Herbal medicines in cardiac patients

Running head: ADVERSE EFFECTS OF HERBAL MEDICINES 1

Adverse Effects of Herbal Medicines in Cardiac Patients

University of South Florida

Alexsandra de Oliveira

ADVERSE EFFECTS OF HERBAL MEDICINES 2

Adverse Effects of Herbal Medicines in Cardiac Patients

Heart disease is the number one cause of death in United States (Center for

Disease Control and Prevention [CDC], 2011). In 2009, 26.8 million noninstitutionalized

adults were diagnosed with heart disease (CDC, 2011). The diagnosis of a cardiac

disease leads to a sequence of treatments that includes the prescription of one or more

medications to help manage the disease. Prescription medication is not the only

resource used by cardiac patients to manage their disease. Gohar, Greenfield,

Beevers, Lip, and Jolly (2008) found that complementary and alternative medicine

(CAM) and home blood pressure devices are common self-care methods used by

hypertensive patients along with the prescribed medication.

CAM is widely used in the U.S with more than 15 million people using herbal

medicines (Tachjian, Maria & Jahangir, 2010). A clinical survey data revealed that 15%

of patients taking allopathic medication also use herbal medicines (Bush et al., 2007).

Research has also shown that the majority of patients do not tell their physicians about

the consumption of herbal medicines (Gardiner, Graham, Legedza, Eisenberg, &

Phillips, 2006). The concomitant use of herbal medicines and allopathic medication can

have detrimental effects to cardiac patients. Gohar et al. (2008) found a significant

association between CAM use and medication nonadherence among the female

participants in their study. Nonadherence to medication in post cardiac infarction

patients, for example, was associated to high risk of death (Ho et al., 2006). Cohen and

Ernst (2010) suggested that there are a large number of cardiac patients consuming

herbal medicines that cause common and/or rare adverse effects.


Although herbal medicines have been used for centuries there is a lack of

scientific evidence about the risks and/or benefits of its use with today’s complex

medication regimen used to treat cardiac patients. The purpose of this literature review

is to explore evidence-based literature related to the risks of the most commonly used

herbal medicines to cardiac patients taking allopathic medication.

Research Question

In cardiac patients, what are the potential adverse effects of herbal medicine

when used in conjunction with the prescribed drug therapy?

Relevance to Nursing Practice

Nurses at all levels of care in a variety of settings including hospitals, cardiac

rehabilitation services, and home care, are involved in assessing medication

management. In this regard, nurses bear the responsibility not only to improve the

patient’s ability to manage their medication regimen, but also to ensure safety regarding

potential adverse effects. Therefore, nurse’s knowledge of scientific evidence about the

potential risks of herbal-drug interactions is desirable when providing medication

education and in assessing drug adherence.

Review of the Literature

Five studies were reviewed that describe potential adverse effects of the

interaction of herbal medicines and some of the most common prescribed cardiac drug

therapy. Mohammed, et al. (2008), sought to investigate possible interactions of herbal

medicines with warfarin in light of genetic variability. Garlic and cranberry were chosen

for this study because are widely consumed in the United States (Mohammed et al.,

2008). The aim of the study was to investigate the possible effects of these two herbal


medicines on the pharmacokinetics and pharmacodynamics of warfarin in subjects with

two specific genotypes (Mohammed et al., 2008).

Mohammed, et al. (2008) conducted an open-label, three-treatment,

randomized crossover clinical trial included 12 healthy males with two known specific

genotypes, CYP2C9 and VKORC1. The garlic product utilized in this study was

selected based on the concentration of allicin per tablet (Mohammed et al., 2008).

Allicin is the most important compound present in garlic involved in the antiplatelet

effects (Mohammed et al., 2008). The cranberry concentrate juice was selected based

on the high concentration of anthocyanin and quercetin due the fact that only these two

compounds were equally found in all products analyzed for this study (Mohammed et

al., 2008). Healthy male subjects were selected between the ages of 18 and 34 years

old (Mohammed et al., 2008). A full medical history, physical examination and clinical

laboratory evaluation was utilized to classify the subjects as healthy (Mohammed et al.,

2008). The subjects were tested for CYP2C9 or VKORC1 genotype, warfarin plasma

protein binding, platelet aggregation and international normalized ratios (Mohammed et

al., 2008). The activity of Factor II, Factor VII and Factor X of coagulation were

measured after the consumption of warfarin alone and after warfarin and cranberry juice

extract ingestion (Mohammed et al., 2008).

The 12 healthy male subjects were randomly assigned in three groups to receive

a single dose of 25mg of warfarin either alone or after two weeks of pre-treatment with

cranberry juice concentrate capsules or enteric-coated garlic tablets (Mohammed et al.,

2008). Cranberry and garlic continued to be consumed for seven days after the

administration of warfarin. After a two week washout period the subjects were crossed


over to receive the different treatment. The well-being and any adverse events were

assessed throughout this study. None of the subjects in this study presented major

bleeding or INR above four (Mohammed et al., 2008).

The results of Mohammed et al. (2008) trial revealed two significant findings.

First, the cranberry and warfarin treatment resulted in a 30% increase in the area under

the INR-time curve. Second, different genotypes react differently in response to the

warfarin and cranberry or warfarin and garlic interaction. The researchers concluded

that subjects with VKORC1 variant type (CT and TTalleles) were more susceptible to

interaction with warfarin and cranberry (Mohammed et al., 2008). Subjects with wild-

type VKORC1 genotype are susceptible to warfarin with garlic interactions by

decreased of warfarin response (Mohammed et al., 2008). Although not statistically

significant, the researchers also found that there was a decrease in activity of all clotting

factors with the concomitant administration of warfarin and cranberry (Mohammed et al.,

2008).

This study presents two important limitations. First, the sample size for the two

specific genotypes was of only 12 subjects’ total. Second, the mean age of the subjects

was 23 years old. The small sample size might have yield the positive interactions

which contradicts Mohammed, et al. (2008) literature review that no herb-drug

interaction with warfarin was observed in previous research. The age of the subjects is

an important factor when considering the applicability of this study in cardiac patients.

Approximately 47% of Americans with cardiovascular disease are 60 years old or older

(Lloyd-Jones et al. 2010). Therefore, further research is necessary including an age

variant to ensure the clinical relevance of the study for the majority of cardiac patients.


Paoletti et al. (2011) hypothesized that possible interactions of oral

anticoagulants with herbal supplements represent a health risk for many individuals.

Through a collection of spontaneous reports the researchers sought to identify all drug

interactions between herbs and oral anticoagulants. The reports were extracted from

the Italian National Institute of Health Database. Initially 379 reports of suspected

adverse reactions to natural products from April 2002 to December 2009 were collected.

The reports with INR modification after herbal consumption were further analyzed to

ensure that individuals were previously stably anticoagulated (Paoletti et al., 2011).

Cases with factors that could interfere with anticoagulant such as illnesses and vitamin

K intake changes were excluded (Paoletti et al., 2011). The researchers identified 12

reports, seven cases of INR reduction in patients treated with warfarin and

acenocoumarol and five cases in which the INR increased (Paoletti et al., 2011).

Among the reported cases of INR reduction due to herb-drug interaction was one case

of warfarin and home-made aloe preparation, one case of acenocoumarol and red

ginseng, one case of warfarin and yeast fermentation of papaya, one case of warfarin

and papaya extract, one case of warfarin and bilberry concentrate juice, one case of

warfarin and a supplement containing several vitamins and fish oil, and one case of

warfarin and green tea (Paoletti et al., 2011). The researchers identified five cases of

INR increases involving the interaction of warfarin and arnica or boswellia-based

products. In one case arnica was used in a form of cream to myalgia and the patient

presented serious adverse effects with elevation of INR after one month of the use of

the cream (Paoletti et al., 2011).


The researchers concluded that the cases analyzed confirmed the existence of

the risk of herbal products and oral anticoagulants. However, the study is limited

because it was unable to identify if common factors such as age or herbal components

were involved in the reported interactions. In addition, the applicability of this study to

clinical practice is compromised because only one case of most herb-anticoagulant

interaction in the study was analyzed. Nevertheless, Paoletti et al. (2011) succeeded in

opening the discussion of a variety of possible herbal interactions with oral

anticoagulants based on reported INR results.

Saw, Bahari, Ang, and Lim (2006) cross-sectional survey sought to determine the

prevalence of herbal use possibly interfering with antiplatelet or anticoagulant therapy in

medical wards in a Malaysian hospital. The survey included 250 patients under

antiplatelet or anticoagulant therapy in the cardiology, neurology, infectious and

nephrology wards. Patients under the age of 18, pregnant women and patients unable

to give consent were excluded from this study (Saw et al., 2006). A questionnaire

including questions on socioeconomic background was developed to document the use

of warfarin or aspirin with herbal medicines (Saw et al., 2006). The herbs that most

concerned the researchers were ginseng, garlic and ginkgo. The population included in

the study consisted of 127 women and 123 men. Of this population 74.4% were in poor

health conditions (Saw et al., 2006). Among the patients 42.2% reported taking herbal

medicine and 31% were taking ginseng, garlic or ginkgo for the past year (Saw et al.,

2006). The survey showed that 40% of the patients were taking antiplatelet and /or

anticoagulant for the past year (Saw et al., 2006).The survey also identified eight

possible interactions involving 50% garlic with aspirin, 37.5% warfarin with ginseng or


ginkgo and 12.5% ginkgo with aspirin (Saw et al., 2006). The majority of the

interactions 62.5% were in patients older than 62 years of age (Saw et al., 2006). The

most common side-effects were headache 22.2% and dizziness 16.7% (Saw et al.,

2006). Finally, the survey revealed that 90% of the patients did not inform their

healthcare provider about the use of herbal medicines (Saw et al., 2006).

Saw et al. (2006) concluded that these findings suggested potential health risks

due to herb-drug interaction for pre or post-operative patients and patients with clotting

disorders. The researchers also recognize that this survey presents limitations because

other factors such as patient characteristics may also interfere in the effects of herb-

drug interactions.

Saw et al. (2006) findings are neither conclusive nor broadly applicable to cardiac

patients. The researchers associated symptoms such as headache and dizziness to

herb-drug interaction based only on the review of the literature. However, most of the

literature on the subject of herb-drug interaction is based on isolated case reports.

Therefore, further research is necessary to verify the applicability of these findings to a

larger population of patients under anticoagulation or antiplatelet therapy.

Gurley, Swain, Williams, Barone, and Battu, (2008) hypothesized that herbal

medicines can interact with drugs that are P-glycoprotein substrates and that those

interactions may be clinically observed. An open-label randomized research model was

used to test the effects of St. John's wort and echinacea, two commonly used herbal

supplements, on the pharmacokinetic effect of digoxin which is a P-glycoprotein

substrate. Clarithromycin and rifampin was used by the researchers as positive controls

for digoxin induction and inhibition. The study subjects were 18 young adults which


included nine females all in good health and were not under any form of medication

therapy (Gurley et al., 2008). The participants were also told to avoid specific foods and

drinks that could interfere with the study. All subjects received all drugs in a random

sequence of supplementation phase first and then medication phase (Gurley et al.,

2008). The supplementation phase which includes St. John's wort or Echinacea lasted

14 days. The medication phase with clarithromycin or rifampin was administered for

seven days (Gurley et al., 2008). St. John's wort was administered three times daily at

300mg dosage, Echinacea three times daily at 2600 mg, clarithromycin was

administered two times a day at 500 mg dosage and rifampin was administered twice a

day at 300mg dosage(Gurley et al., 2008). Digoxin was always administered 24h

before each supplementation or medication phase and on the last day of each therapy

(Gurley et al., 2008).

The results of this study showed that Echinacea had no significant effect on the

blood concentration of digoxin when compared to the positive controls clarithromycin

and rifampin. As a result no clinical effects were noticed (Gurley et al., 2008). The

administration of St. John's wort with digoxin resulted in a significant interaction. The

blood serum concentration of digoxin decreased 35% in the presence of St. John’s wort

(Gurley et al., 2008). The concomitant administration of the positive control rifampin

and digoxin also decreased the concentration of digoxin. Although this study included

equal amounts of gender participants the results did not showed a link between digoxin-

herb interaction and gender. In regards to side effects two subjects had drowsiness

during the St. John’s wort phase (Gurley et al., 2008).


Gurley et al. (2008) study is of unique importance because it compared the

results of the herb-digoxin interaction to already documented digoxin interaction with

rifampin and clarithromycin. This in turns produced a benchmark for evaluation of herb-

digoxin interaction. The study also confirmed the researcher’s hypothesis that clinical

events may be observed due to herb-drug interaction since two subjects during the St.

John’s wort phase had drowsiness. However, a larger sample might be necessary to

ensure statistically significance. Another limitation is that no long term effects of the

concomitant administration of St. John’s wort and digoxin can be evaluated because the

supplementation phase only lasted 14 days. In summary, both the sample size and the

lack of long term effects limit the applicability of these results to clinical practice.

Werba et al. (2008) case report studied the effect of green tea on the simvastatin

tolerability. The authors’ literature review indicated that a patient’s adherence to statins

is directly affected by the most reported adverse effect of the drug; muscle cramps. In

this case report the authors hypothesized that particular foods or fruit juices can also

interact with statins and cause muscle cramps by increasing the bioavailability of the

drug (Werba et al., 2008).

This case report involved a 61 year old male patient of whom a health history

was collected revealing a family history of coronary disease, hypertension and

hypercholesterolemia but no family history of myopathy (Werba et al., 2008). The

subject had been taking antihypertensive and cholesterol-lowering medications for

eleven years (Werba et al., 2008). The cholesterol-lowering drug treatment had been

modified between simvastatin, atorvastatin or rosuvastatin and eventually stopped by

the subject due to intense leg muscle cramps and pain (Werba et al., 2008). A physical


examination of the subject revealed a minimal carotid atheroma upon ultrasonography

(Werba et al., 2008). The subject was classified as generally healthy and physically

active. Upon nutritional history the researchers found that the patient typically drank

three cups of green tea each day to reinforce his health (Werba et al., 2008).

The researchers accessed the bioavailability of simvastatin in order to study the

possible interaction of green tea and the drug by performing a kinetic study. The kinetic

study consisted of two parts. During the first part the subject took simvastatin 20mg/d

for five days and on the sixth day simvastatin was ingested fasting with a cup of green

tea (Werba et al., 2008). During the second part the patient took the same simvastatin

20mg/d for five days and on the sixth day simvastatin was ingested fasting with a cup of

water (Werba et al., 2008). The patient’s plasma level of simvastatin lactone and

simvastatin acid were monitored for a month by a series of blood analysis (Werba et al.,

2008). The results of the kinetic study showed that the levels of simvastatin lactone and

simvastatin acid were both higher during the concomitant ingestion of green tea and

simvastatin. In addition, the researchers reported that after stopping the green tea the

patient continued taking simvastatin 20mg/d with optimal tolerance for three months

(Werba et al., 2008).

The researchers concluded that due to the absence of intolerance during the

withdrawal of green tea and due to the blood results demonstrating high levels of

simvastatin metabolites that the study suggested a clinically relevant green tea-statin

interaction (Werba et al., 2008). In addition, Werba et al. (2008) suggested that upon

more investigation green tea should be considered an unexpected trigger for statin

toxicity.


The main limitation of this study is that only one case was reported and analyzed

which limits the applicability of the results to the overall population or even within the

population of cardiac patients. Another important limitation is that the subject’s level of

CYP450 3A4 the main enzyme that metabolizes simvastatin was not reported in the

study. Werba et al. (2008) literature review stated that in healthy volunteers green tea

had only minor effects on the activity of CYP450 3A4. Therefore, in reporting the

activity levels of this enzyme the authors would be able to narrow the cause of their

findings to an herb-drug interaction rather than a possible individual genetic

predisposition of CYP450 to metabolize simvastatin faster when in the presence of

green tea.

Nevertheless, in the face of lack of research addressing the topic of herb-drug

interaction, the article is of unique value because it raises awareness among health

care professionals about the subject. It also draws scientific conclusions based not only

on laboratory inquiries but also based on clinical events. This intersection of methods is

important for evidence-based nursing practices because it provides nurses with a

clinical target to be observed when assessing medication history and/or drug adherence

in cardiac patients.

Application of the Literature to Practice

The literature does not show conclusive findings in regards to specific adverse

effects of herb-drug interaction in cardiac drug therapy. However, it indicates that high

risk medications such as warfarin and digoxin have the greatest potential to interact with

herbal medicines. The literature is consistent on the fact that the majority of patients do

not tell their health care providers about the use of herbal medicines. In light of such


knowledge nurses should include specific questions in their medication assessment

such as: Do you take any herbal supplements? In addition, nurses must be aware of

the crucial role of educating cardiac patients about the potential risks of combining

herbal and allopathic medications.

Conclusions

There is a lack of research trials investigating the adverse effects cardiac drug

therapy when administrated with herbal medicines. Because heart disease is an

alarming problem in the United States all factors that may influence patient’s ability to

comply with the medication regimen must be addressed. Therefore further research

identifying adverse effects of herb-drug interaction in a short and long term is of extreme

importance for cardiac patients. Until then, nurses must be aware of the most common

herb-cardiac drug interactions and educated patients on the possible risks of combining

herb and allopathic medication.


References

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substances and prescription medications: A clinical survey. Alternative Therapies

in Health and Medicine, 13(2), 30-35.

Cohen, P. A., & Ernst, E. (2010). Safety of herbal supplements: A guide for

cardiologists. Cardiovascular Therapeutics, 28, 246-253. doi:10.1111/j.1755-

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Gohar, F., Greenfield, S. M., Beevers, D. G., Lip, G. Y., & Jolly, K. (2008). Self-care and

adherence to medication: A survey in the hypertension outpatient clinic. BMC

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