Herbal remeoles ano antlcoagulant tberapy

Noab Samuels
Unlt o| Complementary Meolclne, Tel Avlv Sourasky Meolcal Center, Tel Avlv, |srael
5unnary
Herbal remeoles, consloereo to be botb sa|e ano e||ectlve by
most consumers, may lnteract wltb conventlonal orugs. War|a-
rln, a vltamln K antagonlst orlglnally oerlveo |rom tbe sweet
clover plant, bas a narrow tberapeutlc wlnoow wblcb can be
monltoreo uslng protbrombln lnternatlonal normallzeo ratlos
(PT-|NP). Many berbs can lncrease tbe rlsk |or bleeolng wben
comblneo wltb war|arln, eltber by augmentlng tbe antlcoagulant
Keywords
Herbs, war|arln, antlcoagulatlon, antlplatelet, bleeolng
e||ects o| tbe orug (wltb lncreaseo PT-|NP levels) or tbrougb ln-
trlnslc antl-platelet propertles (wltbout alterlng PT-|NP levels).
Tbe lncreaseo rlsk |or bleeolng among sucb patlents may be ol|-
|lcult to preolct, especlally wben |ormulas wblcb contaln many
berbs are useo. Furtber researcb lnto berb-orug lnteractlons ls
warranteo, as are guloellnes |or tbe use o| berbal remeoles by
patlents on cbronlc antlcoagulatlon tberapy.
Thronb Haenost 2005, 93: 3-7
ReviewArticIe
Corresponoence to.
Dr. Noab Samuels
130 Pacbmllevlcb Street
[erusalem 97791, |srael
Tel.. 97225850371, Fa. 97225849825
L-mall. re|plus@netvlslon.net.ll
Pecelveo May 7, 2004
Accepteo a|ter resubmlsslon October 21, 2004
Prepubllsbeo onllne December 8, 2004 DO|. 10.1160/TH04050285
Use of herbaI renedies by patients on
anticoaguIant therapy
Herbal remedies are considered by most consumers to be both
saIe and eIIective, and their use is on the rise (1). Nearly one in
six adults in the United States taking prescription drugs is con-
comitantly using at least one herbal remedy (2), while less than
40 oI patients will disclose the use oI herbal and other alter-
native therapies to their regular physicians or emergency room
staII (1, 3). Although herbal medicines are thought to cause Iewer
adverse and toxic eIIects than conventional drugs due to the
lower concentration oI active components, the use oI certain
herbs may result in severe, even lethal, side eIIects (4). Iegis-
lation requiring licensing Ior herbal remedies has been imple-
mented in only a Iewcountries such as Germany, Erance, Sweden
and Australia, while in the U.S. the Dietary Supplement Health
and EducationAct oI 1994 eliminated the requirement that these
products be reviewed by the Eood and Drug Administration
(EDA).
WarIarin, a drug originally derived Irom the sweet clover
plant, interrupts the vitamin Kdependent posttranslational
modiIication oI coagulation proteins II, VII, IX and X via in-
hibition oI vitamin K epoxide reductase. Dosage oI the drug is
adjusted according to target prothrombin international normal-
ized ratios (PT-INR), which varies according to the indication Ior
treatment. Eew patients on chronic anticoagulant therapy have
completely stable PT INR values, due, in part, to interactions
with certain drugs and Ioods (5), and the annual incidence oI
minor and major bleeding is 24 and 7 episodes per hundred pa-
tients, respectively (6).
Herbal remedies can potentially increase the risk oI sponta-
neous bleeding, as well as augment the anti-coagulant eIIects oI
warIarin (Table 1). This interaction is a result oI a combination oI
Iactors, such as intrinsic anticoagulant and anti-platelet proper-
ties oI the herbs, as well as eIIects on the pharmacokinetics oI
warIarin (Eig. 1). It is thereIore imperative that physicians be
aware oI the use oI such remedies by their patients and advise
them accordingly.
AnticoaguIant effects of herbs
The narrow therapeutic window oI anticoagulant therapy can be
maintained in most cases by close monitoring oI PT-INR values.
However, any sudden change in drug compliance or diet can lead
to dangerous bleeding or clotting in these patients. Many herbs
can augment the eIIects oI warIarin (24, 25) (Table 2), through
one or more mechanisms. More than 1300 naturally occurring
coumarins have been identiIied. Coumarins are ubiquitous in
green plants and structurally similar to warIarin, though not
necessarily with anticoagulant eIIects. The compound dicouma-
rol (a 4-hydroxycoumarin) is Iormed Iromcoumarin through the
3
2005 Scbattauer GmbH, Stuttgart
actions oI Iungi and molds, and its anticoagulant eIIect is equiv-
alent to other pharmaceutical anticoagulants that antagonize vit-
amin K (26).
Some herbs have been Iound to alter the pharmacokinetics oI
warIarin. The Chinese herb Danshen (salvia miltiorrhi:a) is
commonly used in China Ior the treatment oI cardiovascular and
cerebrovascular disease (28, 29). Danshen has been Iound to sig-
niIicantly increase plasma concentrations oI warIarin in rats by
increasing absorption rates as well as decreasing clearance and
apparent volume distribution oI both the R- and S- enantiomers
oI the drug (30, 31). Some herbs have other, non-speciIic antico-
agulant eIIects, such as the non-coumarin herb skullcap (scutel-
laria baicalensis georgi), Iound to have anti-HIV activity (32),
which inhibits coagulation via the Ilavones baicalin and oroxylin
(33). The herb geumfaponicum, used as a diuretic and astringent,
contains seven known tannins which inhibit key serine protei-
nases oI thrombin and Iactor Xa and signiIicantly inhibit Iibri-
nogen hydrolysis (34).
AntipIateIet effects of herbs
Patients on chronic anticoagulation treatment with therapeutic
PT-INRvalues may still be at increased risk Ior bleeding iI given
antiplatelet medications as well. Some herbs, such as winter-
green leaI, sweet birch bark and willow bark, contain methyl sa-
Herb Age / Gender Dosage ConpIication
Garllc 32/F na prolongeo postoperatlve bleeolng (7)
87/M 2g/o spontaneous eploural bematoma (8)
72/M na postoperatlve bleeolng (9)
Glnkgo 8lloba 70/M 80mg/o spontaneous bypbema (10)
33/F 120mg/o spontaneous suboural bematoma (11)
72/F 150mg/o spontaneous suboural bematoma (12)
78/F na lntracerebral bemorrbage (13)
61/M 160mg/o subaracbnolo bemorrbage (14)
Qulllnggao 61/M 1 can/o
*
mucosal bleeolng (15)
Herbal tea 25/F na menometrorrbagla (16)
Glnseng 47/M 3 capsules/o
*
reouceo response to war|arln (17)
44/F Face cream vaglnal bleeolng o/t use o| cream (18)
72/F 200mg vaglnal bleeolng (19)
Dansben 48/F na
*
lncreaseo response to war|arln (20)
Devll's claw
*
patlent on cbronlc antlcoagulatlon tberapy wltb war|arln
66/M
62/M
na
na
*
na
*
na
bleeolng gastrlc carclnoma (21)
pleural bemorrbage (22)
Purpura (23)
TabIe 1: Case reports of
coaguIation conpIications
due to herbs.
Figure 1: AnticoaguIant and antipIateIet properties of herbs.
Agrlmony Garllc Pau o'arco
Angellca Geum japonlcum Plneapple (bromelaln)
Anlse Glnger Poplar
Arnlca Glnkgo blloba Prlckly asb
Asasoetloa Glnseng Peo clover
8ogbean Green tea Peo pepper (casalcln)
8orage seeo Horse cbestnut Pelsbl
Celery Llcorlce Pue
Cbamomllle Lovage root Skullcap
Clove Magnolla bark Sweet clover
Coroyalls yanbuso Meaoowsweet Turmerlc
Dansben Onlon Uassla
Devll's claw Papaln Wlllow bark
Fenugreek Parsley Wlntergreen lea|
Fever|ew Passlon|lower
TabIe 2: Herbs which nay potentiate anticoaguIant effects of
warfarin (based on: Norred [24j and Heck [25j).
4
Samules. Herbs' e||ect on antlcoagulant tberapy
2-2
2-3
2-4
2-5
2-7
2-8
2-10
Samules. Herbs' e||ect on antlcoagulant tberapy
5
licylate, while others may have signiIicant antiplatelet activity
that may even surpass that oI aspirin and indomethacin (35). Gar-
lic preparations are taken by many patients because oI their anti-
lipid and anti-platelet eIIects, signiIicant Iactors in the preven-
tion oI thrombus Iormation (3638). The allicin derivative oI
garlic root has been shown to enhance Iibrinolytic activity and
inhibit platelet aggregation in patients with coronary artery dis-
ease (3941), either via a dose-dependent alteration in the pro-
duction oI arachidonic acid metabolites (i.e. inhibition oI
thromboxane Iormation in platelets (40, 42, 43) or by altering
physiochemical properties (i.e. the ADP-receptor) oI the platelet
membrane (4446).
Other herbs may also aIIect platelet Iunction through in-
hibition oI prostaglandin metabolism. Ginger, used by pregnant
women Ior the relieI oI nausea and vomiting (47, 48), reduces the
production oI PG-endoperoxides and thromboxane through
either inhibition oI platelet cyclooxygenase (COX) (49) or as a
result oI the anti-oxidant components in the herb which suppress
the lipid peroxide essential Ior COX activity (50, 51). EeverIew,
an herb used to treat migraine headaches (5254), suppresses up
to 88 oI prostaglandin production without inhibiting COX
(5559), while clove a common kitchen spice and important
source oI dietary antioxidants (60), contains two antiplatelet
components (eugenol and acetyl eugenol) which inhibit platelet
thromboxane Iormation and increase Iormation oI 12-HPETE,
both oI which are more potent than aspirin in their antiplatelet eI-
Iects (61). Bromelain, a derivative oI pineapple with immuno-
modulatory eIIects (62), also inhibits platelet prostaglandin syn-
thesis (63), while the coumarin-containing herb licorice (with
the 3-arylcoumarin derivative GU-7 |64|) inhibits COX, lip-
oxygenase and peroxidase activity in platelets (65).
Some herbs aIIect platelet Iunction through other mech-
anisms. In addition to is anticoagulant eIIect, the Chinese herb
Danshen inhibits platelet aggregation and release via increasing
intracellular cyclic AMP (66). Ginseng, a popular herb compris-
ing 1520 oI the total annual sales oI botanical products in the
United States (67) (whose real beneIits are still controversial
|68|), inhibits platelet aggregation induced by thrombin or col-
lagen in the rat model (69). Ginkgo biloba, use by Chinese doc-
tors Ior centuries Ior the treatment oI 'chest complaints, has
been shown in clinical studies to be superior to placebo Ior inter-
mittent claudication (70) and (questionably) beneIicial Ior de-
mentia as well (71, 72). The increased risk Ior bleeding in pa-
tients using this herb is thought to be due to a dose-dependent in-
hibition oI PAE-induced platelet aggregation (73). Red pepper
(capsaicin), an herb used to alleviate diabetic neuropathy (74),
inhibits both platelet aggregation and release (75), as well en-
hancing Iibrinolytic activity (76).
HerbaI fornuIas
Herbal Iormulas are an important aspect oI traditional Chinese
medicine, and are termed 'Eang Ji (written / prepared recipes).
Each herb in a Iormula is selected according to its individual
traits as well as the interaction with the other herbs. Together, the
herbal Iormula is believed to harmonize the body`s energies and
heal disease (77). Today many standard Iormulas can be pur-
chased over-thecounter in pharmacies and health Iood stores,
with the quantity and quality oI the contents receiving minimal
mention, iI at all. It is thereIore diIIicult to predict the eIIects oI
these Iormulas on anticoagulant therapy, Iurther increasing the
risk Ior complications.
The herbal Iormula Kangen Karyu (KGK) is used to reduce
blood viscosity and improve microcirculation. KGK contains 6
known herbs (peony root, cnidium root, saIIlower root, saussure
root and Danshen), and has been Iound to signiIicantly enhance
bleeding time (78) as well as suppress the metabolism and elim-
ination oI warIarin (79). KGK may also augment the antithrom-
botic eIIects oI ticlopidine, potentially increasing the risk oI de-
veloping thrombotic thrombocytopenic purpura, a severe ad-
verse eIIect oI this drug (80). Another commonly used Iormula,
the Bak Eoong Pill (BEP), also known as Bai Eeng Wan, is an
over-the-counter traditional Chinese medicine with 26 ingredi-
ent herbs used Ior treating dysmenorrhea, irregular menstrual
cycle and bleeding. BEP inhibits platelet aggregation, while 17
oI its components have been Iound to signiIicantly prolong
thrombin time, 11 prothrombin time and 8 activated partial
thromboplastin times (81).
Discussion
Patients on chronic anticoagulant therapy have unlimited access
to hundreds oI herbs which, with increasing likelihood, they will
eventually purchase and use. Much research is still required to
understand both the in vitro and, more importantly, in vivo eIIects
oI herbs on the pharmacodynamics oI medications such as war-
Iarin. Eor example, Ginkgo biloba extract was Iound to strongly
inhibit the major human cytochrome P450 enzymes CYP2C9,
CYP1A2, CYP2E1 and CYP3A4 (82), as well as competitively
inhibiting the metabolism oI the oral anti-diabetic agent tolbuta-
mide by the enzyme (S)-warIarin 7-hydroxylase in rat liver
microsomes (83). However, a randomized, double-blinded study
Iound that 100mg/day oI Gingko biloba (over a period oI 4
weeks) had no signiIicant eIIect on PT INR levels in patients
treated with warIarin (84). It is possible that the bleeding diathe-
sis associated with this herb is most likely attributable to its eI-
Iects on platelet aggregation alone and not on warIarin metab-
olism.
One oI the major obstacles to understanding herb-drug inter-
actions is the inconsistencies in the quantity and quality oI the
various preparations oI the herbs. Herbal preparations and Ior-
mulas may contain either large or, conversely, insigniIicant
amounts oI active components. In one study oI 50 commercially
produced ginseng preparations, 6 products contained no speciIic
ginsenosides whatsoever, while the remaining 44 had levels
ranging Irom 1.9 to 9.0 (85). Garlic preparations may also
have varied amounts oI active metabolites, depending on the
mode oI preparation (chopped, crushed, cooked, distilled or
homogenized in oil) (43).
The National Center Ior Complementary and Alternative
Medicine (NCCAM) Iact sheet warns consumers that one cannot
assume that because an herbal supplement is 'natural' it is saIe or
without harmIul eIIects. The NCCAM goes on to recommend
that anyone using an herbal supplement should 'do so under the
guidance oI a medical proIessional who has been properly
trained in herbal medicine (86).At the same time, physicians are
being encouraged to try and accept even those 'therapies Ior
which scientiIic support is anecdotal, equivocal or prelimi-
nary.We as a proIession must address the challenge oI discuss-
ing alternative therapies with our patients and put a end to the
don`t ask, don`t tell` approach that characterizes communi-
cation in this area (87).
The Iirst step in preventing unwanted complications oI drug-
herb interactions is Ior the physician to initiate discussion and
learn oI current or planned use oI herbal remedies. Alist oI ques-
tions (Table 3) may help evaluate the risk-beneIit ratio oI the
combination, and more Irequent testing Ior PT-INRand physical
examinations Ior signs oI platelet-related bleeding should help
reduce complications once herbal treatment is initiated. UnIor-
tunately, research in the Iield oI herbal medicine is not consider-
ed 'economical' (88), and it is thereIore helpIul that organizations
such as the NCCAM are Iunding such studies. These studies
should examine both the clinical beneIits and mechanisms oI ac-
tions (such as eIIects on the hepatic cytochrome system) oI her-
bal remedies, and should be conducted among all age groups. It
is also oI utmost importance to study the interaction between her-
bal and conventional therapies, especially Ior medications such
as warIarin whose therapeutic window is so narrow. Patients
should be allowed to beneIit Irom the 'best oI both worlds' with-
out increasing the risk oI iatrogenic complications, both 'chemi-
cal' and 'natural'.
1. |s tbe patlent compllant, ano bave PT-|NP been malntalneo at tberapeutlc
levels ourlng tbe past 3 montbs!
2. Have tbere been any lncloents o| serlous bleeolng ln tbe past! Have tbese
events occurreo even wben PT-|NP levels were ln tbe tberapeutlc range!
3. |s tbere evloence tbat tbe berb or berbal |ormula to be useo bas been
sbown to be o| bene|lt |or tbe oeslreo lnolcatlon!
4. Wbat ls tbe oosage o| tbe berb or berbal |ormula to be useo! Wlll tbls
oosage be lncreaseo over tlme! How long wlll tbe berbal treatment last!
5. Are tbere any otber berbal remeoles belng useo as well
(sucb as teas or creams)!
TabIe 3: Questions to ask before using an herbaI renedy with
warfarin.
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