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(Stroke. 2003;34:840.)
© 2003 American Heart Association, Inc.

Original Contributions

Comparison of Triflusal and Aspirin for Prevention of Vascular Events in Patients After Cerebral Infarction

The TACIP Study: A Randomized, Double-Blind, Multicenter Trial

Jordi Matías-Guiu, MD; José M. Ferro, MD; José Alvarez-Sabín, MD; Ferran Torres, MD; M. Dolores Jiménez, MD; Aida Lago, MD Teresa Melo, MD for the TACIP Investigators

From the Service of Neurology, Hospital General Universitario de Alicante, Alicante, Spain (J.M-G.); Department of Neurology, Hospital Santa Maria, Lisbon, Portugal (J.M.F., T.M.); Cerebrovascular Unit, Service of Neurology, Hospital General i Universitari Vall d’Hebron, Barcelona, Spain (J.A-S.); Biostatistics and Epidemiology Laboratory, Autonomous University of Barcelona, Barcelona, Spain (F.T.); Service of Neurology, Hospital Universitario Virgen de Valme, Sevilla, Spain (M.D.J.); and Service of Neurology, Hospital La Fe, Valencia, Spain (A.L.).

Correspondence to Jordi Matías-Guiu, MD, Service of Neurology, Hospital General Universitario de Alicante, Maestro Alonso 109, E-03010 Alicante, Spain. E-mail matias_jor{at}gva.es

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion Appendix References References

 
Background and Purpose— The efficacy of the antiplatelet agent triflusal for prevention of vascular events after stroke has been reported in a pilot study. However, there is a need to confirm those results in a larger study.

Methods— We performed a randomized, double-blind, multicenter study to test the efficacy of triflusal (600 mg/d) versus aspirin (325 mg/d) for prevention of vascular events in patients with stroke or transient ischemic attack (Triflusal versus Aspirin in Cerebral Infarction Prevention [TACIP]). We assessed a combined end point (incidence of nonfatal ischemic stroke, nonfatal acute myocardial infarction, or vascular death) as well as the incidence of these events separately and the incidence of major hemorrhage.

Results— Of 2113 patients, 1058 received triflusal and 1055 aspirin. The mean follow-up period was 30.1 months. The incidence of combined end point (13.1% for triflusal, 12.4% for aspirin) as well the survival analysis (hazard ratio [HR] for triflusal versus aspirin, 1.09; 95% CI, 0.85 to 1.38) showed no differences between groups. The incidence of nonfatal stroke (HR, 1.09; 95% CI, 0.82 to 1.44), nonfatal acute myocardial infarction (HR, 0.95; 95% CI, 0.46 to 1.98,) and vascular death (HR, 1.22; 95% CI, 0.75 to 1.96) was also similar. A significantly higher incidence of major hemorrhages in the aspirin group was recorded (HR, 0.48; 95% CI, 0.28 to 0.82). The overall incidence of hemorrhage was significantly lower in the triflusal group (16.7% versus 25.2%) (odds ratio, 0.76; 95% CI, 0.67 to 0.86; P<0.001).

Conclusions— This study failed to show significantly superior efficacy of triflusal over aspirin in the long-term prevention of vascular events after stroke, but triflusal was associated with a significantly lower rate of hemorrhagic complications.

Key Words: aspirin • cerebral infarction • controlled clinical trials • hemorrhage • salicylates

	Introduction

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Antiplatelet agents are effective in the secondary prevention of stroke,¹ and aspirin is considered the first-line drug.¹ Other antiplatelet agents such as ticlopidine and clopidogrel or drug combinations (eg, aspirin and dipyridamole) have also been evaluated in this clinical setting.^2–4

Triflusal is an antiplatelet agent structurally related to aspirin that exerts its antithrombotic effect by acting on different targets involved in platelet aggregation and vascular inflammatory processes.^5–7 In addition, triflusal increases nitric oxide synthesis in neutrophils, resulting in increased vasodilatory potential.⁸ Triflusal has already shown its efficacy in several thrombotic diseases.^9–14

In a pilot study¹⁵ comparing triflusal (900 mg/d) and aspirin (330 mg/d), the combined incidence of ischemic stroke, acute myocardial infarction (AMI), or vascular death was similar in both study groups, and there was a reduction of

See Editorial Comment, page 847

approximately 76% in hemorrhagic complications among triflusal-treated patients compared with the aspirin group (P<0.05). These data addressed the hypothesis that triflusal may have a better profile than aspirin in the long-term secondary prevention of stroke and justified the design and development of the present study. The aim of this trial was to assess the potential benefit of triflusal compared with aspirin.

	Subjects and Methods

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Participants
The Triflusal versus Aspirin in Cerebral Infarction Prevention (TACIP) Study was a prospective randomized, multicenter, double-blind, aspirin-controlled trial that took place from March 1996 to September 1999 in 2 countries in Europe (Portugal and Spain) and involved the participation of 43 centers. Recruitment was completed in April 1997. The study was performed according to the Declaration of Helsinki and the European Good Clinical Practice guidelines. Study approval by local research ethics committees was obtained. Decisions regarding the study were made by a steering committee, which was assisted by an executive committee. A data-blind review committee appointed by the executive committee was responsible for validating all reported primary and secondary end points. An independent and masked contract research organization was responsible for coding the information on adverse events as recorded by the investigators according to the World Health Organization adverse reaction terminology. An independent external audit was performed, which did not detect any significant deviation (this guaranteed that the evaluated trial-related activities were conducted and the data were recorded, analyzed, and accurately reported according to the protocol, sponsor’s standard operating procedures, good clinical practice, and applicable regulatory requirements).

Patients aged 40 years were eligible if they had suffered from a transient ischemic attack (TIA) or nondisabling stroke (Oxford Neurological Scale score 2) within the previous 6 months and had given written informed consent. TIA was defined as reversible ischemic neurological deficit with complete functional recovery within 24 hours; the clinical episode should have lasted >15 minutes, with at least 3 episodes within 24 hours for TIAs that lasted <15 minutes. Ischemic stroke was defined as a neurological deficit of vascular origin that persisted without functional recovery or with little improvement for >24 hours. A brain CT scan and/or MRI studies, preferably performed within the first month after the onset of symptoms, was required.

Main exclusion criteria were as follows: evidence of intracerebral hemorrhage or diagnosis of a nonatherothrombotic cause of stroke; history of endarterectomy or indication of this procedure after the qualifying cerebrovascular event; known hypersensitivity to salicylates; need for antiplatelet therapy because of previous ischemic heart disease; active peptic ulcer or history of upper gastrointestinal bleeding; liver or renal dysfunction; severe concomitant medical conditions; malignancy that may potentially increase the risk of hemorrhage; and chronic disorders requiring long-term treatment with systemic nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants, or antiplatelet agents (anticoagulant or antiplatelet therapy until inclusion was not considered an exclusion criterion, only if the aim of the treatment was the vascular brain disease).

Design and Procedures
Patients were randomly assigned, in a double-blind fashion, to receive uncoated capsules of triflusal (600 mg/d) or aspirin (325 mg/d), prepared by Grupo Uriach, Barcelona, Spain. A random list was prepared by an independent statistical center. Treatment with triflusal or aspirin was allocated to the random codes by personnel unrelated to the study. Patients were treated for a minimum of 1 year and a maximum of 3 years.

At baseline, the following was recorded: demographic data, salient features of the qualifying cerebrovascular event, brain CT or MRI scan, general physical examination, chest roentgenograms, ECG, and standard laboratory tests. Follow-up visits were scheduled at days 30 and 90 after inclusion in the study and at 3-month intervals thereafter until visit 14 at month 36. At each visit, information regarding outcome events, adverse events, use of concomitant drugs, and compliance with the study medication was recorded. In addition, a closed questionnaire on possible adverse events regarding the gastrointestinal system and bleeding episodes was administered. Laboratory tests and ECG were repeated at months 12, 24, and 36. Treatment with NSAIDs was discouraged during the study. Treatment with any anticoagulant or antiplatelet agent other than the study drug was allowed only for periods not exceeding 7 days per year of patient inclusion in the study. All patients were followed until completion of the planned 3-year follow-up period even after the onset of a nonfatal primary end point (off medication) or therapy withdrawal.

Outcome Events
Primary outcome events included the first occurrence of vascular death, nonfatal ischemic stroke, or nonfatal AMI (Table 1). Secondary end points were the occurrence of each of these events separately as well as overall mortality, nonvascular death, nonfatal ischemic stroke, any (fatal and nonfatal) ischemic stroke, nonfatal AMI, any AMI, nonfatal cerebral hemorrhage, any cerebral hemorrhage, major systemic hemorrhage (bleeding episode that required hospital admission and/or blood transfusion; any other bleeding was considered minor), any cerebral and major systemic hemorrhage, nonfatal systemic thromboembolism, and any systemic thromboembolism. Any event that led to death within 1 month of its occurrence was considered a fatal event.

View this table: [in this window] [in a new window]   TABLE 1. Primary End Point Definitions

Statistical Analyses
The planned sample size was 2062 patients. The expected incidence in the aspirin group was 18% on the basis of the observed 3-year incidence of vascular events.¹ With an expected loss to follow-up rate of 20% and a 2-sided =0.05, the study was expected to have 80% power to detect a clinically significant absolute reduction of at least 5% in the triflusal group (thus obtaining an absolute rate of vascular events of 13% in the triflusal arm).¹⁶

Statistical analyses were performed for the intention-to-treat population (all randomized patients who had taken at least 1 dose of medication and had made at least 1 assessment of the efficacy variables) and the per-protocol population (with data of all patients while they were on medication). All data on outcome events recorded later than 30 days after permanent treatment discontinuation were censored in the per-protocol population. Survival curves were estimated with the Kaplan-Meier method, and differences were determined with the log-rank test. Cox proportional hazards models were used to estimate relative risks. Clinical end point risk estimates and 95% CIs for the primary and secondary outcome analyses were calculated. Statistical analyses were performed with the use of SAS (version 6.12). An independent statistical center performed the statistical analyses blindly.

	Results

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The trial profile is shown in Figure 1. Of the 2113 patients randomized, 1058 were assigned to treatment with triflusal and 1055 to aspirin. Six patients (3 in each group) who did not take any dose of the study medication were excluded from the study. The intention-to-treat population consisted of 2107 patients (1055 received triflusal, 1052 received aspirin). The mean follow-up was 30.1 months. The per-protocol population included 2025 patients (1018 received triflusal, 1007 received aspirin) with a mean follow-up of 24.4 months. Study medication was early and permanently discontinued for reasons other than primary event or death in 590 patients (306 in the triflusal group, 284 in the aspirin group). Reasons for study drug discontinuation were similar in both groups and included, among others, nonserious adverse event (9.1%), patient’s willingness (8.7%), or serious adverse event (5.9%).

View larger version (26K): [in this window] [in a new window]   Figure 1. Trial profile. ITT indicates intention to treat; PP, per protocol.

No differences were noted between the treatment groups at baseline (Table 2). Most patients were male (65.8%), and the mean age (±SD) was 64.5 (±9.7) years. The qualifying cerebrovascular event was an ischemic stroke in 1557 patients (73.9%) (lacunar stroke in 52% of patients). Imaging studies included brain CT scans in 81.4% of patients, MRI in 7.6%, and both CT and MRI scans in 11%.

View this table: [in this window] [in a new window]   TABLE 2. Summary of Baseline Characteristics

Two hundred sixty-eight patients (12.7%) suffered from an event defined as a primary end point of the study: 138 (13.1%) in the triflusal group and 130 (12.4%) in the aspirin group. The difference was not statistically significant. The survival analysis of triflusal versus aspirin showed a hazard ratio of 1.09 (95% CI, 0.85 to 1.38) (Figure 2). The per-protocol analysis showed a similar incidence of primary end point events without statistically significant differences. In respect to events defined as secondary end points of the trial, statistically significant differences were noted only in the incidence of bleeding episodes (Table 3).

View larger version (20K): [in this window] [in a new window]   Figure 2. Survival analysis of primary end point (nonfatal ischemic stroke, nonfatal AMI, vascular death).

View this table: [in this window] [in a new window]   TABLE 3. Summary of Outcome Events Defined as Secondary End Points of the Trial

Moreover, following the definition of primary end point for clinical trials of antiplatelet drugs used in the Antithrombotic Trialists’ Collaboration,^1,17 we performed an analysis after we recalculated the primary end point in order to include nonfatal hemorrhagic strokes. The overall incidence in both groups did not change greatly: 140 of 1055 (13.3%) in the triflusal versus 136 of 1052 (12.9%) in the aspirin group (P=0.87; odds ratio, 1.03; 95% CI, 0.80 to 1.33).

A total of 31 patients (2.9%) assigned to the aspirin group reported at least 1 major systemic hemorrhage compared with 13 (1.2%) in the triflusal group (relative risk reduction of 58%; 95% CI, 19% to 78%; P=0.006). Any cerebral or major systemic hemorrhages were reported by 42 aspirin-treated patients (4.0%) and 20 triflusal-treated patients (1.9%) (P=0.004), with a relative risk reduction of 52% (95% CI, 18% to 72%). Cumulative risk for any cerebral or major systemic hemorrhages is shown in Figure 3. These findings were confirmed in the analysis of the per-protocol population.

View larger version (19K): [in this window] [in a new window]   Figure 3. Cumulative risk of any cerebral or major systemic hemorrhages.

A total of 1718 patients reported at least 1 adverse event (864 [81.2%] in the triflusal group and 854 [81.9%] in the aspirin group), with at least 1 serious adverse event associated with the study medication in 72 aspirin-treated patients (6.8%) and 60 triflusal-treated patients (5.7%) (P=0.282). As shown in Table 4, the majority of patients suffered from gastrointestinal complaints (39.8% versus 43.6% in the aspirin and triflusal groups, respectively); dyspepsia was significantly more frequently reported by patients given triflusal, while gastric or peptic ulcer occurred significantly more frequently among aspirin-treated subjects.

View this table: [in this window] [in a new window]   TABLE 4. Patients With at Least 1 Adverse Event* (Incidence>0.5%)

Patients treated with aspirin compared with triflusal showed a significantly higher overall incidence of hemorrhagic adverse events (25.2% versus 16.7%; odds ratio, 0.76; 95% CI, 0.67 to 0.86; P<0.001) as well as hemorrhagic adverse events related to the study medication (21.8% versus 13.7%; odds ratio, 0.74; 95% CI, 0.65 to 0.85; P<0.001). The incidence of minor bleeding was also significantly higher in the aspirin group (22.1%) than in the triflusal group (15.2%) (P<0.001).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion Appendix References References

 
In this trial there were no statistically significant differences between triflusal and aspirin at administered doses regarding nonfatal ischemic stroke, nonfatal AMI, and vascular death with regard to either the combined incidence of these events or the incidence of each of them independently. The 95% CIs for the relative effect of triflusal versus aspirin were wide and included 1, and therefore the TACIP Study could not show a significantly superior efficacy of any treatment for the prevention of vascular events in this clinical setting. Instead, it showed that a substantial difference is unlikely. The incidence of major and minor bleeding episodes was significantly reduced by triflusal.

The results reported regarding baseline characteristics of both populations are in agreement with other studies.^18–20 The distribution of men/women (66%/34%) and the percentage of patients who entered the study with TIA as a qualifying cerebrovascular accident (26%) are within the normally accepted limits in clinical trials on secondary prevention of stroke.

The study protocol was designed on the assumption of an incidence of primary end point of 18% in aspirin-treated patients,¹ whereas the results showed a final incidence of 12.4%. Several factors likely played a role (this lower incidence also occurred in other studies on stroke¹⁹).

A nonsignificantly higher overall and vascular mortality was observed in the triflusal group, but in a previous randomized clinical trial in myocardial infarction¹¹ that compared triflusal and aspirin, a nonsignificant higher mortality was observed in the aspirin group, mainly in relation to vascular deaths.

After publication of the results from the first cooperative studies, aspirin has been considered the first-option drug in the secondary prevention of stroke.^19–24 Although other drugs have been reported in the medical literature to have similar^25–27 or even higher efficacy,^4,18,28,29 most therapeutic guidelines^30–32 have maintained that aspirin is the first-choice drug because of its safety and price. Although some controversy still exists, treatment with aspirin at medium doses (75 to 325 mg/d) is the most widely accepted therapeutic regimen, and this regimen was also used in recent studies.^18,19 Recent reviews of randomized trials of antiplatelet therapy^17,33 did not find any significant difference regarding protective effects between high aspirin doses (500 to 1500 mg/d) and medium to low doses (30 to 325 mg/d). However, compared with medium doses, high doses of aspirin showed an increased risk of adverse gastrointestinal effects, while no significant differences were observed between medium (75 to 325 mg/d) and low doses (<75 mg/d).³⁴ There is no evidence that reducing the dose of aspirin would significantly lower its hemorrhagic risk.³⁵

Regarding hemorrhagic complications, their overall incidence was higher in the TACIP Study than in other similar studies.^19,27,36,37 However, the incidence of major hemorrhages was similar. This may be due to the longer follow-up period or to the method of reporting adverse events, since the TACIP Study considered the incidence of hemorrhagic events as one of the secondary end points, and the case report form was carefully designed to collect any information about them.

The risk of aspirin treatment has probably been underestimated, especially when used for long-term therapy.³⁸ Results of the present study provide additional evidence to question the benefit/risk ratio of long-term use of aspirin.

Triflusal has shown a better safety profile than aspirin as a result of convincing evidence of lower hemorrhagic risk, that is, the incidence of major or minor bleeding episodes was significantly lower in the triflusal group, including gastrointestinal bleeding or skin hematomas. In addition, hemorrhages in any organ/system were less frequent among triflusal-treated patients. These findings are consistent with those reported in previous studies.^11,15 Different reasons may explain why triflusal shows an antithrombotic effect with a lower incidence of hemorrhagic complications than aspirin. The inhibition exerted by triflusal on cyclooxygenase and subsequent release of thromboxane B₂ appears to be 10 times less than that of aspirin.³⁹ However, its additional mechanisms of action, such as inhibition of phosphodiesterase and of the release of nitric oxide by human neutrophils,⁸ provide triflusal with enough antithrombotic activity to inhibit platelet hyperactivity observed in prothrombotic states but with preservation of platelet hemostatic function. In the clinical setting, the lack of prolongation of bleeding time by triflusal confirms the preservation of platelet function.¹³

The incidence of dyspepsia was significantly lower in the aspirin group, although this did not seem to be clinically relevant because there were no differences regarding treatment withdrawal. In contrast, aspirin showed a significantly higher incidence of gastric/peptic ulcers. A possible explanation of this contradistinction may be that triflusal is a more acidic compound than aspirin (data on file, Grupo Uriach, Barcelona, Spain), and it probably causes gastric mucosal irritation after oral intake, leading to dyspepsia. On the other hand, the enhanced inhibition of cyclooxygenase by aspirin can lead to a lower synthesis of prostaglandin E₂ in the gastric mucosa,⁷ thus reducing its protective mechanisms against acid and peptic enzymes and subsequently increasing the risk for peptic disease and gastrointestinal bleeding.

Triflusal is associated with a significantly lower incidence of major and minor hemorrhagic complications after long-term therapy with no differences in the incidence of primary efficacy end points. In our study triflusal could prevent 24 major hemorrhagic events (95% CI, 9 to 39) per 1000 patients treated with triflusal instead of aspirin, which is a relevant difference when one takes into account the personal burden of major hemorrhages. This finding may have a significant impact in clinical practice.

Triflusal may be safer than aspirin for long-term prevention of recurrent stroke. Moreover, it may be preferable for future trials evaluating the efficacy and safety of combinations of antiplatelet drugs for primary prevention of stroke in patients at vascular risk.⁴⁰

	Appendix

Top Abstract Introduction Subjects and Methods Results Discussion Appendix References References

 
Contributors
Jordi Matías-Guiu, chairman of the study, member of the Steering Committee and the Executive Committee, prepared and reviewed the protocol, supervised and reviewed the progress of the trial, wrote and revised the manuscript. José M. Ferro, co-chairman of the study, member of the Steering Committee and the Executive Committee, prepared and reviewed the protocol, supervised and reviewed the progress of the trial, wrote and revised the manuscript. José Alvarez-Sabín, member of the Steering Committee and the Executive Committee, prepared and reviewed the protocol, supervised and reviewed the progress of the trial, wrote and revised the manuscript. Ferran Torres, member of the Steering Committee, study statistician, supervised and reviewed the statistical analyses, wrote and revised the manuscript. María-Dolores Jiménez, recruited patients, wrote and revised the manuscript. Aida Lago, recruited patients and was involved in revising the manuscript. Teresa Melo, recruited patients, wrote and revised the manuscript.

TACIP Investigators
Executive Committee: J. Matías-Guiu (chairman), J. Ferro, J. Álvarez-Sabín, G. Calvo. Steering Committee: J. Matías-Guiu, J. Ferro, J. Álvarez-Sabín, A. Gil-Peralta, E. Martínez-Vila, F. Torres, G. Calvo, J.R. Castro Lopes, E. Galve, J.C. Navas (Uriach), V. Oliveira (Tecnifar). Statistical Center: J. Rios, F. Torres, Laboratori de Bioestadística i Epidemiologia, Universitat Autònoma de Barcelona. Monitoring Center: MDS Pharma Services (Spain). Operations Group: I. Izquierdo, G Muñoz (Uriach). External Audit: N. Dent (Country Consultancy Ltd, UK).

Centers
Spain (1557 patients): Hospital Universitario Virgen de Valme, Sevilla (141 patients) (M.D. Jiménez, J.M. Aguilera); Hospital La Fe, Valencia (117 patients) (A. Lago, T. Sevilla, M. Baquero, B. Casanova, J. Vílchez, F. Domínguez); Hospital General Yagüe, Burgos (113 patients) (J.M. Trejo, J.M. Fernández, M. Goñi, F. Iglesias, J. Macarrón, M. Rabasa, M.J. Sedano); Hospital Clínico Universitario, Zaragoza (100 patients) (E. Mostacero, M.L. Ortells, C. Tejero, S. Santos); Hospital Universitario Virgen de la Macarena, Sevilla (96 patients) (M. González); Hospital Vall d’Hebron, Barcelona (84 patients) (J. Sumalla, M. Molins, J. Bosch); Hospital de la Princesa, Madrid (72 patients) (F. López, J. Vivancos, T. León, C. Monforte, R. González); Hospital Carlos Haya, Málaga (69 patients) (O. Fernández, T. Ojea); Hospital General Universitario de Alicante, Alicante (64 patients) (F. Gracia, J.M. Moltó, M.J. González, C. Ruiz); Hospital Universitario Virgen del Rocío, Sevilla (60 patients) (J.R. González, E. Gil, L. Pérez, F. Garzón); Hospital Universitario San Carlos, Madrid (59 patients) (J.A. Egido, J.L. González, J. Carod, M.L. Cuadrado); Hospital del Sagrat Cor, Barcelona (55 patients) (A. Arboix, J. Massons, M. Oliveres); Hospital Gregorio Marañón, Madrid (52 patients) (A.C. Gil Núñez, J.A. Villanueva, M. Ochoa, P. Vázquez); Hospital La Paz, Madrid (47 patients) (E. Díez-Tejedor, J.J. Muñoz, R. Soler); Hospital Miguel Servet, Zaragoza (45 patients) (M. Gracia Naya); Hospital Verge dels Lliris, Alcoi, Alicante (44 patients) (J.M. López, J.M. Camacho, J. Mallada, M.J. Sáenz); Hospital Torrecárdenas, Almería (38 patients) (E. Goberna, J.M. l’Hotellerie de Fallois, T. García, J.J. Asencio, P. Serrano, I. Peralta, A. Casado); Hospital Central de Asturias, Oviedo (38 patients) (R. Navarro, C. Salvador, J.M. Asensi, D. Fernández, B. Blázquez); Hospital Virgen de las Nieves, Granada (33 patients) (T. García, J.F. Maestre, A. Espigares, F.J. Hernández); Hospital de San Juan, Alicante (32 patients) (M.R. Martín, E. Valiente); Hospital General de Catalunya, Sant Cugat del Vallès, Barcelona (31 patients) (L. Soler, E. Balaguer); Hospital Mútua de Terrassa, Terrassa, Barcelona (31 patients) (M. Aguilar, I. Bonaventura, J. Saura, E. Muñoz, A. Rey); Hospital Xeral de Galicia, Santiago de Compostela (27 patients) (P. Cacabelos, A. Aneiros, R. Leira, J. Castillo); Hospital General de Valencia, Valencia (26 patients) (J. Sancho, J.M. Laínez, J. Juni, A. Cervelló); Hospital Nuestra Señora de Aránzazu, San Sebastián-Donosti, Guipúzcoa (22 patients) (J.F. Martí, M. Ruibal, A. de Arce); Hospital Santa Caterina, Girona (20 patients) (A. Turón, S. López, M. Vallmajor, J. Costa); Hospital de Cruces, Barakaldo, Vizcaya (16 patients) (J.C. Gómez, M.M. Mendibe, J.L. Sánchez, A. Sagasta, J. Larrakoechea, J.J. Zarranz); Complejo Hospitalario Xeral-Calde, Lugo (12 patients) (F. Martínez, R. Pego, F. Brañas, J.A. Cortés); Hospital de la Santa Creu i Sant Pau, Barcelona (9 patients) (J.L. Martí -Vilalta, J. Martí-Fábregas); Hospital Xeral-Cies, Vigo (4 patients) (J. Gómez-Alonso, D. Muñoz, J.S. Herrero, S. Gomara).

Portugal (556 patients): Hospital de Santa Maria, Lisboa (116 patients) (T.P. Melo, P. Canhão, F. Falcão); Hospital Geral de Santo António, Porto (90 patients) (M. Correia, C. Correia, G. Lopes, M. Veloso, A.P. Correia); Hospitais da Universidade de Coimbra (73 patients) (L. Cunha, F. Gonçalves, M.A. Ferro, V. Barbosa, C. Machado, M.C. Macário, B. Santiago, E. Monteiro); Hospital de São José, Lisboa (53 patients) (M. Cândido, C.M.D. Araújo, A. Paes Duarte, I. Ramires, P.L. Esperança, M.R.S. Bento); Hospital dos Covões, Centro Hospitalar de Coimbra (44 patients) (A. Dionísio, G. Gonçalves, M. Cardoso, J. Palmeiro); Hospital de São João, Porto (39 patients) (R. Martins, M.J. Rosas, E. Azevedo, F. Coelho, A. Oliveira Silva); Hospital de São Marcos, Braga (35 patients) (J.R. Fontes, E. Lourenço); Hospital de Santo António dos Capuchos, Lisboa (29 patients) (D. Rojão, J.C. Bandeira e Costa); Centro Hospitalar de Vila Nova de Gaia (27 patients) (B. Botelho, J.M. Castro, A. Branco); Hospital do Espírito Santo, Évora (23 patients) (I.L. Henriques, C. Barata, L. Rebocho, J. Correia, A. Leitão); Hospital Fernando Fonseca, Amadora (13 patients) (A.V. Salgado, A.A. Pinto); Hospital Garcia de Orta, Almada (10 patients) (L.B. de Almeida, F. Pita); Hospital Distrital de Faro (4 patients) (C. Basílio).

Possible Conflict of Interest
All members of study committees received financial support from the sponsors for personal and technical expenses (related to study design, contacts with investigators, co-organization and attendance at meetings, and travel expenses). Authors do not own shares in any of the sponsoring companies.

	Acknowledgments

 
This study was supported by Grupo Uriach, Barcelona (Spain) and Tecnifar Indústria Técnica Farmacêutica, Lisboa, Portugal. We thank Marta Pulido, MD, for assistance in editing the manuscript.

Received June 10, 2002; revision received September 12, 2002; accepted October 22, 2002.

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Can Aspirin Ever Be Surpassed for Stroke Prevention?

David C. Tong, MD, Guest Editor
Because of the modest benefit of aspirin for stroke prevention,^1,2 there continues to be interest in identifying more effective and safer agents. In this study, the investigators compared triflusal, an agent with a novel mechanism believed to be different from other antiplatelet drugs, with aspirin in over two thousand stroke patients. The study was appropriately, designed, powered, and executed to identify a clinically relevant difference in efficacy. Unfortunately, triflusal was no better than aspirin in preventing stroke recurrence. Obviously these results indicate that aspirin should remain the cornerstone of antiplatelet therapy for stroke prevention given its well-established clinically important benefit and very modest cost.

Can we learn anything from the negative results of this study? Perhaps. Of importance, the study did report that the risk of cerebral hemorrhage was significantly lower using triflusal, but with a comparable level of stroke protection. This suggests that drugs with good stroke prevention capability are feasible, without increasing the risk of hemorrhagic complications as has been observed in studies of oral GP IIb-IIIa inhibitors in coronary artery disease patients.^3,4 Certainly, if the cost of triflusal was comparable to aspirin, there might be justification for using this agent, given the substantial concern for hemorrhagic complications in our generally older, sicker stroke patients.

Will we ever find a drug that will truly outperform aspirin? Clearly in terms of cost effectiveness it will be hard to beat. Moreover, most head to head trials of single agents versus aspirin to date have shown little or no additional efficacy, as in triflusal study. The recently published data reporting no additional benefit for stroke prevention from warfarin (Warfarin Aspirin Recurrent Stroke Study [WARSS]),⁵ or ticlopidine (African American Antiplatelet Stroke Prevention Study [AAASPS])⁶ versus aspirin clearly reflect this challenge.

What alternative strategies are on the horizon? Almost assuredly we will need to combine different antithrombotic agents. That such combinations may be more effective has already been suggested by the results of the European Stroke Prevention Study (ESPS-2)⁷ in which the combination of aspirin and dipyridamole appeared to provide additional benefit compared with aspirin alone. Similarly, coronary studies of the combination of clopidogrel plus aspirin (Clopidogrel in Unstable Angina to prevent Recurrent Events [CURE]),⁸ have reported additional beneficial effects on the prevention of coronary artery disease morbidity.

While controversy remains over the degree and applicability of the beneficial results observed in these and other studies, it is likely that stroke prevention regimens employing dual or multi-agent antithrombotic treatment will be successful in the future. Already, a number of new studies have been initiated evaluating clopidogrel plus aspirin in high risk patients with vascular disease (eg, MATCH [Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke], CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance], Secondary Prevention of Small Subcortical Stroke [SPS3]). In addition, a head to head comparison of the combination of aspirin plus clopidogrel versus dipyridamole and aspirin (PROFESS [Preventing Regimen for Effectively avoiding Second Strokes]) has recently been announced. These and other similar studies will undoubtedly prove helpful in clarifying the role of combination antiplatelet therapy in individuals with cerebrovascular disease.

Triflusal may also be an appropriate medication to test in combination with other antithrombotics, particularly given the lower hemorrhage risk reported in this study. It would be particularly interesting if further subgroup analysis of the TACIP data should identify patient subtypes with increased hemorrhage risk, where a triflusal combination might have greatest benefit. Another avenue for development may be the use of agents that do not directly affect platelet aggregation, such as the oral thrombin inhibitors, which are already being tested in deep venous thrombosis.⁹ Whether these newer agents alone or in combination can outperform aspirin, remains to be seen.

In any event, it is clear that despite the challenges the quest shall go on for better and more effective preventative agents, assuring us of continued exciting developments in this field for the foreseeable future.

Department of Neurology and Neurological Sciences

Stanford University Medical Center

Stanford Stroke Center

Palo Alto, California

	Footnotes

 
This article was guest edited by Dr John W. Norris, Associate Editor.

	References

Top Abstract Introduction Subjects and Methods Results Discussion Appendix References References

 
1. Antiplatelet Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324: 71–86.[Abstract/Free Full Text]

2. Algra A, van Gijn J. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. J Neurol Neurosurg Psychiatry. 1996; 60: 197–199.[Abstract/Free Full Text]

3. Bhatt DL, Topol EJ. Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes. JAMA. 2000; 284: 1549–1558.[Abstract/Free Full Text]

4. Chew DP, Bhatt DL, Sapp S, Topol EJ. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials. Circulation. 2001; 103: 201–206.[Abstract/Free Full Text]

5. Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, Kistler JP, Albers GW, Pettigrew LC, Adams HP Jr, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2001; 345: 1444–1451.[Abstract/Free Full Text]

6. Gorelick PB, Richardson D, AASPS Investigators. African American Antiplatelet Stroke Prevention Study (AAASPS): Main phase efficacy and safety results. Presented at the 28th International Stroke Conference. Phoenix, Arizona, February 12–15, 2003.

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8. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001; 345: 494–502.[Abstract/Free Full Text]

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