الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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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
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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.