Türk Kardiyol Dern Arş - Arch Turk Soc Cardiol 2012; 40:265-268
TKD|Three case reports of the use of herbal combinations resulted in stent thrombosis: herbal combinations; friend or foe?
||Volume: 40 Issue: 3
Three case reports of the use of herbal combinations resulted in stent thrombosis: herbal combinations; friend or foe?
Bitkisel karışım kullanan ve stent trombozu gelişen üç olgu: Bitkisel karışımlar dost mu, düşman mı?Dr. Mehmet Akif Vatankulu, Dr. Abdurrahman Tasal, Dr. Ercan Erdoğan, Dr. Ömer Göktekin
Summary– Nowadays, herbal combinations are commonly used in Turkey and around the world. In particular, an herbal combination including Tribulus terrestris (TT), Avena sativa (AS), and Panax Ginseng (PG), which may be effective in treatment of atherosclerosis and thrombosis, is used by patients with coronary artery disease. In this paper, we will report three cases with coronary stents who were diagnosed with acute coronary syndrome while using this herbal combination of TT, AS and PG together with anti-aggregant medications. A 45-year-old man presented with chest pain and coronary angiography confirmed a total occluded stent in left anterior descending artery which was implanted a year ago. Balloon dialation was performed to dilate the stent, resulting in full opening of the vessel. The second case, a 53-year-old woman, was admitted to the hospital with chest pain. Coronary angiography confirmed a total occluded stent, which had been implanted three months ago. A balloon was performed to dilate the stent and it was fully opened. The third case, a 62-year-old man, presented with chest pain. Coronary angiography was performed and there was a 98% stenosis of the circumflex stent, which was implanted three months ago. A balloon was performed to dilate the stent and it was fully opened. It was learnt that all three patients had used the same herbal combination (TT, AS and PG) with dual anti-aggregant therapy for three months ago to presentation in the clinic. Patients were discharged with the suggestion not to use this herbal combination with dual anti-aggregant therapy. There were no problems during the four month follow-up period. Stent thrombosis may be caused by interactions between herbal combination (TT, AS and PG) and clopidogrel in these patients under dual antiaggregant therapy.
Key words: Acute coronary syndrome; atherosclerosis; plants; cardiovascular agents/pharmacology; drugs, Chinese herbal; panax; saponins; thrombosis.
Submitted on :: .02.20. 2012 Accepted for publication on: : 04. 27..2012
Address of correspondence: Dr. Mehmet Akif Vatankulu. Bezmialem Vakıf Üniversitesi Tıp Fakültesi, Kardiyoloji Anabilim Dalı, 34093 İstanbul.
Phone: +90 212 - 453 17 00 e-mail: email@example.com
AS Avena sativa
LDL Low density lipoprotein
PG Panax ginseng
TT Tribulus terrestris
Herbal mixtures have been used from prehistoric ages up to now for therapeutical purposes. İn various diseases. The successful outcomes obtained with herbal mixtures in many diseases also formed the basis of modern treatment modalities. Nowadays, herbal mixtures constitute basic components of many drugs. Despite all of their beneficial effects, the impact of herbal mixtures not formulated under the light of scientific evidence, on human health is not completely acknowledged. In recent years, treatment with herbal medications has become extremely prevalent. Especially, herbal mixtures of Tribulus terrestris, Avena sativa and Panax ginseng are used by coronary artery patients.
Herein, we have presented 3 cases with coronary stents who consulted to us with the diagnosis of acute coronary syndrome while they were using a herbal mixture of TT,AS, and PG together with antiaggregant treatments, and we also provided information about the ingredients of these mixtures.
Case 1- A 45-year-old male patient who had undergone stent implantation for a proximal lesion in the left anterior descending artery one year ago, consulted to the emergency service with complaint of chest pain. Coronary angiography of the patient diagnosed as acute coronary syndrome demonstrated completely occluded coronary artery. In the same session balloon dilation was performed, and complete patency was ensured (Figure 1). From patient’s history it was learnt that the he was receiving 2 daily doses of herbal TT, AS, and PG mixture in addition to his antiaggregant treatment (clopidogrel 75 mg, acetylsalycilic acid 100 mg) for the last 3 months. Any coagulation disorder, and a comorbity were not detected during his medical examinations, and the patient was discharged with recommendations against use of herbal mixtures. Any medical problem was not detected during his follow-up visits performed at 4-month intervals.
Case 2- A 53-year-old woman presented to the emergency service with complaints of chest pain who had undergone stent implantation in circumflex branch of the coronary artery. Elevations in cardiac enzymes were detected in the patient whose coronary angiography demonstrated development of in-stent thrombosis (Figure 2). From patient’s history it was learnt that she was regularly receiving herbal mixture of TT, AS, and PG at 2 doses daily for the last 3 months in addition to her routine antiaggregant treatment (clopidogrel 75 mg, and 100 mg acetylsalycilic acid). Any additional abnormality was not detected in the medical status of the patient who had had in-stent balloon angioplasty with resultant complete patency. Subsequently the patient was discharged with recommendations against use of herbal mixtures. Any problem was not detected during further follow-up
Case 3- A 62-year-old male patient who had undergone stent implantation in circumflex artery three months ago, began to use a herbal mixture containing TT, AS, and PG regularly, in addition to his routine antiaggregant therapy (clopidogrel 75 mg, acetylsalicylic acid 100 mg) A lesion causing a 98 % in-stent stenosis was detected on coronary angiograms of the patient who re-consulted again with complaints of chest pain. Balloon dilation achieved full patency. Additional medical problem was not detected during the follow-up period, and the patient was discharged with recommendations against use of herbal mixtures.
Atherosclerosis is a chronic inflammatory process involving immune modulator components, immune cells, and blood lipids Elevations in LDL-cholesterol are strong risk factors in the development of atherosclerosis. In atherosclerosis detection of higher blood levels of inflammatory biomarkers are expected. On the other hand, endothelial dysfunction is the underlying factor in atherosclerosis. Dietary habits also play a very important role in the development of atherosclerosis. In recent years, serious attempts have been made to change Western style dietary pattern Even though desired levels of success have not been accomplished in changing dietary habits yet, herbal mixtures are more readily preferred, and accepted by people. Among them,especially in Turkey, TT, AS, and PG mixtures are preferred, and used by the patients with coronary, and peripheral vascular diseases without any medical surveillance.
Other nomenculature for TT is Fructus tribuli which belongs to Zygophyllaceae family. Especially in Turkey, and Far East it has been used singly or in combination.  TT has many active ingredients (saponins). It has been used in skin, liver, and coronary artery diseases, diabetes mellitus, hypertension, hyperlipidemia, nephrolithiasis, fungal infections, and sexual dysfunction. Some animal experiments in mice demonstrated its vasodilator effects via decreasing ACE activity in cardiovascular system, predominantly in kidneys with resultant regulatory effects on blood pressure [4,5] Besides, in rabbits, their beneficial effects on lipid profiles, and endothelial functions had been displayed. 3] In human beings, some case series indicated that it decreased the frequency of anginal episodes by inducing coronary vasodilation in angina pectoris..
AS is a plant known as oat. In recent years beneficial effects of oat, oat fibers, and their beta glucan containing extracts on lipid profile of men have been demonstrated. Under laboratory conditions, as ingredients of oat plant, vitamin E, phenolic acid, flavonoids, and sterols had improved endothelial dysfunction thanks to their antioxidant, and antiinflammatory effects. Besides,studies on mice using oat bran revealed a decrease in the levels of some inflammatory markers, and an increase in endothelial nitric oxide (eNOS) activity with the blockage of LDL receptors on atherosclerotic lesions. 
An important ingredient of the mixture PG is extracted from red coloured roots of a wild plant (Araliaceae spp.) widely found in the Far East. Similar to other products , PG has many active ingredients, the important ones being ginsenoids. In animal experiments, favourable effects of this herb on the immune system, physical, and mental performances have been demonstrated. Investigations on human volunteers have also displayed its beneficial effects on diabetes, cancer, sexual functions, and immune system. In experimental models, protective effects against ischemic, and reperfusion damage have been indicated. Recent studies on mice have demonstrated antihypertrophic, and antiremodeling effects of ginseng on cardiomyocytes [8,9] However all these favourable results have not been substantiated by well-designed, randomized controlled trials. PG which exerts beneficial effects in experimental animal trials is not recommended for hypertensive patients because of its both hypertensive, and hypotensive effects. In addition, some data suggest that it tends to decrease the effectiveness of warfarin 
Favourable effects of these mixtures on animals have not been demonstrated for human beings.
With increasing use of these mixtures, relevant organ toxicities thought to stem from them are more frequently reported 12]
Platelets play a critical role in the pathogenesis of atherosclerosis, thrombosis, and acute coronary syndromes. Inhibition of platelets is quite important in patients with coronary stents. Presently, aspirin, and clopidogrel are mostly used for inhibition of platelets. In recent years with increasing number of stent thrombosis, aspirin, and clopidogrel resistance have become a current issue. On the other hand, it has been reported that calcium channel blockers, proton pump inhibitors, and some drugs weaken the effectiveness of clopidogrel leading to the development of thrombosis, and acute coronary syndromes.[13,14] These kinds of drug-drug interactions are important problems encountered in modern medicine. Large scale investigations on this issue are still continuing.
Normally, incidence of stent thrombosis developed in our three cases despite dual antiaggregant therapy ranges between 0.5-2 percent. Any cardiac problem did not develop during routine controls in our patients after coronary stenting. Successive occurrence of stent thrombosis in our three patients who routinely used herbal mixtures together with their prescribed medical treatment , weakens the probability of haphazardness of stent thrombosis which is usually seen with a relatively lower incidence. Besides, objective ischemic tests performed during four months after the recommendations against the use of herbal mixtures could not detect an abnormality in their health state. In this case, though not substantiated by laboratory evidence, interaction of herbal ingredients with antiaggregants is a strong probability. These kinds of mixtures containing various extracts without fully known doses, and efficacies might interact with antiaggregants, and especially clopidogrel with a resultant impact on platelet inhibition.
Stent thrombosis, and acute coronary syndrome developed while the patient is on dual antiaggregant therapy might emerge as a result of interactions between concomitantly used herbal mixtures of TT, AS, and PG, and clopidogrel. First of all experimental investigations, followed by randomized controlled clinical studies should be conducted in order to fully clarify this issue.
Conflict of interest: None declared
1. Lusis AJ. Atherosclerosis. Nature 2000;407:233-41.
2. Andersson KE, Svedberg KA, Lindholm MW, Oste R, Hellstrand P. Oats (Avena sativa) reduce atherogenesis in LDL-receptor-deficient mice. Atherosclerosis 2010;212:93-9.
3. Tuncer MA, Yaymaci B, Sati L, Cayli S, Acar G, Altug T, et al. Influence of Tribulus terrestris extract on lipid profile and endothelial structure in developing atherosclerotic lesions in the aorta of rabbits on a high-cholesterol diet. Acta Histochem 2009;111:488-500.
4. Sharifi AM, Darabi R, Akbarloo N. Study of antihypertensive mechanism of Tribulus terrestris in 2K1C hypertensive rats: role of tissue ACE activity. Life Sci 2003;73:2963-71.
5. Phillips OA, Mathew KT, Oriowo MA. Antihypertensive and vasodilator effects of methanolic and aqueous extracts of Tribulus terrestris in rats. J Ethnopharmacol 2006;104:351-5.
6. Wang B, Ma L, Liu T. 406 cases of angina pectoris in coronary heart disease treated with saponin of Tribulus terrestris. Zhong Xi Yi Jie He Za Zhi 1990;10:85-7, 68. [Abstract]
7. Kiefer D, Pantuso T. Panax ginseng. Am Fam Physician 2003;68:1539-42.
8. Guo J, Gan XT, Haist JV, Rajapurohitam V, Zeidan A, Faruq NS, et al. Ginseng inhibits cardiomyocyte hypertrophy and heart failure via NHE-1 inhibition and attenuation of calcineurin activation. Circ Heart Fail 2011;4:79-88.
9. Karmazyn M, Moey M, Gan XT. Therapeutic potential of ginseng in the management of cardiovascular disorders. Drugs 2011;71:1989-2008.
10. Brinker FJ. Herb contraindications and drug interactions: with extensive appendices addressing specific conditions, herb effects, critical medications, and nutritional supplements. 3d ed. Sandy, Ore: Eclectic Medical Publications; 2001.
11. Vogler BK, Pittler MH, Ernst E. The efficacy of ginseng. A systematic review of randomised clinical trials. Eur J Clin Pharmacol 1999;55:567-75.
12. Talasaz AH, Abbasi MR, Abkhiz S, Dashti-Khavidaki S. Tribulus terrestris-induced severe nephrotoxicity in a young healthy male. Nephrol Dial Transplant 2010;25:3792-3.
13. Shah BS, Parmar SA, Mahajan S, Mehta AA. An insight into the Interaction between Clopidogrel and Proton Pump Inhibitors. Curr Drug Metab 2012 Feb 2.
14. Siller-Matula JM, Lang I, Christ G, Jilma B. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol 2008;52:1557-63.
15. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-30.
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