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Kanji et al. Systematic Reviews 2012, 1:26http://www.systematicreviewsjournal.com/content/1/1/26

RESEARCH Open Access

Interactions of commonly used dietarysupplements with cardiovascular drugs:a systematic reviewSalmaan Kanji1, Dugald Seely1,2, Fatemeh Yazdi3, Jennifer Tetzlaff3, Kavita Singh3, Alexander Tsertsvadze3,Andrea C Tricco4, Margaret E Sears3,5, Teik C Ooi6, Michele A Turek7, Becky Skidmore7 and Mohammed T Ansari3*

Abstract

Background: The objective of this systematic review was to examine the benefits, harms and pharmacokineticinteractions arising from the co-administration of commonly used dietary supplements with cardiovascular drugs.Many patients on cardiovascular drugs take dietary supplements for presumed benefits and may be at risk foradverse supplement-drug interactions.

Methods: The Allied and Complementary Medicine Database, the Cochrane Library, EMBASE, InternationalBibliographic Information on Dietary Supplements and MEDLINE were searched from the inception of the review toOctober 2011. Grey literature was also reviewed.Two reviewers independently screened records to identify studies comparing a supplement plus cardiovasculardrug(s) with the drug(s) alone. Reviewers extracted data using standardized forms, assessed the study risk of bias,graded the strength of evidence and reported applicability.

Results: Evidence was obtained from 65 randomized clinical trials, 2 controlled clinical trials and 1 observationalstudy. With only a few small studies available per supplement, evidence was insufficient for all predefined gradableclinical efficacy and harms outcomes, such as mortality and serious adverse events. One long-term pragmatic trialshowed no benefit from co-administering vitamin E with aspirin on a composite cardiovascular outcome. Evidencefor most intermediate outcomes was insufficient or of low strength, suggesting no effect. Incremental benefits werenoted for triglyceridemia with omega-3 fatty acid added to statins; and there was an improvement in levels ofhigh-density lipoprotein cholesterol with garlic supplementation when people also consumed nitrates

Conclusions: Evidence of low-strength indicates benefits of omega-3 fatty acids (plus statin, or calcium channelblockers and antiplatelets) and garlic (plus nitrates or warfarin) on triglycerides and HDL-C, respectively. Safety concerns,however, persist.

Keywords: Cardiovascular drugs, Dietary supplements, Harms, Systematic review

BackgroundThe American Heart Association estimates that morethan 81 million (one in three) American adults have atleast one form of cardiovascular disease (CVD) [1].Pharmaceutical interventions are the front line therapiesfor the prevention and treatment of CVD in addition tolifestyle and dietary recommendations [2-4].

* Correspondence: [email protected] Methods Centre, Clinical Epidemiology Program, Ottawa HospitalResearch Institute, University of Ottawa Evidence-based Practice Center,Ottawa, ON, CanadaFull list of author information is available at the end of the article

© 2012 Kanji et al.; licensee BioMed Central LtCommons Attribution License (http://creativecreproduction in any medium, provided the or

Billions of dollars are spent annually in the US oncomplementary and alternative medicine, and a largeportion of this expenditure is directly on dietary supple-ments [5]. Approximately one-third to nearly two-thirdsof people experiencing CVD use some form of comple-mentary and alternative medicine that includes dietarysupplements, and are thus at risk for potential adverseevents from interactions with pharmacologically activeagents, and non adherence associated with polyphar-macy [6-11]. Evidence of both benefit and harms of

d. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andiginal work is properly cited.

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Kanji et al. Systematic Reviews 2012, 1:26 of 16http://www.systematicreviewsjournal.com/content/1/1/26

adding a supplement to cardiovascular (CV) drugs hasbeen reported [12,13].While much research is available describing drug-drug

interactions in various populations, the evidence is lesswell described for drug-supplement interactions or sim-ply the effects of add-on supplementation, especially inpopulations with CVD. The aim of this extensive synthe-sis review is to examine the evidence for benefits, harms,pharmacokinetic and statistical interactions from co-administration of a set of commonly used dietary sup-plements with CV drugs.

MethodsWe followed a pre-specified and peer-reviewed studyprotocol. The Agency for Healthcare Research and Qual-ity (AHRQ) commissioned the full evidence report,which is available online [14].

Data sources and searchesUsing a peer-reviewed strategy, the Allied and Comple-mentary Medicine Database, the Cochrane Library,EMBASE, International Bibliographic Information onDietary Supplements and MEDLINE, as well as thegrey literature, were searched from study inception untilOctober 2011.

Study selectionA comparative study was eligible if it was published inEnglish or German; other languages were excluded dueto concerns with study quality [15] or applicability [16].We included German language publications given thewell-developed regulations for research, practice and useof dietary supplements in Germany [17-19]. Weincluded studies where a dietary supplement was co-administered with a CV drug(s) compared with the drugalone or co-administered with another supplement, andclinical or surrogate CV efficacy or harms, or pharmaco-kinetic outcomes in any adult population were reported.A dietary supplement was defined as a vitamin, mineral,herb or botanical, amino acid, concentrate or metaboliteor extract, enzymes or tissues intended for ingestion in apill, capsule, tablet, powder or liquid form not repre-sented for use as a conventional food or as the sole itemof a meal or diet [20]. We selected to review specificsupplements of interest based on reported surveys andinput from public and independent technical expertpanels [6,21-26]. We aimed to restrict to common sup-plements and CV medications taken by adults and eld-erly for which current evidence on possible drug-supplement interaction was lacking. Studies were alsoincluded which evaluated the use of coenzyme Q10, Ech-inacea, garlic, ginger, Ginkgo biloba, Panax ginseng,American ginseng (P. quinquefolius), hawthorn, oralmagnesium, niacin (≤250 mg/day), omega-3 fatty acids

or fish oils, red yeast rice extract, resveratrol, vitamin A,vitamin D with or without calcium, vitamin E or vitaminK as supplements. Finally, we included studies thatemployed CV drugs commonly used in outpatient set-tings in the US and Canada. Additional file 1: Table S1.One reviewer screened all titles and abstracts for po-

tential relevance, and a second verified exclusions at thislevel. Two independent reviewers assessed the full publi-cation of any potentially relevant studies, with discrep-ancies resolved by consensus.

Data extraction and quality assessmentStudy characteristics, population, intervention, compara-tor and outcomes data were extracted using standar-dized forms. The extracted outcomes of interest werecategorized into four groups: clinical, intermediate,harms and pharmacokinetic (for example, area under thecurve (AUC), half life of CV drug, maximum of peakconcentration (Cmax), and amount of time that a drugis present at the maximum concentration (tmax)). Thefull list of outcomes considered for this review is pre-sented in Additional file 2: Table S2. One reviewer witha clinical background rated study populations with re-spect to 10-year coronary heart disease (CHD) risk(high, moderate and low) according to the NationalCholesterol Education Program Adult Treatment PanelIII guidelines [27]. When all participants were healthynon-smokers, study level 10-year CHD risk was cate-gorized as low. We assessed risks of bias according tooutcome, using generic items for confounding, selection,performance, detection and attrition bias. Certain qualitycriteria were specific to particular study designs (for ex-ample, allocation generation and concealment appliedonly to randomized clinical trials (RCTs)). The overallstudy risk of bias for pre-specified gradable outcomesAdditional file 1: Table S1 and Additional file 2: Table S2was rated as low, moderate or high, and then independ-ently verified. Similarly, the strength of the body ofevidence [28] and the applicability of the evidencefor outcomes with conclusive results [29] were ratedaccording to the published guidance.

Grading the strength of evidenceA methodologist and a content expert graded thestrength of the body of evidence per each outcome(high, moderate, low or insufficient) based on the follow-ing four domains: overall risk of bias, consistency, dir-ectness and precision [28]. Only a set of pre-specifiedimportant outcomes identified a priori through consul-tations with the Technical Expert Panel was gradedAdditional file 3: Table S3. This was done because cus-tomarily only a subset of important outcomes is chosento grade the strength of evidence - outcomes that are


more meaningful for decision-making given a specificresearch question [28].The strength of evidence was graded as insufficient

when there was no evidence for an outcome, the direc-tion of the estimates was inconsistent across studies,and/or the evidence from the contributing study/studieshad an imprecise statistically non-significant pooled esti-mate (the 95% confidence intervals (CIs) were wideenough to be compatible with either clinical benefit, trueno difference or harm).

Data synthesis and analysisAll analyses compared the combination of a dietary sup-plement plus CV drug(s) with CV drug(s) alone or plusplacebo or plus another dietary supplement.The decision to pool individual study results was based

on the degree of similarity in methodological and clinicalcharacteristics of studies under consideration. Meta-analysis was considered when studies were randomizedtrials that included similar populations, compared thesame type of dietary supplement and CV medication inthe intervention and control groups, and reported theidentical outcome measures in the same statistical for-mat (for example, mean difference (MD) or geometricmean ratio (GMR)). The estimates of post-treatmentMD for continuous outcomes and relative risk (RR) forbinary outcomes (except for rare events) of individualstudies were pooled using a random-effects model byDerSimonian and Laird [30]. The choice of this modelwas based on the assumption that some residual clinicaland methodological diversity might still exist across thepooled studies despite the similarities [31]. For dichot-omous outcomes with event rates < 1%, the Peto oddsratios (ORs) based on a fixed effects model were calcu-lated. The results from studies with zero events in oneof the arms were pooled using the fixed effects Mantel-Haenszel method without continuity correction. Studieswith zero events in both arms were not pooled [31].The degree of statistical heterogeneity across pooled

studies was assessed by visual inspection of the forestplot and the generation of Cochran’s Q (α= 0.10) andthe I2 statistic. We planned to explore clinical (for ex-ample, gender, age, ethnicity) and methodological factors(for example, parallel versus crossover design, risk ofbias, type of analysis, baseline health status) as potentialsources of statistically significant heterogeneity (Chi-square statistic P < 0.10 and/or I2 > 50%).We followed the US Food and Drug Administration

(FDA) guidance for analysis and interpretation of druginteraction pharmacokinetic studies; the two compara-tors are considered bioequivalent (no clinically import-ant difference) if the lower and upper bounds of the90% CI for the GMR were between 0.8 and 1.25 [32].Where applicable, we examined statistical interactions

between supplements and drugs by calculating the syn-ergy index [33].All analyses were performed using Comprehensive Meta

Analysis version 2.2.057, StatsDirect statistical softwareand R: A Language and Environment for Statistical Com-puting, Foundation for Statistical Computing [34-36].

Role of the funding sourceThe AHRQ supported this study but had no role in for-mulating study questions, conducting the systematic re-view, or approving the manuscript for submission andpublication.

ResultsIn total, 32,314 records were screened for eligibility(Figure 1). Sixty-three unique English language studies,including one of observational design, contributed evi-dence to the present review regarding the interactions ofsupplement-drug combinations [37-99]. We found norelevant unique German publications, nor a good qualitysystematic review to obviate the need for de novo synthe-sis of evidence. Most studies had a moderate risk of biasfor the gradable outcomes. A paucity of studies pre-cluded exploration of subgroup heterogeneity and howthis may have affected outcomes. Statistical interactionsbetween supplement(s) and drug(s) were generally notreported.Here, we outline selected results for gradable out-

comes Additional file 3: Table S3 from the systematic re-view [100] limited to American ginseng, coenzyme Q10,Echinacea, garlic, Ginkgo biloba, omega-3 fatty acids andvitamin E. While the full report commissioned by AHRQcan be found at http://www.effectivehealthcare.ahrq.gov/index.cfm) [101], selected results reported here are lim-ited to those that provide some signal of evident or po-tential drug interaction.Overall, evidence for clinical, harms and pharmacoki-

netic outcomes was inconclusive (grade: insufficient). Themajority of the reported evidence was based on inter-mediate efficacy outcomes (grade: insufficient to low).These results represent evidence on: clinical outcomes

of effectiveness from 19 RCTs [37-55] (Table 1); inter-mediate surrogate outcomes from 52 RCTs and two non-RCTs [38,39,41,43,45,48-94] (Tables 2 and 3); harmsidentified from 52 RCTs and a single retrospective co-hort study [37-41,43,45-48,50-68,70-73,76-78,80-84,87,90-99](data available online[100]); and lastly direct evi-dence of pharmacokinetic data on interactions be-tween supplements and CV drugs from 11 RCTs[37,60,63,66,71,83,96,98](data available online [100]).Overall, the majority of included RCTs were of moder-

ate risk of bias with only 25% of the studies explicitlyreporting adequate sequence generation and 9% reportingallocation concealment. Adherence to CV medication was

http://www.effectivehealthcare.ahrq.gov/index.cfm


Scr

een

ing

Elig

ibili

tyIn

clu

ded

Stu

die

s

Records identified by:all searches combined (n = 38,984)

(including search for systematic review and meta-analysis (n = 1,579) + updated search (n= 1,104))

Records screened by title after removing duplicates

(n = 33,224)

Duplicates removed (n = 5,791)

Records excluded at title screening(n = 21,046)

Records screened by title/abstract(n = 12,178)

Full-text articles assessed for eligibility

(n = 2,048)English records (n = 1,980)German records (n = 68)

Studies included in the synthesis of evidence

(n = 80 (70 primary studies))

Records excluded at initial screening(n = 10,105)Language of excluded studies:• English & German (n = 7,212)• Chinese (n = 563)• Russian (n = 490)• French (n = 554)• Italian (n = 242)• Japanese (n = 241)• Other (n = 803)

Studies included in quantitative synthesis

(meta-analysis)(n = 22)

Excluded from synthesis of evidence, with reason (n = 89):• CVD drugs taken by less than 80% of population (n = 72)• No outcome of interest (n = 6)• Systematic review -not current (n = 1) (In two records)• CVD drug not marketed in US (n = 4)• Dose of supplement not stated (n = 1)• Data could not be obtained (n = 1)• Higher level of evidence from RCTs was available—observational studies (n = 1)• Other (n = 2)

Full-text articles excluded, with reason (n = 1,879)No dietary supplement/not a relevant dietary supplement (n = 746)No relevant population (n = 603) Irrelevant study design (reviews or no independent control))(n = 469)Systematic review not meeting criteria for inclusion (n = 39)Not a relevant language (English systematic review or English/ German primary study) (n = 22)

Referencelist

checking(n = 31)

Full text not availablen = 25

Total included (all English records)(n = 169)

Iden

tifi

cati

on

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Summary of evidence search and selection


reported for co-administration of coenzyme Q10 plus sta-tins, omega-3 fatty acids plus statins, and vitamin E plusstatins in five studies [38-40,43,52].

American ginseng (panax quinquefolius)Clinical outcome efficacyNo evidence.

Intermediate outcome efficacy or harmsEvidence from three RCTs for co-administration of gin-seng and warfarin was inconclusive (grade: insufficient)[68-70].

Pharmacokinetic outcomesAmerican ginseng (2 g/day from weeks 2 to 4) caused astatistically significant reduction in the warfarin AUC(between group difference in median change from week1 to week 4, -0.64 μg/mL per day (95% CI −1.25, -0.13))[69]. The clinical significance of this finding is unclearbecause the analysis was not based on GMRs.

Coenzyme Q10Clinical outcome efficacyEvidence for the effect of coenzyme Q10 co-administeredwith angiotensin-converting enzyme inhibitors on all-

Table 1 Gradable clinical outcomes for dietary supplements plus cardiovascular drugsa

Item Supplement(dose)

Cardiovascular drug Number of studies, sample size,characteristic (treatment duration)

Outcome(combination versus control)

Clinical outcomeefficacy

All-cause mortality Coenzyme Q10(100 mg/day)

ACE inhibitors (80% ofparticipants were alsotaking digoxin, furosemide,hydralazine and/or nitrates)

Single study [53]; 30 mostly male patientswith left ventricular dysfunction (3 months)

Death: none versus one

Ginkgo biloba(40 mg fourtimes a day)

Antiplatelet agents Single study [47]; 62 South Asian patients withprevious ischemic stroke (1 month)

No deaths

Omega-3 fattyacids (4 g/day)

Aspirin Single study [46]; 291 patients admitted forcoronary artery bypass grafting (1 year)

Death: five versus four

Statins Single study [37]; 50 healthy nonsmokingadults (2 weeks)

No deaths

Warfarin Single study [46]; 319 patients admittedfor coronary artery bypass grafting (1 year)

Deaths: three versus two

Fenofibrate Single study [55]; 167 participants withhyperglycemia (2 months)

No deaths

Quality of life Coenzyme Q10(100 mg/day)

ACE inhibitors Single study [53]; 30 mostly male patientswith left ventricular dysfunction (3 months)

Minnesota ‘Living withHeart Failure’ questionnaire(mean sum of all scorespost-treatment 26.7 ± 17.9versus 26.5 ± 18.7

Myocardialinfarction

Omega-3 fattyacids (1.8 geicosapentaenoicacid + 1.2 gdocosahexaenoicacid)

Aspirin + calcium channelantagonists

Single study [50]; 58 patients who hadundergone successful coronary angioplasty(6 months)

Acute MI: 4 versus 2

RR 1.70 (95% CI 0.32, 8.84)

Arrhythmia Omega-3 fattyacids (4 g/day)

Statins Single study [41]; 256 patients with persistenthypertriglyceridemia despite statin therapy(2 months)

Arrhythmia: one versus none

Stroke Vitamin E(0.4 g/day)

Aspirin Single study [48]; 100 patients with previousreversible or irreversible ischemic neurologicdeficit (2 years)

Fatal or non-fatal stroke:three versus six

Ischemic stroke,hemorrhagic strokeand transientischemic attack

Vitamin E(600 IU/day)

Aspirin Single study [40]; 19,934 healthy women(10 years)

Composite outcome ofnonfatal MI, nonfatal strokeand vascular death, RR 0.95(95% CI 0.79, 1.13)

aInconclusive results: studies had an imprecise statistically non-significant pooled estimate (the 95% CIs were wide enough to be compatible with either clinicalbenefit, true no difference or harm). ACE: angiotensin-converting enzyme; CI: confidence interval; MI: myocardial infarction; RR: relative risk.


cause mortality and quality of life in one study of mostlymale patients with left ventricular dysfunction was incon-clusive (grade: insufficient) [53]. No differences in adher-ence to statins were noted with co-administration ofcoenzyme Q10 [39].

Intermediate outcome efficacyLow grade evidence was available from one trial indicat-ing no significant difference in high-density lipoprotein-cholesterol (HDL-C) for combination of coenzyme Q10plus fenofibrate versus fenofibrate alone [56].

HarmsEvidence from five RCTs for the combination of coen-zyme Q10 and statins, fenofibrate or angiotensin-

converting enzyme inhibitors was inconclusive (grade:insufficient) [39,53,56-58].

Pharmacokinetic outcomesNo evidence.

EchinaceaClinical outcome efficacyNo evidence.

Intermediate outcome efficacy or harmsEvidence from one study for the combination of Echin-acea and warfarin was inconclusive (grade: low) [97].

Table 2 Gradable intermediate outcomes for dietary supplements plus cardiovascular drugs (low grade evidence)

Outcomemeasures

Dietary supplement Cardiovasculardrug(s)

Conclusion effect estimate Applicability

Lipidprofile

Co-Q10 (200 mg/day) Fenofibrate No difference for HDL-C (one study): MD,1.55 mg/dL(95% CI −6.78, 3.68)

Mean age:

53 years

Mixed gender

High CHD risk

12 weeks treatment

Lipidprofile

Garlic (4 g/day) Nitrates In favor of combination Unknown age, gender

HDL-C (one study): MD, 8.40 mg/dL (95% CI 1.91, 14.89) High CHD risk

12 weeks treatment

Lipidprofile

Omega-3-fish oil(3.6 g/day omega-3to 9.2 g/day fish oil)

Statins In favor of combination Mean age: 45 to 63 years

TG (two studies pooled): MD, -74.95 mg/dL(95% CI −95.80, -54.10)a

Mixed CHD risk

No difference between combination and CV drug alone Mixed gender

HDL-C (six studies pooled): MD, 2.26 mg/dL (95% CI −1.8, 6.3) Up to 25 weeks treatment

LDL-C (five studies pooled): MD, 1.3 mg/dL (95% CI −3.6, 6.2)

Achieving LDL-C targets: RR 0.93 (95% CI 0.84, 1.03)

Achieving HDL-C targets (one study): and 1.00 (95% CI 0.90, 1.10)

Lipidprofile

Omega-3-fish oil(1.8 g/day)+

Calcium channelblockers + aspirin

In favor of combination Mean age: 57 y;

TG (two studies not pooled): MD −81.00 mg/dL(95% CI −125.30, -36.70) and MD −54.00 mg/dL(95% CI −94.1, -13.90)

85% men

High CHD risk

Up to 6 weeks treatment

Lipidprofile

Omega-3-fish oil(3.2 g/day)

Calcium channelblockers + aspirin,or dipyridamole

In favor of CV drug alone Mean age: 56 y;

LDL-C (one study): MD 21.00 mg/dL (95% CI 3.30, 38.70) 100% men

In favor of combination High CHD risk

TG (one study): MD −81.0 mg/dL (95% CI -125.30, -36.70)

Up to 12 weeks treatment

Lipidprofile

Vitamin E(900 mg/day)

Nifedipine In favor of combination Elderly; mixed gender

LDL-C (one study): MD −39.83 mg/dL (95% CI −71.29, -8.37) High CHD risk

12 weeks treatment

In favor of combination

TG (one study): MD, -23.91 mg/dL (95% CI -35.89, -11.93)

Bloodpressure

Omega-3-fish oil(2 g/day)+

Statins In favor of combination Mean age: 44 to 53 y;mixed gender

Systolic blood pressure (one study): MD, -8.50 mmHg(95% CI -16.3, -0.66)

Mixed CHD risk

5 weeks treatment

Systolic blood pressure (one study): median change frombaseline −5.0 versus + 0.3 mmHg

No difference between combination and CV drug alone

Diastolic blood pressure (one study): MD, 0.20 mmHg(95% CI -4.76, 5.16)


Table 2 Gradable intermediate outcomes for dietary supplements plus cardiovascular drugs (low grade evidence)(Continued)

Omega-3-fish oil(4 g/day fish oil)+

Statins Diastolic blood pressure (one study): Median reductions frombaseline -3.30 versus −1.80 to

Mean age: 58 y;Mixed gender

Unclear CHD risk

6 weeks treatmentaBoth studies recruited participant with higher baseline levels of triglyceride (>200 mg/dL). CHD: coronary heart disease; CI: confidence interval; CV: cardiovascular;HDL-C: high density lipoprotein-cholesterol; LDL-cholesterol: low density lipoprotein-C; MD: mean difference (post-treatment values); RR: relative risk; TG:triglycerides.


Pharmacokinetic outcomesResults of one study showed no clinically important buta statistically significant decrease (grade: insufficient) inS-warfarin AUC∞, an increase in drug clearance and anapparent increase in volume of distribution (GMRs: 0.92(90% CI 0.85, 0.99); 1.09 (90% CI 1.01, 1.18); and 1.09(95% CI 1.03, 1.18), respectively) [97].

GarlicClinical outcome efficacyNo evidence.

Intermediate outcome efficacyIn one study [61], a combination of garlic (4 g/day) andnitrates improved mean levels of HDL-C compared withnitrate alone (grade: low). Three other studies providedinsufficient evidence for a combination of garlic pluswarfarin, nitrates, or statin in addition to aspirin [60-62].

HarmsEvidence in four RCTs for garlic co-administered withwarfarin, nitrates, or statins plus aspirin in healthy men[60] or those with CV conditions was inconclusive(grade: insufficient) [59,61,62].

Pharmacokinetic outcomesEvidence from two studies demonstrated neither clinic-ally important (AUC, half-life or clearance; grade: low)[60] nor statistically significant (Cmax; grade: insufficient)[102] interactions between garlic extracts and warfarin.

Ginkgo bilobaClinical outcome efficacyInsufficient evidence was found for the effect of Ginkgobiloba plus antiplatelets (aspirin and/or pentoxifylline)on all-cause mortality (no deaths in either group) inSouth Asians with previous stroke [47].

Intermediate outcome efficacyEvidence from five RCTs for the combination of Ginkgoand acetylsalicylic acid, clopidogrel, ticlopidine, war-farin or cilostazol was inconclusive (grade: insufficient)[63-67].

HarmsSeven studies provided insufficient evidence for harmfor the co-administration with warfarin, digoxin, aspirin,aspirin and/or pentoxifylline, nitrates, cilostazol or clopi-dogrel, or ticlopidine [47,63-67,98].

Pharmacokinetic outcomesThree studies examined pharmacokinetic interaction ofGinkgo biloba and specific CV drugs (ticlopidine, digoxinand warfarin) [63,66,98]. Study results for clearance,AUC, half-life, or Cmax were either clinically not import-ant or statistically non-significant (grade: insufficient).

Omega-3 fatty acidsClinical outcome efficacyEvidence on all-cause mortality for healthy individualsand highly selected patients with dyslipidemia taking sta-tins as an add-on therapy [47], and patients with unclearto high 10-year CHD risk taking aspirin, warfarin orfenofibrate [55], was inconclusive (grade: insufficient).Similarly, evidence on acute myocardial infarction inhigh-risk patients taking a calcium channel antagonistwas inconclusive [50]. Evidence from two studies on theincidence of restenosis following successful coronaryangioplasty in patients taking omega-3 fatty acids as anadd-on to antiplatelet and calcium channel antagonisttherapies was conflicting. One study showed significantlylower rates in the combination group (RR 0.40, 95% CI0.20, 0.82) [51] and the other study reported no signifi-cant difference between the groups (RR 1.33, 95% CI0.76, 2.30) [50].There is inconsistent evidence for a benefit when

omega-3 fatty acids were added to conventional antipla-telet therapy and calcium channel antagonists on rates ofacute myocardial infarction [50,51]. In three short-termRCTs [38,43,52], adherence to CV drugs as judged by pillcount was greater than 95% in both treatment groups.

Intermediate outcome efficacyCo-administration with statins showed no benefit of low-ering low density lipoprotein-cholesterol (LDL-C) (Fig-ure 2) [41,43,52,74,81], total cholesterol [41,43,52,74,81],or of increasing HDL-C (grade: low) (Figure 3)[41,43,52,74,75,81]. However, the effect of adding statins

Table 3 Gradable intermediate outcomes for dietary supplements plus cardiovascular drugs (insufficient gradeevidence)a

Item Supplement (dose) Cardiovasculardrug

Number of studies, sample size, characteristic(treatment duration)

All lipids (Low andhigh densitylipoproteins-cholesterol,triglycerides, totalcholesterol)

Coenzyme Q10(100 to 200 mg/day)

Statins Two studies; 49 hypercholesterolemic patients [57], and44 patients with statin-induced myopathic pain [39]; (12 weeks)

Coenzyme Q10 (200 mg/day) Fenofibrate Participants with type II diabetes and high CHD risk

Garlic (4 g/day) Warfarin Single study [59]; 48 participants with prosthetic heart valves,or diagnosed with deep vein thrombosis, valvular heart diseaseor atrial fibrillation

Garlic (4 mL/day) Statins + aspirin Single study [62]; 23 participants with, or at high risk for,coronary artery disease (1 year)

Garlic (4 g/day) Nitrates Single study [61]; 60 participants with coronary

artery disease (1 year)

Ginkgo biloba (120 mg/day) Aspirin Single study [64]; 50 young healthy men (1 week)

Omega-3 fatty acids (4 g/day) Fenofibrate Single study [55]; 167 participants with unclear CHD risk (8 weeks)

Omega-3 fatty acids (3 g/day) Calcium channelblockers

Single study [49], 22 participants with variant angina (16 weeks)

Omega-3 fatty acids (4 g/day) Niacin + aspirin Single study [77]; 14 participants with atherogenic dyslipidemia(12 weeks)

Omega-3 fatty acids (10 g/day) Aspirin Two studies [80,84]; 30 healthy participants (2 to 3 weeks)

Vitamin E (0.6/day) Gemfibrozil Single study [88]; 67 participants with hyperlipidemia (4 weeks)

Vitamin E (100 mg/day, 100 IU/day) Statins Pooled results for four studies[89,91-93]; 192 highly selectiveparticipants (24 weeks)

Triglycerides Omega-3 fatty acids (4 g/day) ACE inhibitors Two studies [78,79]; 58 participant with renal dysfunction orhypertension (6 to 25 weeks)

Omega-3 fatty acids (4 to 9 g/day) Statins Three studies [38,72,82]; 420 highly selected participants withlow or unclear CHD risk (4 to 18 weeks)

Vitamin E (900 mg/day) Antiplatelet agents Single study [86]; 16 participants with high CHD risk (6 weeks)

Low densitylipoprotein-cholesterol

Omega-3-fish oil (1.8 g/day) Calcium channelblockers + aspirin

Single study [50]; 107 participants with pre-coronary angioplasty(6 weeks)

High densitylipoprotein-cholesterol

Vitamin E (900 mg/day) Nifedipine Single study [94]; 30 participants with high CHD risk (16 weeks)

Omega-3 fatty acids (1.8 g/day) Calcium channelblockers + aspirin

Single study [50]; 107 participants with pre-coronary angioplasty(6 weeks)

Omega-3 fatty acids (3.2 g/day) Calcium channelblockers + aspirin +dipyridamole

Single study [51]; 82 participants with post-coronary angioplasty(12 weeks)

Blood pressure(systolic and diastolic)

Coenzyme Q10 (200 mg/day) Fenofibrate Single study[56]; 80 participants with type II diabetes and highCHD risk (12 weeks)

Garlic (4 g/day) Warfarin Single study [59]; 48 participants with prosthetic heart valves,or diagnosed with deep vein thrombosis, valvular heart diseaseor atrial fibrillation

Ginkgo biloba (120 mg/day) Aspirin Single study [64]; 50 young healthy male volunteers (1 week)

Ginkgo biloba (120 mg/day) Cilostazol Single study [67]; 10 healthy South Asian men (1 day)

Omega-3 fatty acids (10 g/day) Aspirin Two studies [80,84]; 30 healthy participants (2 to 3 weeks)

Omega-3 fatty acids (4 g/day) Beta-adrenergicantagonists

Single study [85]; 25 participants with unclear CHD risk (6 weeks)

Vitamin E (600 mg/day) Furosemide Single study [87]; 24 hypertensive participants (4 weeks)

Gemfibrozil Single study [88]; 67 participants with hyperlipidemia (4 weeks)

Vitamin E (900 mg/day) Nifedipine Single study [94]; 30 participants with high CHD risk (16 weeks)

Internationalnormalized ratio

Echinacea (5 g/day) Warfarin Single study [97]; 12 healthy volunteers (2 weeks)


Table 3 Gradable intermediate outcomes for dietary supplements plus cardiovascular drugs (insufficient gradeevidence)a (Continued)

Garlic (4 g/day) Two studies; 48 participants with high CHD risk [59](12 weeks), and 16 healthy men with known CYP2C9 andVKORC1 genotype [60] (2 weeks)

Ginger (3.6 g/day) Single study [63];12 healthy male volunteers (7 days)

Ginkgo biloba (12 g/day)

Panax ginseng (1.5-2 g/day) Two studies; seven healthy men [70] (1 week), 25 patients withischemic stroke [68] (2 weeks)

Omega-3-fish oil (4 mg/day) Single study [54]; 11 participants with unclear CHD risk (4 weeks)aInconclusive results: studies had an imprecise statistically non-significant pooled estimate (the 95% CIs were wide enough to be compatible with either clinicalbenefit, true no difference or harm). ACE: angiotensin-converting enzyme; CHD: coronary heart disease.


to omega-3 fatty acids in participants with high baselinetriglyceride levels (>200 mg/mL) was beneficial in lower-ing post-treatment triglyceride levels [41,73] (grade: low),as opposed to participants with lower baseline levels oftriglyceride for whom the results were inconclusive(grade: insufficient) [41,43,52,73,74,81]. Significant bene-fits in reducing systolic blood pressure (grade: low)[38,76], but no difference in diastolic blood pressure(grade: low) [74,76] were observed (Table 2).

HarmsInsufficient evidence was available from 22 studies (21 RCTsand one retrospective cohort study) which examinedomega-3 fatty acids plus statins [37,38,41,52,72,76,81-

Figure 2 Omega-3 fatty acids co-administration with statins versus stlevels

83,96,103], aspirin [46,51,77,80,84], aspirin and clopidogrel[99], aspirin in combination with dipyridamole and calciumchannel blockers [51], warfarin [46,54], ramipril and/orirbesartan [78], or fenofibrate [55]. These studies were gen-erally small and underpowered. They recruited healthy par-ticipants or participants with CHD or risk factors for CHD.Meta-analyses of studies comparing omega-3 fatty

acids and statin combinations versus statins aloneyielded inconclusive results for serious adverse events(two studies; RR, 3.64 (95% CI 0.8, 17.2)), withdrawaldue to adverse events (seven studies; RR, 1.2 (95% CI0.6, 2.3)), elevated aspartate aminotransferase (two stud-ies; RR, 0.6 (95% CI 0.3, 1.3)) and elevated alanine trans-aminase (four studies; RR, 0.9 (95% CI 0.5, 1.9)) (grade:

atins alone: post-treatment low density lipoprotein-cholesterol

Figure 3 Omega-3 fatty acids co-administration with statins versus statins alone: post-treatment high density lipoprotein-cholesterollevels.


insufficient) [37,38,41,72,81,83,96]. Non-significant andimprecise pooled estimates were also obtained for totaladverse events and elevated creatine kinase (grade: insuf-ficient). Forest plots are available online [100].

Pharmacokinetic outcomesIn three open-label RCTs of healthy adult volunteers(sample size range 24 to 50) [37,83,96] taking 4 g/dayomega-3 fatty acids and rosuvastatin, atorvastatin,2-hydroxy atorvastatin, or 4-hydroxy atorvastatin, no sta-tistically significant or clinically important differenceswere observed between the treatment and control groupsfor steady state AUC and Cmax GMRs (grade: low).Observed changes in steady state β-hydroxysimvastatinarithmetic means of AUC, Cmax, tmaxclearance and half-life were not statistically significant (grade: insufficient).

Vitamin EClinical outcome efficacyThe evidence for the effect of vitamin E plus aspirin onstroke and transient ischemic attacks in selected patientswith previous neurologic deficit was inconclusive (grade:insufficient) [48]. In one pragmatic trial, 19,934 womenwere randomized to vitamin E (600 IU/day) plus aspirin(100 mg/day) or aspirin alone for 10 years. No signifi-cant differences were noted for the composite outcomeof nonfatal myocardial infarction, nonfatal stroke or vas-cular death (RR 0.95, 95% CI 0.79, 1.13) [40]. Althoughcomponents of the composite outcome were gradable,

shifts in incidence of stroke and heart attack might havebeen obscured in this composite outcome. No differ-ences in adherence to statins were noted with co-administration of vitamin E.

Intermediate outcome efficacyIn one study of 30 elderly patients at high risk of CHD,addition of vitamin E to nifedipine significantly loweredtotal cholesterol, LDL-C (grade: low), triglycerides(grade: low) and systolic blood pressure (inconclusive,grade: insufficient) [94] (Tables 2, 3).

HarmsEvidence from 10 RCTs for co-administration of vitaminE and aspirin, nifedipine, furosemide, or statins in parti-cipants who were healthy, or who had CHD or risk fac-tors for CHD was inconclusive (grade: insufficient).Sample sizes were generally small, except for one studythat recruited over 9,000 women [40].

Pharmacokinetic outcomesNo evidence.

Limitations of the results from the evidenceAcross all combinations of dietary supplements and CVdrugs, the strength of evidence of the gradable outcomesof comparative efficacy or effectiveness was mostlygraded as insufficient. Type II errors could not beexcluded due to the low statistical power of mostly short-


term efficacy trials, particularly with strict inclusion cri-teria excluding patients with uncontrolled comorbiditiesand acute ischemic events. In addition, most studies wereshort-term efficacy trials and thus unable to evaluatelonger term effects from co-administration.Limited findings on intermediate outcomes were avail-

able and the majority of evidence was contributed bysmall RCTs with statistically non-significant results andbroad CIs. This imprecision precluded ruling in or out im-portant benefits or harms, thus the strength of evidencefor several gradable intermediate outcomes was rated in-sufficient. Statistically significant effects were graded aslow strength of evidence because of limitations in the in-ternal validity of studies, surrogacy of outcomes, and oftenabsent reproducibility in the direction of effect estimates(Table 2). Forest plots are available online [100].With respect to harms data, for all supplement-drug

combinations examined, the strength of evidence fromsingle or heterogeneous studies for bleeding, serious ad-verse events, withdrawal due to adverse events, renaldysfunction, hepatotoxicity and prolongation of cor-rected QT interval was insufficient. This was due toeither inconsistent effect estimates across studies (sug-gesting conflicting findings with no obvious explanation)or imprecise estimates (precluding ruling out importantbenefit or harms in underpowered studies with wideconfidence intervals).

DiscussionEvidence gleaned from an initial search yielding over32,000 records identified a considerable knowledge gapregarding the safety and efficacy of combining dietarysupplements with CV drugs.Among 168 records that addressed the relevant possibil-

ity of interaction, 63 studies contributed evidence for syn-thesis. With a few exceptions, there was insufficientevidence to draw any conclusions on particular interac-tions. In addition to an overall lack of evidence, theincluded studies were often underpowered to assess thepredetermined clinically relevant outcomes set for thissynthesis review. As well, many studies had importantmethodological limitations or were poorly generalizable tothe relevant population. The strength of the identified evi-dence was frequently compromised by poor allocationconcealment, and issues related to blinding, study report-ing and potential conflict of interest. Drug interactionsresulting in positive or negative outcomes likely occur, butthe evidence available and identified in this review is insuf-ficient to allow meaningful conclusions with confidence.Available evidence comes primarily from short-term

trials of highly selected participants, with limited externalvalidity. The strength of evidence was low at best, withpoor grading resulting from risks of bias, small samplesizes, and the fact that evidence is largely generated from

intermediate surrogate outcomes rather than primary clin-ical endpoints. While there are data from which we canderive a sense of lack of interactions in some cases, thesmall size of the trials made it difficult to impossible to as-certain the potential for true clinical interaction.Much of the pharmacokinetic research was conducted

on healthy young adults; thus this evidence may not beapplicable to populations with CVD and particularly forolder patients taking CV drugs, due to possible differ-ences in metabolism and the existence of comorbidities.The internal validity of most trials was compromised byflawed design, lack of appropriate allocation conceal-ment and risk of bias. A formal assessment of statisticalinteraction was rarely undertaken. In the absence of cor-roborating pharmacokinetic evidence or assessment forstatistical interaction, it is often impossible to determinewhether a difference in outcome is due to true pharma-cological interaction, or due to more independent addi-tive, or possibly counteracting therapeutic effects.A principal limitation of the included trials was that they

were small and susceptible to type II errors. A marginallyreassuring corollary is that if there was a real, dramaticclinical impact due to an interaction then some clinical ef-fect would likely have been evident despite being under-powered for smaller effect sizes. Of more concern arepossible interactions that could arise through polyphar-macy of prescription drugs, a situation all too common, inparticular for the elderly population.With these caveats in mind, the following is a sum-

mary of the clearer signals from the evidence reviewed.Omega-3 fatty acids (2 to 4 g/day) from fish and/or sup-

plements likely do not interfere with the efficacy of statintherapy or calcium channel blockers in the presence ofantiplatelet agents, and may provide an independent benefitin resolving hypertriglyceridemia. Also, garlic (4 to 10g/day)may not interact negatively with nitrates and warfarin andmay confer independent benefit in improving HDL-C.Interpretation of this report requires the reader to

recognize that dietary supplements in the US are notregulated in the same manner as prescription drugs norare manufacturers of dietary supplements held to thesame standards with respect to providing evidence of ef-ficacy and safety prior to marketing. Dietary supple-ments do not require FDA approval, nor are there anyFDA regulations that require evidence of purity, qualityor composition prior to marketing. This has resulted ina lack of standardization among products both from asingle manufacturer and between manufacturers [104].The lack of manufacturing regulation and labeling stan-dards may result in significant differences between pro-ducts, unbeknownst to the consumer, thereby limitingthe external validity of clinical trials. Furthermore, thereis little reliable published information regarding thesafety of dietary supplements. Until only recently,


manufacturers of dietary supplements were not obligedto report serious adverse events. This is quite differentfrom what is required of prescription drugs.Recent systematic reviews related to the topic of diet-

ary supplement-drug interactions do not address thesame scope, are not comprehensive, do not grade theoutcomes extracted, do not evaluate the quality of evi-dence, or involve different populations of interest. A2005 systematic review by Mills et al. focused on effectsof natural health products on the metabolism of a broadrange of conventional medicines [105]. Consistent withour review, they identified a lack of evidence supportinginteractions between coenzyme Q10 and warfarin,Ginkgo biloba and warfarin, and Ginkgo biloba and di-goxin. Both reviews also identified a shift in AUC of theinternational normalized ratio when American ginsengwas taken in conjunction with warfarin; however, wequestion the clinical significance of this finding.Also in 2005, Desai et al. reviewed interactions between

dietary supplements and antiplatelet agents reported inclinical trials and case reports [106]. With respect to thesupplements considered in our review, Desai concludedthat omega-3 fatty acids along with aspirin led to signifi-cantly greater reductions in adenosine diphosphate-induced platelet aggregation, blood platelet count,thromboxane B2 and restenosis rates, as well as prolongedbleeding time. Vitamin E along with aspirin led to signifi-cantly greater reductions in platelet adhesion, ischemicstroke, recurrent episodes of transient ischemic at-tack, as well as prolonged dental bleeding time.Reviews published by Izzo et al. in 2005 and Skalli

et al. in 2007 described evidence for drug-supplementinteractions, but the majority of evidence was generatedfrom case reports and small case series [107,108]. Themost recent systematic review on dietary supplement-drug interactions, published in 2010 by Kennedy andSeely, examined herb-drug interactions identified fromtrials wherein the herbal impact on hepatic metabolismvia cytochrome P450 isoenzymes was ascertained [109].Their target population was not specifically patients withCVD or CV drugs, and the review evaluated indirect evi-dence limited to herbs metabolized via the cytochromeP450 system. While some of the findings within thesereviews are consistent with ours, our graded evaluationdid not yield similar confidence in conclusions afterevaluating the quality and strength of evidence.A most obvious limitation of our review arose from

the need to scope the work to a manageable yet relevantsynthesis by restricting the number of dietary supple-ments to the sixteen that were considered. This subsetof supplements was based on published North Americanusage surveys and a consensus selection process thatincluded a Technical Experts Panel [6,21-26]. Thus, weomitted drugs and supplements, and related data from

other international sources. The review also did notconsider combinations of multiple dietary supple-ments with CV drugs to make causal inference pos-sible. This limitation has negative implications forexternal validity because people with CVD likely self-prescribe combinations of numerous dietary supple-ments, taken alongside their CV drugs.The greatest strengths of the present review are its

broad search strategy and consideration of extensive lit-erature, and a methodology that focused on the highestquality of evidence. We followed published guidance topool data from studies, grade the strength of evidence,and assess applicability. Based upon preliminary searcheswe did not exclude German language literature, a lan-guage where most negative studies are published [110].In order to minimize over-generalization of evidence, wealso included only studies with more than 80% of parti-cipants taking each CV medication under consideration.While a plethora of strong recommendations was the

hope, we revealed instead a glaring knowledge gapregarding interactions between some of the agents mostcommonly used for their presumed pharmacologicaleffects for serious chronic disease.

ConclusionWith the continuing and increasing burden of CVD,precise recommendations are needed to guide the useof dietary supplements in disease prevention andmanagement. An ungrounded call for avoidance ofdietary supplements in conjunction with pharmaceut-ical treatments may result in the avoidance of poten-tially beneficial supplements, or just as importantlymight be readily ignored, leading to potential harmwith negative interactions. Strategic investment tobuild research capacity to address the importantknowledge gap in the area of dietary supplement-druginteractions should address relevant questions in ap-propriate populations according to disease, geneticmakeup, age, and so on. While awaiting results of fu-ture, adequately powered interventional trials focus-ing on meaningful clinical outcomes, evidence fromwell-conducted prospective observational studiesshould be sought. Electronic health record linkagesbetween databases of dietary supplement use and CVdrug prescription may also add to the equipoise thathas been so insufficiently addressed to date.

Additional files

Additional file 1: Table S1. Selected cardiovascular drugs for currentreview.

Additional file 2: Table S2. List of included outcomes.

Additional file 3: Table S3. a Priori outcomes for grading the strengthof evidence.

http://www.biomedcentral.com/content/supplementary/2046-4053-1-26-S1.doc




AbbreviationsAHRQ: Agency for Healthcare Research and Quality; AUC: area under thecurve; CI: confidence interval; CHD: coronary heart disease; CV: cardiovascular;CVD: cardiovascular disease; FDA: Food and Drug Administration;GMR: geometric mean ratio; HDL-C: high density lipoprotein-cholesterol;INR: International Normalized Ratio; LDL-C: low density lipoprotein-cholesterol; MD: mean difference; OR: odds ratios; RCT: randomized clinicaltrials; RR: relative risk.

Competing interestsThe authors declare that they have no competing interests.

Authors’ contributionSK and DS were involved in the conception and design, data interpretation,reviewing and revising the manuscript critically for important intellectualcontent, and its final approval. FY, KS, AT, ACT and MS analyzed andinterpreted data, reviewed the draft and revised it critically for importantintellectual content, and approved the manuscript. JT was involved in theconception and design, reviewed the draft and revised the manuscriptcritically for important intellectual content, and approved the manuscript.TCO, MAT and BS were involved in the conception and design, reviewed thedraft and revised it critically for important intellectual content, and approvedthe manuscript. MTA was involved in the conception and design, dataanalysis and interpretation, drafting of the manuscript, and final approval ofthe manuscript. All authors read and approved the final manuscript.

DisclaimerThis project was funded under Contract No. HHSA290-2007-10059-I (EPCIII)from the AHRQ, US Department of Health and Human Services. The authorsof this report are responsible for its content. Statements in the report shouldnot be construed as endorsement by the AHRQ, National Institute of Healthor the US Department of Health and Human Services.

AcknowledgmentsThe authors gratefully acknowledge the following individuals for theircontributions to this manuscript: Raymond Daniel, James Galipeau,Mary Gauthier, Mistrel Pratt and Sophia Tsouros assisted with articleacquisition, reference generation, project management, screening, dataextraction, development of the evidence tables, and preparation of theoriginal evidence report; Katja Boehm and Stefania Milazzo assistedwith screening of the German articles; Ranjeeta Mallick and LucyTurner provided statistical support and consultations for data analysis.

Author details1Clinical Epidemiology, The Ottawa Hospital Research Institute and theDepartment of Pharmacy, The Ottawa Hospital, Ottawa, ON, Canada.2Department of Research & Clinical Epidemiology, The Canadian College ofNaturopathic Medicine, Toronto, ON, Canada. 3Ottawa Methods Centre,Clinical Epidemiology Program, Ottawa Hospital Research Institute, Universityof Ottawa Evidence-based Practice Center, Ottawa, ON, Canada. 4Li Ka ShingKnowledge Institute, St Michael’s Hospital, Toronto, ON, Canada. 5Children’sHospital of Eastern Ontario Research Institute, Ottawa, ON, Canada. 6Divisionof Endocrinology and Metabolism, The Ottawa Hospital, University of Ottawa,Ottawa, ON, Canada. 7Division of Cardiology, The Ottawa Hospital, Universityof Ottawa, Ottawa ON, Canada.

Received: 6 December 2011 Accepted: 18 April 2012Published: 31 May 2012

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doi:10.1186/2046-4053-1-26Cite this article as: Kanji et al.: Interactions of commonly used dietarysupplements with cardiovascular drugs: a systematic review. SystematicReviews 2012 1:26.

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