Warfarin and OTCs: An Unrecognized Risky Combination

Medscape Internal Medicine > Adverse Drug Events: Case Challenge Series

Douglas S. Paauw, MD

January 15, 2015

Warfarin and Acetaminophen

The interaction between warfarin and acetaminophen has been a well-kept secret for 30 years. Roughly every 10 years, there's another study that shows this important interaction between acetaminophen and warfarin. Each study may lead to a brief flurry of attention in the popular press that then fades away.

To begin 30 years ago, the first study published in 1984 was a double-blind crossover trial of 15 healthy volunteers who were first anticoagulated on warfarin and then treated with acetaminophen 4 g/day—the maximum recommended dose noted on bottles sold OTC—or placebo. After 2 weeks, an INR was obtained. Patients were then crossed over, and those initially given acetaminophen were now given placebo and vice versa. After an additional 2 weeks, INR measurement was repeated. On average, the INR was 1.75 times higher—almost double—when patients were taking 4 g of acetaminophen daily.

The second study was published 14 years later, in JAMA in 1998.^[2] It was conducted at an anticoagulant therapy unit, in patients who had a target INR of 2.0 to 3.0. An INR was obtained 4 weeks after initiation of warfarin therapy. There were 93 patients with an INR of more than 6.0 (range, 6.1 to 30). Control patients were chosen whose INR was close to the target range (actual values were between 1.7 and 3.3).

Cases and controls were similar in age (mean, 70 years), sex (50% women), race (97% white), duration of warfarin therapy, and reason for anticoagulation. All participants were interviewed and asked about medicines, including any newly prescribed or OTC medications, alcohol consumption, and prescribed and consumed warfarin doses. They were also queried about dietary habits, including recent changes and specifically about intake of foods with high vitamin K content.

Although a range of factors were identified that contributed to an increase in INR, acetaminophen ingestion was independently associated in a dose-dependent manner with having an INR greater than 6.0 (P for trend < .001). Patients taking more than 9 g of acetaminophen per week (eighteen 500-mg tablets) had an odds ratio 0 of 10 (95% confidence interval, 2.6-37.9) for an INR greater than 6.0. Even one half of that dose—nine 500-mg tablets per week—gave an odds ratio of 7.

Another 9 years, and a third study.^[3] A total of 36 patients with stable INRs who were seen at an anticoagulation clinic were randomly assigned to receive acetaminophen 1 g twice daily, acetaminophen 1 g four times daily, or placebo four times daily (12 patients per group) for 4 weeks. The study was terminated early after it was determined that 15 patients experienced an elevation in INR. Just over one half (54%) of the patients receiving acetaminophen exceeded their INR therapeutic range by 0.3 or greater, vs 17% of those taking placebo.

Finally, a study published in 2011 examined 45 patients on stable warfarin therapy.^[4] Patients in this prospective, randomized, parallel (three arms), placebo-controlled study received either 2 or 3 g of acetaminophen daily for 10 days or placebo. The mean maximal increases in INR were 0.70 ± 0.49 and 0.67 ± 0.62 in patients receiving acetaminophen at 2 g/day and 3 g/day, respectively (P = .01). The INR increase became significant on day 3.

So this is real. The take-home message is that the INR should be obtained after 3-5 days in patients taking daily acetaminophen for pain relief. This is not necessary in patients taking an occasional 1-g dose for a headache or another intermittent concern.

Although the bleeding risks of nonsteroidal anti-inflammatory medications and aspirin are well appreciated, leading to a common recommendation for use of acetaminophen as an alternative, acetaminophen must also be recognized as having some degree of risk. In patients using acetaminophen for chronic pain relief, this is an important interaction that should lead to a change in monitoring strategies.

References

1. Rubin RN, Mentzer RL, Budzynski AZ. Potentiation of anticoagulant effect of warfarin by acetaminophen [abstract]. Clin Res. 1984;32:698A.
2. Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA. 1998;279:657-662. Abstract
3. Parra D, Beckey NP, Stevens GR. The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy. Pharmacotherapy. 2007;27:675-683. Abstract
4. Zhang Q, Bal-dit-Sollier C, Drouet L, et al. Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial. Eur J Clin Pharmacol. 2011;67:309-314. Abstract

Common Sense Ebola Measures Save Lives in Africa, Teach US

Medscape Medical News from:

• CHEST 2014: American College of Chest Physicians Meeting
• Jim Kling
• October 28 2014
• 
  

There are things healthcare workers are doing in Africa that professionals here in the United States are not when dealing with Ebola, and that is encouraging infection, warned a physician speaking here at CHEST 2014.

Lewis Rubinson, MD, from the University of Maryland School of Medicine in Baltimore, described the setup at an Ebola treatment center in Kenema, Sierra Leone, where he worked.

Conditions at the center were chaotic and unpredictable, Dr Rubinson explained. The situation required healthcare workers to be consistent and vigilant in their approach because patients who seemed to be faring well could suddenly vomit.

Thirty healthcare workers at the site have already contracted the Ebola virus, and nearly 20 have died. Yet there are healthcare workers who have performed in these conditions and remained uninfected.

Dr Rubinson talked about professionals, including a nurse at Kenema, who remained virus-free after 6 weeks of treating patients. "They have the skills to teach you," he said.

There has been much discussion about using observers to ensure the proper donning and doffing of personal protective suits. In Africa, things have been taken a step further. "We had people who commanded you," said Dr Rubinson.

"You're tired and at risk of making mistakes, so even if you've done the process day in and day out, you're not allowed to do anything without someone ordering you where to stand, how to put your arms out," he said. "They're not passive observers," Dr Rubinson emphasized. "Someone actively takes over safety for you."

With Military Precision

This is a critical measure, Dr Rubinson said, but "that message has been lost in the United States."

"I could never predict when someone was about to vomit on me," he reflected. "You need to do procedures the same way every single time. Everything needs to be choreographed."

This discipline can be very difficult to maintain. "You can get very distracted. If you see a young kid dying, you might want to risk your safety to help, but the rest of the patients will be harmed" if you fall ill and can't contribute to their care, he pointed out.

In a separate presentation, Michael Connor Jr., MD, from Emory University School of Medicine in Atlanta, who treated Ebola patients at his hospital, suggested that the traditional ethics of the doctor–patient relationship is challenged by Ebola. This can take a terrible toll on healthcare workers.

"I will step out on a limb ethically and say it might be that healthcare worker safety supersedes patient outcome because, ultimately, we have to care for other patients, and if we can't, that's a problem," he said.

Another critical issue in the United States is identifying which patients in an emergency department setting are at high risk for Ebola. It is important to be vigilant looking for infections, but there is a risk for overexuberance. For example, a patient arriving from a country like Sierra Leone presenting with stroke symptoms could get flagged for concern about Ebola, even if that patient had no contact with anyone who was ill.

In the United States, "the hospital community, together with the public health community, has to figure out how to manage people so we don't have inadvertent injuries due to withheld treatment because we were isolating someone for Ebola," said Dr Rubinson.

Improvements to diagnostic guidelines would help, he said. The public health system is designed to rule in patients who have a specific illness like Ebola, rather than rule out patients who don't and who need to be treated for something else.

"The more important thing for American hospitals is to identify the person we don't think has Ebola and get confirmation that they don't have it," said Dr Rubinson, "so we can go back to giving them usual care."

The Quandary of Quarantines

Quarantines that have been implemented in New York and New Jersey could create more problems than they solve, said Josh Mugele, MD, from Indiana University School of Medicine in Indianapolis. "I worry that it's going to affect people's willingness to travel to Africa and take care of those patients," he told Medscape Medical News.

A quarantine could also drain resources. Any effort to quarantine doctors and nurses takes them temporarily out of circulation. "They cannot do their critical care jobs, they cannot do their emergency department jobs; it could put stress on the system," said Dr Mugele.

Influenza season could complicate efforts to identify and rule out Ebola cases because symptoms can overlap. "The fortunate thing about Ebola is that upper respiratory symptoms are not the predominant feature," said Dr Rubinson. More worrisome would be if this year's influenza epidemic has a strong gastrointestinal component. In that case, "it'll be really hard to differentiate" Ebola from influenza, he said.

It would be helpful if Ebola screening guidelines included duration of symptoms. Ebola is an acute disease with short-duration symptoms. Diarrhea or vomiting that has been happening for weeks is very unlikely to be Ebola, Dr Rubinson explained.

"The CDC guidelines get the conversation started, but they aren't constructed in a way that reflects how clinicians manage patients," he said. "We're using epidemiologic criteria to make clinical decisions. We need to modify these criteria to reflect how clinicians think, to make them useful to move someone up or down the scale in terms of the likelihood of having Ebola."

Dr Connor and Dr Rubinson have disclosed no relevant financial relationships. Dr Mugele is a consultant to the Indiana State Department of Health.

CHEST 2014: the American College of Chest Physicians Meeting: Presented October 27, 2010.

Tiotropium Showing Promise in Pediatric Asthma

Medscape Medical News from:

• CHEST 2014: American College of Chest Physicians Meeting

JIM KLING
October 31st 2014

AUSTIN — In children with poorly controlled asthma, once-daily tiotropium delivered with the Respimat inhaler improves lung function when added to inhaled corticosteroids, with no apparent change in adverse effects, new research has shown.

The drug and device combination is approved for the treatment of chronic obstructive pulmonary disease (COPD), and the manufacturer, Boehringer Ingelheim, is exploring US Food and Drug Administration approval for asthma.

Anticholinergic medications have long been used to treat acute asthma attacks, but recent evidence suggests that they could be useful as maintenance therapy in refractory patients.

"That got Boehringer Ingelheim interested in looking at the asthma part of this, not just COPD," said Mark Vandewalker, MD, principal investigator for clinical research at The Ozarks in Columbia, Missouri. He presented the research here at CHEST 2014.

In adults with asthma, the combination is an effective add-on to inhaled corticosteroids (N Engl J Med. 2012;367:1198-1207), so this study looked specifically at a pediatric population.

The 48-week phase 3 trial involved adolescents who had asthma for at least 3 months, a forced expiratory volume in 1 second (FEV₁) predicted of 60% to 90%, and a score of at least 1.5 on the Asthma Control Questionnaire 6-point scale.

The age range was 12 to 17 years, 65% of the cohort was male, mean asthma duration was 7.86 years, and mean baseline FEV₁% predicted was 82.8.

Participants had not smoked in the previous year or had never smoked. They were randomized to receive once-daily tiotropium, either 5 μg or 2.5 μg, or placebo, all delivered with the Respimat inhaler. The drug was given as an add-on to inhaled corticosteroids, in doses of budesonide 200 to 400 µg or equivalent for 12- to 14-years-olds and 400 to 800 µg for 14- to 17-years-olds.

The primary end point was peak FEV₁ in the 3 hours after dosing at week 24. The secondary end point was trough (predose) FEV₁ at week 24, which was measured 10 minutes before receiving that day's dose. FEV₁ peak in the 3 hours after the dosing and trough responses were also measured at week 48.

Table 1. Peak FEV₁ for Tiotropium Compared With Placebo

Variable	Adjusted Mean Difference (mL)	P Value
Tiotropium 5 μg
Week 24 FEV₁ area under the curve	174	.0005
Week 48 FEV₁ 3 hours after dosing	174	.0006
Tiotropium 2.5 μg
Week 24 FEV₁ area under the curve	134	.0085
Week 48 FEV₁ 3 hours after dosing	176	.0007

able 2. Trough FEV₁ for Tiotropium Compared With Placebo

Trough FEV₁	Adjusted Mean Difference (mL)	P Value
Tiotropium 5 μg
Week 24	117	.0320
Week 48	157	.0044
Tiotropium 2.5 μg
Week 24	—	ns
Week 48	137	.0154

The adverse-event profile was similar in all three groups, except there were some differences in drug-related adverse events and headache.

"You might think dry mouth would be a concern, and so far it hasn't been," said Dr Vandewalker. "My thought is that that's due to the Respimat device. We do see dry mouth with the older HandiHaler device."

Table 3. Incidence of Adverse Events

Adverse Events	Tiotropium 5 μg (n = 134), %	Tiotropium 2.5 μg (n = 125), %	Placebo (n = 138), %
One or more	62.7	63.2	59.4
Severe	1.5	1.6	2.2
Drug-related	3.0	0.8	0.7
Headache	6.7	5.6	1.4

For children whose asthma is not under control, the drug could be a useful option. "It looks like it was a beneficial treatment. So far, the teenagers are responding in a manner similar to adults — in fact more robustly — which we kind of expect because they haven't had asthma quite as long, so have less damage to their airways. The safety profile has been as good as, if not better than, that seen in adults," Dr Vandewalker added.

The drug would be a welcome addition to pediatric asthma care, according to Chris Carroll, MD, from the University of Connecticut in Hartford, who attended the poster presentation.

"For children with refractory asthma who are on moderate steroids and not well controlled, it would be really nice to have other options. It's great that they're doing pediatric studies because for a lot of medications, they don't bother," he told Medscape Medical News.

He said he finds the data reassuring. "I don't have any specific concerns about safety for this medication," Dr Carroll said.

This study was funded by Boehringer Ingelheim. Dr Vandewalker has received research report from the company. Dr Carroll disclosed no relevant financial relationships.

CHEST 2014: American College of Chest Physicians Meeting: Abstract 1994584. Presented October 29, 2014.