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Use Versus Nonuse of Dietary Supplements in Adults Taking Cardiovascular Drugs - Clinician Summary | AHRQ Effective Health Care Program

Use Versus Nonuse of Dietary Supplements in Adults Taking Cardiovascular Drugs - Clinician Summary | AHRQ Effective Health Care Program

Department of Health and Human Serviceswww.hhs.gov
Agency for Healthcare Research Quality
Clinician Summary – Apr. 10, 2013

Use Versus Nonuse of Dietary Supplements in Adults Taking Cardiovascular Drugs

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Table of Contents


Research Focus for Clinicians

In response to a request from the public regarding the use of dietary supplements by patients currently undergoing pharmacologic cardiovascular treatment, a review was undertake to evaluate the evidence regarding the benefits and harms of concomitant use of dietary supplements with cardiovascular drugs. The systematic review included 70 studies published through September 2011. The full report, listing all studies, is available at www.effectivehealthcare.ahrq.gov/dietary-supplements.cfm. This summary is provided to inform discussions with patients of options and to assist in decisionmaking along with consideration of a patient’s values and preferences. However, reviews of evidence should not be construed to represent clinical recommendations or guidelines.

Background

Estimates suggest that approximately one-third to two-thirds of people suffering from heart failure or other forms of cardiovascular disease (CVD) use dietary supplements.1 These supplements are available in pharmacies, grocery stores, and health food stores and on the Internet. They are often consumed by patients without the knowledge of their health care providers and under the impression that they are safe and beneficial. Such claims of benefit are often unsubstantiated, however. These products do not require U.S. Food and Drug Administration (FDA) approval nor are there any FDA regulations that require evidence of purity, quality, or composition before marketing. Use of dietary supplements for CVD occurs in the setting where, in addition to lifestyle and dietary recommendations, patients receive pharmaceuticals (6.9 prescription drugs on average from 5.9 different drug classes2) to prevent or treat CVD. Patients may be at risk for drug-supplement or supplement-supplement interactions.
On one hand, patients taking supplements may be placed at risk for potential adverse effects from the supplements themselves or from interactions with other pharmacologically active agents. On the other hand, adding a dietary supplement to conventional cardiovascular drugs may confer benefits. Although a substantial amount of research describes drug-drug interactions in various populations, the evidence for drug-supplement interactions is unclear, especially in CVD populations. The evidence for benefits and adverse effects in patients with CVD has not been summarized previously.

Conclusion

Evidence for the use of dietary supplements in combination with cardiovascular drugs was insufficient to permit conclusions about clinical cardiovascular efficacy, effectiveness, and adverse effects (e.g., mortality, thrombotic events, and arrhythmia).
Evidence for most intermediate outcomes (e.g., lipid profile, blood pressure, international normalized ratio (INR), and bleeding and coagulation) was also insufficient or of low strength and suggested no effect. Where an effect on an intermediate outcome might be suggested, studies were often small, at risk of bias, and subject to the uncertainties associated with testing of agents of uncontrolled purity, quality, or composition.
Some findings with low strength of evidence, if acted on by a patient without consulting a physician, could lead to adverse effects.
Furthermore, the interactions of these agents with other noncardiovascular drugs that patients may be taking cannot be predicted from any of these studies. Comorbidities such as renal disease or liver disease that could affect the metabolism, actions, and safety of supplements were not studied.
Advertised claims for dietary supplements should be interpreted cautiously, and clinicians should ask their patients with CVD about their use of supplements, regardless of whether the supplement is to be taken to provide cardiovascular protection or for other purposes.
Details of the comparisons and findings are available in the full report, which can be accessed in the right navigation on this Web page.

Clinical Bottom Line

Clinical Cardiovascular Effectiveness/Efficacy Outcomes
For all combinations of dietary supplements and cardiovascular drugs studied, evidence was inconclusive about the effects of concomitant use of specific dietary supplements (when compared with cardiovascular drugs alone) on clinical cardiovascular effectiveness/efficacy outcomes like mortality and specific cardiovascular or cerebrovascular conditions.
Intermediate Cardiovascular Efficacy Outcomes (Continued summary of the evidence review—not to be construed to represent clinical recommendations or guidelines)

Lipid Profile

Blood Pressure

  • The concomitant use of omega-3 fatty acids with statins improved systolic blood pressure but provided no additional benefit for diastolic blood pressure. evidence low
  • The concomitant use of omega-3 fatty acids with ACE inhibitors provided no additional benefit for either systolic or diastolic blood pressure. evidence low
  • Evidence was inconclusive regarding the effects of concomitant use of all other supplement-drug combinations on blood pressure. evidence insufficient

International Normalized Ratio

  • According to only one small study (n = 70)* of patients who have unstable control of anticoagulation when receiving warfarin, the consistent and regular concomitant use of vitamin K may help improve the percentage of time the INR is in the target therapeutic range and decrease the variability of the INR. This finding may not be applicable to a larger unselected warfarin-treated patient population. evidence low
  • Evidence was inconclusive regarding the effects of concomitant use of all other supplement-drug combinations on INR.evidence insufficient

Bleeding and Coagulation Measures

Evidence was inconclusive regarding the effects of concomitant use of all supplement-drug combinations on bleeding and coagulation measures.evidence insufficient
Clinical or Intermediate Harms Outcomes
For all combinations of dietary supplements and cardiovascular drugs, evidence was inconclusive about the effects of concomitant use of specific dietary supplements (when compared with cardiovascular drugs alone) on clinical or intermediate harms outcomes like organ toxicity or serious adverse effects.evidence insufficient
Pharmacokinetic Outcomes
  • For the concomitant use of Echinacea with warfarin, ginger with warfarin, and Ginkgo biloba with warfarin, there was no evidence of interaction for AUC, Cmax, half-life, or clearance. evidence low
  • For the concomitant use of garlic with warfarin, there was no evidence of interaction for AUC, half-life, or clearance. evidence low
  • For the concomitant use of Ginkgo biloba with ticlopidine, there was no evidence of interaction for AUC, half-life, or Cmax. evidence low
  • For the concomitant use of ginseng with warfarin, there was no evidence of interaction for Cmax, half-life, or clearance. evidence low
  • For the concomitant use of omega-3 fatty acids with rosuvastatin or atorvastatin, there was no evidence of interaction for AUC or Cmax. evidence low
  • Evidence was inconclusive regarding the effects of concomitant use of all other supplement-drug combinations on pharmacokinetic outcomes.evidence insufficient
* Sconce E, Avery P, Wynne H, et al. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood. 2007 Mar 15;109(6):2419-23. PMID: 17110451.

ACE = angiotensin-converting enzyme; AUC = area under the curve (to infinity or at steady-state); Cmax = maximum concentration; HDL-C = high-density lipoprotein cholesterol; INR = international normalized ratio; LDL-C = low-density lipoprotein cholesterol

Strength of Evidence Scale

High: evidence high
There are consistent results from good-quality studies. Further research is very unlikely to change the conclusions.
Moderate: evidence medium
Findings are supported, but further research could change the conclusions.
Low: evidence low
There are very few studies, or existing studies are flawed.
Insufficient:evidence insufficient
Research is either unavailable or does not permit estimation of a treatment effect.


Supplement/Drug Combinations and Outcomes Studied
CombinationOutcomes Studied
BCM = bleeding and coagulation measures; BP = blood pressure; CCE/EO = clinical cardiovascular effectiveness/efficacy outcomes; CIHO = clinical or intermediate harms outcomes; INR = international normalized ratio; LP = lipid profile; PO = pharmacokinetic outcomes
† For triglycerides
†† For high-density lipoprotein cholesterol and low-density lipoprotein cholesterol
Supplement/drug combinations with findings:
coenzyme Q10/fenofibrateLP
Echinacea/warfarinPO
Ginkgo biloba/warfarinPO
Ginkgo biloba/ticlopidinePO
garlic/warfarinLP, PO
garlic/nitratesLP
ginger/warfarinPO
ginseng/warfarinPO
omega-3 fatty acids/ACE inhibitorsBP
omega-3 fatty acids/aspirin + calcium channel blockersLP
omega-3 fatty acids/aspirin + calcium channel blockers + dipyridamoleLP
omega-3 fatty acids/atorvastatinPO
omega-3 fatty acids/simvastatinPO
omega-3 fatty acids/statinsBP, LP†
vitamin E/nifedipineLP
vitamin K/anticoagulantsINR
Supplement/drug combinations with inconclusive findings:
coenzyme Q10/ACE inhibitorsCCE/EO, CIHO
coenzyme Q10/fenofibrateBP, CIHO, LP
coenzyme Q10/statinsCIHO, LP
Echinacea/warfarinBP, CIHO, INR
Ginkgo biloba/antiplatelet agentsBCM, BP, CCE/EO, LP
Ginkgo biloba/aspirinBP, CIHO, LP
Ginkgo biloba/aspirin + pentoxifyllineCIHO
Ginkgo biloba/cilostazolBCM, BP, CIHO
Ginkgo biloba/clopidogrelCIHO
Ginkgo biloba/digoxinCIHO, PO
Ginkgo biloba/nitratesCIHO
Ginkgo biloba/pentoxifyllineCIHO
Ginkgo biloba/ticlopidineCIHO
Ginkgo biloba/warfarinCIHO, INR
garlic/nitratesLP, CIHO
garlic/statinsPO
garlic/statins + aspirinCIHO, LP
garlic/warfarinBP, CIHO, INR, LP, PO
ginger/warfarinINR
ginseng/warfarinCIHO, INR
hawthorn/digoxinCIHO, PO
magnesium/beta-blockersBP, CCE/EO, CIHO
magnesium/hydrochlorothiazideBP, CIHO, LP
niacin (<250 mg="" propranolol="" td="">
CIHO, LP
omega-3 fatty acids/ACE inhibitorsLP
omega-3 fatty acids/aspirinBP, CCE/EO, CIHO, LP
omega-3 fatty acids/aspirin + calcium channel blockersLP
omega-3 fatty acids/aspirin + calcium channel blockers + dipyridamoleCIHO, LP
omega-3 fatty acids/aspirin + clopidogrelCIHO
omega-3 fatty acids/atorvastatinPO
omega-3 fatty acids/beta-blockersBP
omega-3 fatty acids/calcium channel blockersLP
omega-3 fatty acids/fenofibrateCCE/EO,CIHO, LP
omega-3 fatty acids/irbesartanCIHO
omega-3 fatty acids/niacin + aspirinLP
omega-3 fatty acids/ramiprilCIHO
omega-3 fatty acids/ramipril + irbesartanCIHO
omega-3 fatty acids/rosuvastatinPO
omega-3 fatty acids/simvastatinPO
omega-3 fatty acids/statinsCCE/EO, CIHO, LP††
omega-3 fatty acids/warfarinCCE/EO, CIHO, INR
vitamin E/antiplatelet agentsLP
vitamin E/aspirinCCE/EO, CIHO
vitamin E/furosemideBP, CIHO
vitamin E/gemfibrozilBP, LP
vitamin E/nifedipineBP, CIHO, LP
vitamin E/statinsLP
vitamin K/anticoagulantsCCE/EO, INR
vitamin K/warfarinCIHO

Gaps in Knowledge

  • Future research with dietary supplements should involve substances for which the identity of the agents can be clearly ascertained and the chemical composition well characterized and ideally standardized. If the active ingredients or biologic activity is not known, studies to characterize these variables, identify mechanisms of action, and describe safety should precede clinical efficacy studies.
  • As the extant literature is largely based on a few small efficacy studies of limited internal validity that examined intermediate outcomes, future supplement-cardiovascular drug interaction trials should focus on meaningful clinical outcomes, should be appropriately powered and rigorously conducted and reported, and should provide precise measurements of both clinical effectiveness and harms outcomes.
  • Most studies were conducted in speciality settings, excluded patients with comorbidities or uncontrolled comorbidities, and did not include ethnic and racial minorities. Future trials should be representative of the population taking cardiovascular drugs in terms of comorbidities, setting, and racial distribution. They should also collect data and undertake subgroup analyses for age, sex, race, comorbidities (e.g., liver or renal compromise), and genotypic polymorphisms of the cytochrome P450 enzyme.
  • A substantial number of pharmacokinetic interaction studies did not report and analyze pharmacokinetic outcomes according to FDA guidance for bioequivalence studies.

What To Discuss With Your Patients

Given these findings, clinicians may wish to inquire about supplement use among their patients with cardiovascular disease. Topics of discussion include:
  • The importance of informing their clinician about a decision to take a supplement
  • The high uncertainty about the benefits or potential side effects of dietary supplements used in combination with cardiovascular drugs
  • The importance of continuing to take prescribed cardiovascular medication(s) if the patient decides to take a dietary supplement
  • The fact that dietary supplements do not require FDA approval before being advertised and sold, and that there may be uncertainty about the purity, quality, or composition of the supplements
  • The potential but uncharacterized risks for interactions with prescribed medicines or with other supplements

Resource for Patients

Taking Dietary Supplements With Heart, Blood Pressure, or Cholesterol Medicines, A Review of the Research for Adults is a free companion to this clinician research summary. It can help patients with cardiovascular disease who are considering taking dietary supplements in conjunction with their cardiovascular drugs talk with their health care professionals about their options. It provides information about:
  • How much evidence is available concerning the cardiovascular benefits or harms of taking dietary supplements in conjunction with cardiovascular medications
  • Warnings about the lack of regulation or standardization of supplement products sold in stores or on the Internet
  • The importance of discussing the use of supplements with their doctor before adding them to cardiovascular medications, and questions to guide that discussion

Source

The information in this summary is based on Dietary Supplements in Adults Taking Cardiovascular Drugs, Comparative Effectiveness Review No. 51, prepared by the University of Ottawa Evidence-based Practice Center under Contract No. 290-2007-10059-I for the Agency for Healthcare Research and Quality, April 2012.
This summary was prepared by the John M. Eisenberg Center for Clinical Decisions and Communications Science at Baylor College of Medicine, Houston, TX. It was written by Amelia Williamson Smith, M.S., Thomas Workman, Ph.D., Salim Virani, M.D., and Michael Fordis, M.D.
References Cited on Page 1:
  1. Yeh GY, Davis RB, Phillips RS. Use of complementary therapies in patients with cardiovascular disease. Am J Cardiol. 2006 Sep 1;98(5):673-80. PMID: 16923460.
  2. Choudhry NK, Fischer MA, Avorn J, et al. The implications of therapeutic complexity on adherence to cardiovascular medications. Arch Intern Med. 2011 May 9;171(9):814-22.PMID: 21555659.
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