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The onslaught of nutraceuticals
What to do with patients' slew of supplements
by Bonnie Darves



Published in the April 2012 issue of Today's Hospitalist

DAHLIA RIZK, DO, recalls one of her more perplexing recent cases: a 58-year-old man admitted with severe hypercalcemia. The patient was lethargic and confused, with abdominal pain and polyuria—and a calcium level of 15 mg/dL. Even after an extensive workup, the cause of the hypercalcemia eluded the team.

"I looked for the usual causes and then went looking for cancers, but nothing was turning up," recalls Dr. Rizk, medical director of the hospitalist program at Manhattan's Beth Israel Medical Center. "Finally, I walked in and asked him again: 'Are you sure you're
"It's important for patients not to feel judged."

–Dahlia Rizk, DO
Beth Israel Medical Center

not taking anything else that you haven't mentioned?' "

That's when the patient casually pulled a small bottle from his bedside table and said, "I didn't tell you about this one—the vitamin D—because it's from a well-known clinic in England, and it's all natural."

Curious, Dr. Rizk sent the bottle to a specialized lab for analysis. She learned that both the formulations of the pills and the labeling were way off. The pills, listed as containing 40 ug (1600 IU) of vitamin D per pill, actually contained 4600 ug— each. And the label misprinted the recommended dose as 10 pills a day, instead of the one pill that should have been recommended.

"Basically, the patient was taking something on the order of 1,000 times the intended dose," Dr. Rizk recalls. "I called the clinic in England, and the physician who'd prescribed the supplement was also sick with vitamin D toxicity."

While the patient eventually recovered following aggressive hydration and treatment with furosemide and calcitonin, his case isn't an isolated incident. In Seattle, Cara Oliver, MD, a nephrologist who works as a hospitalist at Swedish Medical Center, now sees a lot of vitamin D toxicity, with patients routinely taking 25,000 units of the supplement a day.

"They think they need it just because they live in Seattle," Dr. Oliver points out. Even patients with only mildly high calcium levels—like 11 mg/dL—can present with nausea and altered mental status. "Most of the time, we can turn them around with IV fluids and furosemide," she says, "but I have had to dialyze some patients."

Tip of the iceberg
Both Dr. Rizk's and Dr. Oliver's experience with a single supplement points to a far larger issue: ensuring that supplements and herbals make it on to patients' medications list at admission and, if necessary, come under scrutiny during treatment and at discharge.

While estimates vary as to how many Americans take supplements, clearly a sizeable number of patients have been sold on nutraceuticals, an umbrella term for herbs, dietary supplements, vitamins and other non-prescription substances. Those range from gingko biloba to improve memory to acai berry or bitter orange for weight loss, valerian for insomnia, kava for anxiety, and fish oil, berry extracts, and garlic concentrations for a host of health issues.

While the literature on supplements' safety and effectiveness remains scarce, an observational analysis of Iowa Women's Health Study data published in the Oct. 10, 2011, Archives of Internal Medicine found an association between supplement use and increased mortality.

Study authors recommended that supplements be reserved to treat nutritional deficiencies rather than encouraged for "general and widespread use." And recent headlines have featured reports of patients in their 20s experiencing non-STEMIs linked to their use of workout supplements.

Medication interactions
It's also increasingly clear that many nutraceuticals may be downright dangerous when mixed with prescription medications. Garlic, ginger, gingko and glucosamine, for example, may increase bleeding risk when combined with anticoagulation agents. Conversely, black tea, goldenseal, psyllium and St. John's wort may decrease the effectiveness of anticoagulation therapies and antiplatelets. Even something as seemingly benign as fish oil may, in high doses, increase the effect of antihypertensives.

"If you're having trouble with patients on anticoagulation or having trouble with bleeding, you might want to further investigate whether they're taking any herbal products," advises Michelle Ruha, MD, a medical toxicologist with Banner Health in Phoenix. "Many herbals either inhibit or induce P450 enzymes in the liver, which can ultimately change the blood levels of the drugs."

Ron Hines, PhD, a professor of pediatrics and pharmacology/toxicology at the Medical College of Wisconsin in Milwaukee, who has spent 30 years researching drug metabolism, also points out that nearly half of the "clinically relevant drugs" that hospitalists prescribe are metabolized by the P450 3A4 enzymes.

Those include antivirals, benzodiazepines, statins, macrolide antibiotics, antihistamines, antiarrhythmics, calcium channel blockers, immune modulators and prokinetics. Dr. Hines also cites aripiprazole, buspirone, haloperidol, methadone, sildenafil and several cancer drugs. That's a lot of potential interactions with nutraceuticals that utilize the same pathway.

"It's important for hospitalists to at least be aware of the interactions between herbals and nutraceuticals and prescription drugs," says Dr. Hines, who also is co-chief of clinical pharmacology, pharmacogenetics and teratology, "and make patients aware of the possibilities."

If you ask, they might tell
But there's the rub. Patients may not disclose what they're taking, and hospitalists might not know about the potential effects of supplements on the medications they either start or continue when patients are admitted.

"We're not keyed in enough as physicians because patients aren't thinking that they need to report this to us," Dr. Rizk says. "They don't know that many of these products are based in plants that can have serious consequences or side effects."

Confounding the problem, less than 1% of adverse effects from these products are included in any adverse event-reporting database. "That in and of itself is a big issue," Dr. Rizk says.

Hospitalist John Gardella, MD, vice president of clinical improvement for Novant Health in Charlotte, N.C., agrees. As part of a quality improvement program launched a few years ago, Novant began stationing pharmacy technicians in the ED to gather information from patients on all the medications and supplements they take.

Previously, Dr. Gardella says, ED nurses had been trying to get that information. But pharmacy techs can take more time than nurses—and they are specifically asking patients, "Is there anything else you take for your health that doesn't require a prescription?"

Those lists, Dr. Gardella reports, "are about as good as it gets." When a supplement shows up on a med-rec list, he often has to look it up on UpToDate to find out if there's a potential drug interaction, hepatoxicity or nephrotoxicity. "Or sometimes I'll call the pharmacist," he says.

That's exactly the tack to take, urges Barbara Zarowitz, PharmD, a former hospital pharmacist who is chief clinical officer for Omnicare Inc. in Livonia, Mich., which provides pharmaceutical care for seniors in nursing facilities. Dr. Zarowitz frequently writes about interactions between prescription medicines and herbals or supplements.

"If you suspect that a nutraceutical could be affecting a patient's response to a drug you've prescribed, the answer is probably 'yes,' " she says. "If you are concerned about something your patient is taking, walk down the hall and ask your pharmacist. It's important that we don't bury our heads in the sand."

Doctor-patient perceptions
But patients may be reluctant to talk about supplement use, particularly "if they perceive that you're not receptive to having the conversation," says Jack Killen, MD, deputy director of the NIH's National Center for Complementary and Alternative Medicine in Bethesda, Md., which funds research on dietary supplements and natural products.

Sometimes, Dr. Killen points out, "physicians don't ask because they may not know" about the supplements that patients may cite. But "gather the information like you would any other piece of medical history." It helps to include questions on supplements on any medical history form and to ask patients or family members to bring all therapies, including herbals and supplements, with them to the hospital.

According to Dr. Rizk, hospitalists at Beth Israel have changed how they lead into this discussion. "Now we say, 'It's OK for you to report to me everything that you're taking, including herbals and non-prescription supplements,' " she says. "It's important for patients not to feel judged, and that's been very helpful."

She also avoids the term "alternative medicine." "That already includes a preconceived judgment," she notes. "If I ask about 'alternative regimens,' patients perceive that as, 'My doctors won't be happy, I'll be embarrassed to tell them,' and then we won't know—and that's dangerous." Asking nonjudgmental questions, she adds, "is a competency that doctors have to learn."

Dr. Gardella at Novant Health says that it's important to explain to patients why you're asking for the information. "You need to tell them that it's necessary to manage their care in the hospital," he says. To get a more complete picture of what patients are taking, he recommends asking more open-ended questions—such as "do you take something specific for headache or heartburn?"—to tease out what patients might not think to mention.

Supplements in the hospital?
For Eric Rice, MD, assistant director of hospitalist services for the five-hospital Alegent Health System in Omaha, Neb., it's one thing to obtain the information, but another to know what, if anything, to do with it. He cites the recent case of an 80-year-old woman who reported taking cranberry, blueberry extract, cherry juice concentrate, coenzyme Q-10 and garlic capsules, as well as lisinopril, Lipitor, aspirin and hydrochlorothiazide.

"I remember thinking 'Wow,'" says Dr. Rice, who is also hospitalist site leader at Lakeside Hospital. "In our population, everybody and their mother are on cranberry supplements, and we see a lot of patients on garlic preparations. "Both cranberry and garlic may increase bleeding risk when combined with warfarin.

As for patients continuing to take nutraceuticals in the hospital, Dr. Rice points out, "We don't stock supplements and discourage their inpatient use."

That's the same policy used by Tomas Villanueva, DO, MBA, medical director of hospital medicine at Baptist Hospital of Miami, which is part of Baptist Health of South Florida.

"We've taken the position that unless patients can come up with a viable, evidence-based reason why they're taking a homeopathic remedy, we don't fill those here at the hospital," Dr. Villanueva says. "We explain that we're not picking on nutraceuticals; we just don't have most of them on our formulary."

He and his colleagues also make the point that, if a particular supplement has not been well-studied, hospitalists "won't know its effects on the medications we are giving them here at the hospital."

Occasionally, he admits, patients get upset. "When that happens, if you are open and honestly say, 'I'm not sure if I could be hurting you by continuing the supplement,' nine times out of 10 they'll show some patience."

What to do at discharge
Then there's the issue of how to reconcile patients' use of supplements at discharge. Bradley Rosen, MD, medical director of the nonteaching hospitalist service at Cedars-Sinai in Los Angeles, admits that reconciling nutraceuticals can be sketchy.

To date, Dr. Rosen notes, Cedars hasn't adopted a policy on the issue. "It's pretty much hit or miss whether we put those medications on the list at discharge," he says.

"The reality is that they just tend to fly under the radar." In Seattle, however, Dr. Oliver says, "I do like to discuss everything that patients are going to be discharged on." She'll run down the list of patients' supplements as well as their prescription drugs, asking them for their impression of why they're taking each of them. "If it's potentially dangerous or if it produces a serum level that can be checked, I'll urge patients to make sure it's followed up. I also advise discussing any long-term use of supplements with their primary care physician."

And at Alegent Health, Dr. Rice says the hospitalists don't have any specific policy on reconciling supplements when patients leave the hospital, but they're concerned about it. "If I put patients back on supplements at discharge, am I endorsing them?" he says. "Some colleagues are concerned about the potential liability."

According to Dr. Rice, "I absolutely encourage patients with coronary artery disease and hypertension to steer clear of mah huang." He also tells patients that taking feverfew can modify the way the liver deals with drugs like warfarin.

But while he makes patients aware of possible interactions, "I don't want patients to feel like I'm scolding them or implying that they're stupid for taking them." Patients taking herbals, he notes, "are demonstrating an active engagement in their own care, so I try to make the conversation more inclusive than dictatorial."

By openly acknowledging the effects of nutraceuticals and incorporating them into his care recommendations, "that serves as an affirmation to the patient," he notes. "Once that rapport is established, having a conversation about how we may need to consider stopping supplements is much easier. From the patient's perspective, it's the same as if we were discussing stopping a traditional antihypertensive that wasn't working or was causing an undesired side effect."

That approach proved effective with his 80-year old patient taking the long list of supplements. "I thought it was OK to continue the cranberry extract, garlic and coenzyme Q-10," he says, "but she also complained about the cost of her regular medications." He suggested stopping the cherry juice and blueberry extract, and redirecting that $40 toward her prescriptions.

"She was happy that I validated some of her nutraceuticals and solved a financial issue, without appearing judgmental," Dr. Rice says.

Bonnie Darves is a freelance health care writer based in Seattle.

Nutraceutical resources
  • Natural Medicines Comprehensive Database
  • UpToDate
  • The NIH's National Center for Complementary and Alternative Medicine (NCCAM). See "Herbs at a Glance" section and these NIH resources:

  • ClotCare. See section on herbals and anticoagulants interactions.
  • Food and Drug Administration
  • Clinical Pharmacology
  • Micromedex
  • AltMedDex
  • Natural Standard
  • United States Pharmacopeia (USP)


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