ARTICLE IN PRESS

Complementary Therapies in Clinical Practice (2006) 12, 236–241

www.elsevierhealth.com/journals/ctnm

Potential drug–herb interaction with

antiplatelet/anticoagulant drugs
Jun Tze Sawa,, Mohd Baidi Baharia, Hooi Hoon Anga, Yu Hoe Limb

a
School of Pharmaceutical Sciences, University Science Malaysia, Minden, 11800 Penang, Malaysia
b
Department of Medicine, Penang General Hospital, Jalan Residensi, 10990 Penang, Malaysia

KEYWORDS Summary This is a cross-sectional survey evaluating the use of herbal medicines in
Antiplatelet; medical wards patients that may interfere with the effect of antiplatelet or
Anticoagulant; anticoagulant therapy. Among the 250 patients participated, 42.4% (n ¼ 106) were
Drug–herb interac- taking herbs with 76 patients (71.7%) using herbs for the past 12 months. Overall,
tions; almost 31% (n ¼ 23, N ¼ 76) of patients were taking one or more of the specified
Disclosure herbal medicines [ginseng (Panax ginseng), garlic (Allium sativum), ginkgo (Gingko
biloba) thought to interact with antiplatelet or anticoagulant therapy. The study
showed that 21% (n ¼ 16, N ¼ 76) of patients co-ingested specified herbs with
antiplatelet or anticoagulant therapy, of which half of them were at risk of potential
drug–herb interactions. A large proportion of respondents involved in potential
drug–herb interaction were elderly people (62.5%, n ¼ 5). However, more than 90%
of herbal users did not disclose the use of herbal medicine to their health
professionals. It is thus prudent for all care givers to be aware of the possibility of
drug–herb interaction and inquire about herbal use from patients.
& 2006 Elsevier Ltd. All rights reserved.

Introduction prescription medications.1 Estimates of concurrent

In recent years, the increasing use of herbal
medicine in many countries is widely acknowl-
edged. National survey in United States revealed
that 18% of surveyed adults reported concomitant
use of herbal medicines or high-dose vitamins with
Corresponding author. Present address: School of Pharmacy,
University College Sedaya International, No. 1, Jalan Menara
Gading, UCSI Heights, 56000 Kuala Lumpur, Malaysia.
Tel.: +6 03 91018880/+6 012 6572615; fax: +6 03 91023606.
E-mail addresses: jtsaw@ucsi.edu.my, elsz_5@yahoo.co.uk
(J.T. Saw), baidi@usm.my (M.B. Bahari), hhang@usm.my
(H.H. Ang).
use of complementary and alternative medicine
(CAM) products with allopathic medicine is 39% in
an Australian survey of patients using Chinese
medicine.2 A recent survey by Kuo et al.3 on
medical patients showed that almost half of the
respondents (46%) taking conventional therapy with
herbs, confirming that patients who seek conven-
tional practitioners are at increased likelihood of
exploring alternative treatment, such as herbal
medicines.
One important safety concern with the wide-
spread herbal use is the potential interactions of
herbal medicines with allopathic medicines.

1744-3881/$ - see front matter & 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ctcp.2006.06.002
 ARTICLE IN PRESS
Potential drug–herb interaction with antiplatelet/anticoagulant drugs
A drug–herb interaction can be defined as pharma-
cologic or clinical response to the co-administration
of a traditional drug or pharmaceutical preparation
and a herbal product.4
The prevalence of drug–herb interactions is
extensive but unknown, signifying the negligence
of the consumers in reporting adverse herb reaction
or drug–herb interactions. A survey of 515 herbal
users in UK found that 26% would consult conven-
tional practitioners for a serious adverse drug
reaction but not for similar reaction to herbal
medicines.5 Case reports, case series and clinical
studies underpin the subsistence of clinically
important interactions, where concomitant use of
herbs may imitate, augment or oppose the effect
of allopathic medicine.6 Nevertheless, the lists of
hypothetical interactions are mostly based on
known pharmacological effects of the herbal
medicines or extrapolated from herbal constituents
and lack of validation from clinical trials. Despite
that the clinical significance of drug–herb interac-
tion varies, it is essential to realize that any
interaction has the potential to cause harm and
reporting of any experienced adverse reaction
resultant from herbal medicine is warranted.
Herbs that may augment or inhibit the effect of
anticoagulant or antiplatlet therapy are of parti-
cular interest considering commonness of the latter
treatment for cardiovascular diseases. Top selling
herbal medicine in US market in 1998 including
ginkgo, ginseng and garlic are correlated with
plausible interactions with the above medications.7
The high prevalence of both conventional pharma-
cological therapy and herbal medicines use draws
attention to safety concerns. In addition, antic-
oagulant therapy, especially warfarin, has a narrow
therapeutic index and has been associated with
numerous food and drug interactions.8 This is also
supported by a systematic review of drug–herb
interactions by Fugh-Berman and Ernst,9 indicating
that warfarin was the drug most commonly cited
(n ¼ 18, N ¼ 108).
The objective of our study is to determine the
prevalence of herbal use and assessing the use of
herbal medicines in medical patients that may
interact with antiplatelet or anticoagulant therapy.
Methods
This cross-sectional survey was undertaken in
Penang General Hospital, Malaysia. The study
population consisted of medical patients from
cardiology, neurology, infectious and nephrology
wards. A convenience sample of medical ward
237
patients was recruited from March to May 2005. All
eligible patients were included for participation.
Patients excluded were those below 18 years of age,
pregnant women, individuals unable to give consent
for any reason, including those with neurological
disabilities or language barriers. Concurrently, the
medical record was reviewed for demographic
information, diagnoses and medications.
A questionnaire was designed to document the
use of herbal medicines and concurrent drug
regimen, where anticoagulant (warfarin) or anti-
platelet (aspirin) drugs are of major concern. The
study adopted the definition of herbal medicines as
stipulated in World Health Organisation (WHO)
guidelines for the appropriate use of herbal
medicines 1998. Under this definition, herbal
medicines refer to plant-derived materials or
products with therapeutic or other human health
benefits.
The main emphasis was a specified group of
herbal medicines that had been implicated for
interacting with anticoagulant or antiplatelet ther-
apy: ginseng, garlic and ginkgo.
The questionnaire consisted of two main sec-
tions. The first part of questionnaire contained
questions on demographic and socioeconomic back-
ground of respondents. Information of herbal use
was elicited in second part, specifying name, and
duration of use. In addition, the perception on
herbal use including disclosure to physician was
also documented. All the data collected were
coded and analyzed by using Statistical Package
for the Social Sciences (SPSS) version 13.0.
Results
A total of 250 medical patients were recruited in
the analysis. The final study population consisted of
127 women (50.8%) and 123 men (49.2%) with a
mean age of 52.7 years (SD, 15.05; range, 18–86).
The majority of respondents were Malay patients
(42.4%), Chinese (34%), Indian (22.4%) and others
(1.2%). More than half of the patients’ age fell into
age group 35–59 years (52.8%). Approximately
41.6% of participants had completed secondary
school and 9.6% tertiary education. Most partici-
pants (86%) were married and reported a gross
household income in the lowest category. This was
Ringgit Malaysia (RM) o1000 (61.6%). Almost 60% of
patients were unemployed and for those who were
employed, 62.5% and 27.5% had joined private and
government sector, respectively. Table 1 sum-
marizes sociodemographic characteristics of the
subjects included in the analysis.
 ARTICLE IN PRESS
238 J.T. Saw et al.

Table 1 Descriptive characteristics of the study Table 1 (continued )

population.
Variable No. of User (%) Non-user
Variable No. of User (%) Non-user patients (%)
patients (%) (%)
(%)
Family history of illness
Gender Yes 163 (65.2) 72 (44.2) 91 (55.8)
Male 123 (49.2) 58 (47.2) 65 (52.8) No 69 (27.6) 28 (40.6) 41 (59.4)
Female 127 (50.8) 48 (37.8) 79 (62.2) Unknown 18 (7.2) 6 (33.3) 12 (66.7)
Age (years) Past medical history
18–34 32 (12.8) 12 (37.5) 20 (62.5) Yes 221 (88.4) 90 (40.7) 131 (59.3)
35–59 132 (52.8) 62 (47.0) 70 (53.0) No 29 (11.6) 16 (55.2) 13 (44.8)
60–88 86 (34.4) 32 (37.2) 54 (62.8)
Drug allergy
Ethnic/race Yes 35 (14) 17 (48.6) 18 (51.4)
Malay 106 (42.4) 48 (45.3) 58 (54.7) No 214 (85.6) 89 (41.6) 125 (58.4)
Chinese 85 (34.0) 40 (47.1) 45 (52.9)
Perceived health
Indian 56 (22.4) 18 (32.1) 38 (67.9)
Very poor 4 (1.6) 3 (75.0) 1 (25.0)
Others 3 (1.2) 0 (0) 3 (100)
Poor 186 (74.4) 82 (44.1) 104 (55.9)
Religion Fair 51 (20.4) 18 (35.3) 33 (64.7)
Islam 107 (42.8) 49 (45.8) 58 (54.2) Good 9 (3.6) 3 (33.3) 6 (66.7)
Buddhist 83 (33.2) 39 (47.0) 44 (53.0)
Hinduism 56 (22.4) 18 (32.1) 38 (67.9)
Christianity 1 (0.4) 0 (0) 1 (100)
Others 3 (1.2) 0 (0) 3 (100)
Among 250 respondents, 42.4% (n ¼ 106)
Marital status reported taking herbal medicine with 71.7%
Single 32 (12.8) 11 (34.4) 21 (65.6) (n ¼ 76) having used herbs for the past 1 year. Of
Married 215 (86.0) 93 (43.3) 122 (56.7) these, 31% (n ¼ 23) were taking one or more of the
Divorced 3 (1.2) 2 (66.7) 1 (33.3)
specified herbal medicines (ginseng, garlic, ginkgo)
Working status thought to interact with antiplatelet or antic-
Working 79 (31.6) 35 (44.3) 44 (55.7) oagulant therapy: 11 (14.4%) taking ginseng; 7
Not working 145 (58.0) 55 (37.9) 90 (62.1) (9.2%) garlic and 6 (7.9%) ginkgo. Other herbs with
Retired 26 (10.4) 16 (61.5) 10 (38.5)
similar potential interactions used by patients were
Employment ginger (n ¼ 5, 6.6%), danshen (Salvia miliorrhiza)
Private 50 (62.5) 21 (42.0) 29 (58.0) (n ¼ 4, 5.2%), dong quai (Angelica sinensis) (n ¼ 5,
Self- 8 (10.0) 5 (62.5) 3 (37.5) 6.6%) and chamomile (Matricaria chamomilla)
employed
(n ¼ 1, 1.3%). Overall, 13 people experienced
Government 22 (27.5) 10 (45.5) 12 (54.5)
unwanted side-effects (12.3%, n ¼ 106). The most
Income (monthly) commonly reported side-effects were headache
oRM 1000 154 ( 61.6) 56 (36.4) 98 (63.6) (22.2%) and dizziness (16.7%). Of 23 patients taking
RM 85 (34.0) 42 (49.4) 43 (50.6)
specified herbs, 1 (4.2%) reported adverse reac-
1000–3000
RM 9 (3.6) 7 (77.8) 2 (22.2) tions; this accounted for 0.4% of the total sample.
3000–5000 Almost 40% (n ¼ 99) of surveyed patients were
4RM 5000 2 (0.8) 1 (50.0) 1 (50.0) taking antiplatelet and/or anticoagulant drugs for
the past 12 months. The study showed that 21%
Education level
None 29 (11.6) 7 (24.1) 22 (75.9) (n ¼ 16, N ¼ 76) of patients co-ingested specified
Primary 93 (37.2) 30 (32.3) 63 (67.7) herbs with antiplatelet or anticoagulant therapy, of
Secondary 104 (41.6) 56 (53.8) 48 (46.2) which 10.5% (n ¼ 8) were identified at risk of
Tertiary 24 (9.6) 13 (54.2) 11 (45.8) potential drug–herb interaction. Of eight suspected
Smoking interactions, 50% involved garlic with aspirin; 37.5%
Never 159 (63.6) 58 (36.5) 101 (63.5) warfarin with ginseng or ginkgo and 12.5% ginkgo
Former 72 (28.8) 38 (52.8) 34 (47.2) with aspirin. A large proportion of respondents
Current 19 (7.6) 10 (52.6) 9 (47.4) (62.5%, n ¼ 5) involved in potential drug–herb
Alcohol interaction were elderly patients (465 years).
Never 190 (76.0) 77 (40.5) 113 (59.5) When asked if they had discussed or disclosed the
Former 47 (18.8) 26 (53.1) 21 (46.9) herbal use with any healthcare professionals, more
Current 13 (5.2) 3 (23.1) 10 (76.9) than 90% of herbal users responded that they had
 ARTICLE IN PRESS
Potential drug–herb interaction with antiplatelet/anticoagulant drugs 239

not disclosed use of herbal medicine with conven-
tional practitioners.
Discussion
A high usage of herbal medicine was reported in
this survey sample, confirming previously published
information.10,11 This rate of use mandates atten-
tion from all healthcare professionals with regard
to possible drug–herb interactions.
The fact that herbal medicines are associated
with adverse effects is widely acknowledged.
Around 50% (n ¼ 38, N ¼ 76) of patients in this
study took herbal remedies that could interfere
with the effects of anticoagulant or antiplatelet
drugs (Table 2), of which more than 30% comprised
of ginseng, ginkgo and garlic. This finding corre-
sponds with the documented annual retail sales in
United States where ginkgo, ginseng and garlic are
among the best-selling herbal medicines in 1998
($US 150 million, $US96 million and $US84 million,
respectively).7 The popularity of these herbs as
well as potential interference with anticoagulants
should be highlighted to both healthcare providers
and consumers.
The prevalent of co-ingestion of herbs and
pharmaceutical medications in this survey is con-
sistent with the previous studies.3,12,13 Study
results also suggest that a considerable proportion
of patients took antiplatelet or anticoagulant
therapy at the same time as herbal medicines .
This finding reflects the potential for public health
problems particularly with pre- or post-operative
patients; patients with clotting disorders; those on
anticoagulant therapy and the elderly who may also
have been prescribed aspirin and warfarin.
There have been several published incidences on
drug–herb interactions involving antiplatelet or
anticoagulant drugs. The majority of interactions
identified to date have involved drugs with a
narrow therapeutic index and these require regular
monitoring, particularly in the case of Warfarin. For
example, simultaneous use of warfarin and garlic
can be associated with an increase in blood
international normalized ratio (INR).14 Although
one case report found that co-administration of
ginseng was associated with a decline in INR during
warfarin therapy,15 there have been a number of
randomized controlled trials (RCT) indicating
that ginseng did not affect the pharmacokinetics
and pharmacodynamics of warfarin in human
subjects.16,17
Since most of the suspected interactions are
identified through case reporting and not exhaus-
tive clinical trials, the causal relationship between
these two entities is difficult to be quantified
as there may be other causal factors involved such
as patient characteristics. Further research is
required to understand and explore the in vivo
effects of herbs on prescription medications.
However, the lack of an established surveillance
system for side-effects of herbs continues
to impede the documentation of herb-induced
interactions.
Adverse effects of herbal medicines
The reported adverse effect due to herbal medi-
cines was slightly higher than previous studies.18
Contrary to findings by Bensoussan et al.2 indicating
gastrointestinal symptoms and skin reactions as
most common side-effects of herbal medicines,
headache and dizziness were mainly reported in this
study. Apart from inherent toxicities of herbal
medicines, side-effects may also occur as a result
of misidentification of materials (herbs with inap-
propriate botanical identification), lack of standar-
dization (inconsistent quality or quantities of herbs
constituents), contamination of plant materials
(by pesticides, microorganisms) and adulteration
(illegal adding of conventional pharmaceuticals to
herbal products).19

Table 2 Interaction between herbs and anticoagulant/antiplatelet.

Name (Latin) Anticoagulant/antiplatelet Potential interaction

Panax (Panax ginseng) Warfarin Decreased INR27

Garlic (Allium sativum) Warfarin, Aspirin May increase risk of bleeding28
Ginkgo (Ginkgo biloba) Warfarin, Aspirin Increased risk of bleeding29
Chamomile (Matricaria chamomilla) Warfarin May increase bleeding time30
Dong quai (Angelica sinensis) Warfarin Increased bleeding time31
Dan shen (Salvia miliorrhiza) Warfarin Increased bleeding time32
Ginger (Zingiber officinale) Warfarin May enhance risk of bleeding33
 ARTICLE IN PRESS
240
Difficulties in standardizing the regulation of
Herbal medicines
Regulations governing herbal medicine vary by
country.
Herbal products in United States are regulated as
dietary supplement and marketed without prior
approval of their safety and efficacy by the Food
and Drug Administrator (FDA). In contrast to this in
Germany, products can only be registered if based
on approximately 300 monographs on herbs with
concise information.20 In Malaysia, the Ministry of
Health implemented registration for traditional
medicines under the Control of Drugs and Cos-
metics Regulations 1984. The quality and safety
requirements subjected include limits for heavy
metals (Poison Act 1952, Revised 1989), limits for
microbial contamination, absence of steroids and
other adulterants (Poison Act 1952, Revised 1989),
limits of disintegration time (Pharmacopoeial Stan-
dards), claimed indications (Medicines Act—Adver-
tisement and Sale, 1956, Revised 1983), prohibition
of herbs with known adverse effects, prohibition of
endangered animal species (Wildlife Protection Act
1972), compliance to Good Manufacturing Practice
(GMP) and approved marketing authorization from
the importing countries.21
An intriguing finding of our study is that vast
majority (490%) of the patients do not reveal or
disclose the herbal use with their healthcare
professionals, which corroborate previous find-
ings.22,23 This low disclosure rate may predispose
patients to greater risk of bleeding complications or
harmful effects.
It is thus of utmost importance to initiate
discussion with patients regarding any herbal use
in order to evaluate the risk benefits of herbal
remedies. Patients should also be alerted to
potential adverse effects caused by herbs. The
general belief that herbs are safe is not evident
even though a recent survey showed that 90% of
CAM users considered the products safe, compared
with 65% of non-users.24 The National Center for
Complementary and Alternative Medicine (NCCAM)
fact sheet warns consumers that one cannot assume
herbal supplement is ‘natural’ and therefore safe.
It also recommends that herbal supplement should
be used under the guidance of a medical profes-
sional who has been properly trained in herbal
medicine.25
In view of high prevalence of herbal use in
patients taking antiplatelet or anticoagulant drugs,
information about herbal use must be obtained
from patients routinely. Patients on anticoagulant
therapy should be warned against the concurrent
use of ginkgo, danshen, dong quai or garlic.
J.T. Saw et al.
Alternatively, thay should receive blood INR mea-
surements within a week of starting any herbal
products.6
Despite the study focusing on the interactions
between specified herbal medicines, antiplatelet
and anticoagulant drugs, all other herbs may be
potentially associated with the risk of interactions
with conventional therapies. Therefore, doctor–
patient communication is vital in preventing
unwanted pharmaceutical complications of drug–
herb interactions and discussion about herbal
utilization should be carried out on an ongoing
basis.
It is strongly recommended that all conventional
practitioners attain basic competency in the area
of herbal medicine and CAM education should be
integrated into existing curriculum and continuing
education programmes.26
Our survey has several limitations. Information
from non-respondents cannot be obtained. One
should also exert caution when attempting to
generalize from a certain sample sizes. It is also
acknowledged that interpretation of the definition
of a herbal medicine may differ among patients
from various sociocultural backgrounds. Future
studies might include wider sampling of diverse
cultures to elicit further information on the impact
of herbal medicines on blood coagulation.
In conclusion, many patients take herbal medi-
cines that are known to interact with antiplatelet
or anticoagulant drugs. Interactions between these
herbal medicines and allopathic medicine may
predispose to serious clinical consequences. Clin-
ical practitioners should be aware of this and
ensure thorough case histories are taken that
include enquiring about herbal self-medication as
well as prescribed herbal and allopathic medicines.
Patients should also be encouraged to communicate
their herbal use and be more critically aware when
obtaining information about herbal medications.
Acknowledgement
We thank Dato Dr. Lim Yu Hoe, Head of the Medical
Department in Penang General Hospital for approv-
ing the study and all the staff in medical wards for
their help and cooperation.
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