with moderate to very severe COPD through effects that are independent of its anticoagulant activity.

AB - Background COPD is an inflammatory airway disease characterised by progressive airflow limitation and air trapping, leading to lung hyperinflation and exercise limitation. Acute worsening of symptoms, including dyspnea, cough and sputum production, occurs during exacerbations which are associated with significantly reduced health related quality of life, and increased morbidity and mortality. Chronic bronchial mucus production and productive cough are risk factors for exacerbations. Medicines targeting bronchoconstriction and airway inflammation are the current mainstays of COPD therapy. However, there is growing concern with an increased risk of pneumonia in patients with COPD receiving regular inhaled corticosteroids and there is therefore a need to find safer alternative treatments. Previous studies have indicated that inhalation of unfractionated heparin (UFH) treats local inflammation, mucus hypersecretion and lung injury, without systemic anticoagulation, and is safe. Therefore, our primary objective was to demonstrate that inhaled UFH significantly improves lung function (FEV1) over 21 days of treatment in patients with COPD receiving pulmonary rehabilitation and that UFH provides a novel, safe and effective way of treating this complex disease. Methods Forty patients with moderate to very severe COPD admitted to the IRCCS San Raffaele Pisana Hospital for 21 days pulmonary rehabilitation were randomised to receive nebulised inhaled UFH (75,000 or 150,000 IU BID) or placebo for 21 days. All patients also received nebulised salbutamol (1 mg) and beclomethasone dipropionate (400 μg) BID over the same period. Lung function was measured at day 0, 7, 14 and 21 of treatment and at a follow-up visit 7 days post-treatment. Exercise capacity (6MWT) and dyspnoea (Borg score) were measured before and after treatment. In pre-clinical studies, the ability of basic proteins found in COPD sputum to neutralise the anticoagulant activity of heparin was determined using the AMAX heparin assay kit. Main results At both doses, UFH significantly increased FVC following 7 days of treatment and 150,000 IU BID significantly increased FEV1 (+249 ± 69 ml compared with placebo) at this time, an effect maintained to the 28 day follow-up. Clinically significant improvement in exercise capacity and dyspnoea were seen after 21 days of treatment with both doses of UFH. There were no serious adverse events or effects on systemic coagulation. Pre-clinical studies demonstrated that the basic proteins lactoferrin, platelet factor-4 (PF-4), IL-8 and polyarginine, as a model of the eosinophil cationic protein (ECP), found in COPD sputum neutralise the anticoagulant activity of heparin. Conclusion Inhaled nebulised UFH is safe and provides additional clinical benefit for patients with moderate to very severe COPD through effects that are independent of its anticoagulant activity.

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KW - Clinical trial

KW - COPD

KW - Inhaled

KW - Lung function

KW - Unfractionated heparin

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