DLBS1033 treatment for ischemic stroke patients and clinical outcomes: systematic review of randomized controlled trial study

DLBS1033 is a lumbrokinase earned from extraction of earthworms, Lumbricus rubellus . Lumbrokinase has 2 main activities: (cid:977)ibrinolytic and (cid:977)ib-rinogenolytic – these activities reduce blood viscosity and platelet aggregation. With all of those properties, DLBS1033 will be a promising agent in patients with ischemic stroke. The objective of this research is to identify the advantage of DLBS1033 in ischemic stroke patients’ clinical outcome. We used Pub Med, Cochrane, and Clinical Key as our major database for this systematic review. ”DLBS1033”, ”lumbrokinase”, and ”stroke” keywords selected to particularize the search. The 2 authors calculated each of the studies using Jadad score. Only certain studies with scores above 3 will be included for further review using PRISMA checklist. There were 27 studies relating to DLBS1033 or lumbrokinase and stroke. Further examination by 2 authors resulted in 23 articles being removed leaving 2 studies. Subjects in all of the said studies are ischemic stroke patients; predominantly male patients. All of the said studies compare DLBS1033 with standard therapy; either utilizing DLBS1033 as an additional therapy or as a separate therapy. Clinical outcomes were measured using NIHSS and BI. Compared to standard therapy, DLBS1033 proved successful in improving clinical outcomes among patients with ischemic stroke. It’s also found to be safe with none serious adverse events and signi(cid:977)icantly has lower bleeding events.

DLBS1033, lumbrokinase, Lumbricus rubellus, stroke, stroke treatment, clinical outcome ABSTRACT DLBS1033 is a lumbrokinase earned from extraction of earthworms, Lumbricus rubellus. Lumbrokinase has 2 main activities: ibrinolytic and ibrinogenolytic -these activities reduce blood viscosity and platelet aggregation. With all of those properties, DLBS1033 will be a promising agent in patients with ischemic stroke. The objective of this research is to identify the advantage of DLBS1033 in ischemic stroke patients' clinical outcome. We used Pub Med, Cochrane, and Clinical Key as our major database for this systematic review. "DLBS1033", "lumbrokinase", and "stroke" keywords selected to particularize the search. The 2 authors calculated each of the studies using Jadad score. Only certain studies with scores above 3 will be included for further review using PRISMA checklist. There were 27 studies relating to DLBS1033 or lumbrokinase and stroke. Further examination by 2 authors resulted in 23 articles being removed leaving 2 studies. Subjects in all of the said studies are ischemic stroke patients; predominantly male patients. All of the said studies compare DLBS1033 with standard therapy; either utilizing DLBS1033 as an additional therapy or as a separate therapy. Clinical outcomes were measured using NIHSS and BI. Compared to standard therapy, DLBS1033 proved successful in improving clinical outcomes among patients with ischemic stroke. It's also found to be safe with none serious adverse events and signi icantly has lower bleeding events.

INTRODUCTION
Stroke can be described as emerging signs of cerebral dysfunction those last more than 24 hours (Aho et al., 1980). Ischemic stroke and hemorrhagic stroke are 2 varieties of stroke, distinguished by their pathomechanism, whether the blood vessel is blocked or burst (Caplan, 2009).
Stroke has claimed the third spot as the major cause of premature death and disability-adjusted life years lost in 2017 (IHME, 2018). Three quarters of stroke patients diagnosed with ischemic stroke. Stroke responsible for almost 6,500,000 deaths (half of them due to ischemic stroke), 113,000,000 disability-adjusted life years lost (0.58 times more often due to ischemic stroke), and 10,300,000 million new cases worldwide in 2013 (Feigin et al., 2013).
No standard therapy has currently been established for ischemic stroke treatment.
Several therapies that are frequently used to treat ischemic stroke attack including thrombolytic therapy, antiplatelet agents, anticoagulants and neuroprotective agents (Adams et al., 2007). Some thrombolytic agents like urokinase (uPA), streptokinase (SK) and tissue urokinase (t-PA) are all typically used to dissolve clots in ischemic stroke. However they're not speci ic to ibrin and have severe side effects like heavy blood loss (Vernooij, 2009;Delaney et al., 2007). Further, medication with rtPA features a limitation of time. The aforementioned medication should be used less than 3 hours after stroke (Caplan, 2009). Additionally, there are emerging resistance to therapy with the foremost established antiplatelets, aspirin, and clopidogrel (Musallam et al., 2011;Cuisset and Cayla, 2010;Wang et al., 2006). DLBS1033 is a lumbrokinase earned from extraction of earthworms, Lumbricus rubellus (Trisina et al., 2011). For thousands of years, earthworms have widely been utilized in Indonesia, China, Japan, and therefore the Far East to treat various chronic diseases (Willem & Minne, cited in Simangunsong et al ., 2016). In 1991, Japanese researchers were the irst to use the word 'lumbrokinase' that refers to a cluster of serine protease enzyme in earthworms. Lumbrokinase has 2 main activities: ibrinolytic and ibrinogenolytic -these activities reduce blood viscosity and platelet aggregation (Mihara et al., 1991).
Unlike other thrombolytic agents, such as urokinase (uPA), streptokinase (SK), and tissue plaminogen activator (t-PA); lumbrokinase is extremely speci ic to ibrin as a substrate and doesn't cause excessive bleeding (Hrženjak et al., 1998). Lumbrokinase has both antithrombotic and thrombolytic activities; thus, unlike the anticoagulants, lumbrokinase suppresses new clots formation and breaks up clots that have already been formed (Trisina et al., 2011;Kurnia and Tjandrawinata, 2011). Lumbrokinase has not shown any adverse effects on the functions of the systema nervosum, systema respiratorium, cardiovascular vessels, or the liver and kidney (16, 17). DLBS1033 has been proven through its toxicological studies in animal (Sukandar et al., 2014) and safety studies in human (Ortiz and Sacco, 2014;Yunaidi et al., 2011). With all of those properties, lumbrokinase will be a promising agent in patients with ischemic stroke.

MATERIALS AND METHODS
We used Pub Med, Cochrane, and Clinical Key as our major database for this systematic review. "DLBS1033", "lumbrokinase", and "stroke" keywords selected to particularize the search.
The selected studies must have these subsequent standards: (i) the study was published in the past 10 years, (ii) full text available in English, (iii) justify the advantage of DLBS1033 as add on therapy in standard therapy of ischemic stroke. Studies other than randomized controlled trial (RCT) won't be reviewed any further.
The 2 authors calculated each of the studies using Jadad score. There are 5 components in Jadad score with score of 5 as the maximum grade. One point is going to be added for each component the study met (Berger and Alperson, 2009) . Only certain studies with scores above 3 will be included for further review using PRISMA checklist. Twenty seven items of PRISMA checklist are used to evaluate systematic review (Liberati et al., 2009).

RESULTS AND DISCUSSION
As shown in Figure 1, there were 27 studies relating to DLBS1033 or lumbrokinase and stroke. After discounting 2 duplicates, there were 25 studies. Further examination by 2 authors resulted in 23 articles being removed leaving 2 studies. Both of those studies were available in full-text articles.
Jadad score was utilized in this systematic review to evaluate the standard of every study. All of the studies graded with score of 3 as shown in Table 1. Table 2 showing the summary of included studies. Ischemic stroke patients were the subjects and DLBS1033 or lumbrokinase were compared with standard therapy for stroke in all studies. National Institutes of Health Stroke Scale (NIHSS) were used to evaluate clinical outcomes in study by Cao et al. (2013). Study by Setyopranoto et al. (2016) used Barthel Index (BI) to measure clinical outcomes. Table 3 summarized the conclusion of every study. DLBS1033 improves patients' clinical outcome. DLBS1033 was considered to be safe for patients with ischemic stroke.

Measurement
NIHSS is disability assessment tool focused on neurological impairment utilized in RCT by Cao et al. (2013). NIHSS contains 15-item impairment scale and each scale graded on an ordinal scale (Kwah and Diong, 2014). Normal is described as 0; therefore, the bigger the score, the more severe the neurological impairment (the maximum score is 42) (Ortiz and Sacco, 2014).
Study by Setyopranoto et al. (2016) was using BI. BI consists of 10 item-scale (Mahoney and Barthel, 1965). The sum total score ranging from 0 to 100; zero considered as the most severe dependency (Quinn et al., 2011). Scoring on the BI can be classi ied into: patient able to live independently, dependent (either minimally, partially, or totally), and total dependence (Shinar et al., 1988).     (Setyopranoto et al., 2016).

Safety
A study by Cao et al. (2013) reported cerebrovascular injuries in 5.93 percent patients: 2 transient ischemic attack, 4 cerebral infarctions, and 1 bleeding within the control group at the 12-month follow up. There was 1 additional event of organ ischemia event within the control group. There were 1.04 percent cerebrovascular incidents inside the lumbrokinase group (1 transient ischemic attack and 1 cerebral infarction), 1 cardiovascular event, and 1 lower gastrointestinal bleeding. Disparities in total vascular and cerebrovascular events among 2 groups were statistically signi icant (p: 0.046 and p: 0.016). Adverse events were dizziness, nauseating, and vomiting reported from ive subjects in lumbrokinase group and seven subjects in control group. Setyopranoto et al. (2016) found neither signi icantly bleeding events nor adverse events.

CONCLUSIONS
Compared to standard therapy, DLBS1033 turned out successful in improving clinical outcomes among patients with ischemic stroke. It's also found to be safe with none serious adverse events and signi icantly has lower bleeding events.

ACKNOWLEDGEMENT
This systematic review was personally funded by 2 authors.