1
CORRESPONDENCE Letters to the Editor Herbal Products Review What Do We Really Know? In the recent paper by Tachjian et al. (1), the investigators highlight several important points concerning the use of herbal supplements: 1) their use is widespread, especially among certain important subgroups, such as patients taking prescription medica- tions; 2) disclosure of complementary and alternative medicine use by patients to their physicians remains low; and 3) potentially dangerous herb-drug interactions may be missed. I applaud the investigators for undertaking a topic that is important not only for patients with cardiovascular diseases but also for those with cancer and other chronic diseases. However, a variety of shortcomings in their methods and conclusions detract from the overall importance of their message. The conclusion that “herbal remedy use is increasing dramati- cally” (1) is overstated. In fact, the use of complementary and alternative medicine therapies by U.S. adults appears to have leveled off in the years between the 2002 and 2007 National Health Interview Surveys (2,3). Although the use of a few complementary and alternative medicine therapies was noted to have increased in the interim, herbal supplements were not among those named. More important but missing from the investigators’ review, however, is that an estimated 15 million adults in 1997 concurrently took prescription medications with herbal remedies or high-dose vitamin supplements (4). The discussion of herb and drug metabolism is oversimplified and potentially misleading. For example, the investigators imply that cytochrome P450 (CYP) 3A4 is responsible for over 50% of all prescription medication metabolism. Although 50% may be an overstated estimate of the contribution of CYP 3A4 (5), more important is to understand that clinical consequences of CYP 3A4 inhibitors are most likely to be observed for drugs that are solely (or at least mainly) metabolized by CYP 3A4; additionally, inhibitory effects are dependent on the amount of inhibition achieved. So, for example, although the investigators’ Table 2 (1) correctly identifies sertraline and fluoxetine as CYP 3A4 substrates, sertraline is metabolized primarily by CYP 2C9 and fluoxetine by CYP 2D6. Additionally, both drugs are considered weak inhibitors of CYP 3A4. Finally, important studies were missed or left out of the investigators’ systematic review. For example, although hawthorn (Crataegus spp.) is thought to enhance the activity of digitalis, the only study to examine the potential interaction between the 2 agents in humans (6) concluded that there were no differences in standard pharmacokinetic parameters for digoxin with or without concurrent hawthorn administration. Contrary to the investigators’ assertion that no systematic safety assessments of hawthorn exist, a systematic review of the adverse event profile of hawthorn pooled data from 5,577 patients and concluded that adverse events were uncommon and most often mild; there were no reports of drug interactions or deaths (7). The only evidence of a hawthorn– digitalis interaction is based on a few studies in rat and guinea pig myocytes; there are no case reports (8). The perpetuation of a hawthorn– digitalis interaction is a result of the investigators’ citing reviews rather than primary publications. *Gary N. Asher, MD, MPH *Department of Family Medicine University of North Carolina 590 Manning Drive, Aycock Building, CB#7595 Chapel Hill, North Carolina 27599-7595 E-mail: [email protected] doi:10.1016/j.jacc.2010.03.076 REFERENCES 1. Tachjian A, Maria V, Jahangir A. Use of herbal products and potential interactions in patients with cardiovascular diseases. J Am Coll Cardiol 2010;55:515–25. 2. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report 2008:1–23. 3. Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementary and alternative medicine use among adults: United States, 2002. Adv Data 2004:1–19. 4. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990 –1997: results of a follow-up national survey. JAMA 1998;280:1569 –75. 5. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994;270:414 –23. 6. Tankanow R, Tamer HR, Streetman DS, et al. Interaction study between digoxin and a preparation of hawthorn (Crataegus oxyacantha). J Clin Pharmacol 2003;43:637– 42. 7. Daniele C, Mazzanti G, Pittler MH, Ernst E. Adverse-event profile of Crataegus spp.: a systematic review. Drug Saf 2006;29:523–35. 8. Stargrove M, Treasure J, McKee D. Herb, Nutrient, and Drug Interactions. St. Louis, MO: Mosby, 2008. Importance of Providing Cardiologists With Useful Advice on Herb-Drug Interactions The American Herbal Products Association agrees with the importance Tachjian et al. (1) placed on doctor-patient commu- nication and education. Since 2001, the American Herbal Prod- ucts Association has recommended that consumers tell their doctors which herbs they are taking and that doctors become sufficiently informed to provide useful advice for their patients who use herbs (2). It is therefore unfortunate that the Tachjian et al. (1) report was not more accurate and failed to discern between actual safety risks, theoretical ones, and false reports. Journal of the American College of Cardiology Vol. 56, No. 11, 2010 © 2010 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc.

Herbal Products Review: What Do We Really Know?

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Page 1: Herbal Products Review: What Do We Really Know?

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Journal of the American College of Cardiology Vol. 56, No. 11, 2010© 2010 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc.

CORRESPONDENCE

Letters to the Editor

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erbal Products Reviewhat Do We Really Know?

n the recent paper by Tachjian et al. (1), the investigatorsighlight several important points concerning the use of herbalupplements: 1) their use is widespread, especially among certainmportant subgroups, such as patients taking prescription medica-ions; 2) disclosure of complementary and alternative medicine usey patients to their physicians remains low; and 3) potentiallyangerous herb-drug interactions may be missed. I applaud thenvestigators for undertaking a topic that is important not only foratients with cardiovascular diseases but also for those with cancernd other chronic diseases. However, a variety of shortcomings inheir methods and conclusions detract from the overall importancef their message.

The conclusion that “herbal remedy use is increasing dramati-ally” (1) is overstated. In fact, the use of complementary andlternative medicine therapies by U.S. adults appears to haveeveled off in the years between the 2002 and 2007 National

ealth Interview Surveys (2,3). Although the use of a fewomplementary and alternative medicine therapies was noted toave increased in the interim, herbal supplements were not amonghose named. More important but missing from the investigators’eview, however, is that an estimated 15 million adults in 1997oncurrently took prescription medications with herbal remediesr high-dose vitamin supplements (4).

The discussion of herb and drug metabolism is oversimplifiednd potentially misleading. For example, the investigators implyhat cytochrome P450 (CYP) 3A4 is responsible for over 50% of allrescription medication metabolism. Although 50% may be anverstated estimate of the contribution of CYP 3A4 (5), moremportant is to understand that clinical consequences of CYP 3A4nhibitors are most likely to be observed for drugs that are solely (or ateast mainly) metabolized by CYP 3A4; additionally, inhibitory effectsre dependent on the amount of inhibition achieved. So, for example,lthough the investigators’ Table 2 (1) correctly identifies sertralinend fluoxetine as CYP 3A4 substrates, sertraline is metabolizedrimarily by CYP 2C9 and fluoxetine by CYP 2D6. Additionally,oth drugs are considered weak inhibitors of CYP 3A4.

Finally, important studies were missed or left out of thenvestigators’ systematic review. For example, although hawthornCrataegus spp.) is thought to enhance the activity of digitalis, thenly study to examine the potential interaction between the 2gents in humans (6) concluded that there were no differences intandard pharmacokinetic parameters for digoxin with or withoutoncurrent hawthorn administration. Contrary to the investigators’ssertion that no systematic safety assessments of hawthorn exist,systematic review of the adverse event profile of hawthorn pooledata from 5,577 patients and concluded that adverse events werencommon and most often mild; there were no reports of drugnteractions or deaths (7). The only evidence of a hawthorn–

igitalis interaction is based on a few studies in rat and guinea pig s

yocytes; there are no case reports (8). The perpetuation of aawthorn–digitalis interaction is a result of the investigators’ citingeviews rather than primary publications.

Gary N. Asher, MD, MPH

Department of Family Medicineniversity of North Carolina90 Manning Drive, Aycock Building, CB#7595hapel Hill, North Carolina 27599-7595-mail: [email protected]

doi:10.1016/j.jacc.2010.03.076

EFERENCES

. Tachjian A, Maria V, Jahangir A. Use of herbal products and potentialinteractions in patients with cardiovascular diseases. J Am Coll Cardiol2010;55:515–25.

. Barnes PM, Bloom B, Nahin RL. Complementary and alternativemedicine use among adults and children: United States, 2007. NatlHealth Stat Report 2008:1–23.

. Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementaryand alternative medicine use among adults: United States, 2002. AdvData 2004:1–19.

. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternativemedicine use in the United States, 1990–1997: results of a follow-upnational survey. JAMA 1998;280:1569–75.

. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP.Interindividual variations in human liver cytochrome P-450 enzymesinvolved in the oxidation of drugs, carcinogens and toxic chemicals:studies with liver microsomes of 30 Japanese and 30 Caucasians.J Pharmacol Exp Ther 1994;270:414–23.

. Tankanow R, Tamer HR, Streetman DS, et al. Interaction studybetween digoxin and a preparation of hawthorn (Crataegus oxyacantha).J Clin Pharmacol 2003;43:637–42.

. Daniele C, Mazzanti G, Pittler MH, Ernst E. Adverse-event profile ofCrataegus spp.: a systematic review. Drug Saf 2006;29:523–35.

. Stargrove M, Treasure J, McKee D. Herb, Nutrient, and DrugInteractions. St. Louis, MO: Mosby, 2008.

mportance of Providingardiologists With Usefuldvice on Herb-Drug Interactions

he American Herbal Products Association agrees with themportance Tachjian et al. (1) placed on doctor-patient commu-ication and education. Since 2001, the American Herbal Prod-cts Association has recommended that consumers tell theiroctors which herbs they are taking and that doctors becomeufficiently informed to provide useful advice for their patients whose herbs (2). It is therefore unfortunate that the Tachjian et al. (1)eport was not more accurate and failed to discern between actual

afety risks, theoretical ones, and false reports.