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* Department of Medicine, Harbor-UCLA Medical Center, UCLA David Geffen School of Medicine, Torrance, CA 90502 and Wakunaga of America Co., Mission Viejo, CA 92691
4 To whom correspondence should be addressed: E-mail: ysniihara{at}msn.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • aged garlic extract • warfarin • oral anticoagulation therapy • S-allylcysteine
Aged garlic extract (AGE)5 has been shown to be useful in many areas of health maintenance (1,2). It has been associated with improvement of the cholesterol profile (3,4), and specifically HDL, which positively affects cardiac risk (5–7), stimulates the immune system (8), prevents certain cancers (8), mitigates the effects of oxidants (9), normalizes blood pressure (3,10), and improves circulation (11,12). Due to garlic's known complications, its use has been cautiously discouraged for patients who are on anticoagulation therapy. Today, however, there are many antiplatelet agents, such as Plavix® (clopidogrel) and aspirin, that are prescribed routinely in conjunction with anticoagulants such as warfarin. Because garlic extracts have many potential medical benefits, the risk of increased bleeding, especially in patients on anticoagulation therapy, needs to be revisited (13).
A large number of patients are on AGE extract or other garlic-based agents for various medical indications such as hypercholesterolemia and hypertension. These patients may also suffer from ailments like deep vein thrombosis, which require anticoagulation therapy. Other than a study by Rosenfeld et al. (13) there are essentially no reliable data to help medical providers determine the disposition of garlic during anticoagulation treatment. Therefore, this study examines the safety of using AGE in patients on oral anticoagulation (warfarin) therapy.
We chose AGE because of the ample publications in peer-reviewed journals regarding its use. In addition, AGE is unique and different from other garlic preparations. The long-term extraction process, called the aging process, is designed to eliminate odor, toxicity, and hemorrhage-causing, oil-soluble, sulfur compounds. Quality control is strictly followed in compliance with pharmaceutical Good Manufacturing Practices. The principal preparation for AGE appears in the U.S. Pharmacopoeia/National Formulary official monograph as Garlic Fluid Extract.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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Of the 66 enrolled patients, 48 (30 men and 18 women with a mean age of 56 ± 10 y) completed the protocol. The Institutional Review Board of Harbor-UCLA Research and Education Institute approved this project.
Aged garlic extract. AGE (Kyolic®), provided by Wakunaga of America, was formulated by soaking sliced raw garlic in aqueous ethanol solution for up to 20 mo at room temperature. The extract was filtered and concentrated under reduced pressure at low temperature. The procedure is described in the United States Pharmacopoeia/National Formulary monograph under Garlic Fluid Extract. The AGE used in this trial contained 305 g/L of extracted solids; S-allylcysteine, the most abundant water-soluble organosulfur compound in AGE, was present at a concentration of 1.47 g/L.
The administering of aged garlic extract.
After obtaining consent, each patient was seen at baseline for an interview, a physical examination, and baseline blood tests. A urine pregnancy test was also done for each woman of childbearing age. Each subject had blood drawn after fasting for 12-h. For all subjects, a blood sample of 
15 cc was drawn from an arm vein by the phlebotomist. The sample was centrifuged and the serum separated. Samples were stored at –70°C. After randomization, participants were started on either the AGE or the placebo at a dose of 5 mL twice daily for 12 wk. Participants were instructed to self-administer the study medication and keep the liquid containers refrigerated during the study.
At weeks 0, 4, and 8, a 1-mo supply of study medication (AGE or placebo) was given to each participant. Diaries were supplied to patients for monitoring warfarin and study-medication intake and compliance. The dose of warfarin was recorded for every encounter. At weeks 2, 6, and 10, patients were interviewed by telephone to collect any adverse-event information. At week 4, 8, and 12, patients were re-evaluated with a short physical examination and interview. Blood tests were performed.
Statistical analysis. Differences of all parameters were expressed to subtract the value at the end of the study (after 12 wks from entry). Comparisons of mean relative changes were made with the Student's t test.
Comparisons of all parameters between the AGE and placebo groups were made with the Student's t test. Continuous variables were presented as means ± SD. All statistical tests were 2-tailed, and P < 0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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Anticoagulation therapy in itself carries the risk of bleeding complications. The presence of independent variables such as the duration of anticoagulation, number of comorbid conditions, and prolonged international normalized ratios may mitigate or potentiate risk (16–25). In this study, patients were on oral anticoagulation therapy on an outpatient basis for at least 12 wk. The indications for the use of warfarin were atrial fibrillation, cardiac valve replacement, pulmonary embolism, and deep vein thrombosis.
This trial found no bleeding associated with the concomitant use of AGE and oral anticoagulation therapy, which suggests that there is no blood-thinning synergism between them. This could be due to close observation and monitoring (biweekly telephone follow-ups and monthly study visits). Maintaining appropriate international normalized ratio levels may have precluded any untoward signs and symptoms from getting out of control. Gender differences did not affect the results significantly because neither AGE nor the placebo group had any episode of notable hemorrhagic complications.
Garlic is alleged to be associated with acquired platelet dysfunction that can cause bleeding in some situations. However, compared with other antiplatelet agents used routinely with warfarin for various indications, AGE is unlikely to be a more potent antiplatelet agent (26).
Clinical studies show the intake of S-allyl cysteine is followed by a decrease of fats or blood lipids, including triglycerides and serum cholesterol, inhibition of platelet aggregation, enhancement of circulation, and decrease in blood pressure.
The literature is replete with indications that show a positive effect of AGE on the lipoprotein profile (3–7). As anticipated, our study also showed a positive increase in the HDL fraction, but no decrease in the total cholesterol picture. This result may be caused by short-term consumption compared with previous studies. Again, the gender differences upon entering the study need to be considered. However, the finding is consistent with previous data in the literature as noted above.
This study demonstrated that there was no increase in the incidence of hemorrhages with AGE use in patients on oral anticoagulation (warfarin) therapy. The results suggest that use of AGE may be carefully administered along with anticoagulation therapy, provided that close monitoring is mandated (27). Further study is necessary to confirm the safety of AGE for patients on oral anticoagulation treatment.
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FOOTNOTES |
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2 Author disclosure: Harunobu Amagase is employed by Wakunaga of America, Co., Ltd.
3 The Wakunaga of America Co., Ltd., Mission Viejo, California 92691 provided funding for this study.
5 Abbreviation used: AGE, aged garlic extract.
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LITERATURE CITED |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Sumiyoshi H. New pharmaceutical activities of garlic and its constituents. Nippon Yakurigaku Zasshi. 1997;110: Suppl 1:93P–7P.
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24. Moriyasu H, Yasaka M, Oita J, Yamaguchi T. Warfarin therapy for secondary prevention of cardioembolic stroke with nonvalvular atrial fibrillation – a retrospective study. Rinsho Shinkeigaku. 1993;33:850–5.[Medline]
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28. Palareti G, Leali N, Cocheri S, Poggi M, Manotti C, D'Angelo A, Pengo V, Erba N, Moia M, et al. Bleeding complications of oral anticoagulant treatment: an inception: cohort, prospective collaborative study (ISCOAT). Italian study on complications of oral anticoagulant therapy. Lancet. 1996;348:423–8.[Medline]
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