THE CASE

An 80-year-old man sought medical advice over the phone because he’d had sharp anal pain for 4 days. The pain increased during sitting and defecation. He was told he most likely had an acute anal fissure and was instructed to treat it with sitz baths, a stool-bulking agent, and a topical anesthetic. Despite these treatments, he continued to have intense anal pain.

Two days later, he presented to our practice complaining of severe anal discomfort and perianal swelling that made it almost impossible to sit. The patient led an active lifestyle and was otherwise healthy. He did not recall any injury to the perianal area.

THE DIAGNOSIS

During examination, we noted tender, erythematous swelling over the right perianal region at the 9 o’clock position without fluctuance, discharge, or ulceration. A digital rectal examination revealed a foreign body lying transversely across the anus about 2.5 cm from the anal verge. A pelvic x-ray confirmed the presence of a foreign body—a pin (FIGURE 1).

DISCUSSION

Anal pain is a common symptom that is usually caused by hemorrhoids, fissures, fistulas, or abscesses.¹ Anal pain is rarely reported to be secondary to the ingestion of sharp foreign bodies, which can produce problems in the lower gastrointestinal tract.

Foreign body ingestion is most common in children ages 6 months to 6 years.² When it occurs in adults, it tends to involve those who are older, patients without teeth, prisoners, patients under the influence of drugs or alcohol, or those with intellectual disabilities or psychiatric disorders.^2,3

The foreign bodies that adults most commonly unintentionally ingest are bones from fish or other animals.^2,4 Most of these pass through the alimentary tract uneventfully within a week.^2,5,6 Swallowed bones have been known to cause perianal abscesses and anal fistulae, which can cause extreme pain.⁷

The presence of foreign bodies is not always easy to spot

In our patient’s case, the diagnosis was made by a careful digital rectal examination; however, a foreign body in an abscess cavity can be missed during a digital exam.⁸ In our patient’s case, a pelvic x-ray confirmed the presence and location of the pin.

Radiography is recommended as an initial screening method and is especially useful for determining the location of radiodense foreign bodies.² However, most swallowed foreign bodies, such as non-radiodense fish bones, wood, thorns, plastic, small aluminum objects, and glass, cannot be detected by this method.³ Non-radiodense foreign bodies can be identified using computed tomography scanning.⁹

Removal is typically straightforward

The best method of removing a foreign body in the perianal region is by dilating the anus and then cutting the object in half. Alternatively, the object can be carefully dislodged from the anal canal by freeing one of the impacted ends. Care must be taken while removing the object to avoid accidental injury.

This procedure can be performed in any primary care setting that is adequately equipped for minor surgical services. Consider referral to a secondary care specialist based on the level of risk involved and the physician’s skills and training.

Our patient. After a complete assessment, we prepared the patient for gentle anal dilatation under intravenous conscious sedation. We carefully transected the 3.5 cm pin using a nail splitter (FIGURE 2). Because there was no abscess cavity, no other procedure was needed. We prescribed oral amoxicillin/clavulanic acid 500/125 mg every 8 hours for 7 days to treat a local infection.

After the procedure, we asked the patient about the pin. He said he had no idea how he could have ingested it and didn’t recall any abdominal pain during the previous month. Follow-up was normal, and he recovered without any complications.

THE TAKEAWAY

Consider the possibility of ingested sharp foreign bodies as a cause of severe anal pain, and perform a local and digital rectal examination. Radiography is recommended as an initial screening method. Following anal dilatation, the object can be removed by cutting it in half or by freeing one of the impacted ends.

THE CASE

An 80-year-old man sought medical advice over the phone because he’d had sharp anal pain for 4 days. The pain increased during sitting and defecation. He was told he most likely had an acute anal fissure and was instructed to treat it with sitz baths, a stool-bulking agent, and a topical anesthetic. Despite these treatments, he continued to have intense anal pain.

Two days later, he presented to our practice complaining of severe anal discomfort and perianal swelling that made it almost impossible to sit. The patient led an active lifestyle and was otherwise healthy. He did not recall any injury to the perianal area.

THE DIAGNOSIS

During examination, we noted tender, erythematous swelling over the right perianal region at the 9 o’clock position without fluctuance, discharge, or ulceration. A digital rectal examination revealed a foreign body lying transversely across the anus about 2.5 cm from the anal verge. A pelvic x-ray confirmed the presence of a foreign body—a pin (FIGURE 1).

DISCUSSION

Anal pain is a common symptom that is usually caused by hemorrhoids, fissures, fistulas, or abscesses.¹ Anal pain is rarely reported to be secondary to the ingestion of sharp foreign bodies, which can produce problems in the lower gastrointestinal tract.

Foreign body ingestion is most common in children ages 6 months to 6 years.² When it occurs in adults, it tends to involve those who are older, patients without teeth, prisoners, patients under the influence of drugs or alcohol, or those with intellectual disabilities or psychiatric disorders.^2,3

The foreign bodies that adults most commonly unintentionally ingest are bones from fish or other animals.^2,4 Most of these pass through the alimentary tract uneventfully within a week.^2,5,6 Swallowed bones have been known to cause perianal abscesses and anal fistulae, which can cause extreme pain.⁷

The presence of foreign bodies is not always easy to spot

In our patient’s case, the diagnosis was made by a careful digital rectal examination; however, a foreign body in an abscess cavity can be missed during a digital exam.⁸ In our patient’s case, a pelvic x-ray confirmed the presence and location of the pin.

Radiography is recommended as an initial screening method and is especially useful for determining the location of radiodense foreign bodies.² However, most swallowed foreign bodies, such as non-radiodense fish bones, wood, thorns, plastic, small aluminum objects, and glass, cannot be detected by this method.³ Non-radiodense foreign bodies can be identified using computed tomography scanning.⁹

Removal is typically straightforward

The best method of removing a foreign body in the perianal region is by dilating the anus and then cutting the object in half. Alternatively, the object can be carefully dislodged from the anal canal by freeing one of the impacted ends. Care must be taken while removing the object to avoid accidental injury.

This procedure can be performed in any primary care setting that is adequately equipped for minor surgical services. Consider referral to a secondary care specialist based on the level of risk involved and the physician’s skills and training.

Our patient. After a complete assessment, we prepared the patient for gentle anal dilatation under intravenous conscious sedation. We carefully transected the 3.5 cm pin using a nail splitter (FIGURE 2). Because there was no abscess cavity, no other procedure was needed. We prescribed oral amoxicillin/clavulanic acid 500/125 mg every 8 hours for 7 days to treat a local infection.

After the procedure, we asked the patient about the pin. He said he had no idea how he could have ingested it and didn’t recall any abdominal pain during the previous month. Follow-up was normal, and he recovered without any complications.

THE TAKEAWAY

Consider the possibility of ingested sharp foreign bodies as a cause of severe anal pain, and perform a local and digital rectal examination. Radiography is recommended as an initial screening method. Following anal dilatation, the object can be removed by cutting it in half or by freeing one of the impacted ends.

THE CASE

An 80-year-old man sought medical advice over the phone because he’d had sharp anal pain for 4 days. The pain increased during sitting and defecation. He was told he most likely had an acute anal fissure and was instructed to treat it with sitz baths, a stool-bulking agent, and a topical anesthetic. Despite these treatments, he continued to have intense anal pain.

Two days later, he presented to our practice complaining of severe anal discomfort and perianal swelling that made it almost impossible to sit. The patient led an active lifestyle and was otherwise healthy. He did not recall any injury to the perianal area.

THE DIAGNOSIS

During examination, we noted tender, erythematous swelling over the right perianal region at the 9 o’clock position without fluctuance, discharge, or ulceration. A digital rectal examination revealed a foreign body lying transversely across the anus about 2.5 cm from the anal verge. A pelvic x-ray confirmed the presence of a foreign body—a pin (FIGURE 1).

DISCUSSION

Anal pain is a common symptom that is usually caused by hemorrhoids, fissures, fistulas, or abscesses.¹ Anal pain is rarely reported to be secondary to the ingestion of sharp foreign bodies, which can produce problems in the lower gastrointestinal tract.

Foreign body ingestion is most common in children ages 6 months to 6 years.² When it occurs in adults, it tends to involve those who are older, patients without teeth, prisoners, patients under the influence of drugs or alcohol, or those with intellectual disabilities or psychiatric disorders.^2,3

The foreign bodies that adults most commonly unintentionally ingest are bones from fish or other animals.^2,4 Most of these pass through the alimentary tract uneventfully within a week.^2,5,6 Swallowed bones have been known to cause perianal abscesses and anal fistulae, which can cause extreme pain.⁷

The presence of foreign bodies is not always easy to spot

In our patient’s case, the diagnosis was made by a careful digital rectal examination; however, a foreign body in an abscess cavity can be missed during a digital exam.⁸ In our patient’s case, a pelvic x-ray confirmed the presence and location of the pin.

Radiography is recommended as an initial screening method and is especially useful for determining the location of radiodense foreign bodies.² However, most swallowed foreign bodies, such as non-radiodense fish bones, wood, thorns, plastic, small aluminum objects, and glass, cannot be detected by this method.³ Non-radiodense foreign bodies can be identified using computed tomography scanning.⁹

Removal is typically straightforward

The best method of removing a foreign body in the perianal region is by dilating the anus and then cutting the object in half. Alternatively, the object can be carefully dislodged from the anal canal by freeing one of the impacted ends. Care must be taken while removing the object to avoid accidental injury.

This procedure can be performed in any primary care setting that is adequately equipped for minor surgical services. Consider referral to a secondary care specialist based on the level of risk involved and the physician’s skills and training.

Our patient. After a complete assessment, we prepared the patient for gentle anal dilatation under intravenous conscious sedation. We carefully transected the 3.5 cm pin using a nail splitter (FIGURE 2). Because there was no abscess cavity, no other procedure was needed. We prescribed oral amoxicillin/clavulanic acid 500/125 mg every 8 hours for 7 days to treat a local infection.

After the procedure, we asked the patient about the pin. He said he had no idea how he could have ingested it and didn’t recall any abdominal pain during the previous month. Follow-up was normal, and he recovered without any complications.

THE TAKEAWAY

Consider the possibility of ingested sharp foreign bodies as a cause of severe anal pain, and perform a local and digital rectal examination. Radiography is recommended as an initial screening method. Following anal dilatation, the object can be removed by cutting it in half or by freeing one of the impacted ends.

In its 2014 report, “The Health Consequences of Smoking—50 Years of Progress,”¹ the US Surgeon General concluded that, while significant improvements have been made since the publication of its landmark 1964 report, cigarette smoking remains a major public health problem. It is the leading cause of preventable death, increasing the risks of such common causes of mortality as cardiovascular disease, pulmonary disease, and malignancy. Cigarette smoking is responsible for an estimated 443,000 deaths annually.²

Overall, 42 million US adults and about 3 million middle and high school students smoke, despite the availability of an array of pharmacologic interventions to help them quit.¹ Half of those who continue to smoke will die from a tobacco-related cause. Stopping before the age of 50 years cuts the risk in half, and quitting before age 30 almost completely negates it.³

The number of cigarettes smoked per day and how long a patient is awake before smoking that first cigarette are important factors in determining which medication to select for smoking cessation.

The most recent comprehensive smoking cessation guideline, sponsored by the US Public Health Service, was published in 2008.⁴ The US Preventive Services Task Force (USPSTF) recommendation that “clinicians ask all adults about tobacco use and provide tobacco cessation interventions” for those who smoke was issued one year later.⁵ Since then, multiple studies have assessed the merits of the various medications, forms of nicotine replacement therapy (NRT), and counseling aimed at helping smokers maintain abstinence from tobacco.

This article reviews the guideline and provides family physicians with an evidence-based update.

The guideline: Treating tobacco use and dependence

Prescribing a first-line medication (bupropion SR, varenicline, nicotine gum, nicotine inhaler, nicotine lozenge, nicotine nasal spray, or nicotine patch) for every patient who seeks to quit smoking is a key component of the 2008 guideline (See TABLE W1).⁴ The only exceptions: patients for whom such agents are medically contraindicated and groups for which there is insufficient evidence of effectiveness, such as pregnant women and adolescents.

The use of any of these medications as a single agent nearly doubles the likelihood of success compared with placebo, with an average cessation rate of 25% (TABLE 1).⁴

Combination therapy (pairing a nicotine patch and an additional agent) was found to be even more effective, with some combinations attaining success rates as high as 65%.⁴

Second-line therapies, including clonidine and nortriptyline, were also cited as effective, with an average cessation rate of 24%.⁴ Although the meta-analyses that these averages were based on did not include head-to-head comparisons, subsequent studies that also showed efficacy did include such comparisons.

Counseling is an essential component

In one of the meta-analyses on which the guideline was based, the combination of counseling and medication proved to be more effective than either intervention alone. Individual, group, and telephone counseling were all effective (odds ratio [OR]=1.7 [1.4-2.0], 1.3 [1.1-1.6], and 1.2 [1.1-1.4], respectively), provided they included practical help that emphasized problem solving and skills training, as well as social support. The benefits of a team-based approach were evident from the finding that counseling provided by more than one type of clinician had higher effect sizes (OR=2.5 [1.9-3.4] when 2 different clinical disciplines were involved and 2.4 [2.1-2.9] for 3 or more disciplines).⁴

The guideline also found state-sponsored quit lines, accessible at no charge via 800-QUIT-NOW, are an effective option. (For more information about this and other resources, see TABLE W2.)

For patients who aren’t ready to stop smoking, the guideline recommends motivational interviewing⁴—a direct, patient-centered technique used to explore and work through ambivalence. Further information about this method is available at motivational interviewing.org/.

In counseling patients considering a quit attempt, it is important to present all options. A smoking history is needed, too, because factors such as the number of cigarettes smoked per day, how long a patient is typically awake before smoking the first cigarette of the day, and level of dependence are important factors in determining medication and dosage. Consider the advantages and disadvantages of the various medications (TABLE 2)^4,6,7 or methods used for prior quit attempts and reasons for relapse, if appropriate; and patient preference.

Evidence update: What's best?

Since 2009, many clinical trials have examined the best way to help smokers quit. Here’s a closer look at the latest evidence.

NRT boosts long-term cessation

Quitting smoking by age 50 cuts the risk of a smoking-related death in half, and quitting by age 30 almost completely negates it.

A 2012 Cochrane review examined 150 trials and found that every type of NRT—gum, lozenge, patch, inhaler, and nasal spray—was associated with long-term cessation (relative risk [RR]=1.60; 95% CI, 1.53-1.68).⁸ This effect was essentially unchanged regardless of the duration, setting, or intensity of supportive therapy offered, and no single type of NRT was more effective than any other. However, combining a short-acting form like a lozenge with a long-acting patch was found to be more effective than either one alone (RR=1.34; 95% CI, 1.18-1.51).

Starting the NRT before the patient quit did not improve cessation rates over traditional start times (RR=1.18; 95% CI 0.98-1.41). Neither was there an added benefit to using NRT beyond the recommended 24-week prescription period,⁹ although doing so was found to be safe. Another 2012 Cochrane review looked specifically at the use of pharmacologic smoking cessation interventions during pregnancy and concluded that there was still not sufficient data to document efficacy for this patient population.¹⁰

Adherence. In deciding on which type of NRT to prescribe, it is important to consider not only patient preference and previous efforts, but also the latest evidence. A study comparing various NRT formulations found patient adherence to be highest with the patch, followed by nicotine gum, which had a higher compliance rate than either the nicotine inhaler or nasal spray.¹¹

Varenicline is still a first-line agent

Among the various types of nicotine replacement therapy, the patch has the highest adherence rate.

Since the 2008 guideline recommended this partial nicotinic receptor agonist/antagonist as a first-line pharmacologic agent, additional meta-analyses have confirmed its long-term efficacy in smokers who are ready to quit.^12,13 A 2012 Cochrane review found varenicline to increase long-term cessation compared with placebo (RR=2.27; 95% CI, 2.02-2.55).¹³ It also showed varenicline to be more effective than bupropion SR (RR=1.52; 95% CI, 1.22-1.88), but about as effective as NRT (RR=1.13; 95% CI, 0.94-1.35).

Newer data suggest that varenicline may also be effective for those who are willing to cut down on smoking but not yet ready to give up cigarettes completely. Used for 24 weeks by those who were initially resistant to quitting, researchers found varenicline nearly tripled the cessation rate at 52 weeks compared with placebo (RR=2.7; 95% CI, 2.1-3.5).¹⁴

Latest evidence on safety. Additional concerns about the safety of varenicline have been raised, however, since the 2008 guideline was published. In 2009, the US Food and Drug Administration (FDA) required that black box warnings be added to the labels of both varenicline and bupropion SR based on post-marketing safety reports showing the risk of neuropsychiatric symptoms, including suicidality.¹⁵ In 2011, a large case control study by the FDA Adverse Event Reporting System also showed an increased risk of suicidality in patients taking these drugs.¹⁶

Follow-up studies, however, including a large prospective cohort study and a large meta-analysis, failed to show an increased association with neuropsychiatric adverse effects.^17,18 A smaller randomized controlled trial (RCT) showed that in smokers diagnosed with schizophrenia and bipolar disorder, maintenance therapy with varenicline was effective in preventing smoking relapse for up to 52 weeks. Abstinence rates were 60% for those in the varenicline group vs 19% for those in the placebo group (OR=6.2; 95% CI, 2.2-19.2). Although no increased risk of adverse psychiatric events was found in this study, it was not powered to detect them.¹⁹ Also of note: a meta-analysis of 14 RCTs showed an increased rate of cardiovascular events associated with varenicline.²⁰ There are concerns about methodologic flaws in this meta-analysis, however, and 2 subsequent meta-analyses failed to find a cardiovascular risk.^21,22

The higher quality studies that have been published since the original concerns about varenicline's safety are reassuring, but it is still essential to carefully weigh the risks and benefits of varenicline. Review cardiac and psychiatric history and conduct a suicidality assessment before prescribing it as a smoking cessation aid, and provide close follow-up.

A closer look at antidepressants

Bupropion SR, an atypical antidepressant, was also listed as a first-line treatment in the 2008 guideline. A 2014 Cochrane review of 90 studies confirmed the evidence for this recommendation.⁶ Monotherapy with this agent was found to significantly increase rates of long-term cessation (RR=1.62; 95% CI, 1.49-1.76). No increased risk of serious adverse events was identified compared with placebo. As already noted, associations with neuropsychiatric symptoms were found, but this risk must be considered with any antidepressant.

Bupropion’s efficacy was not significantly different from that of NRT, but moderate evidence suggests that it is less effective than varenicline, (RR=0.68; 95% CI, 0.56-0.83). Other classes of antidepressants, including selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors, were found to be ineffective for smoking cessation.⁶

Nortriptyline, a tricyclic antidepressant, was not significantly different from bupropion SR (RR, 1.30; 95% CI, 0.93-1.82) in efficacy for smoking cessation, but it lacks FDA approval for this purpose and is not considered a first-line agent.⁶

Second-line agents

Clonidine is an alpha-2 adrenergic receptor agonist that was originally used to treat hypertension but found to be effective for smoking cessation in a meta-analysis performed for the 2008 guideline.⁴ Like nortriptyline, however, clonidine is not FDA-approved for this purpose and is not considered a first-line agent.⁵ A 2013 Cochrane meta-analysis further showed that clonidine is effective for smoking cessation vs placebo (RR=1.63; 95% CI, 1.22-2.18),⁷ but suggested that its significant dose-related adverse effects, including postural hypotension and sedation, could limit its usefulness.

Combination therapies are highly effective

Evidence for various combinations of smoking cessation pharmacotherapy continues to mount.^23-26 Perhaps the most compelling evidence comes from a comparative effectiveness trial that randomized 1346 patients in 12 primary care clinics to nicotine patches, nicotine lozenges, bupropion SR, a combination of patch plus lozenge, and bupropion SR plus lozenge. The 6-month abstinence rate was 30% for the bupropion SR plus lozenge combination, the most effective option. The combination was superior to either patch or bupropion SR monotherapy (OR, 0.56 and 0.54, respectively).²³ Based on data from the 2008 guideline, similar combinations (eg, nicotine patch plus nicotine gum or bupropion SR plus the patch) are likely to be equally effective. The 2008 guideline also supports a nicotine patch and nicotine inhaler combination.

Another study found varenicline combined with the patch to be highly effective, with a 65% abstinence rate at 24 weeks vs 47% for varenicline alone (number needed to treat [NNT]=6; 95% CI, 4-11).²⁴

In heavy smokers—defined as those who smoke ≥20 cigarettes daily—a varenicline and bupropion SR combination was more effective than varenicline alone (NNT= 9; 95% CI, 4.6-71.6), but the combination can lead to increased anxiety and depression.²⁵ A smaller study found triple therapy using nicotine patch plus inhaler plus bupropion SR to be more effective than the nicotine patch alone (35% abstinence vs 19% abstinence at 26 weeks; NNT=6).²⁶ Consider using these combinations in patients who have high nicotine dependency levels or have been unable to quit using a single first-line agent.

What role do e-cigarettes play?

The use of electronic cigarettes or “vapes”—battery-operated devices that deliver nicotine to the user through vapor—has increased significantly since their US introduction in 2007. A recent study found that “ever use” of e-cigarettes increased from 1.8% in 2010 to 13% in 2013; current use increased from 0.3% to 6.8% in the same time frame.²⁷ “Vaping,” as inhaling on an e-cigarette is sometimes known, causes a sensor to detect airflow and initiate the heating element to vaporize the liquid solution within the cartridge, which contains propylene glycol, flavoring, and nicotine.

Higher quality studies published since initial safety concerns for varenicline were raised are reassuring, but it's still essential to weigh the drug's risks and benefits for each patient.

There is limited evidence of the efficacy of e-cigarettes for smoking cessation, but there is support for their role in reducing the quantity of conventional cigarettes smoked. A 2014 Cochrane review of 2 RCTs evaluating e-cigarette efficacy for smoking cessation or reduction found evidence of increased abstinence at 6 months in users of e-cigarettes containing nicotine compared with placebo e-cigarettes (9% vs 4%; RR=2.29; 95% CI, 1.05-4.96). Additionally, e-cigarette use was associated with >50% decrease in cigarette smoking vs placebo (36% vs 27%; RR=1.31; 95% CI, 1.02-1.68) or patch (61% vs 44%; RR=1.41; 95% CI, 1.20-1.67).²⁸

A survey published after the review also showed a correlation between cigarette reduction (but not cessation) after one year of e-cigarette use.²⁹ A subsequent RCT conducted in a controlled laboratory setting found that e-cigarettes were highly effective in reducing cessation-related cravings.³⁰ And at 8-month follow-up, 44% of those using e-cigarettes were found to have at least a 50% reduction in the use of conventional cigarettes—and complete cessation in some cases.

Concerns about health effects

E-cigarettes have generally been thought to be safer than conventional cigarettes, given that they mainly deliver nicotine and propylene glycol instead of the more toxic chemicals—eg, benzene, carbon monoxide, and formaldehyde—released by conventional cigarettes.³¹ Carcinogens have also been found in e-cigarettes, but at significantly lower levels.³¹ However, a systematic review found wide variation in the toxin content of e-cigarettes.³² In addition, recent reports have detailed incidents in which e-cigarette devices were alleged to have exploded, causing severe bodily harm.³³

Adverse effects of e-cigarettes include minor irritation of the throat, mouth, and lungs. Among cigarette-naive patients, light-headedness, throat irritation, dizziness, and cough were most commonly reported. No serious adverse events have been reported, but the lack of long-term safety data is a source of concern.³²

Additionally, minimal regulatory oversight of the e-cigarette industry exists. Currently, the FDA only has authority to regulate e-cigarettes that are marketed for therapeutic purposes, although the agency is seeking to extend its oversight to all e-cigarettes.

The bottom line: More data on safety and regulatory oversight are needed before recommendations on the use of e-cigarettes as a smoking cessation tool can be made.

Looking ahead

A systematic review found a wide variation in the toxin content of e-cigarettes.

Several novel pharmacotherapies have been evaluated for smoking cessation in recent years. Among them is a nicotine vaccine that several drug companies have been pursuing. In theory, such a vaccine would create an immunologic reaction to nicotine in a smoker, thereby preventing the substance from reaching the brain and providing rewarding stimuli. A 2008 Cochrane review of 4 trials assessing the efficacy of nicotine vaccines for tobacco cessation found that none showed efficacy.³⁴

Naltrexone, an opioid antagonist, has shown efficacy in helping those with opioid or alcohol dependence achieve abstinence from these substances, raising the possibility that it might aid in smoking cessation, as well. A 2013 Cochrane review of 8 trials found that this was not the case: Compared with placebo, naltrexone was not beneficial when used alone (RR=1.00; 95% CI, 0.66-1.51) or as an adjunct to NRT compared with NRT alone (RR=0.95; 95% CI, 0.70-1.30).³⁵

Cytisine, an extract from plants in the Faboideae family, has been used in Eastern Europe for decades for smoking cessation. It appears to work as a nicotine receptor partial agonist similar to varenicline. The extract does not have FDA approval, but the National Institutes of Health’s Center for Complementary and Integrative Health is sponsoring early-stage safety trials that could lead to its approval in the United States.³⁶

A 2012 Cochrane review identified 2 recent RCTs evaluating cytisine and found it to be effective in increasing smoking cessation rates vs placebo (RR=3.98; 95% CI, 2.01-7.87).¹³

CORRESPONDENCE
Paul Bornemann, MD, 3209 Colonial Drive, Columbia, SC 29203; [email protected].

ACKNOWLEDGEMENT
The authors thank Matt Orr, PhD, and Kathryn E. Bornemann for their help with this manuscript.

In its 2014 report, “The Health Consequences of Smoking—50 Years of Progress,”¹ the US Surgeon General concluded that, while significant improvements have been made since the publication of its landmark 1964 report, cigarette smoking remains a major public health problem. It is the leading cause of preventable death, increasing the risks of such common causes of mortality as cardiovascular disease, pulmonary disease, and malignancy. Cigarette smoking is responsible for an estimated 443,000 deaths annually.²

Overall, 42 million US adults and about 3 million middle and high school students smoke, despite the availability of an array of pharmacologic interventions to help them quit.¹ Half of those who continue to smoke will die from a tobacco-related cause. Stopping before the age of 50 years cuts the risk in half, and quitting before age 30 almost completely negates it.³

The number of cigarettes smoked per day and how long a patient is awake before smoking that first cigarette are important factors in determining which medication to select for smoking cessation.

The most recent comprehensive smoking cessation guideline, sponsored by the US Public Health Service, was published in 2008.⁴ The US Preventive Services Task Force (USPSTF) recommendation that “clinicians ask all adults about tobacco use and provide tobacco cessation interventions” for those who smoke was issued one year later.⁵ Since then, multiple studies have assessed the merits of the various medications, forms of nicotine replacement therapy (NRT), and counseling aimed at helping smokers maintain abstinence from tobacco.

This article reviews the guideline and provides family physicians with an evidence-based update.

The guideline: Treating tobacco use and dependence

Prescribing a first-line medication (bupropion SR, varenicline, nicotine gum, nicotine inhaler, nicotine lozenge, nicotine nasal spray, or nicotine patch) for every patient who seeks to quit smoking is a key component of the 2008 guideline (See TABLE W1).⁴ The only exceptions: patients for whom such agents are medically contraindicated and groups for which there is insufficient evidence of effectiveness, such as pregnant women and adolescents.

The use of any of these medications as a single agent nearly doubles the likelihood of success compared with placebo, with an average cessation rate of 25% (TABLE 1).⁴

Combination therapy (pairing a nicotine patch and an additional agent) was found to be even more effective, with some combinations attaining success rates as high as 65%.⁴

Second-line therapies, including clonidine and nortriptyline, were also cited as effective, with an average cessation rate of 24%.⁴ Although the meta-analyses that these averages were based on did not include head-to-head comparisons, subsequent studies that also showed efficacy did include such comparisons.

Counseling is an essential component

In one of the meta-analyses on which the guideline was based, the combination of counseling and medication proved to be more effective than either intervention alone. Individual, group, and telephone counseling were all effective (odds ratio [OR]=1.7 [1.4-2.0], 1.3 [1.1-1.6], and 1.2 [1.1-1.4], respectively), provided they included practical help that emphasized problem solving and skills training, as well as social support. The benefits of a team-based approach were evident from the finding that counseling provided by more than one type of clinician had higher effect sizes (OR=2.5 [1.9-3.4] when 2 different clinical disciplines were involved and 2.4 [2.1-2.9] for 3 or more disciplines).⁴

The guideline also found state-sponsored quit lines, accessible at no charge via 800-QUIT-NOW, are an effective option. (For more information about this and other resources, see TABLE W2.)

For patients who aren’t ready to stop smoking, the guideline recommends motivational interviewing⁴—a direct, patient-centered technique used to explore and work through ambivalence. Further information about this method is available at motivational interviewing.org/.

In counseling patients considering a quit attempt, it is important to present all options. A smoking history is needed, too, because factors such as the number of cigarettes smoked per day, how long a patient is typically awake before smoking the first cigarette of the day, and level of dependence are important factors in determining medication and dosage. Consider the advantages and disadvantages of the various medications (TABLE 2)^4,6,7 or methods used for prior quit attempts and reasons for relapse, if appropriate; and patient preference.

Evidence update: What's best?

Since 2009, many clinical trials have examined the best way to help smokers quit. Here’s a closer look at the latest evidence.

NRT boosts long-term cessation

Quitting smoking by age 50 cuts the risk of a smoking-related death in half, and quitting by age 30 almost completely negates it.

A 2012 Cochrane review examined 150 trials and found that every type of NRT—gum, lozenge, patch, inhaler, and nasal spray—was associated with long-term cessation (relative risk [RR]=1.60; 95% CI, 1.53-1.68).⁸ This effect was essentially unchanged regardless of the duration, setting, or intensity of supportive therapy offered, and no single type of NRT was more effective than any other. However, combining a short-acting form like a lozenge with a long-acting patch was found to be more effective than either one alone (RR=1.34; 95% CI, 1.18-1.51).

Starting the NRT before the patient quit did not improve cessation rates over traditional start times (RR=1.18; 95% CI 0.98-1.41). Neither was there an added benefit to using NRT beyond the recommended 24-week prescription period,⁹ although doing so was found to be safe. Another 2012 Cochrane review looked specifically at the use of pharmacologic smoking cessation interventions during pregnancy and concluded that there was still not sufficient data to document efficacy for this patient population.¹⁰

Adherence. In deciding on which type of NRT to prescribe, it is important to consider not only patient preference and previous efforts, but also the latest evidence. A study comparing various NRT formulations found patient adherence to be highest with the patch, followed by nicotine gum, which had a higher compliance rate than either the nicotine inhaler or nasal spray.¹¹

Varenicline is still a first-line agent

Among the various types of nicotine replacement therapy, the patch has the highest adherence rate.

Since the 2008 guideline recommended this partial nicotinic receptor agonist/antagonist as a first-line pharmacologic agent, additional meta-analyses have confirmed its long-term efficacy in smokers who are ready to quit.^12,13 A 2012 Cochrane review found varenicline to increase long-term cessation compared with placebo (RR=2.27; 95% CI, 2.02-2.55).¹³ It also showed varenicline to be more effective than bupropion SR (RR=1.52; 95% CI, 1.22-1.88), but about as effective as NRT (RR=1.13; 95% CI, 0.94-1.35).

Newer data suggest that varenicline may also be effective for those who are willing to cut down on smoking but not yet ready to give up cigarettes completely. Used for 24 weeks by those who were initially resistant to quitting, researchers found varenicline nearly tripled the cessation rate at 52 weeks compared with placebo (RR=2.7; 95% CI, 2.1-3.5).¹⁴

Latest evidence on safety. Additional concerns about the safety of varenicline have been raised, however, since the 2008 guideline was published. In 2009, the US Food and Drug Administration (FDA) required that black box warnings be added to the labels of both varenicline and bupropion SR based on post-marketing safety reports showing the risk of neuropsychiatric symptoms, including suicidality.¹⁵ In 2011, a large case control study by the FDA Adverse Event Reporting System also showed an increased risk of suicidality in patients taking these drugs.¹⁶

Follow-up studies, however, including a large prospective cohort study and a large meta-analysis, failed to show an increased association with neuropsychiatric adverse effects.^17,18 A smaller randomized controlled trial (RCT) showed that in smokers diagnosed with schizophrenia and bipolar disorder, maintenance therapy with varenicline was effective in preventing smoking relapse for up to 52 weeks. Abstinence rates were 60% for those in the varenicline group vs 19% for those in the placebo group (OR=6.2; 95% CI, 2.2-19.2). Although no increased risk of adverse psychiatric events was found in this study, it was not powered to detect them.¹⁹ Also of note: a meta-analysis of 14 RCTs showed an increased rate of cardiovascular events associated with varenicline.²⁰ There are concerns about methodologic flaws in this meta-analysis, however, and 2 subsequent meta-analyses failed to find a cardiovascular risk.^21,22

The higher quality studies that have been published since the original concerns about varenicline's safety are reassuring, but it is still essential to carefully weigh the risks and benefits of varenicline. Review cardiac and psychiatric history and conduct a suicidality assessment before prescribing it as a smoking cessation aid, and provide close follow-up.

A closer look at antidepressants

Bupropion SR, an atypical antidepressant, was also listed as a first-line treatment in the 2008 guideline. A 2014 Cochrane review of 90 studies confirmed the evidence for this recommendation.⁶ Monotherapy with this agent was found to significantly increase rates of long-term cessation (RR=1.62; 95% CI, 1.49-1.76). No increased risk of serious adverse events was identified compared with placebo. As already noted, associations with neuropsychiatric symptoms were found, but this risk must be considered with any antidepressant.

Bupropion’s efficacy was not significantly different from that of NRT, but moderate evidence suggests that it is less effective than varenicline, (RR=0.68; 95% CI, 0.56-0.83). Other classes of antidepressants, including selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors, were found to be ineffective for smoking cessation.⁶

Nortriptyline, a tricyclic antidepressant, was not significantly different from bupropion SR (RR, 1.30; 95% CI, 0.93-1.82) in efficacy for smoking cessation, but it lacks FDA approval for this purpose and is not considered a first-line agent.⁶

Second-line agents

Clonidine is an alpha-2 adrenergic receptor agonist that was originally used to treat hypertension but found to be effective for smoking cessation in a meta-analysis performed for the 2008 guideline.⁴ Like nortriptyline, however, clonidine is not FDA-approved for this purpose and is not considered a first-line agent.⁵ A 2013 Cochrane meta-analysis further showed that clonidine is effective for smoking cessation vs placebo (RR=1.63; 95% CI, 1.22-2.18),⁷ but suggested that its significant dose-related adverse effects, including postural hypotension and sedation, could limit its usefulness.

Combination therapies are highly effective

Evidence for various combinations of smoking cessation pharmacotherapy continues to mount.^23-26 Perhaps the most compelling evidence comes from a comparative effectiveness trial that randomized 1346 patients in 12 primary care clinics to nicotine patches, nicotine lozenges, bupropion SR, a combination of patch plus lozenge, and bupropion SR plus lozenge. The 6-month abstinence rate was 30% for the bupropion SR plus lozenge combination, the most effective option. The combination was superior to either patch or bupropion SR monotherapy (OR, 0.56 and 0.54, respectively).²³ Based on data from the 2008 guideline, similar combinations (eg, nicotine patch plus nicotine gum or bupropion SR plus the patch) are likely to be equally effective. The 2008 guideline also supports a nicotine patch and nicotine inhaler combination.

Another study found varenicline combined with the patch to be highly effective, with a 65% abstinence rate at 24 weeks vs 47% for varenicline alone (number needed to treat [NNT]=6; 95% CI, 4-11).²⁴

In heavy smokers—defined as those who smoke ≥20 cigarettes daily—a varenicline and bupropion SR combination was more effective than varenicline alone (NNT= 9; 95% CI, 4.6-71.6), but the combination can lead to increased anxiety and depression.²⁵ A smaller study found triple therapy using nicotine patch plus inhaler plus bupropion SR to be more effective than the nicotine patch alone (35% abstinence vs 19% abstinence at 26 weeks; NNT=6).²⁶ Consider using these combinations in patients who have high nicotine dependency levels or have been unable to quit using a single first-line agent.

What role do e-cigarettes play?

The use of electronic cigarettes or “vapes”—battery-operated devices that deliver nicotine to the user through vapor—has increased significantly since their US introduction in 2007. A recent study found that “ever use” of e-cigarettes increased from 1.8% in 2010 to 13% in 2013; current use increased from 0.3% to 6.8% in the same time frame.²⁷ “Vaping,” as inhaling on an e-cigarette is sometimes known, causes a sensor to detect airflow and initiate the heating element to vaporize the liquid solution within the cartridge, which contains propylene glycol, flavoring, and nicotine.

Higher quality studies published since initial safety concerns for varenicline were raised are reassuring, but it's still essential to weigh the drug's risks and benefits for each patient.

There is limited evidence of the efficacy of e-cigarettes for smoking cessation, but there is support for their role in reducing the quantity of conventional cigarettes smoked. A 2014 Cochrane review of 2 RCTs evaluating e-cigarette efficacy for smoking cessation or reduction found evidence of increased abstinence at 6 months in users of e-cigarettes containing nicotine compared with placebo e-cigarettes (9% vs 4%; RR=2.29; 95% CI, 1.05-4.96). Additionally, e-cigarette use was associated with >50% decrease in cigarette smoking vs placebo (36% vs 27%; RR=1.31; 95% CI, 1.02-1.68) or patch (61% vs 44%; RR=1.41; 95% CI, 1.20-1.67).²⁸

A survey published after the review also showed a correlation between cigarette reduction (but not cessation) after one year of e-cigarette use.²⁹ A subsequent RCT conducted in a controlled laboratory setting found that e-cigarettes were highly effective in reducing cessation-related cravings.³⁰ And at 8-month follow-up, 44% of those using e-cigarettes were found to have at least a 50% reduction in the use of conventional cigarettes—and complete cessation in some cases.

Concerns about health effects

E-cigarettes have generally been thought to be safer than conventional cigarettes, given that they mainly deliver nicotine and propylene glycol instead of the more toxic chemicals—eg, benzene, carbon monoxide, and formaldehyde—released by conventional cigarettes.³¹ Carcinogens have also been found in e-cigarettes, but at significantly lower levels.³¹ However, a systematic review found wide variation in the toxin content of e-cigarettes.³² In addition, recent reports have detailed incidents in which e-cigarette devices were alleged to have exploded, causing severe bodily harm.³³

Adverse effects of e-cigarettes include minor irritation of the throat, mouth, and lungs. Among cigarette-naive patients, light-headedness, throat irritation, dizziness, and cough were most commonly reported. No serious adverse events have been reported, but the lack of long-term safety data is a source of concern.³²

Additionally, minimal regulatory oversight of the e-cigarette industry exists. Currently, the FDA only has authority to regulate e-cigarettes that are marketed for therapeutic purposes, although the agency is seeking to extend its oversight to all e-cigarettes.

The bottom line: More data on safety and regulatory oversight are needed before recommendations on the use of e-cigarettes as a smoking cessation tool can be made.

Looking ahead

A systematic review found a wide variation in the toxin content of e-cigarettes.

Several novel pharmacotherapies have been evaluated for smoking cessation in recent years. Among them is a nicotine vaccine that several drug companies have been pursuing. In theory, such a vaccine would create an immunologic reaction to nicotine in a smoker, thereby preventing the substance from reaching the brain and providing rewarding stimuli. A 2008 Cochrane review of 4 trials assessing the efficacy of nicotine vaccines for tobacco cessation found that none showed efficacy.³⁴

Naltrexone, an opioid antagonist, has shown efficacy in helping those with opioid or alcohol dependence achieve abstinence from these substances, raising the possibility that it might aid in smoking cessation, as well. A 2013 Cochrane review of 8 trials found that this was not the case: Compared with placebo, naltrexone was not beneficial when used alone (RR=1.00; 95% CI, 0.66-1.51) or as an adjunct to NRT compared with NRT alone (RR=0.95; 95% CI, 0.70-1.30).³⁵

Cytisine, an extract from plants in the Faboideae family, has been used in Eastern Europe for decades for smoking cessation. It appears to work as a nicotine receptor partial agonist similar to varenicline. The extract does not have FDA approval, but the National Institutes of Health’s Center for Complementary and Integrative Health is sponsoring early-stage safety trials that could lead to its approval in the United States.³⁶

A 2012 Cochrane review identified 2 recent RCTs evaluating cytisine and found it to be effective in increasing smoking cessation rates vs placebo (RR=3.98; 95% CI, 2.01-7.87).¹³

CORRESPONDENCE
Paul Bornemann, MD, 3209 Colonial Drive, Columbia, SC 29203; [email protected].

ACKNOWLEDGEMENT
The authors thank Matt Orr, PhD, and Kathryn E. Bornemann for their help with this manuscript.

In its 2014 report, “The Health Consequences of Smoking—50 Years of Progress,”¹ the US Surgeon General concluded that, while significant improvements have been made since the publication of its landmark 1964 report, cigarette smoking remains a major public health problem. It is the leading cause of preventable death, increasing the risks of such common causes of mortality as cardiovascular disease, pulmonary disease, and malignancy. Cigarette smoking is responsible for an estimated 443,000 deaths annually.²

Overall, 42 million US adults and about 3 million middle and high school students smoke, despite the availability of an array of pharmacologic interventions to help them quit.¹ Half of those who continue to smoke will die from a tobacco-related cause. Stopping before the age of 50 years cuts the risk in half, and quitting before age 30 almost completely negates it.³

The number of cigarettes smoked per day and how long a patient is awake before smoking that first cigarette are important factors in determining which medication to select for smoking cessation.

The most recent comprehensive smoking cessation guideline, sponsored by the US Public Health Service, was published in 2008.⁴ The US Preventive Services Task Force (USPSTF) recommendation that “clinicians ask all adults about tobacco use and provide tobacco cessation interventions” for those who smoke was issued one year later.⁵ Since then, multiple studies have assessed the merits of the various medications, forms of nicotine replacement therapy (NRT), and counseling aimed at helping smokers maintain abstinence from tobacco.

This article reviews the guideline and provides family physicians with an evidence-based update.

The guideline: Treating tobacco use and dependence

Prescribing a first-line medication (bupropion SR, varenicline, nicotine gum, nicotine inhaler, nicotine lozenge, nicotine nasal spray, or nicotine patch) for every patient who seeks to quit smoking is a key component of the 2008 guideline (See TABLE W1).⁴ The only exceptions: patients for whom such agents are medically contraindicated and groups for which there is insufficient evidence of effectiveness, such as pregnant women and adolescents.

The use of any of these medications as a single agent nearly doubles the likelihood of success compared with placebo, with an average cessation rate of 25% (TABLE 1).⁴

Combination therapy (pairing a nicotine patch and an additional agent) was found to be even more effective, with some combinations attaining success rates as high as 65%.⁴

Second-line therapies, including clonidine and nortriptyline, were also cited as effective, with an average cessation rate of 24%.⁴ Although the meta-analyses that these averages were based on did not include head-to-head comparisons, subsequent studies that also showed efficacy did include such comparisons.

Counseling is an essential component

In one of the meta-analyses on which the guideline was based, the combination of counseling and medication proved to be more effective than either intervention alone. Individual, group, and telephone counseling were all effective (odds ratio [OR]=1.7 [1.4-2.0], 1.3 [1.1-1.6], and 1.2 [1.1-1.4], respectively), provided they included practical help that emphasized problem solving and skills training, as well as social support. The benefits of a team-based approach were evident from the finding that counseling provided by more than one type of clinician had higher effect sizes (OR=2.5 [1.9-3.4] when 2 different clinical disciplines were involved and 2.4 [2.1-2.9] for 3 or more disciplines).⁴

The guideline also found state-sponsored quit lines, accessible at no charge via 800-QUIT-NOW, are an effective option. (For more information about this and other resources, see TABLE W2.)

For patients who aren’t ready to stop smoking, the guideline recommends motivational interviewing⁴—a direct, patient-centered technique used to explore and work through ambivalence. Further information about this method is available at motivational interviewing.org/.

In counseling patients considering a quit attempt, it is important to present all options. A smoking history is needed, too, because factors such as the number of cigarettes smoked per day, how long a patient is typically awake before smoking the first cigarette of the day, and level of dependence are important factors in determining medication and dosage. Consider the advantages and disadvantages of the various medications (TABLE 2)^4,6,7 or methods used for prior quit attempts and reasons for relapse, if appropriate; and patient preference.

Evidence update: What's best?

Since 2009, many clinical trials have examined the best way to help smokers quit. Here’s a closer look at the latest evidence.

NRT boosts long-term cessation

Quitting smoking by age 50 cuts the risk of a smoking-related death in half, and quitting by age 30 almost completely negates it.

A 2012 Cochrane review examined 150 trials and found that every type of NRT—gum, lozenge, patch, inhaler, and nasal spray—was associated with long-term cessation (relative risk [RR]=1.60; 95% CI, 1.53-1.68).⁸ This effect was essentially unchanged regardless of the duration, setting, or intensity of supportive therapy offered, and no single type of NRT was more effective than any other. However, combining a short-acting form like a lozenge with a long-acting patch was found to be more effective than either one alone (RR=1.34; 95% CI, 1.18-1.51).

Starting the NRT before the patient quit did not improve cessation rates over traditional start times (RR=1.18; 95% CI 0.98-1.41). Neither was there an added benefit to using NRT beyond the recommended 24-week prescription period,⁹ although doing so was found to be safe. Another 2012 Cochrane review looked specifically at the use of pharmacologic smoking cessation interventions during pregnancy and concluded that there was still not sufficient data to document efficacy for this patient population.¹⁰

Adherence. In deciding on which type of NRT to prescribe, it is important to consider not only patient preference and previous efforts, but also the latest evidence. A study comparing various NRT formulations found patient adherence to be highest with the patch, followed by nicotine gum, which had a higher compliance rate than either the nicotine inhaler or nasal spray.¹¹

Varenicline is still a first-line agent

Among the various types of nicotine replacement therapy, the patch has the highest adherence rate.

Since the 2008 guideline recommended this partial nicotinic receptor agonist/antagonist as a first-line pharmacologic agent, additional meta-analyses have confirmed its long-term efficacy in smokers who are ready to quit.^12,13 A 2012 Cochrane review found varenicline to increase long-term cessation compared with placebo (RR=2.27; 95% CI, 2.02-2.55).¹³ It also showed varenicline to be more effective than bupropion SR (RR=1.52; 95% CI, 1.22-1.88), but about as effective as NRT (RR=1.13; 95% CI, 0.94-1.35).

Newer data suggest that varenicline may also be effective for those who are willing to cut down on smoking but not yet ready to give up cigarettes completely. Used for 24 weeks by those who were initially resistant to quitting, researchers found varenicline nearly tripled the cessation rate at 52 weeks compared with placebo (RR=2.7; 95% CI, 2.1-3.5).¹⁴

Latest evidence on safety. Additional concerns about the safety of varenicline have been raised, however, since the 2008 guideline was published. In 2009, the US Food and Drug Administration (FDA) required that black box warnings be added to the labels of both varenicline and bupropion SR based on post-marketing safety reports showing the risk of neuropsychiatric symptoms, including suicidality.¹⁵ In 2011, a large case control study by the FDA Adverse Event Reporting System also showed an increased risk of suicidality in patients taking these drugs.¹⁶

Follow-up studies, however, including a large prospective cohort study and a large meta-analysis, failed to show an increased association with neuropsychiatric adverse effects.^17,18 A smaller randomized controlled trial (RCT) showed that in smokers diagnosed with schizophrenia and bipolar disorder, maintenance therapy with varenicline was effective in preventing smoking relapse for up to 52 weeks. Abstinence rates were 60% for those in the varenicline group vs 19% for those in the placebo group (OR=6.2; 95% CI, 2.2-19.2). Although no increased risk of adverse psychiatric events was found in this study, it was not powered to detect them.¹⁹ Also of note: a meta-analysis of 14 RCTs showed an increased rate of cardiovascular events associated with varenicline.²⁰ There are concerns about methodologic flaws in this meta-analysis, however, and 2 subsequent meta-analyses failed to find a cardiovascular risk.^21,22

The higher quality studies that have been published since the original concerns about varenicline's safety are reassuring, but it is still essential to carefully weigh the risks and benefits of varenicline. Review cardiac and psychiatric history and conduct a suicidality assessment before prescribing it as a smoking cessation aid, and provide close follow-up.

A closer look at antidepressants

Bupropion SR, an atypical antidepressant, was also listed as a first-line treatment in the 2008 guideline. A 2014 Cochrane review of 90 studies confirmed the evidence for this recommendation.⁶ Monotherapy with this agent was found to significantly increase rates of long-term cessation (RR=1.62; 95% CI, 1.49-1.76). No increased risk of serious adverse events was identified compared with placebo. As already noted, associations with neuropsychiatric symptoms were found, but this risk must be considered with any antidepressant.

Bupropion’s efficacy was not significantly different from that of NRT, but moderate evidence suggests that it is less effective than varenicline, (RR=0.68; 95% CI, 0.56-0.83). Other classes of antidepressants, including selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors, were found to be ineffective for smoking cessation.⁶

Nortriptyline, a tricyclic antidepressant, was not significantly different from bupropion SR (RR, 1.30; 95% CI, 0.93-1.82) in efficacy for smoking cessation, but it lacks FDA approval for this purpose and is not considered a first-line agent.⁶

Second-line agents

Clonidine is an alpha-2 adrenergic receptor agonist that was originally used to treat hypertension but found to be effective for smoking cessation in a meta-analysis performed for the 2008 guideline.⁴ Like nortriptyline, however, clonidine is not FDA-approved for this purpose and is not considered a first-line agent.⁵ A 2013 Cochrane meta-analysis further showed that clonidine is effective for smoking cessation vs placebo (RR=1.63; 95% CI, 1.22-2.18),⁷ but suggested that its significant dose-related adverse effects, including postural hypotension and sedation, could limit its usefulness.

Combination therapies are highly effective

Evidence for various combinations of smoking cessation pharmacotherapy continues to mount.^23-26 Perhaps the most compelling evidence comes from a comparative effectiveness trial that randomized 1346 patients in 12 primary care clinics to nicotine patches, nicotine lozenges, bupropion SR, a combination of patch plus lozenge, and bupropion SR plus lozenge. The 6-month abstinence rate was 30% for the bupropion SR plus lozenge combination, the most effective option. The combination was superior to either patch or bupropion SR monotherapy (OR, 0.56 and 0.54, respectively).²³ Based on data from the 2008 guideline, similar combinations (eg, nicotine patch plus nicotine gum or bupropion SR plus the patch) are likely to be equally effective. The 2008 guideline also supports a nicotine patch and nicotine inhaler combination.

Another study found varenicline combined with the patch to be highly effective, with a 65% abstinence rate at 24 weeks vs 47% for varenicline alone (number needed to treat [NNT]=6; 95% CI, 4-11).²⁴

In heavy smokers—defined as those who smoke ≥20 cigarettes daily—a varenicline and bupropion SR combination was more effective than varenicline alone (NNT= 9; 95% CI, 4.6-71.6), but the combination can lead to increased anxiety and depression.²⁵ A smaller study found triple therapy using nicotine patch plus inhaler plus bupropion SR to be more effective than the nicotine patch alone (35% abstinence vs 19% abstinence at 26 weeks; NNT=6).²⁶ Consider using these combinations in patients who have high nicotine dependency levels or have been unable to quit using a single first-line agent.

What role do e-cigarettes play?

The use of electronic cigarettes or “vapes”—battery-operated devices that deliver nicotine to the user through vapor—has increased significantly since their US introduction in 2007. A recent study found that “ever use” of e-cigarettes increased from 1.8% in 2010 to 13% in 2013; current use increased from 0.3% to 6.8% in the same time frame.²⁷ “Vaping,” as inhaling on an e-cigarette is sometimes known, causes a sensor to detect airflow and initiate the heating element to vaporize the liquid solution within the cartridge, which contains propylene glycol, flavoring, and nicotine.

Higher quality studies published since initial safety concerns for varenicline were raised are reassuring, but it's still essential to weigh the drug's risks and benefits for each patient.

There is limited evidence of the efficacy of e-cigarettes for smoking cessation, but there is support for their role in reducing the quantity of conventional cigarettes smoked. A 2014 Cochrane review of 2 RCTs evaluating e-cigarette efficacy for smoking cessation or reduction found evidence of increased abstinence at 6 months in users of e-cigarettes containing nicotine compared with placebo e-cigarettes (9% vs 4%; RR=2.29; 95% CI, 1.05-4.96). Additionally, e-cigarette use was associated with >50% decrease in cigarette smoking vs placebo (36% vs 27%; RR=1.31; 95% CI, 1.02-1.68) or patch (61% vs 44%; RR=1.41; 95% CI, 1.20-1.67).²⁸

A survey published after the review also showed a correlation between cigarette reduction (but not cessation) after one year of e-cigarette use.²⁹ A subsequent RCT conducted in a controlled laboratory setting found that e-cigarettes were highly effective in reducing cessation-related cravings.³⁰ And at 8-month follow-up, 44% of those using e-cigarettes were found to have at least a 50% reduction in the use of conventional cigarettes—and complete cessation in some cases.

Concerns about health effects

E-cigarettes have generally been thought to be safer than conventional cigarettes, given that they mainly deliver nicotine and propylene glycol instead of the more toxic chemicals—eg, benzene, carbon monoxide, and formaldehyde—released by conventional cigarettes.³¹ Carcinogens have also been found in e-cigarettes, but at significantly lower levels.³¹ However, a systematic review found wide variation in the toxin content of e-cigarettes.³² In addition, recent reports have detailed incidents in which e-cigarette devices were alleged to have exploded, causing severe bodily harm.³³

Adverse effects of e-cigarettes include minor irritation of the throat, mouth, and lungs. Among cigarette-naive patients, light-headedness, throat irritation, dizziness, and cough were most commonly reported. No serious adverse events have been reported, but the lack of long-term safety data is a source of concern.³²

Additionally, minimal regulatory oversight of the e-cigarette industry exists. Currently, the FDA only has authority to regulate e-cigarettes that are marketed for therapeutic purposes, although the agency is seeking to extend its oversight to all e-cigarettes.

The bottom line: More data on safety and regulatory oversight are needed before recommendations on the use of e-cigarettes as a smoking cessation tool can be made.

Looking ahead

A systematic review found a wide variation in the toxin content of e-cigarettes.

Several novel pharmacotherapies have been evaluated for smoking cessation in recent years. Among them is a nicotine vaccine that several drug companies have been pursuing. In theory, such a vaccine would create an immunologic reaction to nicotine in a smoker, thereby preventing the substance from reaching the brain and providing rewarding stimuli. A 2008 Cochrane review of 4 trials assessing the efficacy of nicotine vaccines for tobacco cessation found that none showed efficacy.³⁴

Naltrexone, an opioid antagonist, has shown efficacy in helping those with opioid or alcohol dependence achieve abstinence from these substances, raising the possibility that it might aid in smoking cessation, as well. A 2013 Cochrane review of 8 trials found that this was not the case: Compared with placebo, naltrexone was not beneficial when used alone (RR=1.00; 95% CI, 0.66-1.51) or as an adjunct to NRT compared with NRT alone (RR=0.95; 95% CI, 0.70-1.30).³⁵

Cytisine, an extract from plants in the Faboideae family, has been used in Eastern Europe for decades for smoking cessation. It appears to work as a nicotine receptor partial agonist similar to varenicline. The extract does not have FDA approval, but the National Institutes of Health’s Center for Complementary and Integrative Health is sponsoring early-stage safety trials that could lead to its approval in the United States.³⁶

A 2012 Cochrane review identified 2 recent RCTs evaluating cytisine and found it to be effective in increasing smoking cessation rates vs placebo (RR=3.98; 95% CI, 2.01-7.87).¹³

CORRESPONDENCE
Paul Bornemann, MD, 3209 Colonial Drive, Columbia, SC 29203; [email protected].

ACKNOWLEDGEMENT
The authors thank Matt Orr, PhD, and Kathryn E. Bornemann for their help with this manuscript.

An over-the-counter botanical acne regimen outperformed a conventional acne regimen, with improved skin appearance and fewer lesions after 12 weeks of treatment, in a double-blind randomized controlled trial.

Eighty individuals aged 12 years and older with mild to moderate acne were randomized either to a three-step botanical-based acne treatment regimen (Receutics) consisting of a skin cleanser, breakout treatment, and tone and complexion corrector twice daily, or the currently marketed acne treatment kit, Proactiv (Guthy-Renker).

The botanical-based acne treatment contains a range of botanical ingredients, including algae and lentil seed extracts; cranberry seed, grape seed, and pumpkin seed oils; and allantoin; with 3.4% benzoyl peroxide as the active ingredient. The active ingredient in the cleanser is 2% salicylic acid, and niacinamide is the active ingredient in the tone and complexion corrector; both also contain botanical ingredients.

In the study, published in December, the investigator, Dr. Zoe Diana Draelos, reported that the botanical regimen achieved a significantly greater reduction in lesion count, in terms of closed comedones and inflammatory lesions, by week four, compared with the control treatment (J Drugs Dermatol. 2015 Dec; 14 [12]:1418-21).

This effect persisted at 12 weeks, with fewer closed comedones (P = .006). The botanical regimen also achieved greater reductions in pus, erythema, lesion height, and inflammation at weeks 2 and 4; although this difference disappeared by week 12. By week four and onwards, the botanical regimen also outperformed the conventional treatment on all blinded, investigator-assessed cosmetic appearance parameters, including skin tone, blemishes, erythema, and overall appearance.

While both treatments were effective at improving acne, Dr. Draelos, of Dermatology Consulting Services, High Point, N.C., said the botanical three-step regimen had the advantage of cosmetic ingredients such as emollients, anti-inflammatory/antioxidants, and “sensitive skin modulators.”

“This study demonstrates the value of combining monographed acne ingredients with advanced cosmeceutical technology,” she wrote.

The author received a grant from manufacturer Receutics to conduct the study.

An over-the-counter botanical acne regimen outperformed a conventional acne regimen, with improved skin appearance and fewer lesions after 12 weeks of treatment, in a double-blind randomized controlled trial.

Eighty individuals aged 12 years and older with mild to moderate acne were randomized either to a three-step botanical-based acne treatment regimen (Receutics) consisting of a skin cleanser, breakout treatment, and tone and complexion corrector twice daily, or the currently marketed acne treatment kit, Proactiv (Guthy-Renker).

The botanical-based acne treatment contains a range of botanical ingredients, including algae and lentil seed extracts; cranberry seed, grape seed, and pumpkin seed oils; and allantoin; with 3.4% benzoyl peroxide as the active ingredient. The active ingredient in the cleanser is 2% salicylic acid, and niacinamide is the active ingredient in the tone and complexion corrector; both also contain botanical ingredients.

In the study, published in December, the investigator, Dr. Zoe Diana Draelos, reported that the botanical regimen achieved a significantly greater reduction in lesion count, in terms of closed comedones and inflammatory lesions, by week four, compared with the control treatment (J Drugs Dermatol. 2015 Dec; 14 [12]:1418-21).

This effect persisted at 12 weeks, with fewer closed comedones (P = .006). The botanical regimen also achieved greater reductions in pus, erythema, lesion height, and inflammation at weeks 2 and 4; although this difference disappeared by week 12. By week four and onwards, the botanical regimen also outperformed the conventional treatment on all blinded, investigator-assessed cosmetic appearance parameters, including skin tone, blemishes, erythema, and overall appearance.

While both treatments were effective at improving acne, Dr. Draelos, of Dermatology Consulting Services, High Point, N.C., said the botanical three-step regimen had the advantage of cosmetic ingredients such as emollients, anti-inflammatory/antioxidants, and “sensitive skin modulators.”

“This study demonstrates the value of combining monographed acne ingredients with advanced cosmeceutical technology,” she wrote.

The author received a grant from manufacturer Receutics to conduct the study.

An over-the-counter botanical acne regimen outperformed a conventional acne regimen, with improved skin appearance and fewer lesions after 12 weeks of treatment, in a double-blind randomized controlled trial.

Eighty individuals aged 12 years and older with mild to moderate acne were randomized either to a three-step botanical-based acne treatment regimen (Receutics) consisting of a skin cleanser, breakout treatment, and tone and complexion corrector twice daily, or the currently marketed acne treatment kit, Proactiv (Guthy-Renker).

The botanical-based acne treatment contains a range of botanical ingredients, including algae and lentil seed extracts; cranberry seed, grape seed, and pumpkin seed oils; and allantoin; with 3.4% benzoyl peroxide as the active ingredient. The active ingredient in the cleanser is 2% salicylic acid, and niacinamide is the active ingredient in the tone and complexion corrector; both also contain botanical ingredients.

In the study, published in December, the investigator, Dr. Zoe Diana Draelos, reported that the botanical regimen achieved a significantly greater reduction in lesion count, in terms of closed comedones and inflammatory lesions, by week four, compared with the control treatment (J Drugs Dermatol. 2015 Dec; 14 [12]:1418-21).

This effect persisted at 12 weeks, with fewer closed comedones (P = .006). The botanical regimen also achieved greater reductions in pus, erythema, lesion height, and inflammation at weeks 2 and 4; although this difference disappeared by week 12. By week four and onwards, the botanical regimen also outperformed the conventional treatment on all blinded, investigator-assessed cosmetic appearance parameters, including skin tone, blemishes, erythema, and overall appearance.

While both treatments were effective at improving acne, Dr. Draelos, of Dermatology Consulting Services, High Point, N.C., said the botanical three-step regimen had the advantage of cosmetic ingredients such as emollients, anti-inflammatory/antioxidants, and “sensitive skin modulators.”

“This study demonstrates the value of combining monographed acne ingredients with advanced cosmeceutical technology,” she wrote.

The author received a grant from manufacturer Receutics to conduct the study.

PRACTICE CHANGER
Stop using low molecular weight heparin (LMWH) for surgical procedures to “bridge” low- to moderate-risk patients with atrial fibrillation (CHADS₂ score ≤ 4) who are receiving warfarin. The risks outweigh the benefits.¹

STRENGTH OF RECOMMENDATION
B: Based on a single good-quality randomized controlled trial.¹

CASE  A 75-year-old man comes to your office for surgical clearance before right knee replacement surgery. He has diabetes and high blood pressure and is taking warfarin for atrial fibrillation. He is scheduled for surgery in a week. What is the safest way to manage his warfarin in the perioperative period?

More than 2 million people are being treated with oral anticoagulation in North America to prevent stroke or to prevent or treat venous thromboembolism.² Since 2010, several new oral anticoagulants have been approved, including dabigatran, apixaban, and rivaroxaban. These new medications have a shorter half-life than older anticoagulants, which enables them to be stopped one to two days before surgery.

On the other hand, warfarin—which remains a common choice for anticoagulation—has a three- to seven-day onset and elimination.^3,4 This long clinical half-life presents a special challenge during the perioperative period. To reduce the risk for operative bleeding, the warfarin must be stopped days prior to the procedure, but clinicians often worry that this will increase the risk for arterial or venous thromboembolism, including stroke.

An estimated 250,000 patients need perioperative management of their anticoagulation each year.⁵ As the US population continues to age and the incidence of conditions requiring anticoagulation (particularly atrial fibrillation) increases, this number is only going to rise.⁶

Current guidelines on bridging. American College of Chest Physicians (ACCP) guidelines recommend transition to “a short-acting anticoagulant, consisting of subcutaneous low molecular weight heparin (LMWH) or intravenous unfractionated heparin, for a 10- to 12-day period during interruption of vitamin K antagonist (VKA) therapy.”⁵Furthermore, for an appropriate bridging regimen, the ACCP guidelines recommend stopping VKA therapy five days prior to the procedure and utilizing LMWH from within 24 to 48 hours of stopping VKA therapy until up to 24 hours before surgery.⁵ Postoperatively, VKA or LMWH therapy should be reinitiated within 24 hours and 24 to 72 hours, respectively, depending on the patient’s risk for bleeding during surgery.⁵

These guidelines recommend using CHADS₂ scoring (see the table) to determine arterial thromboembolism (ATE) risk in atrial fibrillation.^3,5 Patients at low risk for ATE (CHADS₂ score, 0-2) should not be bridged, and patients at high risk (CHADS₂ score, 5-6) should always be bridged.⁵ These guidelines are less clear about bridging recommendations for patients considered to be at moderate risk (CHADS₂ score, 3-4).

Previous evidence on bridging. A 2012 meta-analysis of 34 studies evaluated the safety and efficacy of perioperative bridging with heparin in patients receiving VKA.⁷Researchers found no difference in ATE events in eight studies that compared groups that received bridging vs groups that simply stopped anticoagulation (odds ratio [OR], 0.80).⁷ The group that received bridging had an increased risk for overall bleeding in 13 studies and of major bleeding in five studies.⁷This meta-analysis was limited by poor study quality and variation in the indication for VKA therapy.

A 2015 subgroup analysis of a larger cohort study of patients receiving anticoagulants for atrial fibrillation found an increased risk for bleeding when their anticoagulation was interrupted for procedures (OR for major bleeding, 3.84).⁸

Douketis et al¹ conducted a randomized trial to clarify the need for and safety of bridging anticoagulation for ATE in patients with atrial fibrillation who were receiving warfarin.

Continue for study summary >>

STUDY SUMMARY
When it comes to stroke/TIA, there’s no advantage to bridging
This double-blind, placebo-controlled trial compared bridging with dalteparin, a form of LMWH, to placebo among 1,884 patients with atrial fibrillation who were taking warfarin and whose anticoagulation therapy needed to be interrupted for an elective procedure. Patients were included if they were receiving warfarin to prevent stroke and had been taking it for at least 12 weeks, with a goal International Normalized Ratio (INR) of 2.0 to 3.0. Exclusion criteria included having a mechanical heart valve or having a stroke/transient ischemic attack (TIA; 12 weeks prior) or major bleeding (six weeks prior). Patients undergoing cardiac, intracranial, and intraspinal surgeries were also excluded from the study.

The mean CHADS₂ score was 2.3; 38.3% of patients had a CHADS₂ score ≥ 3, and 9.4% of patients had a history of stroke. Forty-four percent of patients underwent a gastrointestinal procedure, 17.2% underwent a cardiothoracic procedure, and 9.2% underwent an orthopedic procedure.

Patients stopped taking warfarin five days before their procedure and began subcutaneous dalteparin (100 IU/kg) or an identical placebo three days before the procedure. The dalteparin/placebo was stopped 24 hours before the procedure and restarted after the procedure, until the patient’s INR was in the therapeutic range. Warfarin was resumed on the evening of the procedure or the following day.

The primary efficacy outcome was ATE, including stroke, TIA, or systemic embolism. The primary safety endpoint was major bleeding (defined as bleeding at a critical anatomic site, symptomatic or clinically overt bleeding, or a decrease in hemoglobin > 2 g/dL). Secondary efficacy and safety outcomes included minor bleeding, acute myocardial infarction, deep vein thrombosis, pulmonary embolism, and death. Outcomes were assessed within 37 days of the procedure.

The incidence of ATE was 0.4% (four events) in the no-bridging group vs 0.3% (three events) in the bridging group. Major bleeding occurred in 1.3% of the no-bridging group (12 events) and in 3.2% of the bridging group (29 events), indicating that no bridging was superior in terms of the major bleeding outcome (number needed to harm [NNH], 53; relative risk [RR], 0.41).

The no-bridging group also had significantly fewer minor bleeds in comparison to the bridging group (NNH, 11; 12% vs 20.9%). There were no differences between groups in other secondary outcomes.

Continue for what's new >>

WHAT’S NEW
High-quality evidence suggests it’s OK to stop warfarin before surgery
This is the largest good-quality study to evaluate perioperative bridging in patients with atrial fibrillation who were at low or moderate risk for ATE (CHADS₂ score, 0-4). Previous studies suggested bridging increased bleeding and offered limited benefit for reducing the risk for ATE. However, this is the first study to include a large group of moderate-risk patients (CHADS₂ score, 3-4). This trial provides high-quality evidence to support the practice of simply stopping warfarin in the perioperative period, rather than bridging with LMWH.

CAVEATS
Findings might not apply to patients at highest risk
Most patients in this study had a CHADS₂ score ≤ 3. About 3% had a CHADS₂ score ≥ 5. It’s not clear whether these findings apply to patients with a CHADS₂ score of 5 or 6.

This trial categorized ATE risk using the CHADS₂ score, rather than the CHA₂DS₂-VASc, which includes additional risk factors and may more accurately predict stroke risk. Both patients who received bridging therapy and those who did not had a lower rate of stroke than predicted by CHADS₂. This may reflect a limit of the predictive value of CHADS₂ but should not have affected the rate of bleeding or ATE outcomes in this study.

Continue for challenges to implementation >>

CHALLENGES TO IMPLEMENTATION
Providers may hesitate to disregard current guidelines
Strokes are devastating events for patients, families, and clinicians, and they pose a greater risk for morbidity and mortality compared to bleeding. However, this study suggests patients who receive bridging have a higher risk for bleeding than stroke, which is in contrast to some providers’ experience and current recommendations.

A clinician caring for a patient who’s had a stroke may be inclined to recommend bridging despite the lack of efficacy and evidence of bleeding risk. Additionally, until guidelines reflect the most current research, clinicians may be reluctant to provide care in contrast to these recommendations.

REFERENCES
1. Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373:823-833.
2. Guyatt GH, Akl EA, Crowther M, et al; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:7S-47S.
3. Clark NP, Witt DM, Davies LE, et al. Bleeding, recurrent venous thromboembolism and mortality risks during warfarin interruption for invasive procedures. JAMA Intern Med. 2015; 175:1163-1168.
4. Lip GY, Lane DA. Stroke prevention in atrial fibrillation: a systematic review.JAMA. 2015;313:1950-1962.
5. Douketis JD, Spyropoulos AC, Spencer FA, et al; American College of Chest Physicians. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:e326S-e350S.
6. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence.Circulation. 2006;114:119-125.
7. Siegal D, Yudin J, Kaatz S, et al. Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates.Circulation. 2012;126:1630-1639.
8. Steinberg B, Peterson E, Kim S, et al; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Investigators and Patients. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF).Circulation. 2015;131:488-494.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(12):794-795, 800.

PRACTICE CHANGER
Stop using low molecular weight heparin (LMWH) for surgical procedures to “bridge” low- to moderate-risk patients with atrial fibrillation (CHADS₂ score ≤ 4) who are receiving warfarin. The risks outweigh the benefits.¹

STRENGTH OF RECOMMENDATION
B: Based on a single good-quality randomized controlled trial.¹

CASE  A 75-year-old man comes to your office for surgical clearance before right knee replacement surgery. He has diabetes and high blood pressure and is taking warfarin for atrial fibrillation. He is scheduled for surgery in a week. What is the safest way to manage his warfarin in the perioperative period?

More than 2 million people are being treated with oral anticoagulation in North America to prevent stroke or to prevent or treat venous thromboembolism.² Since 2010, several new oral anticoagulants have been approved, including dabigatran, apixaban, and rivaroxaban. These new medications have a shorter half-life than older anticoagulants, which enables them to be stopped one to two days before surgery.

On the other hand, warfarin—which remains a common choice for anticoagulation—has a three- to seven-day onset and elimination.^3,4 This long clinical half-life presents a special challenge during the perioperative period. To reduce the risk for operative bleeding, the warfarin must be stopped days prior to the procedure, but clinicians often worry that this will increase the risk for arterial or venous thromboembolism, including stroke.

An estimated 250,000 patients need perioperative management of their anticoagulation each year.⁵ As the US population continues to age and the incidence of conditions requiring anticoagulation (particularly atrial fibrillation) increases, this number is only going to rise.⁶

Current guidelines on bridging. American College of Chest Physicians (ACCP) guidelines recommend transition to “a short-acting anticoagulant, consisting of subcutaneous low molecular weight heparin (LMWH) or intravenous unfractionated heparin, for a 10- to 12-day period during interruption of vitamin K antagonist (VKA) therapy.”⁵Furthermore, for an appropriate bridging regimen, the ACCP guidelines recommend stopping VKA therapy five days prior to the procedure and utilizing LMWH from within 24 to 48 hours of stopping VKA therapy until up to 24 hours before surgery.⁵ Postoperatively, VKA or LMWH therapy should be reinitiated within 24 hours and 24 to 72 hours, respectively, depending on the patient’s risk for bleeding during surgery.⁵

These guidelines recommend using CHADS₂ scoring (see the table) to determine arterial thromboembolism (ATE) risk in atrial fibrillation.^3,5 Patients at low risk for ATE (CHADS₂ score, 0-2) should not be bridged, and patients at high risk (CHADS₂ score, 5-6) should always be bridged.⁵ These guidelines are less clear about bridging recommendations for patients considered to be at moderate risk (CHADS₂ score, 3-4).

Previous evidence on bridging. A 2012 meta-analysis of 34 studies evaluated the safety and efficacy of perioperative bridging with heparin in patients receiving VKA.⁷Researchers found no difference in ATE events in eight studies that compared groups that received bridging vs groups that simply stopped anticoagulation (odds ratio [OR], 0.80).⁷ The group that received bridging had an increased risk for overall bleeding in 13 studies and of major bleeding in five studies.⁷This meta-analysis was limited by poor study quality and variation in the indication for VKA therapy.

A 2015 subgroup analysis of a larger cohort study of patients receiving anticoagulants for atrial fibrillation found an increased risk for bleeding when their anticoagulation was interrupted for procedures (OR for major bleeding, 3.84).⁸

Douketis et al¹ conducted a randomized trial to clarify the need for and safety of bridging anticoagulation for ATE in patients with atrial fibrillation who were receiving warfarin.

Continue for study summary >>

STUDY SUMMARY
When it comes to stroke/TIA, there’s no advantage to bridging
This double-blind, placebo-controlled trial compared bridging with dalteparin, a form of LMWH, to placebo among 1,884 patients with atrial fibrillation who were taking warfarin and whose anticoagulation therapy needed to be interrupted for an elective procedure. Patients were included if they were receiving warfarin to prevent stroke and had been taking it for at least 12 weeks, with a goal International Normalized Ratio (INR) of 2.0 to 3.0. Exclusion criteria included having a mechanical heart valve or having a stroke/transient ischemic attack (TIA; 12 weeks prior) or major bleeding (six weeks prior). Patients undergoing cardiac, intracranial, and intraspinal surgeries were also excluded from the study.

The mean CHADS₂ score was 2.3; 38.3% of patients had a CHADS₂ score ≥ 3, and 9.4% of patients had a history of stroke. Forty-four percent of patients underwent a gastrointestinal procedure, 17.2% underwent a cardiothoracic procedure, and 9.2% underwent an orthopedic procedure.

Patients stopped taking warfarin five days before their procedure and began subcutaneous dalteparin (100 IU/kg) or an identical placebo three days before the procedure. The dalteparin/placebo was stopped 24 hours before the procedure and restarted after the procedure, until the patient’s INR was in the therapeutic range. Warfarin was resumed on the evening of the procedure or the following day.

The primary efficacy outcome was ATE, including stroke, TIA, or systemic embolism. The primary safety endpoint was major bleeding (defined as bleeding at a critical anatomic site, symptomatic or clinically overt bleeding, or a decrease in hemoglobin > 2 g/dL). Secondary efficacy and safety outcomes included minor bleeding, acute myocardial infarction, deep vein thrombosis, pulmonary embolism, and death. Outcomes were assessed within 37 days of the procedure.

The incidence of ATE was 0.4% (four events) in the no-bridging group vs 0.3% (three events) in the bridging group. Major bleeding occurred in 1.3% of the no-bridging group (12 events) and in 3.2% of the bridging group (29 events), indicating that no bridging was superior in terms of the major bleeding outcome (number needed to harm [NNH], 53; relative risk [RR], 0.41).

The no-bridging group also had significantly fewer minor bleeds in comparison to the bridging group (NNH, 11; 12% vs 20.9%). There were no differences between groups in other secondary outcomes.

Continue for what's new >>

WHAT’S NEW
High-quality evidence suggests it’s OK to stop warfarin before surgery
This is the largest good-quality study to evaluate perioperative bridging in patients with atrial fibrillation who were at low or moderate risk for ATE (CHADS₂ score, 0-4). Previous studies suggested bridging increased bleeding and offered limited benefit for reducing the risk for ATE. However, this is the first study to include a large group of moderate-risk patients (CHADS₂ score, 3-4). This trial provides high-quality evidence to support the practice of simply stopping warfarin in the perioperative period, rather than bridging with LMWH.

CAVEATS
Findings might not apply to patients at highest risk
Most patients in this study had a CHADS₂ score ≤ 3. About 3% had a CHADS₂ score ≥ 5. It’s not clear whether these findings apply to patients with a CHADS₂ score of 5 or 6.

This trial categorized ATE risk using the CHADS₂ score, rather than the CHA₂DS₂-VASc, which includes additional risk factors and may more accurately predict stroke risk. Both patients who received bridging therapy and those who did not had a lower rate of stroke than predicted by CHADS₂. This may reflect a limit of the predictive value of CHADS₂ but should not have affected the rate of bleeding or ATE outcomes in this study.

Continue for challenges to implementation >>

CHALLENGES TO IMPLEMENTATION
Providers may hesitate to disregard current guidelines
Strokes are devastating events for patients, families, and clinicians, and they pose a greater risk for morbidity and mortality compared to bleeding. However, this study suggests patients who receive bridging have a higher risk for bleeding than stroke, which is in contrast to some providers’ experience and current recommendations.

A clinician caring for a patient who’s had a stroke may be inclined to recommend bridging despite the lack of efficacy and evidence of bleeding risk. Additionally, until guidelines reflect the most current research, clinicians may be reluctant to provide care in contrast to these recommendations.

REFERENCES
1. Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373:823-833.
2. Guyatt GH, Akl EA, Crowther M, et al; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:7S-47S.
3. Clark NP, Witt DM, Davies LE, et al. Bleeding, recurrent venous thromboembolism and mortality risks during warfarin interruption for invasive procedures. JAMA Intern Med. 2015; 175:1163-1168.
4. Lip GY, Lane DA. Stroke prevention in atrial fibrillation: a systematic review.JAMA. 2015;313:1950-1962.
5. Douketis JD, Spyropoulos AC, Spencer FA, et al; American College of Chest Physicians. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:e326S-e350S.
6. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence.Circulation. 2006;114:119-125.
7. Siegal D, Yudin J, Kaatz S, et al. Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates.Circulation. 2012;126:1630-1639.
8. Steinberg B, Peterson E, Kim S, et al; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Investigators and Patients. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF).Circulation. 2015;131:488-494.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(12):794-795, 800.

PRACTICE CHANGER
Stop using low molecular weight heparin (LMWH) for surgical procedures to “bridge” low- to moderate-risk patients with atrial fibrillation (CHADS₂ score ≤ 4) who are receiving warfarin. The risks outweigh the benefits.¹

STRENGTH OF RECOMMENDATION
B: Based on a single good-quality randomized controlled trial.¹

CASE  A 75-year-old man comes to your office for surgical clearance before right knee replacement surgery. He has diabetes and high blood pressure and is taking warfarin for atrial fibrillation. He is scheduled for surgery in a week. What is the safest way to manage his warfarin in the perioperative period?

More than 2 million people are being treated with oral anticoagulation in North America to prevent stroke or to prevent or treat venous thromboembolism.² Since 2010, several new oral anticoagulants have been approved, including dabigatran, apixaban, and rivaroxaban. These new medications have a shorter half-life than older anticoagulants, which enables them to be stopped one to two days before surgery.

On the other hand, warfarin—which remains a common choice for anticoagulation—has a three- to seven-day onset and elimination.^3,4 This long clinical half-life presents a special challenge during the perioperative period. To reduce the risk for operative bleeding, the warfarin must be stopped days prior to the procedure, but clinicians often worry that this will increase the risk for arterial or venous thromboembolism, including stroke.

An estimated 250,000 patients need perioperative management of their anticoagulation each year.⁵ As the US population continues to age and the incidence of conditions requiring anticoagulation (particularly atrial fibrillation) increases, this number is only going to rise.⁶

Current guidelines on bridging. American College of Chest Physicians (ACCP) guidelines recommend transition to “a short-acting anticoagulant, consisting of subcutaneous low molecular weight heparin (LMWH) or intravenous unfractionated heparin, for a 10- to 12-day period during interruption of vitamin K antagonist (VKA) therapy.”⁵Furthermore, for an appropriate bridging regimen, the ACCP guidelines recommend stopping VKA therapy five days prior to the procedure and utilizing LMWH from within 24 to 48 hours of stopping VKA therapy until up to 24 hours before surgery.⁵ Postoperatively, VKA or LMWH therapy should be reinitiated within 24 hours and 24 to 72 hours, respectively, depending on the patient’s risk for bleeding during surgery.⁵

These guidelines recommend using CHADS₂ scoring (see the table) to determine arterial thromboembolism (ATE) risk in atrial fibrillation.^3,5 Patients at low risk for ATE (CHADS₂ score, 0-2) should not be bridged, and patients at high risk (CHADS₂ score, 5-6) should always be bridged.⁵ These guidelines are less clear about bridging recommendations for patients considered to be at moderate risk (CHADS₂ score, 3-4).

Previous evidence on bridging. A 2012 meta-analysis of 34 studies evaluated the safety and efficacy of perioperative bridging with heparin in patients receiving VKA.⁷Researchers found no difference in ATE events in eight studies that compared groups that received bridging vs groups that simply stopped anticoagulation (odds ratio [OR], 0.80).⁷ The group that received bridging had an increased risk for overall bleeding in 13 studies and of major bleeding in five studies.⁷This meta-analysis was limited by poor study quality and variation in the indication for VKA therapy.

A 2015 subgroup analysis of a larger cohort study of patients receiving anticoagulants for atrial fibrillation found an increased risk for bleeding when their anticoagulation was interrupted for procedures (OR for major bleeding, 3.84).⁸

Douketis et al¹ conducted a randomized trial to clarify the need for and safety of bridging anticoagulation for ATE in patients with atrial fibrillation who were receiving warfarin.

Continue for study summary >>

STUDY SUMMARY
When it comes to stroke/TIA, there’s no advantage to bridging
This double-blind, placebo-controlled trial compared bridging with dalteparin, a form of LMWH, to placebo among 1,884 patients with atrial fibrillation who were taking warfarin and whose anticoagulation therapy needed to be interrupted for an elective procedure. Patients were included if they were receiving warfarin to prevent stroke and had been taking it for at least 12 weeks, with a goal International Normalized Ratio (INR) of 2.0 to 3.0. Exclusion criteria included having a mechanical heart valve or having a stroke/transient ischemic attack (TIA; 12 weeks prior) or major bleeding (six weeks prior). Patients undergoing cardiac, intracranial, and intraspinal surgeries were also excluded from the study.

The mean CHADS₂ score was 2.3; 38.3% of patients had a CHADS₂ score ≥ 3, and 9.4% of patients had a history of stroke. Forty-four percent of patients underwent a gastrointestinal procedure, 17.2% underwent a cardiothoracic procedure, and 9.2% underwent an orthopedic procedure.

Patients stopped taking warfarin five days before their procedure and began subcutaneous dalteparin (100 IU/kg) or an identical placebo three days before the procedure. The dalteparin/placebo was stopped 24 hours before the procedure and restarted after the procedure, until the patient’s INR was in the therapeutic range. Warfarin was resumed on the evening of the procedure or the following day.

The primary efficacy outcome was ATE, including stroke, TIA, or systemic embolism. The primary safety endpoint was major bleeding (defined as bleeding at a critical anatomic site, symptomatic or clinically overt bleeding, or a decrease in hemoglobin > 2 g/dL). Secondary efficacy and safety outcomes included minor bleeding, acute myocardial infarction, deep vein thrombosis, pulmonary embolism, and death. Outcomes were assessed within 37 days of the procedure.

The incidence of ATE was 0.4% (four events) in the no-bridging group vs 0.3% (three events) in the bridging group. Major bleeding occurred in 1.3% of the no-bridging group (12 events) and in 3.2% of the bridging group (29 events), indicating that no bridging was superior in terms of the major bleeding outcome (number needed to harm [NNH], 53; relative risk [RR], 0.41).

The no-bridging group also had significantly fewer minor bleeds in comparison to the bridging group (NNH, 11; 12% vs 20.9%). There were no differences between groups in other secondary outcomes.

Continue for what's new >>

WHAT’S NEW
High-quality evidence suggests it’s OK to stop warfarin before surgery
This is the largest good-quality study to evaluate perioperative bridging in patients with atrial fibrillation who were at low or moderate risk for ATE (CHADS₂ score, 0-4). Previous studies suggested bridging increased bleeding and offered limited benefit for reducing the risk for ATE. However, this is the first study to include a large group of moderate-risk patients (CHADS₂ score, 3-4). This trial provides high-quality evidence to support the practice of simply stopping warfarin in the perioperative period, rather than bridging with LMWH.

CAVEATS
Findings might not apply to patients at highest risk
Most patients in this study had a CHADS₂ score ≤ 3. About 3% had a CHADS₂ score ≥ 5. It’s not clear whether these findings apply to patients with a CHADS₂ score of 5 or 6.

This trial categorized ATE risk using the CHADS₂ score, rather than the CHA₂DS₂-VASc, which includes additional risk factors and may more accurately predict stroke risk. Both patients who received bridging therapy and those who did not had a lower rate of stroke than predicted by CHADS₂. This may reflect a limit of the predictive value of CHADS₂ but should not have affected the rate of bleeding or ATE outcomes in this study.

Continue for challenges to implementation >>

CHALLENGES TO IMPLEMENTATION
Providers may hesitate to disregard current guidelines
Strokes are devastating events for patients, families, and clinicians, and they pose a greater risk for morbidity and mortality compared to bleeding. However, this study suggests patients who receive bridging have a higher risk for bleeding than stroke, which is in contrast to some providers’ experience and current recommendations.

A clinician caring for a patient who’s had a stroke may be inclined to recommend bridging despite the lack of efficacy and evidence of bleeding risk. Additionally, until guidelines reflect the most current research, clinicians may be reluctant to provide care in contrast to these recommendations.

REFERENCES
1. Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373:823-833.
2. Guyatt GH, Akl EA, Crowther M, et al; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:7S-47S.
3. Clark NP, Witt DM, Davies LE, et al. Bleeding, recurrent venous thromboembolism and mortality risks during warfarin interruption for invasive procedures. JAMA Intern Med. 2015; 175:1163-1168.
4. Lip GY, Lane DA. Stroke prevention in atrial fibrillation: a systematic review.JAMA. 2015;313:1950-1962.
5. Douketis JD, Spyropoulos AC, Spencer FA, et al; American College of Chest Physicians. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:e326S-e350S.
6. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence.Circulation. 2006;114:119-125.
7. Siegal D, Yudin J, Kaatz S, et al. Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates.Circulation. 2012;126:1630-1639.
8. Steinberg B, Peterson E, Kim S, et al; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Investigators and Patients. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF).Circulation. 2015;131:488-494.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(12):794-795, 800.

Clinical question: What is the value of ultra-brief cognitive assessments in predicting hospital outcomes?

Background: Cognitive assessment tools can be used to predict patient outcomes in the hospital setting. Physician time constraints limit use of longer traditional cognitive testing, and little is known about the effectiveness of ultra-brief (less than one minute) assessments and their predictive value.

Study design: Secondary data analysis of a quality improvement project.

Setting: Tertiary, Veterans Administration hospital.

Synopsis: Using data from a prior inpatient database, 3,232 patients over the age of 60 were screened on admission using the modified Richmond Agitation and Sedation Scale (mRASS) for arousal and the months of the year backwards (MOTYB) for attention. Abnormal mRASS and incorrect MOTYB predicted negative hospital outcomes: increased length of stay (incident rate ratio 1.23, 95% CI 1.17-1.3); increased restraint use (risk ratio 5.05, 95% CI); increased hospital mortality (RR 3.46, 95% CI 1.24-9.63); and decreased rates of being discharged home (RR 2.97, 95% CI: 2.42-3.64).

This study highlights the value of two ultra-brief cognitive assessment tools in the prediction of potential poor outcomes during inpatient admission. Hospitalists need to identify high-risk patients, and these tools allow for rapid assessment at the time of admission, without a significant time constraint for the busy hospitalist.

Bottom Line: The use of ultra-brief cognitive assessment tools in patients over age 60 can predict negative inpatient outcomes.

Citation: Yevchak AM, Doherty K, Archambault EG, Kelly B, Fonda JR, Rudolph JL. The association between an ultra-brief cognitive screening in older adults and hospital outcomes. J Hosp Med. 2015;10(10):651-657.

Clinical question: What is the value of ultra-brief cognitive assessments in predicting hospital outcomes?

Background: Cognitive assessment tools can be used to predict patient outcomes in the hospital setting. Physician time constraints limit use of longer traditional cognitive testing, and little is known about the effectiveness of ultra-brief (less than one minute) assessments and their predictive value.

Study design: Secondary data analysis of a quality improvement project.

Setting: Tertiary, Veterans Administration hospital.

Synopsis: Using data from a prior inpatient database, 3,232 patients over the age of 60 were screened on admission using the modified Richmond Agitation and Sedation Scale (mRASS) for arousal and the months of the year backwards (MOTYB) for attention. Abnormal mRASS and incorrect MOTYB predicted negative hospital outcomes: increased length of stay (incident rate ratio 1.23, 95% CI 1.17-1.3); increased restraint use (risk ratio 5.05, 95% CI); increased hospital mortality (RR 3.46, 95% CI 1.24-9.63); and decreased rates of being discharged home (RR 2.97, 95% CI: 2.42-3.64).

This study highlights the value of two ultra-brief cognitive assessment tools in the prediction of potential poor outcomes during inpatient admission. Hospitalists need to identify high-risk patients, and these tools allow for rapid assessment at the time of admission, without a significant time constraint for the busy hospitalist.

Bottom Line: The use of ultra-brief cognitive assessment tools in patients over age 60 can predict negative inpatient outcomes.

Citation: Yevchak AM, Doherty K, Archambault EG, Kelly B, Fonda JR, Rudolph JL. The association between an ultra-brief cognitive screening in older adults and hospital outcomes. J Hosp Med. 2015;10(10):651-657.

Clinical question: What is the value of ultra-brief cognitive assessments in predicting hospital outcomes?

Background: Cognitive assessment tools can be used to predict patient outcomes in the hospital setting. Physician time constraints limit use of longer traditional cognitive testing, and little is known about the effectiveness of ultra-brief (less than one minute) assessments and their predictive value.

Study design: Secondary data analysis of a quality improvement project.

Setting: Tertiary, Veterans Administration hospital.

Synopsis: Using data from a prior inpatient database, 3,232 patients over the age of 60 were screened on admission using the modified Richmond Agitation and Sedation Scale (mRASS) for arousal and the months of the year backwards (MOTYB) for attention. Abnormal mRASS and incorrect MOTYB predicted negative hospital outcomes: increased length of stay (incident rate ratio 1.23, 95% CI 1.17-1.3); increased restraint use (risk ratio 5.05, 95% CI); increased hospital mortality (RR 3.46, 95% CI 1.24-9.63); and decreased rates of being discharged home (RR 2.97, 95% CI: 2.42-3.64).

This study highlights the value of two ultra-brief cognitive assessment tools in the prediction of potential poor outcomes during inpatient admission. Hospitalists need to identify high-risk patients, and these tools allow for rapid assessment at the time of admission, without a significant time constraint for the busy hospitalist.

Bottom Line: The use of ultra-brief cognitive assessment tools in patients over age 60 can predict negative inpatient outcomes.

Citation: Yevchak AM, Doherty K, Archambault EG, Kelly B, Fonda JR, Rudolph JL. The association between an ultra-brief cognitive screening in older adults and hospital outcomes. J Hosp Med. 2015;10(10):651-657.

Clinical question: What are criteria for appropriate and inappropriate use of PICCs?

Background: PICCs are commonly used in medical care in a variety of clinical contexts; however, criteria defining the appropriate use of PICCs and practices related to PICC placement have not been previously established.

Study design: A multispecialty panel classified indications for PICC use as appropriate or inappropriate using the RAND/UCLA Appropriateness Method.

Synopsis: Selected appropriate PICC uses include:

• Infusion of peripherally compatible infusates, intermittent infusions, or infrequent phlebotomy in patients with poor or difficult venous access when the expected duration of use is at least six days;
• Phlebotomy at least every eight hours when the expected duration of use is at least six days; and
• Invasive hemodynamic monitoring in a critically ill patient only if the duration of use is expected to exceed 15 days.

  Selected appropriate PICC-related practices:

• Verify PICC tip position using a chest radiograph only after non-ECG or non-fluoroscopically guided PICC insertion;
• Provide an interval without a PICC to allow resolution of bacteremia when managing PICC-related bloodstream infections; and
• For PICC-related DVT, provide at least three months of systemic anticoagulation if not otherwise contraindicated.

Selected inappropriate PICC-related practices:

• Adjustment of PICC tips that reside in the lower third of the superior vena cava, cavoatrial junction, or right atrium; and
• Removal or replacement of PICCs that are clinically necessary, well positioned, and functional in the setting of PICC-related DVT or without evidence of catheter-associated bloodstream infection.

Bottom line: A multispecialty expert panel provides guidance for appropriate use of PICCs and PICC-related practices.

Citation: Chopra V, Flanders SA, Saint S, et al. The Michigan appropriateness guide for intravenous catheters (MAGIC): results from a multispecialty panel using the RAND/UCLA appropriateness method. Ann Intern Med. 2015;163(6):S1-S40.

Clinical question: What are criteria for appropriate and inappropriate use of PICCs?

Background: PICCs are commonly used in medical care in a variety of clinical contexts; however, criteria defining the appropriate use of PICCs and practices related to PICC placement have not been previously established.

Study design: A multispecialty panel classified indications for PICC use as appropriate or inappropriate using the RAND/UCLA Appropriateness Method.

Synopsis: Selected appropriate PICC uses include:

• Infusion of peripherally compatible infusates, intermittent infusions, or infrequent phlebotomy in patients with poor or difficult venous access when the expected duration of use is at least six days;
• Phlebotomy at least every eight hours when the expected duration of use is at least six days; and
• Invasive hemodynamic monitoring in a critically ill patient only if the duration of use is expected to exceed 15 days.

  Selected appropriate PICC-related practices:

• Verify PICC tip position using a chest radiograph only after non-ECG or non-fluoroscopically guided PICC insertion;
• Provide an interval without a PICC to allow resolution of bacteremia when managing PICC-related bloodstream infections; and
• For PICC-related DVT, provide at least three months of systemic anticoagulation if not otherwise contraindicated.

Selected inappropriate PICC-related practices:

• Adjustment of PICC tips that reside in the lower third of the superior vena cava, cavoatrial junction, or right atrium; and
• Removal or replacement of PICCs that are clinically necessary, well positioned, and functional in the setting of PICC-related DVT or without evidence of catheter-associated bloodstream infection.

Bottom line: A multispecialty expert panel provides guidance for appropriate use of PICCs and PICC-related practices.

Citation: Chopra V, Flanders SA, Saint S, et al. The Michigan appropriateness guide for intravenous catheters (MAGIC): results from a multispecialty panel using the RAND/UCLA appropriateness method. Ann Intern Med. 2015;163(6):S1-S40.

Clinical question: What are criteria for appropriate and inappropriate use of PICCs?

Background: PICCs are commonly used in medical care in a variety of clinical contexts; however, criteria defining the appropriate use of PICCs and practices related to PICC placement have not been previously established.

Study design: A multispecialty panel classified indications for PICC use as appropriate or inappropriate using the RAND/UCLA Appropriateness Method.

Synopsis: Selected appropriate PICC uses include:

• Infusion of peripherally compatible infusates, intermittent infusions, or infrequent phlebotomy in patients with poor or difficult venous access when the expected duration of use is at least six days;
• Phlebotomy at least every eight hours when the expected duration of use is at least six days; and
• Invasive hemodynamic monitoring in a critically ill patient only if the duration of use is expected to exceed 15 days.

  Selected appropriate PICC-related practices:

• Verify PICC tip position using a chest radiograph only after non-ECG or non-fluoroscopically guided PICC insertion;
• Provide an interval without a PICC to allow resolution of bacteremia when managing PICC-related bloodstream infections; and
• For PICC-related DVT, provide at least three months of systemic anticoagulation if not otherwise contraindicated.

Selected inappropriate PICC-related practices:

• Adjustment of PICC tips that reside in the lower third of the superior vena cava, cavoatrial junction, or right atrium; and
• Removal or replacement of PICCs that are clinically necessary, well positioned, and functional in the setting of PICC-related DVT or without evidence of catheter-associated bloodstream infection.

Bottom line: A multispecialty expert panel provides guidance for appropriate use of PICCs and PICC-related practices.

Citation: Chopra V, Flanders SA, Saint S, et al. The Michigan appropriateness guide for intravenous catheters (MAGIC): results from a multispecialty panel using the RAND/UCLA appropriateness method. Ann Intern Med. 2015;163(6):S1-S40.

Q) All I hear about is the shortage of kidneys for transplantation. A friend of mine is on the local transplant list, and it is eight years long! Are there any ideas out there to grow your own kidneys?

Eight years is a long time for people dealing with the physical and emotional effects of kidney disease coupled with hemodialysis or peritoneal dialysis. Your friend is one of 110,000 patients (as of January 2015) in the United States on the United Network for Organ Sharing (UNOS) kidney transplant waiting list.¹ The UNOS/Organ Procurement and Transplant Network (OPTN) implemented new polices in 2014 to shorten the wait.

Among them: For pediatric patients (those younger than 18), the wait list time starts when the glomerular filtration rate (GFR) is ≤ 20 mL/min or the child starts dialysis. UNOS also has attempted to match posttransplant survival time of the graft with posttransplant survival time of the recipient through use of calculations that classify kidneys on the basis of how long they are likely to function once transplanted. Priority is now given to candidates with high immune system sensitivity or uncommon blood types, as they are less likely to obtain a kidney otherwise.²

The million-dollar question is how to obtain a kidney transplant in a timely fashion. Grave robbing, in case you are wondering, is not a viable option! Nor is transplant tourism (traveling outside the US to obtain an organ transplant), which confers a higher risk for severe infectious complications and acute rejection, possibly related to less extensive donor screening.³

There are other possibilities: Living donors can donate one kidney. Or, as is becoming increasingly common, paired organ transplants can be arranged. These occur when a patient in need of a kidney has a willing but incompatible donor; if a different match can be found, a “swap” is orchestrated, in which Donor A’s kidney is transplanted into Recipient B and Donor B’s kidney is given to Recipient A. This can be and has been done with multiple donors and recipients—in some cases, dozens—allowing the gift of donation to go on and on. (See “Trading Kidneys: Innovative Program Could Save Thousands of Lives” for an overview of how this concept started.)

Some exciting research is going on with regard to 3D printing of kidneys; they are miniature for now but showing survival of the printed cells. Another area of exploration is regenerative medicine; researchers in the field are investigating the bioengineering of organs by taking the “scaffolding” of an organ and implanting a patient’s own cells to “grow” a new organ (which, if successful, would also eliminate the need for immunosuppressants). Other signs of progress include recent news that scientists are getting lab-grown kidneys to work in ­animals.

It will be several years before any of these options will be viable. In the meantime, it never hurts to ask loved ones if they are willing to donate a kidney. Best wishes to your friend. —DC

Della Connor, PhD, RN, FNP-BC
East Texas Nephrology Associates, Lufkin, Texas

REFERENCES
1. Organ Procurement and Transplantation Network. http://optn.transplant.hrsa.gov. Accessed December 10, 2015.
2. Organ Procurement and Transplantation Network. New OPTN requirements and resources for the living donor kidney transplant programs. Prog Transplant. 2013;23(2):117.
3. Gill J, Madhira BR, Gjertson D, et al. Transplant tourism in the United States: a single-center experience. Clin J Am Soc Nephrol. 2008;3(6):1820-1828.

Q) All I hear about is the shortage of kidneys for transplantation. A friend of mine is on the local transplant list, and it is eight years long! Are there any ideas out there to grow your own kidneys?

Eight years is a long time for people dealing with the physical and emotional effects of kidney disease coupled with hemodialysis or peritoneal dialysis. Your friend is one of 110,000 patients (as of January 2015) in the United States on the United Network for Organ Sharing (UNOS) kidney transplant waiting list.¹ The UNOS/Organ Procurement and Transplant Network (OPTN) implemented new polices in 2014 to shorten the wait.

Among them: For pediatric patients (those younger than 18), the wait list time starts when the glomerular filtration rate (GFR) is ≤ 20 mL/min or the child starts dialysis. UNOS also has attempted to match posttransplant survival time of the graft with posttransplant survival time of the recipient through use of calculations that classify kidneys on the basis of how long they are likely to function once transplanted. Priority is now given to candidates with high immune system sensitivity or uncommon blood types, as they are less likely to obtain a kidney otherwise.²

The million-dollar question is how to obtain a kidney transplant in a timely fashion. Grave robbing, in case you are wondering, is not a viable option! Nor is transplant tourism (traveling outside the US to obtain an organ transplant), which confers a higher risk for severe infectious complications and acute rejection, possibly related to less extensive donor screening.³

There are other possibilities: Living donors can donate one kidney. Or, as is becoming increasingly common, paired organ transplants can be arranged. These occur when a patient in need of a kidney has a willing but incompatible donor; if a different match can be found, a “swap” is orchestrated, in which Donor A’s kidney is transplanted into Recipient B and Donor B’s kidney is given to Recipient A. This can be and has been done with multiple donors and recipients—in some cases, dozens—allowing the gift of donation to go on and on. (See “Trading Kidneys: Innovative Program Could Save Thousands of Lives” for an overview of how this concept started.)

Some exciting research is going on with regard to 3D printing of kidneys; they are miniature for now but showing survival of the printed cells. Another area of exploration is regenerative medicine; researchers in the field are investigating the bioengineering of organs by taking the “scaffolding” of an organ and implanting a patient’s own cells to “grow” a new organ (which, if successful, would also eliminate the need for immunosuppressants). Other signs of progress include recent news that scientists are getting lab-grown kidneys to work in ­animals.

It will be several years before any of these options will be viable. In the meantime, it never hurts to ask loved ones if they are willing to donate a kidney. Best wishes to your friend. —DC

Della Connor, PhD, RN, FNP-BC
East Texas Nephrology Associates, Lufkin, Texas

REFERENCES
1. Organ Procurement and Transplantation Network. http://optn.transplant.hrsa.gov. Accessed December 10, 2015.
2. Organ Procurement and Transplantation Network. New OPTN requirements and resources for the living donor kidney transplant programs. Prog Transplant. 2013;23(2):117.
3. Gill J, Madhira BR, Gjertson D, et al. Transplant tourism in the United States: a single-center experience. Clin J Am Soc Nephrol. 2008;3(6):1820-1828.

Q) All I hear about is the shortage of kidneys for transplantation. A friend of mine is on the local transplant list, and it is eight years long! Are there any ideas out there to grow your own kidneys?

Eight years is a long time for people dealing with the physical and emotional effects of kidney disease coupled with hemodialysis or peritoneal dialysis. Your friend is one of 110,000 patients (as of January 2015) in the United States on the United Network for Organ Sharing (UNOS) kidney transplant waiting list.¹ The UNOS/Organ Procurement and Transplant Network (OPTN) implemented new polices in 2014 to shorten the wait.

Among them: For pediatric patients (those younger than 18), the wait list time starts when the glomerular filtration rate (GFR) is ≤ 20 mL/min or the child starts dialysis. UNOS also has attempted to match posttransplant survival time of the graft with posttransplant survival time of the recipient through use of calculations that classify kidneys on the basis of how long they are likely to function once transplanted. Priority is now given to candidates with high immune system sensitivity or uncommon blood types, as they are less likely to obtain a kidney otherwise.²

The million-dollar question is how to obtain a kidney transplant in a timely fashion. Grave robbing, in case you are wondering, is not a viable option! Nor is transplant tourism (traveling outside the US to obtain an organ transplant), which confers a higher risk for severe infectious complications and acute rejection, possibly related to less extensive donor screening.³

There are other possibilities: Living donors can donate one kidney. Or, as is becoming increasingly common, paired organ transplants can be arranged. These occur when a patient in need of a kidney has a willing but incompatible donor; if a different match can be found, a “swap” is orchestrated, in which Donor A’s kidney is transplanted into Recipient B and Donor B’s kidney is given to Recipient A. This can be and has been done with multiple donors and recipients—in some cases, dozens—allowing the gift of donation to go on and on. (See “Trading Kidneys: Innovative Program Could Save Thousands of Lives” for an overview of how this concept started.)

Some exciting research is going on with regard to 3D printing of kidneys; they are miniature for now but showing survival of the printed cells. Another area of exploration is regenerative medicine; researchers in the field are investigating the bioengineering of organs by taking the “scaffolding” of an organ and implanting a patient’s own cells to “grow” a new organ (which, if successful, would also eliminate the need for immunosuppressants). Other signs of progress include recent news that scientists are getting lab-grown kidneys to work in ­animals.

It will be several years before any of these options will be viable. In the meantime, it never hurts to ask loved ones if they are willing to donate a kidney. Best wishes to your friend. —DC

Della Connor, PhD, RN, FNP-BC
East Texas Nephrology Associates, Lufkin, Texas

REFERENCES
1. Organ Procurement and Transplantation Network. http://optn.transplant.hrsa.gov. Accessed December 10, 2015.
2. Organ Procurement and Transplantation Network. New OPTN requirements and resources for the living donor kidney transplant programs. Prog Transplant. 2013;23(2):117.
3. Gill J, Madhira BR, Gjertson D, et al. Transplant tourism in the United States: a single-center experience. Clin J Am Soc Nephrol. 2008;3(6):1820-1828.

X-ray of the hand of a patient

with Fanconi anemia

Researchers say they have established the cause of a subtype of Fanconi anemia (FA)—a de novo mutation in 1 allele of RAD51, a gene responsible for repairing DNA damage.

The team made this discovery in a child with an FA-like syndrome who has healthy parents and a healthy sister.

“The particular mutation in this patient was a surprise to us,” said Patrick May, PhD, of the University of Luxembourg.

“It occurred only in 1 of the 2 RAD51 gene copies, which every person carries in the genome, but every RAD51 gene copy was normal in the child’s parents.”

Dr May and his colleagues described the mutation in Nature Communications.

Specifically, the researchers found a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in 1 allele of RAD51.

They said this heterozygous mutation causes a novel FA subtype, dubbed “FA-R,” which appears to be the first subtype of FA caused by a dominant-negative mutation.

The patient the researchers analyzed has microcephaly and mental retardation but has reached adulthood without the bone marrow failure and pediatric cancers typically observed in patients with FA.

Until this case, researchers believed that mutations leading to FA showed recessive inheritance and therefore had to be derived from both parents to lead to FA. Spontaneous mutations of the RAD51 gene like in this case had not been observed.

Dr May and his colleagues said their finding has implications for genetic counseling of families with a high risk for FA. Previously, people who wanted to have children but had relatives suffering from FA were screened for mutations in 1 of the 17 genes connected with the disease. Now, the risk of having a child with FA has to be recalculated.

“Furthermore, understanding this mutation teaches us more about how the RAD51 gene product protects the DNA and how disruptions of DNA repair may lead to leukemia and solid tumors,” Dr May said. “Of course, understanding the origins of human cancer will help us diagnose it with more confidence earlier and devise new therapies to prevent or mitigate it.”

X-ray of the hand of a patient

with Fanconi anemia

Researchers say they have established the cause of a subtype of Fanconi anemia (FA)—a de novo mutation in 1 allele of RAD51, a gene responsible for repairing DNA damage.

The team made this discovery in a child with an FA-like syndrome who has healthy parents and a healthy sister.

“The particular mutation in this patient was a surprise to us,” said Patrick May, PhD, of the University of Luxembourg.

“It occurred only in 1 of the 2 RAD51 gene copies, which every person carries in the genome, but every RAD51 gene copy was normal in the child’s parents.”

Dr May and his colleagues described the mutation in Nature Communications.

Specifically, the researchers found a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in 1 allele of RAD51.

They said this heterozygous mutation causes a novel FA subtype, dubbed “FA-R,” which appears to be the first subtype of FA caused by a dominant-negative mutation.

The patient the researchers analyzed has microcephaly and mental retardation but has reached adulthood without the bone marrow failure and pediatric cancers typically observed in patients with FA.

Until this case, researchers believed that mutations leading to FA showed recessive inheritance and therefore had to be derived from both parents to lead to FA. Spontaneous mutations of the RAD51 gene like in this case had not been observed.

Dr May and his colleagues said their finding has implications for genetic counseling of families with a high risk for FA. Previously, people who wanted to have children but had relatives suffering from FA were screened for mutations in 1 of the 17 genes connected with the disease. Now, the risk of having a child with FA has to be recalculated.

“Furthermore, understanding this mutation teaches us more about how the RAD51 gene product protects the DNA and how disruptions of DNA repair may lead to leukemia and solid tumors,” Dr May said. “Of course, understanding the origins of human cancer will help us diagnose it with more confidence earlier and devise new therapies to prevent or mitigate it.”

X-ray of the hand of a patient

with Fanconi anemia

Researchers say they have established the cause of a subtype of Fanconi anemia (FA)—a de novo mutation in 1 allele of RAD51, a gene responsible for repairing DNA damage.

The team made this discovery in a child with an FA-like syndrome who has healthy parents and a healthy sister.

“The particular mutation in this patient was a surprise to us,” said Patrick May, PhD, of the University of Luxembourg.

“It occurred only in 1 of the 2 RAD51 gene copies, which every person carries in the genome, but every RAD51 gene copy was normal in the child’s parents.”

Dr May and his colleagues described the mutation in Nature Communications.

Specifically, the researchers found a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in 1 allele of RAD51.

They said this heterozygous mutation causes a novel FA subtype, dubbed “FA-R,” which appears to be the first subtype of FA caused by a dominant-negative mutation.

The patient the researchers analyzed has microcephaly and mental retardation but has reached adulthood without the bone marrow failure and pediatric cancers typically observed in patients with FA.

Until this case, researchers believed that mutations leading to FA showed recessive inheritance and therefore had to be derived from both parents to lead to FA. Spontaneous mutations of the RAD51 gene like in this case had not been observed.

Dr May and his colleagues said their finding has implications for genetic counseling of families with a high risk for FA. Previously, people who wanted to have children but had relatives suffering from FA were screened for mutations in 1 of the 17 genes connected with the disease. Now, the risk of having a child with FA has to be recalculated.

“Furthermore, understanding this mutation teaches us more about how the RAD51 gene product protects the DNA and how disruptions of DNA repair may lead to leukemia and solid tumors,” Dr May said. “Of course, understanding the origins of human cancer will help us diagnose it with more confidence earlier and devise new therapies to prevent or mitigate it.”

Birth control pills

A study published in Blood indicates that women on anticoagulants can take estrogen-containing contraception or hormone replacement therapy

without an increased risk of venous thromboembolism (VTE) or uterine bleeding.

If a woman is diagnosed with VTE, she is often advised to stop hormone therapy, even while receiving anticoagulant therapy, because she is thought to have an increased risk of VTE recurrence.

However, this practice is based on the known association between hormone therapy and increased clotting risk in the absence of anticoagulants. The safety of the concurrent use of these medications had not been previously explored.

“While it has been common practice among healthcare providers to avoid prescribing hormone therapy and anticoagulants at the same time, there has been no evidence to support this decision,” said study author Ida Martinelli, MD, of the A. Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy.

“We conducted this study to address the fear felt by both the physician and patient when making the decision to stop or continue hormone therapy in this setting.”

The researchers compared the incidences of recurrent VTE and abnormal uterine bleeding in 1888 women who received anticoagulants with or without concurrent hormone therapy.

The team analyzed data from the EINSTEIN DVT and PE study, which was performed to evaluate the safety and efficacy of 2 anticoagulants—the direct oral anticoagulant rivaroxaban and the current standard of care, a low-molecular-weight heparin (enoxaparin) followed by a vitamin K antagonist (VKA).

Women of child-bearing potential were advised to use adequate methods of contraception to avoid birth defects.

Of all the women in the study, 475 used hormone therapy during the analysis period. Medications used included estrogen-only pills, combined estrogen-progestogen contraceptives, and progestin-only contraceptives.

Participants were questioned about symptoms or signs of recurrent VTE and bleeding, including uterine bleeding, during each follow-up visit.

Seven recurrent VTEs occurred while patients were using hormone therapy, while 38 events occurred during a period when patients were not using hormone therapy.

Based on this analysis, the researchers concluded that women on anticoagulants and hormone therapy experienced recurrent VTE at a rate of 3.7% per year. In contrast, those not on hormone therapy had a recurrence rate of 4.7% per year.

The incidence of abnormal uterine bleeding in patients on hormonal therapy was 22.5%, compared to 21.4% for women not on hormone therapy.

According to the study authors, the similar incidence of VTE and abnormal uterine bleeding in women who did and did not receive hormone therapy suggest that combined use of these therapies is safe.

The study also showed that abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA. The bleeding rate was estimated at 29.8% per year for patients on rivaroxaban and 15.5% per year in the enoxaparin/VKA group.

The researchers said this outcome suggests the need for further studies on rivaroxaban, which may be preferred for its convenience over enoxaparin/VKA.

“For the first time, we demonstrate that women suffering from blood clots can safely take hormone-containing contraceptives or hormone replacement therapy with anticoagulants, providing women the freedom to choose the method of birth control and other hormone-containing medications they prefer,” Dr Martinelli said.

“While further investigation is needed to evaluate the inconvenience of abnormal uterine bleeding with rivaroxaban and the other direct oral anticoagulants, these results dispel former misconceptions and should allow clinicians to confidently treat their patients who take blood thinners and hormones concurrently.”

Birth control pills

A study published in Blood indicates that women on anticoagulants can take estrogen-containing contraception or hormone replacement therapy

without an increased risk of venous thromboembolism (VTE) or uterine bleeding.

If a woman is diagnosed with VTE, she is often advised to stop hormone therapy, even while receiving anticoagulant therapy, because she is thought to have an increased risk of VTE recurrence.

However, this practice is based on the known association between hormone therapy and increased clotting risk in the absence of anticoagulants. The safety of the concurrent use of these medications had not been previously explored.

“While it has been common practice among healthcare providers to avoid prescribing hormone therapy and anticoagulants at the same time, there has been no evidence to support this decision,” said study author Ida Martinelli, MD, of the A. Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy.

“We conducted this study to address the fear felt by both the physician and patient when making the decision to stop or continue hormone therapy in this setting.”

The researchers compared the incidences of recurrent VTE and abnormal uterine bleeding in 1888 women who received anticoagulants with or without concurrent hormone therapy.

The team analyzed data from the EINSTEIN DVT and PE study, which was performed to evaluate the safety and efficacy of 2 anticoagulants—the direct oral anticoagulant rivaroxaban and the current standard of care, a low-molecular-weight heparin (enoxaparin) followed by a vitamin K antagonist (VKA).

Women of child-bearing potential were advised to use adequate methods of contraception to avoid birth defects.

Of all the women in the study, 475 used hormone therapy during the analysis period. Medications used included estrogen-only pills, combined estrogen-progestogen contraceptives, and progestin-only contraceptives.

Participants were questioned about symptoms or signs of recurrent VTE and bleeding, including uterine bleeding, during each follow-up visit.

Seven recurrent VTEs occurred while patients were using hormone therapy, while 38 events occurred during a period when patients were not using hormone therapy.

Based on this analysis, the researchers concluded that women on anticoagulants and hormone therapy experienced recurrent VTE at a rate of 3.7% per year. In contrast, those not on hormone therapy had a recurrence rate of 4.7% per year.

The incidence of abnormal uterine bleeding in patients on hormonal therapy was 22.5%, compared to 21.4% for women not on hormone therapy.

According to the study authors, the similar incidence of VTE and abnormal uterine bleeding in women who did and did not receive hormone therapy suggest that combined use of these therapies is safe.

The study also showed that abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA. The bleeding rate was estimated at 29.8% per year for patients on rivaroxaban and 15.5% per year in the enoxaparin/VKA group.

The researchers said this outcome suggests the need for further studies on rivaroxaban, which may be preferred for its convenience over enoxaparin/VKA.

“For the first time, we demonstrate that women suffering from blood clots can safely take hormone-containing contraceptives or hormone replacement therapy with anticoagulants, providing women the freedom to choose the method of birth control and other hormone-containing medications they prefer,” Dr Martinelli said.

“While further investigation is needed to evaluate the inconvenience of abnormal uterine bleeding with rivaroxaban and the other direct oral anticoagulants, these results dispel former misconceptions and should allow clinicians to confidently treat their patients who take blood thinners and hormones concurrently.”

Birth control pills

A study published in Blood indicates that women on anticoagulants can take estrogen-containing contraception or hormone replacement therapy

without an increased risk of venous thromboembolism (VTE) or uterine bleeding.

If a woman is diagnosed with VTE, she is often advised to stop hormone therapy, even while receiving anticoagulant therapy, because she is thought to have an increased risk of VTE recurrence.

However, this practice is based on the known association between hormone therapy and increased clotting risk in the absence of anticoagulants. The safety of the concurrent use of these medications had not been previously explored.

“While it has been common practice among healthcare providers to avoid prescribing hormone therapy and anticoagulants at the same time, there has been no evidence to support this decision,” said study author Ida Martinelli, MD, of the A. Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy.

“We conducted this study to address the fear felt by both the physician and patient when making the decision to stop or continue hormone therapy in this setting.”

The researchers compared the incidences of recurrent VTE and abnormal uterine bleeding in 1888 women who received anticoagulants with or without concurrent hormone therapy.

The team analyzed data from the EINSTEIN DVT and PE study, which was performed to evaluate the safety and efficacy of 2 anticoagulants—the direct oral anticoagulant rivaroxaban and the current standard of care, a low-molecular-weight heparin (enoxaparin) followed by a vitamin K antagonist (VKA).

Women of child-bearing potential were advised to use adequate methods of contraception to avoid birth defects.

Of all the women in the study, 475 used hormone therapy during the analysis period. Medications used included estrogen-only pills, combined estrogen-progestogen contraceptives, and progestin-only contraceptives.

Participants were questioned about symptoms or signs of recurrent VTE and bleeding, including uterine bleeding, during each follow-up visit.

Seven recurrent VTEs occurred while patients were using hormone therapy, while 38 events occurred during a period when patients were not using hormone therapy.

Based on this analysis, the researchers concluded that women on anticoagulants and hormone therapy experienced recurrent VTE at a rate of 3.7% per year. In contrast, those not on hormone therapy had a recurrence rate of 4.7% per year.

The incidence of abnormal uterine bleeding in patients on hormonal therapy was 22.5%, compared to 21.4% for women not on hormone therapy.

According to the study authors, the similar incidence of VTE and abnormal uterine bleeding in women who did and did not receive hormone therapy suggest that combined use of these therapies is safe.

The study also showed that abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA. The bleeding rate was estimated at 29.8% per year for patients on rivaroxaban and 15.5% per year in the enoxaparin/VKA group.

The researchers said this outcome suggests the need for further studies on rivaroxaban, which may be preferred for its convenience over enoxaparin/VKA.

“For the first time, we demonstrate that women suffering from blood clots can safely take hormone-containing contraceptives or hormone replacement therapy with anticoagulants, providing women the freedom to choose the method of birth control and other hormone-containing medications they prefer,” Dr Martinelli said.

“While further investigation is needed to evaluate the inconvenience of abnormal uterine bleeding with rivaroxaban and the other direct oral anticoagulants, these results dispel former misconceptions and should allow clinicians to confidently treat their patients who take blood thinners and hormones concurrently.”