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Abstract Asthma and COPD are among the most widespread obstructive pulmonary diseases on a global scale. Despite the availability of targeted therapies, management of these conditions remains challenging. Therefore, we aimed to assess the effectiveness and safety of inhaled heparin and its derivatives as an alternative or complementary treatment for asthma and COPD. Our analysis demonstrated that inhaled heparin significantly improves pulmonary function, particularly FEV1, and PC20, without increasing the risk of bleeding in adult asthmatic and COPD patients, whether used alone or in combination with other therapies, especially for those with severe or critical conditions. Subgroup analysis revealed that adding UFH as a treatment, at a dose of 1000IU/Kg, at least 20 minutes prior to an allergen or exercise provocation test, yielded the highest significant pooled estimate. Most randomized controlled trials did not demonstrate any adverse events and those that did were rare and mild, such as headache and self-limited bronchospasm, with no serious adverse events reported. Our findings reveal a significant statistical advantage in using inhaled heparin to improve FEV1% in adult asthmatic patients, with a high level of evidence to support this claim. These results are consistent with Yang’s meta-analysis (28) that examined the use of injectable LMWH in COPD patients and found that it improves FEV1 (MD = 0.19, 95% CI: 0.09–0.29, P = 0.0002) but increases the risk of hemorrhage. In addition, heparin may have benefits for various lung diseases. Two meta-analyses by Xiangyue in 2020 (66) and Xinghao in 2020 (67) concluded that low-dose heparin injection and LMWH can improve oxygenation and lung function in patients with acute respiratory distress syndrome (ARDS)/ Acute lung injury (ALI), reduce mortality, but may also increase the risk of bleeding. This meta-analysis extends the systematic review of the inflammatory protective effect of heparin, focusing on the inhaled form for bronchoconstriction-associated diseases (15). Moreover, the Mongale review, (20 studies, 536patients), found that earlier studies have indicated that inhalation of UFH treats local inflammation, mucus hypersecretion, and lung injury without systemic anticoagulation or any incidence of pulmonary hemorrhage (68). The inhalation of heparin suppresses the initial reaction to allergens and exercise-induced asthma, likely by preventing the release of mediators from mast cells. Our finding matches the conclusion of Fr¨ohlich review (69) for using oral inhalation is the best way to deliver protein (such as heparin) and peptides for diseases affecting the lungs (e.g. asthma, COVID-19, etc). In addition to Petris’ review (70) found that anticoagulation therapy is very important for COPD patients and can reduce their risk of mortality due to some bronchopulmonary changes and pulmonary embolism. Also, it was noted that the antioxidant properties of heparin can contribute to decreased inflammation and safeguard anti- proteins against oxidative inactivation, limit reactive oxygen species (ROS)-induced mucus hypersecretion, and counteract the oxidative stress as a feature of bronchial asthma and COPD, with their wide-ranging effects in the airways and lung parenchyma specifically in COPD patients(13). The positive outcomes of heparin found in the literature for the pulmonary route require a focus on the preparation and evaluation of heparin in advanced drug delivery systems, speci fically nano/microparticles and liposomes(22). Moreover, timing is a very important factor in heparin inhalation because the effect of inhaled heparin is not immediate like the short-acting B2 agonist. According to Yildiz et al review(14), inhaled heparin is safe and beneficial for treating lung diseases. Discussion 18 Strengthens: This is the first specific meta-analysis addressing inhaled heparin for asthma and COPD patients. Our comprehensive updated search in 15 databases to synthesize all published evidence regarding this topic, besides all studies included in this meta-analysis were RCT, with high to moderate GRADE evidence. This facilitates the decision of using this important and widely available drug. Sub-group analysis helps in deciding the best dose, time, and formula of heparin because using subtherapeutic doses makes biased negative results. Limitation: This meta-analysis majority of included studies are for adult asthmatic patients. Conclusion: For COPD patients and children asthmatic patients need more studies for using inhaled heparin in these conditions. New drug delivery formulations need in vivo research to ensure their efficacy in bronchoconstriction diseases. Most of the included studies were cross-over designs with low sample sizes and of high risk of bias, thus we need new research regarding this important route of administration for this drug. The study suggests that inhaled heparin and its derivatives in asthma or COPD exacerbations may be beneficial and could be prescribed in addition to the standard therapy. The right dose, timing, frequency, and duration of heparin therapy should be considered to achieve the best clinical outcomes for those patien. |