Yonsei Med J.  2015 Sep;56(5):1227-1234. 10.3349/ymj.2015.56.5.1227.

Effect of Triflusal on Primary Vascular Dysregulation Compared with Aspirin: A Double-Blind, Randomized, Crossover Trial

• Shin S
• Kim KJ
• Cho IJ
• Hong GR
• Jang Y
• Chung N
• Rah YM
• Chang HJ

• KMID: 2163613
• DOI: http://doi.org/10.3349/ymj.2015.56.5.1227

Abstract

PURPOSE
Primary vascular dysregulation (PVD) is a condition in which the response to cold temperature or external stimuli is abnormal. We investigated whether triflusal use results in amelioration of PVD symptoms and improvement of several related parameters compared with aspirin.
MATERIALS AND METHODS
Eighty-eight PVD patients (54% female, 56+/-8 years) were randomly selected to receive either triflusal (300 mg, b.i.d.) or aspirin (150 mg, b.i.d.) for a period of 6 weeks followed by crossover. PVD was defined as both red-blood-cell standstill in video-assisted microscopic capillaroscopy during cold stimulation using carbon dioxide gas and a score of more than 7 points in a validated questionnaire. Efficacy of treatment was assessed by 1) cold intolerance symptom severity (CISS) score, 2) finger Doppler indices, and 3) indocyanine green perfusion imaging.
RESULTS
The use of triflusal resulted in a greater improvement in CISS score (44.5+/-18.4 vs. 51.9+/-16.2; p<0.001) and in mean radial peak systolic velocity (69.8+/-17.2 vs. 66.1+/-16.4; p=0.011) compared to aspirin. Furthermore, significant differences were also observed in perfusion rates on indocyanine green perfusion imaging between triflusal and aspirin (45.6+/-25.8 vs. 51.6+/-26.9; p=0.020).
CONCLUSION
Triflusal was more effective and demonstrated a more consistent impact on the improvement of symptoms and blood flow in patients with PVD than aspirin.

Keyword

Primary vascular dysregulation; triflusal; finger Doppler; endothelin-1; microvascular circulation

MeSH Terms

Adult
Aspirin/*therapeutic use
Cardiovascular Diseases/*drug therapy
Cross-Over Studies
Double-Blind Method
Female
Humans
Indocyanine Green
Male
Middle Aged
Perfusion Imaging
Platelet Aggregation Inhibitors/*therapeutic use
Recurrence
Salicylates/*therapeutic use
Treatment Outcome
Aspirin
Indocyanine Green
Platelet Aggregation Inhibitors
Salicylates

Figure

• 

  Fig. 1 Study design. This study was a double-blind, randomized, crossover design. The selected patients were given either triflusal or aspirin for 6 weeks. After a washout period of 2 weeks, the drugs were crossed over, and the patients were given the drug they had not received for 6 more weeks. CISS, cold intolerance symptom severity; PSV, peak systolic velocity; ICG, indocyanine green.

• 

  Fig. 2 Primary, secondary, and exploratory endpoints. (A) Although the CISS scores of Aspirin and Triflusal groups both decreased by week 6, only the CISS score of Triflusal group decreased further by week 14 after cross-over, while that of Aspirin group remained unchanged. Overall, both Aspirin and Triflusal were effective in relieving symptoms, but Triflusal group had significantly more improved symptoms compared with Aspirin group. (B) Although radial PSV was increased in both Aspirin and Triflusal groups by week 6, it was increased further only in Triflusal group by week 14 after cross-over while the Aspirin group showed no further change. Overall, although both Aspirin and Triflusal groups had increased radial PSV, the Triflusal group showed a more significantly increased PSV compared with Aspirin group. (C) ICG perfusion scan was significantly increased in the group that was treated with Triflusal compared with baseline or those treated with Aspirin. (D) ET-1 was significantly decreased in Triflusal group compared with Aspirin group by week 6, and this significant decreased was also observed after the cross-over. CISS, cold intolerance symptom severity; PSV, peak systolic velocity; ICG, indocyanine green.

Reference

1. Frank SM, Raja SN, Bulcao C, Goldstein DS. Age-related thermoregulatory differences during core cooling in humans. Am J Physiol Regul Integr Comp Physiol. 2000; 279:R349–R354.

2. Pettit SE, Marchand I, Graham T. Gender differences in cardiovascular and catecholamine responses to cold-air exposure at rest. Can J Appl Physiol. 1999; 24:131–147.

3. Nagashima K, Yoda T, Yagishita T, Taniguchi A, Hosono T, Kanosue K. Thermal regulation and comfort during a mild-cold exposure in young Japanese women complaining of unusual coldness. J Appl Physiol (1985). 2002; 92:1029–1035.

4. Flammer J, Pache M, Resink T. Vasospasm, its role in the pathogenesis of diseases with particular reference to the eye. Prog Retin Eye Res. 2001; 20:319–349.

5. Belch J. Raynaud's phenomenon. Cardiovasc Res. 1997; 33:25–30.

6. Flammer J, Konieczka K, Flammer AJ. The primary vascular dysregulation syndrome: implications for eye diseases. EPMA J. 2013; 4:14.

7. Murdoch D, Plosker GL. Triflusal: a review of its use in cerebral infarction and myocardial infarction, and as thromboprophylaxis in atrial fibrillation. Drugs. 2006; 66:671–692.

8. Campia U, Choucair WK, Bryant MB, Quyyumi AA, Cardillo C, Panza JA. Role of cyclooxygenase products in the regulation of vascular tone and in the endothelial vasodilator function of normal, hypertensive, and hypercholesterolemic humans. Am J Cardiol. 2002; 89:286–290.

9. De la Cruz JP, Pavia J, Garcia-Arnes J, Sanchez de la Cuesta F. Effects of triflusal and acetylsalicylic acid on platelet aggregation in whole blood of diabetic patients. Eur J Haematol. 1988; 40:232–236.

10. De Miguel LS, Jiménez A, Montón M, Farré J, Del Mar Arriero M, Rodríguez-Feo JA, et al. A 4-trifluoromethyl derivative of salicylate, triflusal, stimulates nitric oxide production by human neutrophils: role in platelet function. Eur J Clin Invest. 2000; 30:811–817.

11. Gasser P, Flammer J. Blood-cell velocity in the nailfold capillaries of patients with normal-tension and high-tension glaucoma. Am J Ophthalmol. 1991; 111:585–588.

12. Teuchner B, Orgül S, Ulmer H, Haufschild T, Flammer J. Reduced thirst in patients with a vasospastic syndrome. Acta Ophthalmol Scand. 2004; 82:738–740.

13. Pache M, Kräuchi K, Cajochen C, Wirz-Justice A, Dubler B, Flammer J, et al. Cold feet and prolonged sleep-onset latency in vasospastic syndrome. Lancet. 2001; 358:125–126.

14. Flammer J, Orgül S, Costa VP, Orzalesi N, Krieglstein GK, Serra LM, et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res. 2002; 21:359–393.

15. Ruijs AC, Jaquet JB, Daanen HA, Hovius SE. Cold intolerance of the hand measured by the CISS questionnaire in a normative study population. J Hand Surg Br. 2006; 31:533–536.

16. Jeong IK, King GL. New perspectives on diabetic vascular complications: the loss of endogenous protective factors induced by hyperglycemia. Diabetes Metab J. 2011; 35:8–11.

17. Mozaffarieh M, Fontana Gasio P, Schötzau A, Orgül S, Flammer J, Kräuchi K. Thermal discomfort with cold extremities in relation to age, gender, and body mass index in a random sample of a Swiss urban population. Popul Health Metr. 2010; 8:17.

18. Saner H, Würbel H, Mahler F, Flammer J, Gasser P. Microvasculatory evaluation of vasospastic syndromes. Adv Exp Med Biol. 1987; 220:215–218.

19. Wunderlich K, Zimmerman C, Gutmann H, Teuchner B, Flammer J, Drewe J. Vasospastic persons exhibit differential expression of ABC-transport proteins. Mol Vis. 2003; 9:756–761.

20. Kang S, Chung KH, Kim TY, Ahn S, Ha JW, Rim S, et al. The inhibitory effect of triflusal (Disgren)on the platelet aggregation in healthy volunteers: impedance method with the whole blood. Korean Circ J. 1998; 28:707–714.

21. Matías-Guiu J, Ferro JM, Alvarez-Sabín J, Torres F, Jiménez MD, Lago A, et al. Comparison of triflusal and aspirin for prevention of vascular events in patients after cerebral infarction: the TACIP Study: a randomized, double-blind, multicenter trial. Stroke. 2003; 34:840–848.

22. Cruz-Fernández JM, López-Bescós L, García-Dorado D, López García-Aranda V, Cabadés A, Martín-Jadraque L, et al. Randomized comparative trial of triflusal and aspirin following acute myocardial infarction. Eur Heart J. 2000; 21:457–465.

23. McNeely W, Goa KL. Triflusal. Drugs. 1998; 55:823–833.

24. De La Cruz JP, Villalobos MA, García PJ, Smith-Agreda JM, Sánchez de la Cuesta F. Effects of triflusal and its main metabolite HTB on platelet interaction with subendothelium in healthy volunteers. Eur J Clin Pharmacol. 1995; 47:497–502.

25. de la Cruz JP, Mata JM, Sanchez de la Cuesta F. Triflusal vs aspirin on the inhibition of human platelet and vascular cyclooxygenase. Gen Pharmacol. 1992; 23:297–300.

26. García-Rafanell J, Ramis J, Gomez L, Forn J. Effect of triflusal and other salicylic acid derivatives on cyclic AMP levels in rat platelets. Arch Int Pharmacodyn Ther. 1986; 284:155–165.

27. Bayón Y, Alonso A, Sánchez Crespo M. 4-trifluoromethyl derivatives of salicylate, triflusal and its main metabolite 2-hydroxy-4-trifluoromethylbenzoic acid, are potent inhibitors of nuclear factor kappaB activation. Br J Pharmacol. 1999; 126:1359–1366.

28. Aceves M, Dueñas A, Gómez C, San Vicente E, Crespo MS, García-Rodríguez C. A new pharmacological effect of salicylates: inhibition of NFAT-dependent transcription. J Immunol. 2004; 173:5721–5729.

29. Sánchez de Miguel L, Casado S, Farré J, García-Durán M, Rico LA, Montón M, et al. Comparison of in vitro effects of triflusal and acetysalicylic acid on nitric oxide synthesis by human neutrophils. Eur J Pharmacol. 1998; 343:57–65.

30. Whitehead SN, Massoni E, Cheng G, Hachinski VC, Cimino M, Balduini W, et al. Triflusal reduces cerebral ischemia induced inflammation in a combined mouse model of Alzheimer's disease and stroke. Brain Res. 2010; 1366:246–256.

31. Husain S, Andrews NP, Mulcahy D, Panza JA, Quyyumi AA. Aspirin improves endothelial dysfunction in atherosclerosis. Circulation. 1998; 97:716–720.