Comparison of the Therapeutic Efficacy of Ozagrel Alone and Ozagrel Plus Edaravone Therapy for Acute Ischemic Stroke Patients : a Prospective Study

● Original

Comparison of the Therapeutic Efficacy of Ozagrel Alone and Ozagrel Plus Edaravone Therapy for Acute Ischemic Stroke Patients : A Prospective Study

Ken-ichiro Katsura, Toshiya Katsumata Takaharu Fukuchi and Yasuo Katayama

Abstract Objective : This study was performed to compare the efficacy of ozagrel alone and ozagrel plus edaravone treatments for acute ischemic stroke patients. Methods : Thirty patients with acute atherothrombotic infarction or lacunar infarction within 24 h after onset were enrolled in this study. They were randomly allocated into an ozagrel-alone treatment group（n＝12） or an ozagrel plus edaravone treatment group（n＝18）. Other treatments were similar and common to both groups. Patients with an NIH stroke scale（NIHSS）of more than 12 on admission were excluded. Results : There was no significant difference between the two groups in Barthel index at discharge. The delta NIHSS and delta Barthel index also showed no difference between groups. Multivariate analysis revealed that patient age was the sole significant factor influencing the Barthel index at discharge, and the difference of drug therapy did not give significant influence on prognosis. Conclusion : For patients with cerebral infarction with NIHSS less than 12, ozagrel plus edaravone treatment failed to show significant superior efficacy than ozagrel-alone treatment. Ozagrel-alone may be an effective treatment to start treating patients with relatively mild atherothrombotic infarction or lacunar infarction. （Cerebral Blood Flow and Metabolism 17 : 17―22, 2005） Key words : ozagrel Na, edaravone, atherothrombotic infarction, lacunar infarction

ischemic stroke1～3）, leading to secondary deteriora- Introduction tion of CBF in the penumbra area and further ex- pansion of the infarction4）.Twomajortrialsofaspi- It is well understood that brain tissue under ische- rin in acute ischemic stroke revealed that early aspi- mia is in a state of severe energy failure. Without ef- rin use produces a small but significantly better fective recovery of cerebral blood flow（CBF）, prognosis5,6）. Antiplatelet therapy therefore shows ischemic tissue will die and end in pannecrosis, i.e. promise in treating ischemic stroke. However, the infarction. In order to minimize ischemic brain in- antiplatelet activity of aspirin is limited, probably be- jury in stroke, early restoration of CBF is vital. Re- cause it also inhibits prostaglandin I2 which may lead

7） cent therapy of thrombolysis with tissue plasmino- to decreased CBF . A selective thromboxane A2 gen activator is promising, however, the majority of （TXA2）synthase inhibitor, sodium ozagrel（OKY- patients are outside its scope at present. Most pa- 046）, is free from this drawback. tients with cerebral infarction still receive antiplate- Edaravone is a free radical scavenger with antioxi- let or anticoagulant therapy which leaves room to be dant properties. Animal experiments showed signifi- improved. Platelet activation is enhanced after cant protection against cerebral ischemia8）. Random- ized, double-blind, placebo controlled clinical trials

The Second Department of Internal Medicine, Nippon have demonstrated the neuroprotective effects of Medical School, Tokyo, Japan edaravone in patients with acute cerebral infarc-

―17― 脳循環代謝第 17 巻第 1 号 tion9）. which were our usual therapies for cerebral infarc- Since the effects of ozagrel and edaravone are dif- tion. Other drugs, e.g. glycerol, were similarly used ferent in their action, theoretically, their combination in all groups. If the diagnosis had to be changed（e.g. may be beneficial to patients, apart from the cost of cardioembolic infarction）or if the symptom of the pa- the therapy. There are no reports prospectively tients worsened significantly and received additional comparing the efficacy between ozagrel alone and drugs, those patients were excluded. ozagrel plus edaravone treatments. In this study, patients with acute cerebral infarc- Statistics tion were randomized to ozagrel alone treatment, The baseline characteristics of the patients were and ozagrel plus edaravone treatment groups, and analyzed by the chi square test. To test the differ- examined various parameters including NIHSS and ence between ozagrel and ozagrel plus edaravone Barthel index to evaluate the efficacy of therapies. groups, the t-test was used. The factors influencing the Bathel index at discharge were evaluated by Subjects and Methods multivariate analysis with the Cox hazard model. To test if the variables selected were appropriate or Study design not, the Wald test, Score test, and Likelihood ratio Between December 2001 and June 2003, patients test were performed. The level of significance was with acute cerebral infarction who were admitted to set at p＜0.05（two-tailed）. the Nippon Medical School Hospital within 24 h after onset were allocated in the sequential order to either Results an ozagrel-alone treatment group, or sodium ozagrel plus edaravone treatment group. All patients re- Enrollment of patients ceived similar therapy except for those drugs. Between Dec 2001 and June 2003, 46 patients were enrolled into this study. One patient with Patients NIHSS of 20 was excluded from ozagrel alone Consecutive patients who were admitted to our groups（Grubbs-Smirnov test p＜0.01）. Patients who hospital with cerebral infarction, and within 24 h af- had been diagnosed as stroke by on call doctors ter onset, were allocated to this study. Patients were were evaluated with MRI by several neurologists on neurologically evaluated and diagnosed together the next day. If there was no lesion with MRI（DWI） with molecular marker and imaging device（CT, and the symptoms were disappeared, the diagnosis MRI, MRA）data, according to the category of NIND- was changed to TIA or non vascular disease. If the SIII10） by several neurologists. Lacunar infarction cardioembolic strokes were suggested by molecular was diagnosed if the diameter of ischemic lesion was markers or examinations of heart including echocar- less than 1.5 cm and major atherosclerosis was not diogram, the diagnosis was changed. Thus, as a re- observed with MR angiography. If patients were di- sult of different diagnosis, 13 patients were excluded. agnosed with cardioembolic infarction or others（e.g. Two patients who showed significant worsening transient ischemic attack, non vascular accident）, symptoms, one in each group, were excluded. Per- they were excluded. Thus, the types of stroke in- centage of patients with atherothrombotic infarction volved were atherothorombotic infarction and lucu- was 41.6％ and 38.8％ for ozagrel alone group and nar infarction. Patients with severe symptoms（NIH ozagrel plus edaravone group, respectively. stroke scale（NIHSS）of more than 12）were excluded. Informed consent was obtained. Clinical profile The baseline characteristics of the 30 patients are Therapy shown in Table 1. There was no significant differ- Patients included in this study received sodium ence between the treated groups in age, gender, ozagrel（160 mg!day）, or sodium ozagrel（160 mg! NIHSS, past history of cerebrovascular disease（Old day）plus edaravone（60 mg!day）for two weeks, CVA）, and risk factors of hypertension, diabetes

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Table 1. Baseline characteristics of patients

Ozagrel Ozagrel plus alone Edaravone P （n=12）（n=18） Mean（SD） 64.9（9.3） 68.1（11.1） n.s. Age Median（range） 65 （53-80） 67 （47-87）

Gender Male 61.5% 50.0% n.s.

Mean（SD） 3.9（3.6） 3.8（2.5） n.s. NIHSS at admission Median（range） 3 （0-11） 3 （0-8）

Barthel index at 2 Mean（SD） 81.3（25） 77.2（27.4） n.s. weeks after admission

Old CVA 16.7% 22.2% n.s.

Hypertension 58.3% 55.6% n.s. Diabetes Mellitus 33.3% 11.1% n.s. Risk Factor Hyperlipidemia 58.3% 33.3% n.s. Smoking 66.7% 44.4% n.s.

Old CVA : old cerebral vascular accident.

Table 2. Effects of drug therapy evaluated with NIHSS and Barthel indices

Ozagrel Ozagrel plus alone Edaravone P （n=12）（n=18）

NIHSS at discharge 1.3（ 2.1） 1.6（ 1.6） n.s. Barthel index at discharge 93.8（17.5） 91.7（16.0） n.s. Delta NIHSS 2.6（ 2.2） 2.2（ 1.8） n.s. Delta Barthel index 12.5（19.5） 14.4（20.8） n.s.

NIHSS : NIH stroke scale. Data show the mean（SD）. Delta NIHSS and delta Barthel indices were calculated as the discharge score minus either admission or two-week scores, respectively.

mellitus, hyperlipidemia, and smoking. Table 3. Multivariate analysis of factors influencing the Barthel index at discharge using Cox regression Outcome The NIHSS was evaluated at admission and dis- Variable HR 95%CI P charge. The Barthel index was evaluated two weeks Age 1.05 1.00-1.10 0.034 ＊ after admission and at discharge（around 4-5 weeks Gender Female 2.04 0.89-4.66 0.090 after onset）. The Delta NIHSS and delta Barthel in- Malea 1 dices were calculated as the discharge score minus NIHSS at admission 1.14 0.96-1.36 0.124 either admission or two-week scores, respectively. Drug therapy The differences between the NIHSS and Barthel in- Ozagrel 1.09 0.51-2.33 0.817 dices are shown in Table 2. There were no signifi- Ozagrel ＋ 1 Edaravonea cant differences between the ozagrel and ozagrel HR : hazard ratio, CI : confidence interval. aReference plus edaravone group. variable, ＊statistically significant.

Factors influencing prognosis Multivariate analysis was performed with age, pendent variables are continued variables of the gender, NIHSS on admission, and the drug therapy Barthel index at discharge. To test if variables are group as independent variables. Cox models of the to be included in this model, the Wald test, Score multivariate regression were used, because the de- test and Likelihood ratio test were performed. The

―19― 脳循環代謝第 17 巻第 1 号 results were p＝0.0484, 0.0389, and 0.0443, respec- edaravone in lacunar infarction22）. If a large number tively. Since all the tests showed significance, the of severe cases were collected for a similar study, variables could be included as shown in Table 3 with the results might be different. this model. It would be reasonable that the factor influencing The drug therapy showed no significant influence the Barthel index at discharge is patient age as on the Barthel index at discharge（p＝0.817）.Only shown in Table 3. The NIHSS on admission showed patient age was a significant factor influencing the no significance in these groups. This was also valid Barthel index at discharge. for patients with relatively mild symptoms. We selected consecutive patients with atheroth- Discussion rombotic and lacunar infarction within 24 h after onset because of the limited use of edaravone under It is known that brain damage develops not only the healthcare insurance system. Edaravone was ap- during the ischemic period but also after the start of proved on June 2001 for clinical use with cerebral in- reperfusion. Many studies have suggested that farction in Japan. At that time, its use was not com- thromboxane A2（TXA2）, a strong vasoconstrictor mon in the clinical field, and a comparative study be- and platelet aggregator, plays an important role in tween single treatment and combination treatment the development of brain damage after cerebral was necessary. Therefore, we tried to start this ischemia-reperfusion11～13）. Furthermore, the imbal- study. This study is the first prospective study for ance of TXA2 and prostaglandin I2（PGI2）was also evaluating the efficacy of the combination therapy. suggested to contribute to post-ischemic hypoperfu- This study shows no difference between ozagrel-

11） sion . Ozagrel, a selective TXA2 synthetase inhibitor alone treatment and ozagrel plus edaravone treat- is reported to be protective against cerebral infarc- ment in patients with acute cerebral infarction with tion14～17） and subarachnoid hemorrhage18,19）. relatively mild symptoms. If we expanded the study Free radicals generated during ischemia and!or including patients with severe symptom, i.e. severe reperfusion also play an important role in the devel- brain edema, there would be a possibility to get the opment of brain damage20,21）. The reflow to previous result that ozagrel plus edaravone group would ischemic tissue results in the massive production of show better prognosis than ozagrel alone group. To oxygen free radical, which enhances ischemic brain obtain more detailed and generalized information, damage. After randomized, double-blind, placebo the study with larger number of patients would be controlled clinical trials, edaravone is known to have necessary. neuroprotective effects9） and the effects on brain In conclusion, ozagrel alone treatment may be edema are also suggested in several preliminary enough effective to start treating patients with studies. Edaravone is now widely used in Japan for atherothrombotic infarction or lacunar infarction patients with cerebral infarction. with NIHSS on admission less than 12. Further Since ozagrel and edaravone have different pro- study is necessary to state if the combination ther- tective mechanisms, we thought the ozagrel plus apy have a superior efficacy for patients with se- edaravone group would show superior efficacy. How- verer symptoms. ever, the results showed no additional efficacy of edaravone over ozagrel treatment. Since patients Acknowledgements with severe symptoms（NIHSS of more than 12） Authors are grateful to doctors in the Second Department were excluded because of too few cases（one patient of Internal Medicine for evaluating the patients. influenced the results too much, Grubbs-Smirnov test p＜0.01）, our results should be interpreted with References 1）van Kooten F, Ciabattoni G, Patrono C, Schmitz P, patients with relatively mild symptoms（NIHSS of van Gijn J, Koudstaal P : Evidence for episodic plate- around 4, less than or equal to 11）（see Table 1）. let activation in acute ischemic stroke. Stroke 25 : The result is consistent with the previous retrospec- 278―281, 1994 tive study showing no additional improvement by

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2）Grau AJ, Ruf A, Vogt A, Lichy C, Buggle F, pertensive rats. Eur J Pharmacol 169 : 75―83, 1989 Patscheke H, Hacke W : Increased fraction of circulat- 13）Roy MW, Dempsey RJ, Cowen DE, Donaldson DL, ing activated platelets in acute and previous cere- Young AB : Thromboxane synthetase inhibition with brovascular ischemia. Thromb Haemostasis 27 : 431― imidazole increases blood flow in ischemic penumbra. 434, 1998 Neurosurgery 22 : 317―328, 1988 3）Zeller JA, Tschoepe D, Kessler C : Circulating plate- 14）Oishi M, Mochizuki Y, Hara M, Yoshihashi H, Takasu lets show increased activation in patients with acute T : Effects of sodium ozagrel on hemostatic markers cerebral ischemia. Thromb Haemostasis 81 : 373―377, and cerebral blood flow in lacunar infarction. Clin 1999 Neuropharmacol 19 : 526―531, 1996 4）Figols J, Cervos-Navarro J, Sampaolo S, Feerszt R : 15）Ichikawa K, Tazawa S, Hamano S, Kojima M, Hiraku Microthrombi in the development of ischemic irre- S : Effect of ozagrel on locomotor and motor coordina- versible brain infarct. In : Stroke and Mirocirculation. tion after transient cerebral ischemia in experimental ed by J Cervos-Navarro, FR, Raven Press, New York, animal models. Pharmacology 59 : 257―265, 1999 1987, pp 69―74 16）Arii K, Igarashi H, Arii T, Katayama Y : The effect of 5）CAST（Chinese Acute Stoke Trial）Collaborative ozagrel sodium on photochemical thrombosis in rat : Group : CAST : randomized placebo-controlled trial of therapeutic window and combined therapy with early aspitin use in 20,000 patients with acute ischae- heparin sodium. Life Sci 71 : 2983―2994, 2002 mic stroke. Lancet 349 : 1641―1649, 1997 17）Imamura T, Kiguchi S, Kobayashi K, Ichikawa K, 6）International Stoke Trial Collaborative Group : The Yamazaki Y, Kojima M : Effect of ozagrel, a selective international stroke trial（IST）:a randomised trial of thromboxane A2-synthetase inhibito, on cerebral in- aspirin, subcutaneous heparin, both, or neither among farction in rats. Arzneimittelforschung 53 : 688―694, 19,4435 patients with acute ischaemic stroke. Lancet 2003 349 : 1569―1581, 1997 18）Komatsu H, Takehana Y, Hamano S, Ujiie A, Hiraku 7）Bednar MM, Gross CE : Aspirin reduces experimental S : Beneficial effect of OKY-046, a selective thrombox- cerebral blood flow in vivo. Neurol Res 21 : 488―490, ane A 2 inhibito, on experimental cerebral vaso- 1999 spasm. Jpn J Pharmacol 41 : 381―391, 1986 8）Abe K, Yuki S, Kogure K : Strong attenuation of 19）Suzuki S, Sano K, Handa H, Asano T, Tamura A, ischemic and postischemic brain edema in rats by a Yonekawa Y, Ono H, Tachibana N, Hanaoka K : Clini- novel free radical scavenger. Stroke 19 : 480―485, cal study of OKY-046, a thromboxane synthetase in- 1988 hibitor, in prevention of cerebral vasospasm and after 9）Edaravone Acute Infarction Study Group : Effect of a subarachnoid haemorrhage due to aneurysmal rup- novel free radical scavenger, edaravone（MCI-186）,on ture : A randomized double-blind study. Neurol Res acute brain infarction. Randomized, placebo-contro- 11 : 79―88, 1989 lled, double-blind study at multicenters. Cerebrovasc 20）Siesj"BK, Agardh C-D, Bengtsson F : Free radicals Dis 15 : 222―229, 2003 and brain damage. Cerebrovasc. Brain Metab Rev 1 : 10）NINDs ad Hoc Committee : Classification of cere- 165―211, 1989 brovascular diseases III. Stroke 21 : 673―676, 1990 21）Siesj" BK, Katsura K, Kristi!n T : Acidosis-related 11）Chen ST, Hsu CY, Hoga EL, Yatsu FM : Thrombox- damage. Advance in Neurology 71 : 209―233, 1996 ane, prostacyclin, and leukotrienes in cerebral ische- 22）Takabatake Y, Uno E, Wakamatsu K, Yamazaki N, mia. Neurology 36 : 466―470, 1986 Hashimoto N, Tsuchiya Y : The clinical effect of com- 12）Sadoshima S, Ooboshi H, Okada Y, Yao H, Ishizuka T, bination therapy with edaravone and sodium ozagrel Fujishima M : Effects of thromboxane synthetase in- for acute cerebral infarction. No to Shinkei 55 : 589― hibitor on cerebral circulation and metabolism during 593, 2003 experimental cerebral ischemia in spontaneously hy-

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脳梗塞治療におけるオザグレル単独およびオザグレル＋エダラボン併用療法の比較―前向き研究―

桂研一郎，勝又俊弥，福地孝明，片山泰朗

日本医科大学第二内科

脳梗塞治療における，オザグレルナトリウム（O）単独およびオザグレルナトリウム＋エダラボン（O＋E）併用治療の効果を比較した．発症 24 時間以内のアテローム血栓性脳梗塞およびラクナ梗塞患者 30 名を対象とした．患者はランダムに O 単独群（12 名）および O＋E 群（18 名）に振り分けられ治療された．他の治療は両群で差違はなかった．入院時 NIHSS で 12 点以上の患者は除外した．退院時 Barthel index（BI），∆NIHSS および ∆BI は両群で有意な差はみられなかった．多変量解析では，退院時 BI に影響を与える因子は患者の年齢のみであり，治療薬剤の差違は予後に影響を与えなかった．NIHSS で 11 点以下の脳梗塞患者では O＋E 併用治療は O 単独治療よりも有意に優れた効果はみられなかった．O 単独療法は比較的軽症のアテローム血栓性脳梗塞またはラクナ梗塞に対してまず行う治療として適していると考えられる．キーワード：オザグレル，エダラボン，併用療法，アテローム血栓性脳梗塞，ラクナ梗塞

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