Steven Dentali, PhD03.01.05
A man in his 70s recovering from a chest infection has a poor appetite, doesn't eat and drinks only cranberry juice for weeks. He does this while taking his heart medication-an anticonvulsant drug-and his anti-clotting medicine-coumadin. Tests show that his ability to form blood clots is greatly diminished and, after admission to the hospital, he dies from internal bleeding. Did his consumption of cranberry juice affect his ability to metabolize coumadin? Can cranberry juice affect blood clotting in people that are eating well and not on drugs? What about fish oil and extracts of ginkgo, garlic or ginseng? How do they affect the estimated four million patients in the U.S. on antithrombotic therapy? Should they stop taking supplements? Should the supplement bottles or the drugs be labeled, and if so, which ones? And what should the warnings or cautions say?
These were the types of questions the National Institutes of Health (NIH) hoped to get a handle on during its conference on dietary supplements, coagulation and antithrombotic therapies held in Bethesda, MD, in mid-January. This event brought together experts in hemostasis (blood clotting) and anticoagulant therapies to consider the effects dietary supplement use may have on patients undergoing long-term anticoagulant therapies. While the effects of vitamin K (found in green leafy vegetables) on warfarin/coumadin therapy are well known (it reverses the anti-clotting effect of the drug), the effects of other foods and dietary supplements on platelet function (also important for blood clotting) and anticoagulation therapies are less well known.
Supplement/drug interaction issues are heating up, with a handful of case reports indicating that something significant might be occurring. With the approval of a newer generation of anticoagulant drugs held up, drugs that are much safer than coumadin may not be just around the corner. Currently, people on anticoagulant medication are advised to either not eat sources of vitamin K or, in what may be a more enlightened but difficult to manage approach, are advised to not introduce changes in their dietary habits. What we need to learn and communicate is what people taking supplements, and the doctors that give them anti-coagulant medication, should know.
This conference was sponsored by the National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the Office of Dietary Supplements (ODS), the NIH Clinical Center (CC), the National Center for Complementary and Alternative Medicine (NCCAM), the National Institute of Neurological Disorders and Stroke (NINDS), the NIH Foundation and the Office of Rare Diseases (ORD) at the NIH. The goals were to examine the effects of dietary supplements on hemostasis and antithrombotic therapies, identify knowledge gaps, develop strategies to inform patients and practitioners about dietary supplement use when dealing with antithrombotic therapy and begin developing a framework for clinical guidelines for practitioners, and formulate a research agenda.
A majority of presenters were academics and practitioners, few of which could be described as "supplement friendly." Some obvious DSHEA detractors, such as the AMA and representatives of the American Society of Health-System Pharmacists, were so far off the mark with regard to the scientific focus of the conference, not to mention their (mis)understanding of supplement regulations, that their time was misspent, in my opinion. Regardless of legal or regulatory issues, questions of basic science and clinical relevance for patients taking antithrombotic therapies (an estimated four million patients) remain and require answers.
It was mentioned more than once during the conference that test tube results often did not prove to be clinically relevant when human studies were initiated. A cursory search of the scientific literature shows that foods that may inhibit clotting include onions, garlic, turmeric, horseradish, cloves, ginger, red wine, tomatoes, dark chocolate and extra virgin olive oil. The natural antithrombotic effects from these common foods may possibly offer protection against stroke, though the extent of the effect, if any, remains to be proven. And their interactions with antithrombotic therapies, like those of dietary supplements, are also unknown.
The conference began with presentations discussing the mechanisms of clotting and the inhibition of clotting. Case reports that may indicate interactions between coumarin anticoagulants, such as warfarin, and dietary supplements, such as the one with cranberry juice and others involving ginkgo and ginseng, for example, were described. Like adverse event reporting, case reports "may overestimate the clinical importance of certain interactions and, in general, do not allow for confirmatory assessment of confounding factors that might have led to the clinical response," reported Ann Wittokowsky, PharmD, director, Anticoagulant Services, University of Washington Medical Center.
Another speaker, Peter De Smet, PharmD, PhD, of the Scientific Institute of Dutch Pharmacists, presented the opinion that a few good case reports could provide better evidence than a clinical study that might be too small to show important interactions. I found this to be an interesting point of view in that the anecdotal, in some situations, is elevated above a proper clinical trial if the anecdotal evidence is good and the trial is small. This suggests that the "gold standard" of a randomized, double-blind, placebo-controlled clinical trial may not always shine so brightly. I'm waiting for Mr. De Smet to offer the same opinion when it comes to herbal effectiveness, as well as adverse drug/herb interactions.
Prof. Edzard Ernst, MD, PhD, from the Complementary Medicine Peninsula Medical School of Devon, U.K., gave a talk on the essentials of conducting systematic reviews of the clinical literature on complementary and alternative medicine (CAM) therapies. The goal of this type of review is to obtain reproducible information and to minimize bias. The first step in the procedure, he explained, is to assemble an interdisciplinary team. For example, if you are reviewing clinical trials that involve a botanical study material then you should have an appropriate expert in that herb involved. Research questions then need to be defined, in addition to the protocol of how the study of the clinical trials is to be conducted in what is also known as a meta-review. Publication bias should also be checked for, if possible. The basis of doing a systematic review is to examine one therapy for one indication. Looking at drug/herb interactions is simply a variation of this approach.
One speaker indicated that he refuses patients in his clinical practice that insist on using supplements, while another saw little problem with supplement use. The latter decided to use the same approach that applies when matching anticoagulant drug dose to a patient's diet. The use of outpatient anticoagulant drug therapy must be carefully monitored because too little drug can allow clots to form in the patient's blood and too much can lead to bleeding problems. As long as the patient is consistent in his/her diet and supplement use then anticoagulant drug dose can be adjusted accordingly.
One useful suggestion of where we go from here was to conduct studies with outpatients already receiving warfarin therapy. This patient population, already under a doctor's care, could be closely monitored. Calls for increased basic research were also heard. Concerns were raised about the general safety of dietary supplements, and the suggestion of a product registry was strongly supported by Dr. Mary Palmer, MD, of George Washington University Hospital. Christopher Borgert, PhD, of Applied Pharmacology and Toxicology, Gainesville, FL, explained the criteria required to establish significant interactions in clinical trials-criteria that are seldom met in popular literature reports that warn of supplement interaction dangers.
As a panel member of the session alongside representatives of patient care organizations, I explained the position of the American Herbal Products Association (AHPA) and stated that label recommendations, consumer and physician messages, and clinical guidelines should be developed based on knowledge of clinically significant interactions. I pointed out that AHPA has already developed consumer directed labeling guidance for a few specific botanical ingredients and that we are advocates for the development and implementation of a mandatory adverse event reporting (AER) system. I also made the points that the beneficial antithrombotic effects from natural products are well known and form the basis for the "aspirin a day" therapy, and that AHPA believes it is advisable for patients to inform their prescribing physician or pharmacist that they are using herbs when undergoing drug therapy.
This meeting was an important first step in determining what we know regarding the effects of dietary supplements on coagulation and antithrombotic therapies, and how we should proceed in the future. It is hoped that the conference will ultimately stimulate basic and clinical research directed toward obtaining useful information that may be passed along to consumers and their healthcare providers. The conference agenda can be viewed via http://www.nhlbi.nih.gov/meetings/coagulation/index.htm. A bibliography of 754 citations from January 1965 through December 2004 that was handed out will be updated and available soon on the Office of Dietary Supplements website, http://ods.od.nih.gov/.
The NIH is planning on writing up the conference for its website, in addition to submitting a report for publication in a peer-reviewed journal.NW
About the author: Steven Dentali is vice president of scientific and technical affairs for the American Herbal Products Association (AHPA), Silver Spring, MD. He can be reached at 301-588-1171; E-mail: sdentali@ahpa.org.
These were the types of questions the National Institutes of Health (NIH) hoped to get a handle on during its conference on dietary supplements, coagulation and antithrombotic therapies held in Bethesda, MD, in mid-January. This event brought together experts in hemostasis (blood clotting) and anticoagulant therapies to consider the effects dietary supplement use may have on patients undergoing long-term anticoagulant therapies. While the effects of vitamin K (found in green leafy vegetables) on warfarin/coumadin therapy are well known (it reverses the anti-clotting effect of the drug), the effects of other foods and dietary supplements on platelet function (also important for blood clotting) and anticoagulation therapies are less well known.
Supplement/drug interaction issues are heating up, with a handful of case reports indicating that something significant might be occurring. With the approval of a newer generation of anticoagulant drugs held up, drugs that are much safer than coumadin may not be just around the corner. Currently, people on anticoagulant medication are advised to either not eat sources of vitamin K or, in what may be a more enlightened but difficult to manage approach, are advised to not introduce changes in their dietary habits. What we need to learn and communicate is what people taking supplements, and the doctors that give them anti-coagulant medication, should know.
This conference was sponsored by the National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the Office of Dietary Supplements (ODS), the NIH Clinical Center (CC), the National Center for Complementary and Alternative Medicine (NCCAM), the National Institute of Neurological Disorders and Stroke (NINDS), the NIH Foundation and the Office of Rare Diseases (ORD) at the NIH. The goals were to examine the effects of dietary supplements on hemostasis and antithrombotic therapies, identify knowledge gaps, develop strategies to inform patients and practitioners about dietary supplement use when dealing with antithrombotic therapy and begin developing a framework for clinical guidelines for practitioners, and formulate a research agenda.
Assessing the Conference Environment
A majority of presenters were academics and practitioners, few of which could be described as "supplement friendly." Some obvious DSHEA detractors, such as the AMA and representatives of the American Society of Health-System Pharmacists, were so far off the mark with regard to the scientific focus of the conference, not to mention their (mis)understanding of supplement regulations, that their time was misspent, in my opinion. Regardless of legal or regulatory issues, questions of basic science and clinical relevance for patients taking antithrombotic therapies (an estimated four million patients) remain and require answers.
It was mentioned more than once during the conference that test tube results often did not prove to be clinically relevant when human studies were initiated. A cursory search of the scientific literature shows that foods that may inhibit clotting include onions, garlic, turmeric, horseradish, cloves, ginger, red wine, tomatoes, dark chocolate and extra virgin olive oil. The natural antithrombotic effects from these common foods may possibly offer protection against stroke, though the extent of the effect, if any, remains to be proven. And their interactions with antithrombotic therapies, like those of dietary supplements, are also unknown.
The conference began with presentations discussing the mechanisms of clotting and the inhibition of clotting. Case reports that may indicate interactions between coumarin anticoagulants, such as warfarin, and dietary supplements, such as the one with cranberry juice and others involving ginkgo and ginseng, for example, were described. Like adverse event reporting, case reports "may overestimate the clinical importance of certain interactions and, in general, do not allow for confirmatory assessment of confounding factors that might have led to the clinical response," reported Ann Wittokowsky, PharmD, director, Anticoagulant Services, University of Washington Medical Center.
Another speaker, Peter De Smet, PharmD, PhD, of the Scientific Institute of Dutch Pharmacists, presented the opinion that a few good case reports could provide better evidence than a clinical study that might be too small to show important interactions. I found this to be an interesting point of view in that the anecdotal, in some situations, is elevated above a proper clinical trial if the anecdotal evidence is good and the trial is small. This suggests that the "gold standard" of a randomized, double-blind, placebo-controlled clinical trial may not always shine so brightly. I'm waiting for Mr. De Smet to offer the same opinion when it comes to herbal effectiveness, as well as adverse drug/herb interactions.
Prof. Edzard Ernst, MD, PhD, from the Complementary Medicine Peninsula Medical School of Devon, U.K., gave a talk on the essentials of conducting systematic reviews of the clinical literature on complementary and alternative medicine (CAM) therapies. The goal of this type of review is to obtain reproducible information and to minimize bias. The first step in the procedure, he explained, is to assemble an interdisciplinary team. For example, if you are reviewing clinical trials that involve a botanical study material then you should have an appropriate expert in that herb involved. Research questions then need to be defined, in addition to the protocol of how the study of the clinical trials is to be conducted in what is also known as a meta-review. Publication bias should also be checked for, if possible. The basis of doing a systematic review is to examine one therapy for one indication. Looking at drug/herb interactions is simply a variation of this approach.
One speaker indicated that he refuses patients in his clinical practice that insist on using supplements, while another saw little problem with supplement use. The latter decided to use the same approach that applies when matching anticoagulant drug dose to a patient's diet. The use of outpatient anticoagulant drug therapy must be carefully monitored because too little drug can allow clots to form in the patient's blood and too much can lead to bleeding problems. As long as the patient is consistent in his/her diet and supplement use then anticoagulant drug dose can be adjusted accordingly.
What's on the Horizon?
One useful suggestion of where we go from here was to conduct studies with outpatients already receiving warfarin therapy. This patient population, already under a doctor's care, could be closely monitored. Calls for increased basic research were also heard. Concerns were raised about the general safety of dietary supplements, and the suggestion of a product registry was strongly supported by Dr. Mary Palmer, MD, of George Washington University Hospital. Christopher Borgert, PhD, of Applied Pharmacology and Toxicology, Gainesville, FL, explained the criteria required to establish significant interactions in clinical trials-criteria that are seldom met in popular literature reports that warn of supplement interaction dangers.
As a panel member of the session alongside representatives of patient care organizations, I explained the position of the American Herbal Products Association (AHPA) and stated that label recommendations, consumer and physician messages, and clinical guidelines should be developed based on knowledge of clinically significant interactions. I pointed out that AHPA has already developed consumer directed labeling guidance for a few specific botanical ingredients and that we are advocates for the development and implementation of a mandatory adverse event reporting (AER) system. I also made the points that the beneficial antithrombotic effects from natural products are well known and form the basis for the "aspirin a day" therapy, and that AHPA believes it is advisable for patients to inform their prescribing physician or pharmacist that they are using herbs when undergoing drug therapy.
This meeting was an important first step in determining what we know regarding the effects of dietary supplements on coagulation and antithrombotic therapies, and how we should proceed in the future. It is hoped that the conference will ultimately stimulate basic and clinical research directed toward obtaining useful information that may be passed along to consumers and their healthcare providers. The conference agenda can be viewed via http://www.nhlbi.nih.gov/meetings/coagulation/index.htm. A bibliography of 754 citations from January 1965 through December 2004 that was handed out will be updated and available soon on the Office of Dietary Supplements website, http://ods.od.nih.gov/.
The NIH is planning on writing up the conference for its website, in addition to submitting a report for publication in a peer-reviewed journal.NW
About the author: Steven Dentali is vice president of scientific and technical affairs for the American Herbal Products Association (AHPA), Silver Spring, MD. He can be reached at 301-588-1171; E-mail: sdentali@ahpa.org.
