Complementary Therapies in Medicine (2014) 22, 354—361
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevierhealth.com/journals/ctim
Safflower yellow for acute ischemic stroke: A systematic review of randomized controlled trials Siyuan Fan a, Nan Lin a, Guangliang Shan b, Pingping Zuo c, Liying Cui a,∗ a
Department of Neurology, Peking Union Medical College Hospital, China Department of Epidemiology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China c Department of Pharmacology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China Available online 9 January 2014 b
KEYWORDS Safflower yellow; Acute ischemic stroke; Systematic review; Meta-analysis
Summary Objectives: Stroke is one of the most common causes of mortality worldwide. Safflower yellow is widely used for the treatment of acute ischemic stroke in China. Several trials comparing safflower yellow and placebo or no intervention were unavailable for prior meta-analysis. Here, we present an updated and expanded systematic review, including four new trials, to evaluate the efficacy and safety of safflower yellow for the treatment of acute ischemic stroke. Methods: A comprehensive search was performed in Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, the Allied and Complementary Medicine Database (AMED), China National Knowledge Infrastructure (CNKI), China Biological Medicine Database (CBM), CQVIP Information and Wanfang Database until January 2013. Only randomized controlled trials (RCTs) evaluating the efficacy and safety of safflower yellow for acute ischemic stroke were included. Two researchers (Fan, S.Y. and Lin, N.) independently extracted data, assessed the study quality, and selected trials for inclusion. Results: 7 RCTs with 762 participants were included. None of the included studies were of high methodological quality. The meta-analysis showed that safflower yellow was more effective assessed by neurological improvement rate [odds ratio (OR), 3.11; 95% confidence interval (CI) 2.06—4.68, P < 0.05] compared with control group. No death was reported in any of the included studies during the follow up period. Only four trials reported adverse events, and skin rash was observed in the treatment group of one trial.
∗ Corresponding author at: Department of Neurology, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Dong Cheng District, Beijing 100730, China. Tel.: +86 10 69156114; fax: +86 10 69156114. E-mail address: [email protected] (L. Cui).
0965-2299/$ — see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ctim.2014.01.001
Safflower yellow for acute ischemic stroke
355
Conclusions: Safflower yellow seems to be effective and safe in the treatment of acute ischemic stroke. However, RCTs of high methodological quality are warranted before drawing any conclusion on the efficacy or safety of safflower yellow for acute ischemic stroke. © 2014 Elsevier Ltd. All rights reserved.
Contents Introduction.............................................................................................................. Methods.................................................................................................................. Criteria for study selection .......................................................................................... Search methods ..................................................................................................... Data collection and analysis ......................................................................................... Results ................................................................................................................... Description of studies ............................................................................................... Risk of bias of the trials analyzed ................................................................................... Effect of intervention ............................................................................................... Discussion ................................................................................................................ Limitations of the trials included in this review ..................................................................... Limitations and strengths of this review ............................................................................. Agreements and disagreements with other reviews.................................................................. Implications for practice ............................................................................................ Implications for research ............................................................................................ Conflict of interest statement............................................................................................ Acknowledgements..................................................................................................... References .............................................................................................................
Introduction Stroke is the second most common cause of mortality worldwide1,2 and the third commonest cause of mortality in China,3 accounting for 9.6%2 and 21.3%3 of total deaths respectively. Stroke is also the fifth leading cause of disease burden in low and middle-income countries (quantified by disability-adjusted life years) and the second leading cause of disease burden in high-income countries2 ; 67.3 to 80.5% of strokes are ischemic in origin, with the remaining being mainly haemorrhagic.4 Intravenous thrombolysis using recombinant tissue plasminogen activator (rtPA) is currently the only approved treatment for acute ischemic stroke.5 However, rtPA is often underused, primarily because of delayed admission of patients to stroke centres.5 It is estimated that fewer than 2% of patients receive this treatment in most countries.5 Given the time-dependent restrictions around rtPA administration and associated problems, patients with acute ischemic stroke are in urgent need of new and promising neuroprotectants. Chinese herbal medicine (CHM) plays an important role in this area of research. Safflower (Carthamus tinctorius L.) is used extensively for the treatment of acute ischemic stroke in China. The constituents of safflower include pigments, flavonoids, and phenolic acid. The content of safflower yellow in safflower extracts has been reported as 24.90—40.34%.6 Hydroxysafflor yellow A is a major component of safflower yellow.7 The protective effect of hydroxysafflor yellow A in ischemic stroke has been investigated in previous studies8—25 ; which have shown effects of anti-thrombosis,8,14 anti-coagulation,21 anti-excitotoxication,9,10,22 anti-oxidation/anti-nitrosative stress,11,12,17,18,23,25
355 355 355 356 356 356 356 357 357 358 358 358 358 359 359 359 359 359
anti-inflammation,15,19 anti-apoptosis,16,22,23 anti-calcium dysregulation,11 and protectection of endothelial cells.16,20,24 Other constituents of safflower yellow, like hydroxysafflor yellow B and nicotiflorin, have also been shown to protect neurons.26—28 Since the reporting of 3 prior Chinese systematic reviews69—71 of predominantly trials comparing safflower yellow and another CHM (other CHMs were used in the control group), several trials, comparing the efficacy and safety of safflower yellow and placebo or no intervention for acute ischemic stroke, had been published. There are four new trials34—37 identified in this review compared with previous reviews. Here we present an updated and expanded systematic review and meta-analysis, applying Cochrane Collaboration guidelines for systematic reviews, to evaluate the efficacy and safety of safflower yellow for the treatment of acute ischemic stroke, in order to provide the best available evidence for clinical practice, and to advance research on neuroprotectants for acute ischemic stroke.
Methods Criteria for study selection Only RCTs were eligible for inclusion. Quasi-randomised controlled trials were excluded, such as those that used an admission sequence for treatment allocation. Studies were eligible, when the patients treated were 18—80 years of age and the clinical diagnosis of acute ischemic stroke had been confirmed within 7 days of the event. The diagnosis had to be determined using a focal neurological deficit measurable on the National Institute
356 of Health Stroke Scale (NIHSS), Scandinavian Stroke Scale (SSS), MONICA (MONItoring trends and determinants of CArdiovascular disease) diagnostic criteria,29 or Modified Edinburgh-Scandinavian Stroke Scale (MESSS)30 ; computerized tomography (CT) or magnetic resonance imaging (MRI) had to demonstrate no evidence of intracranial haemorrhage. Trials involving safflower yellow versus placebo or no intervention were eligible, regardless of administration route, dosage, or length of treatment. Co-interventions were allowed if they were offered equally to each study arm. However, trials that involved other CHMs, used in either the treatment or control group, were excluded. The primary efficacy outcomes were death or neurological improvement rate, i.e. the proportion of patients with marked neurological improvement (assessed using a neurological deficit scale, e.g. NIHSS). The secondary outcome measure was the patients’ global neurological deficit scale score.
Search methods We searched the following electronic databases and trials and research registers: CENTRAL (Issue 12, 2012); Medline (1966—2013); Embase (1974—2013); AMED (1985—2013); CNKI (1979—2013); CBM (1979—2013); CQVIP Information (1989—2013), and Wanfang Database (1979—2013). The search string used was (‘‘safflower yellow’’ OR ‘‘safflor yellow’’ OR ‘‘carthamin yellow’’) AND (‘‘stroke’’ OR ‘‘cerebral infarction’’ OR ‘‘brain infarction’’ OR ‘‘cerebral ischemia’’ OR ‘‘brain ischemia’’).
Data collection and analysis Two review authors (Fan, S.Y. and Lin, N.) independently extracted data relating to the participants, methods, interventions, outcomes and results. This information was recorded on a data extraction form. For instances where the two reviewers’ entries did not match, a third person (Shan, G.L.) was involved for verification purposes. The statistical significant level for a two-sided test for each primary hypothesis was 0.05. If sufficient data were available we planned to conduct a meta-analysis using RevMan 5.2. The results are presented as Mantel—Haenszel odds ratios (OR), with 95% confidence intervals (CI) for dichotomous outcomes and the standardized mean difference (SMD) with 95% CI for continuous outcomes (using a fixed-effect approach unless there was significant heterogeneity, in which case a random-effects statistical model was used). We tested heterogeneity between trials results using a standard chi-squared test and the I-squared (I2 ) statistic; a value greater than 50% was considered to have substantial heterogeneity. If there was evidence of heterogeneity, we performed a sensitivity analysis to exclude trials that were of poor quality. If sufficient trials were identified, we tested for potential publication bias using a funnel plot.
S. Fan et al.
Results Description of studies We identified 2,738 references through the electronic and hand searches. We initially identified 39 potentially eligible trials (after excluding 2699 references that were not relevant by reading titles and abstracts). Eventually seven trials were included in our review31—37 ; summary details of these trials are described in Table 1. Of the 39 initial trials, 32 trials were excluded for the following reasons: two trials38,39 because they reported only blood test results as the outcome; another two trials40,41 were excluded because they were quasi-randomised trials; one trial42 because it included participants with transient ischemic attacks; one trial43 because the outcome differed from commonly-used outcomes; one trial44 because the trial recruited patients with an interval from stroke onset to start of treatment longer than 7 days (i.e. 14 days); one trial45 because the diagnosis criteria of ischemic stroke and whether CT/MRI was used were not specified (when we telephoned the author they refused to divulge this information); and 24 trials46—66 because the control group in these trials received another active therapy (that is, safflower yellow versus another drug). All of the included studies were published in Chinese between 2008 and 2011 and involved a total of 762 participants, all of whom were of Chinese ethnicity. Every trial reported the average age of the participants, which ranged from 52.8 to 65.8 years. All the included trials reported the inclusion criteria; four trials32,34,36,37 described the exclusion criteria. The diagnosis of ischemic stroke in each study was made according to Chinese national criteria.30 All the included trials used safflower yellow plus a conventional treatment or another treatment, compared with the other treatment alone. Intravenous preparations of safflower yellow were used in every study; the safflower yellow doses ranged from 80 mg to 100 mg per day and the course of treatment ranged from 14 to 15 days. The interval from stroke onset to start of treatment was less than 72 h in all of the trials. None of the participants in the trials included received intravenous thrombolysis. In four trials,31,33,34,37 the neurological improvement rate was assessed by MESSS, which was recommended at the Second National Cerebrovascular Diseases Conference (NCDC) in China,30 and then revised at the Fourth NCDC.30 MESSS-quantified neurological deficits were assessed in eight categories, including consciousness, eye movement, facial palsy, speech, motor power of the arms, hands and legs, and gait. Total scores on the MESSS ranged from 0 to 45, with higher values reflecting more severe cerebral infarcts (
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevierhealth.com/journals/ctim
Safflower yellow for acute ischemic stroke: A systematic review of randomized controlled trials Siyuan Fan a, Nan Lin a, Guangliang Shan b, Pingping Zuo c, Liying Cui a,∗ a
Department of Neurology, Peking Union Medical College Hospital, China Department of Epidemiology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China c Department of Pharmacology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China Available online 9 January 2014 b
KEYWORDS Safflower yellow; Acute ischemic stroke; Systematic review; Meta-analysis
Summary Objectives: Stroke is one of the most common causes of mortality worldwide. Safflower yellow is widely used for the treatment of acute ischemic stroke in China. Several trials comparing safflower yellow and placebo or no intervention were unavailable for prior meta-analysis. Here, we present an updated and expanded systematic review, including four new trials, to evaluate the efficacy and safety of safflower yellow for the treatment of acute ischemic stroke. Methods: A comprehensive search was performed in Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, the Allied and Complementary Medicine Database (AMED), China National Knowledge Infrastructure (CNKI), China Biological Medicine Database (CBM), CQVIP Information and Wanfang Database until January 2013. Only randomized controlled trials (RCTs) evaluating the efficacy and safety of safflower yellow for acute ischemic stroke were included. Two researchers (Fan, S.Y. and Lin, N.) independently extracted data, assessed the study quality, and selected trials for inclusion. Results: 7 RCTs with 762 participants were included. None of the included studies were of high methodological quality. The meta-analysis showed that safflower yellow was more effective assessed by neurological improvement rate [odds ratio (OR), 3.11; 95% confidence interval (CI) 2.06—4.68, P < 0.05] compared with control group. No death was reported in any of the included studies during the follow up period. Only four trials reported adverse events, and skin rash was observed in the treatment group of one trial.
∗ Corresponding author at: Department of Neurology, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Dong Cheng District, Beijing 100730, China. Tel.: +86 10 69156114; fax: +86 10 69156114. E-mail address: [email protected] (L. Cui).
0965-2299/$ — see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ctim.2014.01.001
Safflower yellow for acute ischemic stroke
355
Conclusions: Safflower yellow seems to be effective and safe in the treatment of acute ischemic stroke. However, RCTs of high methodological quality are warranted before drawing any conclusion on the efficacy or safety of safflower yellow for acute ischemic stroke. © 2014 Elsevier Ltd. All rights reserved.
Contents Introduction.............................................................................................................. Methods.................................................................................................................. Criteria for study selection .......................................................................................... Search methods ..................................................................................................... Data collection and analysis ......................................................................................... Results ................................................................................................................... Description of studies ............................................................................................... Risk of bias of the trials analyzed ................................................................................... Effect of intervention ............................................................................................... Discussion ................................................................................................................ Limitations of the trials included in this review ..................................................................... Limitations and strengths of this review ............................................................................. Agreements and disagreements with other reviews.................................................................. Implications for practice ............................................................................................ Implications for research ............................................................................................ Conflict of interest statement............................................................................................ Acknowledgements..................................................................................................... References .............................................................................................................
Introduction Stroke is the second most common cause of mortality worldwide1,2 and the third commonest cause of mortality in China,3 accounting for 9.6%2 and 21.3%3 of total deaths respectively. Stroke is also the fifth leading cause of disease burden in low and middle-income countries (quantified by disability-adjusted life years) and the second leading cause of disease burden in high-income countries2 ; 67.3 to 80.5% of strokes are ischemic in origin, with the remaining being mainly haemorrhagic.4 Intravenous thrombolysis using recombinant tissue plasminogen activator (rtPA) is currently the only approved treatment for acute ischemic stroke.5 However, rtPA is often underused, primarily because of delayed admission of patients to stroke centres.5 It is estimated that fewer than 2% of patients receive this treatment in most countries.5 Given the time-dependent restrictions around rtPA administration and associated problems, patients with acute ischemic stroke are in urgent need of new and promising neuroprotectants. Chinese herbal medicine (CHM) plays an important role in this area of research. Safflower (Carthamus tinctorius L.) is used extensively for the treatment of acute ischemic stroke in China. The constituents of safflower include pigments, flavonoids, and phenolic acid. The content of safflower yellow in safflower extracts has been reported as 24.90—40.34%.6 Hydroxysafflor yellow A is a major component of safflower yellow.7 The protective effect of hydroxysafflor yellow A in ischemic stroke has been investigated in previous studies8—25 ; which have shown effects of anti-thrombosis,8,14 anti-coagulation,21 anti-excitotoxication,9,10,22 anti-oxidation/anti-nitrosative stress,11,12,17,18,23,25
355 355 355 356 356 356 356 357 357 358 358 358 358 359 359 359 359 359
anti-inflammation,15,19 anti-apoptosis,16,22,23 anti-calcium dysregulation,11 and protectection of endothelial cells.16,20,24 Other constituents of safflower yellow, like hydroxysafflor yellow B and nicotiflorin, have also been shown to protect neurons.26—28 Since the reporting of 3 prior Chinese systematic reviews69—71 of predominantly trials comparing safflower yellow and another CHM (other CHMs were used in the control group), several trials, comparing the efficacy and safety of safflower yellow and placebo or no intervention for acute ischemic stroke, had been published. There are four new trials34—37 identified in this review compared with previous reviews. Here we present an updated and expanded systematic review and meta-analysis, applying Cochrane Collaboration guidelines for systematic reviews, to evaluate the efficacy and safety of safflower yellow for the treatment of acute ischemic stroke, in order to provide the best available evidence for clinical practice, and to advance research on neuroprotectants for acute ischemic stroke.
Methods Criteria for study selection Only RCTs were eligible for inclusion. Quasi-randomised controlled trials were excluded, such as those that used an admission sequence for treatment allocation. Studies were eligible, when the patients treated were 18—80 years of age and the clinical diagnosis of acute ischemic stroke had been confirmed within 7 days of the event. The diagnosis had to be determined using a focal neurological deficit measurable on the National Institute
356 of Health Stroke Scale (NIHSS), Scandinavian Stroke Scale (SSS), MONICA (MONItoring trends and determinants of CArdiovascular disease) diagnostic criteria,29 or Modified Edinburgh-Scandinavian Stroke Scale (MESSS)30 ; computerized tomography (CT) or magnetic resonance imaging (MRI) had to demonstrate no evidence of intracranial haemorrhage. Trials involving safflower yellow versus placebo or no intervention were eligible, regardless of administration route, dosage, or length of treatment. Co-interventions were allowed if they were offered equally to each study arm. However, trials that involved other CHMs, used in either the treatment or control group, were excluded. The primary efficacy outcomes were death or neurological improvement rate, i.e. the proportion of patients with marked neurological improvement (assessed using a neurological deficit scale, e.g. NIHSS). The secondary outcome measure was the patients’ global neurological deficit scale score.
Search methods We searched the following electronic databases and trials and research registers: CENTRAL (Issue 12, 2012); Medline (1966—2013); Embase (1974—2013); AMED (1985—2013); CNKI (1979—2013); CBM (1979—2013); CQVIP Information (1989—2013), and Wanfang Database (1979—2013). The search string used was (‘‘safflower yellow’’ OR ‘‘safflor yellow’’ OR ‘‘carthamin yellow’’) AND (‘‘stroke’’ OR ‘‘cerebral infarction’’ OR ‘‘brain infarction’’ OR ‘‘cerebral ischemia’’ OR ‘‘brain ischemia’’).
Data collection and analysis Two review authors (Fan, S.Y. and Lin, N.) independently extracted data relating to the participants, methods, interventions, outcomes and results. This information was recorded on a data extraction form. For instances where the two reviewers’ entries did not match, a third person (Shan, G.L.) was involved for verification purposes. The statistical significant level for a two-sided test for each primary hypothesis was 0.05. If sufficient data were available we planned to conduct a meta-analysis using RevMan 5.2. The results are presented as Mantel—Haenszel odds ratios (OR), with 95% confidence intervals (CI) for dichotomous outcomes and the standardized mean difference (SMD) with 95% CI for continuous outcomes (using a fixed-effect approach unless there was significant heterogeneity, in which case a random-effects statistical model was used). We tested heterogeneity between trials results using a standard chi-squared test and the I-squared (I2 ) statistic; a value greater than 50% was considered to have substantial heterogeneity. If there was evidence of heterogeneity, we performed a sensitivity analysis to exclude trials that were of poor quality. If sufficient trials were identified, we tested for potential publication bias using a funnel plot.
S. Fan et al.
Results Description of studies We identified 2,738 references through the electronic and hand searches. We initially identified 39 potentially eligible trials (after excluding 2699 references that were not relevant by reading titles and abstracts). Eventually seven trials were included in our review31—37 ; summary details of these trials are described in Table 1. Of the 39 initial trials, 32 trials were excluded for the following reasons: two trials38,39 because they reported only blood test results as the outcome; another two trials40,41 were excluded because they were quasi-randomised trials; one trial42 because it included participants with transient ischemic attacks; one trial43 because the outcome differed from commonly-used outcomes; one trial44 because the trial recruited patients with an interval from stroke onset to start of treatment longer than 7 days (i.e. 14 days); one trial45 because the diagnosis criteria of ischemic stroke and whether CT/MRI was used were not specified (when we telephoned the author they refused to divulge this information); and 24 trials46—66 because the control group in these trials received another active therapy (that is, safflower yellow versus another drug). All of the included studies were published in Chinese between 2008 and 2011 and involved a total of 762 participants, all of whom were of Chinese ethnicity. Every trial reported the average age of the participants, which ranged from 52.8 to 65.8 years. All the included trials reported the inclusion criteria; four trials32,34,36,37 described the exclusion criteria. The diagnosis of ischemic stroke in each study was made according to Chinese national criteria.30 All the included trials used safflower yellow plus a conventional treatment or another treatment, compared with the other treatment alone. Intravenous preparations of safflower yellow were used in every study; the safflower yellow doses ranged from 80 mg to 100 mg per day and the course of treatment ranged from 14 to 15 days. The interval from stroke onset to start of treatment was less than 72 h in all of the trials. None of the participants in the trials included received intravenous thrombolysis. In four trials,31,33,34,37 the neurological improvement rate was assessed by MESSS, which was recommended at the Second National Cerebrovascular Diseases Conference (NCDC) in China,30 and then revised at the Fourth NCDC.30 MESSS-quantified neurological deficits were assessed in eight categories, including consciousness, eye movement, facial palsy, speech, motor power of the arms, hands and legs, and gait. Total scores on the MESSS ranged from 0 to 45, with higher values reflecting more severe cerebral infarcts (
