Evidence gleaned from an initial search yielding over 32,000 records identified a considerable knowledge gap regarding the safety and efficacy of combining dietary supplements with CV drugs.
Among 168 records that addressed the relevant possibility of interaction, 63 studies contributed evidence for synthesis. With a few exceptions, there was insufficient evidence to draw any conclusions on particular interactions. In addition to an overall lack of evidence, the included studies were often underpowered to assess the predetermined clinically relevant outcomes set for this synthesis review. As well, many studies had important methodological limitations or were poorly generalizable to the relevant population. The strength of the identified evidence was frequently compromised by poor allocation concealment, and issues related to blinding, study reporting and potential conflict of interest. Drug interactions resulting in positive or negative outcomes likely occur, but the evidence available and identified in this review is insufficient to allow meaningful conclusions with confidence.
Available evidence comes primarily from short-term trials of highly selected participants, with limited external validity. The strength of evidence was low at best, with poor grading resulting from risks of bias, small sample sizes, and the fact that evidence is largely generated from intermediate surrogate outcomes rather than primary clinical endpoints. While there are data from which we can derive a sense of lack of interactions in some cases, the small size of the trials made it difficult to impossible to ascertain the potential for true clinical interaction.
Much of the pharmacokinetic research was conducted on healthy young adults; thus this evidence may not be applicable to populations with CVD and particularly for older patients taking CV drugs, due to possible differences in metabolism and the existence of comorbidities. The internal validity of most trials was compromised by flawed design, lack of appropriate allocation concealment and risk of bias. A formal assessment of statistical interaction was rarely undertaken. In the absence of corroborating pharmacokinetic evidence or assessment for statistical interaction, it is often impossible to determine whether a difference in outcome is due to true pharmacological interaction, or due to more independent additive, or possibly counteracting therapeutic effects.
A principal limitation of the included trials was that they were small and susceptible to type II errors. A marginally reassuring corollary is that if there was a real, dramatic clinical impact due to an interaction then some clinical effect would likely have been evident despite being underpowered for smaller effect sizes. Of more concern are possible interactions that could arise through polypharmacy of prescription drugs, a situation all too common, in particular for the elderly population.
With these caveats in mind, the following is a summary of the clearer signals from the evidence reviewed.
Omega-3 fatty acids (2 to 4 g/day) from fish and/or supplements likely do not interfere with the efficacy of statin therapy or calcium channel blockers in the presence of antiplatelet agents, and may provide an independent benefit in resolving hypertriglyceridemia. Also, garlic (4 to 10g/day) may not interact negatively with nitrates and warfarin and may confer independent benefit in improving HDL-C.
Interpretation of this report requires the reader to recognize that dietary supplements in the US are not regulated in the same manner as prescription drugs nor are manufacturers of dietary supplements held to the same standards with respect to providing evidence of efficacy and safety prior to marketing. Dietary supplements do not require FDA approval, nor are there any FDA regulations that require evidence of purity, quality or composition prior to marketing. This has resulted in a lack of standardization among products both from a single manufacturer and between manufacturers . The lack of manufacturing regulation and labeling standards may result in significant differences between products, unbeknownst to the consumer, thereby limiting the external validity of clinical trials. Furthermore, there is little reliable published information regarding the safety of dietary supplements. Until only recently, manufacturers of dietary supplements were not obliged to report serious adverse events. This is quite different from what is required of prescription drugs.
Recent systematic reviews related to the topic of dietary supplement-drug interactions do not address the same scope, are not comprehensive, do not grade the outcomes extracted, do not evaluate the quality of evidence, or involve different populations of interest. A 2005 systematic review by Mills et al. focused on effects of natural health products on the metabolism of a broad range of conventional medicines . Consistent with our review, they identified a lack of evidence supporting interactions between coenzyme Q10 and warfarin, Ginkgo biloba and warfarin, and Ginkgo biloba and digoxin. Both reviews also identified a shift in AUC of the international normalized ratio when American ginseng was taken in conjunction with warfarin; however, we question the clinical significance of this finding.
Also in 2005, Desai et al. reviewed interactions between dietary supplements and antiplatelet agents reported in clinical trials and case reports . With respect to the supplements considered in our review, Desai concluded that omega-3 fatty acids along with aspirin led to significantly greater reductions in adenosine diphosphate-induced platelet aggregation, blood platelet count, thromboxane B2 and restenosis rates, as well as prolonged bleeding time. Vitamin E along with aspirin led to significantly greater reductions in platelet adhesion, ischemic stroke, recurrent episodes of transient ischemic attack, 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-supplement interactions, but the majority of evidence was generated from case reports and small case series [107, 108]. The most recent systematic review on dietary supplement-drug interactions, published in 2010 by Kennedy and Seely, examined herb-drug interactions identified from trials wherein the herbal impact on hepatic metabolism via cytochrome P450 isoenzymes was ascertained . Their target population was not specifically patients with CVD or CV drugs, and the review evaluated indirect evidence limited to herbs metabolized via the cytochrome P450 system. While some of the findings within these reviews are consistent with ours, our graded evaluation did not yield similar confidence in conclusions after evaluating 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 relevant synthesis by restricting the number of dietary supplements to the sixteen that were considered. This subset of supplements was based on published North American usage surveys and a consensus selection process that included a Technical Experts Panel [6, 21–26]. Thus, we omitted drugs and supplements, and related data from other international sources. The review also did not consider combinations of multiple dietary supplements with CV drugs to make causal inference possible. This limitation has negative implications for external validity because people with CVD likely self-prescribe combinations of numerous dietary supplements, taken alongside their CV drugs.
The greatest strengths of the present review are its broad search strategy and consideration of extensive literature, and a methodology that focused on the highest quality of evidence. We followed published guidance to pool data from studies, grade the strength of evidence, and assess applicability. Based upon preliminary searches we did not exclude German language literature, a language where most negative studies are published . In order to minimize over-generalization of evidence, we also included only studies with more than 80% of participants taking each CV medication under consideration.
While a plethora of strong recommendations was the hope, we revealed instead a glaring knowledge gap regarding interactions between some of the agents most commonly used for their presumed pharmacological effects for serious chronic disease.