The September 2018 Practice Alert, “CDC recommendations for the 2018-2019 influenza season” contained an error (J Fam Pract. 2018. 67:550-553). On page 552, under “Available vaccine products,” the article listed “one standard dose IIV4 intradermal option.” This was incorrect. Sanofi Pasteur, the manufacturer of standard dose Intradermal IIV4, discontinued the production and supply of Fluzone Intradermal Quadrivalent vaccine at the conclusion of the 2017-2018 influenza season.

The September 2018 Practice Alert, “CDC recommendations for the 2018-2019 influenza season” contained an error (J Fam Pract. 2018. 67:550-553). On page 552, under “Available vaccine products,” the article listed “one standard dose IIV4 intradermal option.” This was incorrect. Sanofi Pasteur, the manufacturer of standard dose Intradermal IIV4, discontinued the production and supply of Fluzone Intradermal Quadrivalent vaccine at the conclusion of the 2017-2018 influenza season.

The September 2018 Practice Alert, “CDC recommendations for the 2018-2019 influenza season” contained an error (J Fam Pract. 2018. 67:550-553). On page 552, under “Available vaccine products,” the article listed “one standard dose IIV4 intradermal option.” This was incorrect. Sanofi Pasteur, the manufacturer of standard dose Intradermal IIV4, discontinued the production and supply of Fluzone Intradermal Quadrivalent vaccine at the conclusion of the 2017-2018 influenza season.

In the Clinical Inquiry, “Does prophylactic azithromycin reduce the number of COPD exacerbations or hospitalizations?” (J Fam Pract. 2018;67:384-385), Lyon et al state that azithromycin “doesn’t benefit patients ≤65 years, patients with GOLD [Global Initiative for Obstructive Lung Disease] stage IV COPD [chronic obstructive pulmonary disease], current smokers, or patients not using oxygen (strength of recommendation [SOR]: B, randomized controlled trials [RCTs]).” These categorical statements are misleading, and clinicians should ignore most of them when considering azithromycin for their patients with severe COPD.

It would be more accurate to say that there may be a diminished efficacy of azithromycin for patients with GOLD IV COPD and age ≤65 years.

The authors cited groups that were identified in a posthoc analysis¹ of the only large trial involving azithromycin for the treatment of COPD to date.²P values for the interaction of azithromycin with GOLD stage (P=.04), smoking (P=.03), and age (P=.02) were significant, but the mean effects (hazard ratios [HRs]) for GOLD stage IV, smoking, and age ≤65 were .84, .99, and .84, respectively. It would be more accurate to say that there may be a diminished efficacy of azithromycin for patients with GOLD IV COPD and age ≤65 years. Only smokers appear to show no response, although the lower end of the 95% confidence interval was 0.71. The P value for the interaction of azithromycin with no long-term oxygen use (P=.23) was not significant, and it is incorrect to infer that oxygen use or nonuse predicts response.

The authors correctly state that the “significance of the results is limited because the study was not originally powered for this level of subgroup analysis,” but this statement is buried later in the article.

David L. Hahn, MD, MS
Madison, Wis

1. Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189:1503-1508.

2. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698.

Continue to: Author's response...

Author’s response:

Your statement that the evidence-based answer regarding the lack of benefit of azithromycin in patients ≤65 years of age, with stage IV COPD, current smokers, and patients not using oxygen is “misleading” is a bit of an overstatement.

It is fair to say, however, that our statement regarding lack of efficacy among these subgroups of patients should be softened a bit since the data are from subgroup analyses, which should never be the source of definitive conclusions. And you point out that the 95% confidence intervals [CIs] of the HRs for these subgroups of patients do not include a potentially significant effect (0.68, 0.71, 0.61, and 0.65, respectively), so it is possible there is a Type II error, which would lead one to conclude there is no effect for these subgroups when there is one.

Regarding oxygen therapy, in this Clinical Inquiry, we presented data from the direct subgroup analysis, which revealed no difference in COPD exacerbations between the azithromycin and placebo groups for patients not receiving long-term supplemental oxygen (HR=0.80; 95% CI, 0.62-1.03); however, you are correct to point out that the oxygen use subgroup interaction (patients on oxygen vs patients not on oxygen), which we did not include in this Clinical Inquiry, did not reach significance (P=.23), casting some doubt on the authors’ conclusion of no effect for patients not on oxygen.

On the whole, I feel this Clinical Inquiry accurately summarized the existing evidence and that additional research is needed to better define the utility of azithromycin in these subgroups of patients.

Corey Lyon, DO
Denver, Colo

In the Clinical Inquiry, “Does prophylactic azithromycin reduce the number of COPD exacerbations or hospitalizations?” (J Fam Pract. 2018;67:384-385), Lyon et al state that azithromycin “doesn’t benefit patients ≤65 years, patients with GOLD [Global Initiative for Obstructive Lung Disease] stage IV COPD [chronic obstructive pulmonary disease], current smokers, or patients not using oxygen (strength of recommendation [SOR]: B, randomized controlled trials [RCTs]).” These categorical statements are misleading, and clinicians should ignore most of them when considering azithromycin for their patients with severe COPD.

It would be more accurate to say that there may be a diminished efficacy of azithromycin for patients with GOLD IV COPD and age ≤65 years.

The authors cited groups that were identified in a posthoc analysis¹ of the only large trial involving azithromycin for the treatment of COPD to date.²P values for the interaction of azithromycin with GOLD stage (P=.04), smoking (P=.03), and age (P=.02) were significant, but the mean effects (hazard ratios [HRs]) for GOLD stage IV, smoking, and age ≤65 were .84, .99, and .84, respectively. It would be more accurate to say that there may be a diminished efficacy of azithromycin for patients with GOLD IV COPD and age ≤65 years. Only smokers appear to show no response, although the lower end of the 95% confidence interval was 0.71. The P value for the interaction of azithromycin with no long-term oxygen use (P=.23) was not significant, and it is incorrect to infer that oxygen use or nonuse predicts response.

The authors correctly state that the “significance of the results is limited because the study was not originally powered for this level of subgroup analysis,” but this statement is buried later in the article.

David L. Hahn, MD, MS
Madison, Wis

1. Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189:1503-1508.

2. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698.

Continue to: Author's response...

Author’s response:

Your statement that the evidence-based answer regarding the lack of benefit of azithromycin in patients ≤65 years of age, with stage IV COPD, current smokers, and patients not using oxygen is “misleading” is a bit of an overstatement.

It is fair to say, however, that our statement regarding lack of efficacy among these subgroups of patients should be softened a bit since the data are from subgroup analyses, which should never be the source of definitive conclusions. And you point out that the 95% confidence intervals [CIs] of the HRs for these subgroups of patients do not include a potentially significant effect (0.68, 0.71, 0.61, and 0.65, respectively), so it is possible there is a Type II error, which would lead one to conclude there is no effect for these subgroups when there is one.

Regarding oxygen therapy, in this Clinical Inquiry, we presented data from the direct subgroup analysis, which revealed no difference in COPD exacerbations between the azithromycin and placebo groups for patients not receiving long-term supplemental oxygen (HR=0.80; 95% CI, 0.62-1.03); however, you are correct to point out that the oxygen use subgroup interaction (patients on oxygen vs patients not on oxygen), which we did not include in this Clinical Inquiry, did not reach significance (P=.23), casting some doubt on the authors’ conclusion of no effect for patients not on oxygen.

On the whole, I feel this Clinical Inquiry accurately summarized the existing evidence and that additional research is needed to better define the utility of azithromycin in these subgroups of patients.

Corey Lyon, DO
Denver, Colo

In the Clinical Inquiry, “Does prophylactic azithromycin reduce the number of COPD exacerbations or hospitalizations?” (J Fam Pract. 2018;67:384-385), Lyon et al state that azithromycin “doesn’t benefit patients ≤65 years, patients with GOLD [Global Initiative for Obstructive Lung Disease] stage IV COPD [chronic obstructive pulmonary disease], current smokers, or patients not using oxygen (strength of recommendation [SOR]: B, randomized controlled trials [RCTs]).” These categorical statements are misleading, and clinicians should ignore most of them when considering azithromycin for their patients with severe COPD.

It would be more accurate to say that there may be a diminished efficacy of azithromycin for patients with GOLD IV COPD and age ≤65 years.

The authors cited groups that were identified in a posthoc analysis¹ of the only large trial involving azithromycin for the treatment of COPD to date.²P values for the interaction of azithromycin with GOLD stage (P=.04), smoking (P=.03), and age (P=.02) were significant, but the mean effects (hazard ratios [HRs]) for GOLD stage IV, smoking, and age ≤65 were .84, .99, and .84, respectively. It would be more accurate to say that there may be a diminished efficacy of azithromycin for patients with GOLD IV COPD and age ≤65 years. Only smokers appear to show no response, although the lower end of the 95% confidence interval was 0.71. The P value for the interaction of azithromycin with no long-term oxygen use (P=.23) was not significant, and it is incorrect to infer that oxygen use or nonuse predicts response.

The authors correctly state that the “significance of the results is limited because the study was not originally powered for this level of subgroup analysis,” but this statement is buried later in the article.

David L. Hahn, MD, MS
Madison, Wis

1. Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189:1503-1508.

2. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698.

Continue to: Author's response...

Author’s response:

Your statement that the evidence-based answer regarding the lack of benefit of azithromycin in patients ≤65 years of age, with stage IV COPD, current smokers, and patients not using oxygen is “misleading” is a bit of an overstatement.

It is fair to say, however, that our statement regarding lack of efficacy among these subgroups of patients should be softened a bit since the data are from subgroup analyses, which should never be the source of definitive conclusions. And you point out that the 95% confidence intervals [CIs] of the HRs for these subgroups of patients do not include a potentially significant effect (0.68, 0.71, 0.61, and 0.65, respectively), so it is possible there is a Type II error, which would lead one to conclude there is no effect for these subgroups when there is one.

Regarding oxygen therapy, in this Clinical Inquiry, we presented data from the direct subgroup analysis, which revealed no difference in COPD exacerbations between the azithromycin and placebo groups for patients not receiving long-term supplemental oxygen (HR=0.80; 95% CI, 0.62-1.03); however, you are correct to point out that the oxygen use subgroup interaction (patients on oxygen vs patients not on oxygen), which we did not include in this Clinical Inquiry, did not reach significance (P=.23), casting some doubt on the authors’ conclusion of no effect for patients not on oxygen.

On the whole, I feel this Clinical Inquiry accurately summarized the existing evidence and that additional research is needed to better define the utility of azithromycin in these subgroups of patients.

Corey Lyon, DO
Denver, Colo

EVIDENCE SUMMARY

A meta-analysis of 15 RCTs (5583 women) compared intentional artificial rupture of the amniotic membranes during labor (amniotomy) with intention to preserve the membranes (no amniotomy). The study found no differences in any of the measured primary outcomes: length of first stage of labor, cesarean section, maternal satisfaction with childbirth, or Apgar score <7 at 5 minutes.¹

Investigators included 9 trials with both nulliparous and multiparous women and 6 trials with only nulliparous women. Thirteen trials compared amniotomy with intention to preserve the membranes, and 2 trials performed amniotomy in the control group if the membranes were intact at full cervical dilation.

Amniotomy doesn’t affect first-stage labor or cesarean risk

Five trials (1127 women) reported no difference in length of the first stage of labor between the amniotomy and no amniotomy groups (mean difference [MD]= −20 minutes; 95% confidence interval [CI], −96 to 55). Subgroups of primiparous and multiparous women showed no difference (MD= −58 minutes; 95% CI, −153 to 37 and MD= +23 minutes; 95% CI, −51 to 97, respectively).

Nine trials (5021 women) reported no significant difference in cesarean section risk overall or when compared by parity, multiparous vs primiparous (risk ratio [RR]= 1.27; 95% CI, 0.99-1.63). One trial (84 women) found no difference in maternal satisfaction scores with childbirth experience. Six trials (3598 women) that reported risk of low Apgar score (<4 at 1 minute or <7 at 5 minutes) found no difference overall (RR=0.53; 95% CI, 0.28-1.00), or when compared by parity (multiparous vs primiparous).

Amniotomy doesn’t shorten spontaneous labor nor improve length of first-stage labor, cesarean section rate, or maternal satisfaction with childbirth.

Investigators reported that the included trials varied in quality and described the following limitations: inconsistent or unspecified timing of amniotomy during labor, proportion of women in the control group undergoing amniotomy, and ≥30% of women not getting the allocated treatment in all but one of the trials.

Secondary outcomes: Amniotomy reduces oxytocin use

Eight trials (4264 women) evaluated oxytocin augmentation and found that amniotomy decreased its use in multiparous (RR=0.43; 95% CI, 0.30-0.60), but not primiparous, women.

Eight trials (1927 women) reported length of second stage of labor as a secondary outcome, with no difference overall (MD= −1.33 minutes; 95% CI, −2.92 to 0.26). Amniotomy produced a statistical but not clinically significant shortening in subanalysis of primiparous women (MD= −5.43 minutes; 95% CI, −9.98 to −0.89) but not multiparous women.

Continue to: Three trials...

Three trials (1695 women) evaluated dysfunctional labor, defined as no progress in cervical dilation in 2 hours or ineffective uterine contractions. Amniotomy reduced dysfunctional labor in both primiparous (RR=0.49; 95% CI, 0.33-0.73) and multiparous women (RR=0.44; 95% CI, 0.31-0.62).

No differences found in other maternal and fetal outcomes

Investigators reported no differences in other secondary maternal outcomes: instrumental vaginal birth (10 trials, 5121 women); pain relief (8 trials, 3475 women); postpartum hemorrhage (2 trials, 1822 women); serious maternal morbidity or death (3 trials, 1740 women); umbilical cord prolapse (2 trials, 1615 women); and cesarean section for fetal distress, prolonged labor, or antepartum hemorrhage (1 RCT, 690 women).

Investigators also found no differences in secondary fetal outcomes: serious neonatal morbidity or perinatal death (8 trials, 3397 women); neonatal admission to neonatal intensive care (5 trials, 2686 women); abnormal fetal heart rate tracing in first stage of labor (4 trials, 1284 women); meconium aspiration (2 trials, 1615 women); and fetal acidosis (2 trials, 1014 women). Similarly, 1 RCT (39 women) that compared amniotomy with intent to preserve membranes in spontaneous labors that became prolonged found no difference in cesarean section, maternal satisfaction, or Apgar scores.

A few studies claim shorter labor with amniotomy

However, a later Iranian RCT (300 women) reported that early amniotomy shortened labor (labor duration: 7.5 ± 0.7 hours with amniotomy vs 9.9 ± 1.0 hours without amniotomy; P<.001) and reduced the risk of dystocia (RR=0.81; 95% CI, 0.59-0.90) and cesarean section (RR=0.82; 95% CI, 0.66-0.90).²

A similar Nigerian RCT (214 women) and an Indian RCT (144 women) both claimed that amniotomy also shortened labor (4.7 ± 0.9 hours vs 5.9 ± 1.3, and 3.9 ± 2 hours vs 6.1 ± 2.8 hours, respectively).^3,4 In neither trial, however, did investigators explain how the difference was significant when the duration of labor times overlapped within the margin of error.

EVIDENCE SUMMARY

A meta-analysis of 15 RCTs (5583 women) compared intentional artificial rupture of the amniotic membranes during labor (amniotomy) with intention to preserve the membranes (no amniotomy). The study found no differences in any of the measured primary outcomes: length of first stage of labor, cesarean section, maternal satisfaction with childbirth, or Apgar score <7 at 5 minutes.¹

Investigators included 9 trials with both nulliparous and multiparous women and 6 trials with only nulliparous women. Thirteen trials compared amniotomy with intention to preserve the membranes, and 2 trials performed amniotomy in the control group if the membranes were intact at full cervical dilation.

Amniotomy doesn’t affect first-stage labor or cesarean risk

Five trials (1127 women) reported no difference in length of the first stage of labor between the amniotomy and no amniotomy groups (mean difference [MD]= −20 minutes; 95% confidence interval [CI], −96 to 55). Subgroups of primiparous and multiparous women showed no difference (MD= −58 minutes; 95% CI, −153 to 37 and MD= +23 minutes; 95% CI, −51 to 97, respectively).

Nine trials (5021 women) reported no significant difference in cesarean section risk overall or when compared by parity, multiparous vs primiparous (risk ratio [RR]= 1.27; 95% CI, 0.99-1.63). One trial (84 women) found no difference in maternal satisfaction scores with childbirth experience. Six trials (3598 women) that reported risk of low Apgar score (<4 at 1 minute or <7 at 5 minutes) found no difference overall (RR=0.53; 95% CI, 0.28-1.00), or when compared by parity (multiparous vs primiparous).

Amniotomy doesn’t shorten spontaneous labor nor improve length of first-stage labor, cesarean section rate, or maternal satisfaction with childbirth.

Investigators reported that the included trials varied in quality and described the following limitations: inconsistent or unspecified timing of amniotomy during labor, proportion of women in the control group undergoing amniotomy, and ≥30% of women not getting the allocated treatment in all but one of the trials.

Secondary outcomes: Amniotomy reduces oxytocin use

Eight trials (4264 women) evaluated oxytocin augmentation and found that amniotomy decreased its use in multiparous (RR=0.43; 95% CI, 0.30-0.60), but not primiparous, women.

Eight trials (1927 women) reported length of second stage of labor as a secondary outcome, with no difference overall (MD= −1.33 minutes; 95% CI, −2.92 to 0.26). Amniotomy produced a statistical but not clinically significant shortening in subanalysis of primiparous women (MD= −5.43 minutes; 95% CI, −9.98 to −0.89) but not multiparous women.

Continue to: Three trials...

Three trials (1695 women) evaluated dysfunctional labor, defined as no progress in cervical dilation in 2 hours or ineffective uterine contractions. Amniotomy reduced dysfunctional labor in both primiparous (RR=0.49; 95% CI, 0.33-0.73) and multiparous women (RR=0.44; 95% CI, 0.31-0.62).

No differences found in other maternal and fetal outcomes

Investigators reported no differences in other secondary maternal outcomes: instrumental vaginal birth (10 trials, 5121 women); pain relief (8 trials, 3475 women); postpartum hemorrhage (2 trials, 1822 women); serious maternal morbidity or death (3 trials, 1740 women); umbilical cord prolapse (2 trials, 1615 women); and cesarean section for fetal distress, prolonged labor, or antepartum hemorrhage (1 RCT, 690 women).

Investigators also found no differences in secondary fetal outcomes: serious neonatal morbidity or perinatal death (8 trials, 3397 women); neonatal admission to neonatal intensive care (5 trials, 2686 women); abnormal fetal heart rate tracing in first stage of labor (4 trials, 1284 women); meconium aspiration (2 trials, 1615 women); and fetal acidosis (2 trials, 1014 women). Similarly, 1 RCT (39 women) that compared amniotomy with intent to preserve membranes in spontaneous labors that became prolonged found no difference in cesarean section, maternal satisfaction, or Apgar scores.

A few studies claim shorter labor with amniotomy

However, a later Iranian RCT (300 women) reported that early amniotomy shortened labor (labor duration: 7.5 ± 0.7 hours with amniotomy vs 9.9 ± 1.0 hours without amniotomy; P<.001) and reduced the risk of dystocia (RR=0.81; 95% CI, 0.59-0.90) and cesarean section (RR=0.82; 95% CI, 0.66-0.90).²

A similar Nigerian RCT (214 women) and an Indian RCT (144 women) both claimed that amniotomy also shortened labor (4.7 ± 0.9 hours vs 5.9 ± 1.3, and 3.9 ± 2 hours vs 6.1 ± 2.8 hours, respectively).^3,4 In neither trial, however, did investigators explain how the difference was significant when the duration of labor times overlapped within the margin of error.

EVIDENCE SUMMARY

A meta-analysis of 15 RCTs (5583 women) compared intentional artificial rupture of the amniotic membranes during labor (amniotomy) with intention to preserve the membranes (no amniotomy). The study found no differences in any of the measured primary outcomes: length of first stage of labor, cesarean section, maternal satisfaction with childbirth, or Apgar score <7 at 5 minutes.¹

Investigators included 9 trials with both nulliparous and multiparous women and 6 trials with only nulliparous women. Thirteen trials compared amniotomy with intention to preserve the membranes, and 2 trials performed amniotomy in the control group if the membranes were intact at full cervical dilation.

Amniotomy doesn’t affect first-stage labor or cesarean risk

Five trials (1127 women) reported no difference in length of the first stage of labor between the amniotomy and no amniotomy groups (mean difference [MD]= −20 minutes; 95% confidence interval [CI], −96 to 55). Subgroups of primiparous and multiparous women showed no difference (MD= −58 minutes; 95% CI, −153 to 37 and MD= +23 minutes; 95% CI, −51 to 97, respectively).

Nine trials (5021 women) reported no significant difference in cesarean section risk overall or when compared by parity, multiparous vs primiparous (risk ratio [RR]= 1.27; 95% CI, 0.99-1.63). One trial (84 women) found no difference in maternal satisfaction scores with childbirth experience. Six trials (3598 women) that reported risk of low Apgar score (<4 at 1 minute or <7 at 5 minutes) found no difference overall (RR=0.53; 95% CI, 0.28-1.00), or when compared by parity (multiparous vs primiparous).

Amniotomy doesn’t shorten spontaneous labor nor improve length of first-stage labor, cesarean section rate, or maternal satisfaction with childbirth.

Investigators reported that the included trials varied in quality and described the following limitations: inconsistent or unspecified timing of amniotomy during labor, proportion of women in the control group undergoing amniotomy, and ≥30% of women not getting the allocated treatment in all but one of the trials.

Secondary outcomes: Amniotomy reduces oxytocin use

Eight trials (4264 women) evaluated oxytocin augmentation and found that amniotomy decreased its use in multiparous (RR=0.43; 95% CI, 0.30-0.60), but not primiparous, women.

Eight trials (1927 women) reported length of second stage of labor as a secondary outcome, with no difference overall (MD= −1.33 minutes; 95% CI, −2.92 to 0.26). Amniotomy produced a statistical but not clinically significant shortening in subanalysis of primiparous women (MD= −5.43 minutes; 95% CI, −9.98 to −0.89) but not multiparous women.

Continue to: Three trials...

Three trials (1695 women) evaluated dysfunctional labor, defined as no progress in cervical dilation in 2 hours or ineffective uterine contractions. Amniotomy reduced dysfunctional labor in both primiparous (RR=0.49; 95% CI, 0.33-0.73) and multiparous women (RR=0.44; 95% CI, 0.31-0.62).

No differences found in other maternal and fetal outcomes

Investigators reported no differences in other secondary maternal outcomes: instrumental vaginal birth (10 trials, 5121 women); pain relief (8 trials, 3475 women); postpartum hemorrhage (2 trials, 1822 women); serious maternal morbidity or death (3 trials, 1740 women); umbilical cord prolapse (2 trials, 1615 women); and cesarean section for fetal distress, prolonged labor, or antepartum hemorrhage (1 RCT, 690 women).

Investigators also found no differences in secondary fetal outcomes: serious neonatal morbidity or perinatal death (8 trials, 3397 women); neonatal admission to neonatal intensive care (5 trials, 2686 women); abnormal fetal heart rate tracing in first stage of labor (4 trials, 1284 women); meconium aspiration (2 trials, 1615 women); and fetal acidosis (2 trials, 1014 women). Similarly, 1 RCT (39 women) that compared amniotomy with intent to preserve membranes in spontaneous labors that became prolonged found no difference in cesarean section, maternal satisfaction, or Apgar scores.

A few studies claim shorter labor with amniotomy

However, a later Iranian RCT (300 women) reported that early amniotomy shortened labor (labor duration: 7.5 ± 0.7 hours with amniotomy vs 9.9 ± 1.0 hours without amniotomy; P<.001) and reduced the risk of dystocia (RR=0.81; 95% CI, 0.59-0.90) and cesarean section (RR=0.82; 95% CI, 0.66-0.90).²

A similar Nigerian RCT (214 women) and an Indian RCT (144 women) both claimed that amniotomy also shortened labor (4.7 ± 0.9 hours vs 5.9 ± 1.3, and 3.9 ± 2 hours vs 6.1 ± 2.8 hours, respectively).^3,4 In neither trial, however, did investigators explain how the difference was significant when the duration of labor times overlapped within the margin of error.

In these first decades of the 21st century, the United States is the richest, strongest, most innovative nation on the planet. Americans like to chant “We’re Number 1”—and by many measures, they’re right. But in one crucial area of human endeavor—keeping people healthy—the mighty United States is a third-rate power.

All the other industrialized democracies have significantly better health outcomes than the United States—longer life expectancy, better recovery rates from illness or injury, less infant mortality.¹ Yet these nations spend, on average, half as much as the United States does for health care.¹ And these other rich democracies guarantee health care for everyone—while the United States leaves 29 million people ages <65 years with no health insurance, and another 50 million with deductibles so high that they are effectively uninsured.^2,3

This disgraceful state of affairs is not the fault of the nation’s physicians. Rather, the problems with health care in the United States stem from the system that American providers have to work in.

Health care has become big business. As the physician-turned-reporter Dr. Elisabeth Rosenthal notes in An American Sickness: How Healthcare Became Big Business, profits have come to matter more than patients for much of the $3.3 trillion US health care industry.^4,5 And the financial winners in our system—notably the “Big Four” health insurance giants, the for-profit hospital chains, and “Big Pharma”—fight hard to protect their profits. When the Affordable Care Act (“ObamaCare”) was first proposed, one of its main goals was to cut the administrative costs of health insurance, to force the private insurers to run their business as efficiently as Medicare. The insurance industry didn’t like that; its lobbyists fought back, successfully. As passed, the law allows the insurers to add up to 20% in administrative fees to every doctor and hospital bill—which adds hundreds of billions of dollars to the nation’s total health care spending every year.

Primary care doctors earn significantly less than specialists. But it doesn’t have to be that way.

Then there’s the problem that health-care economists call “specialty distribution imbalance.” In plain English, this means that the United States has too many doctors working in narrow (but highly compensated) subspecialties and not enough in the primary care fields of family medicine, internal medicine, and pediatrics. This is one more area where our country is out of sync with other industrialized democracies.

When I traveled the world studying health care systems, economists and government health ministers regularly told me that an efficient system should have 2 primary care providers for every 1 specialist. That is, primary care should make up about 66% of the overall physician work force.

If a 2:1 ratio of primary care providers to specialists is right, then the United States is upside down.

Most rich countries come close to this desired ratio. In the United Kingdom, family doctors working out of their own offices (it’s called a “surgery”) and treating patients on the local High Street (that is, Main Street), control 70% of the National Health Service (NHS) budget.⁶ “That’s the framework of the NHS, and of course we want to keep it,” John Reid, the UK’s former Minister of Health, told me. “If you just pop into your doctor’s surgery on the high street, that’s often just as effective, but never as expensive, as waiting to see a specialist.”

Continue to: If that 2:1 ratio is the right proportion...

If that 2:1 ratio is the right proportion for an effective health care system, the United States is upside down. For decades now, some two-thirds of new medical graduates have gone into narrower specialties, leaving our country with a serious shortage of primary care physicians.⁷ This situation helps to explain the higher cost and poorer overall outcomes that characterize American health care.

“Health care is often delivered according to a model that concentrates on diseases, high technology, and specialist care,” a report from the World Health Organization noted.⁸ “The results are...higher overall costs, and exclusion of people who cannot pay.” The report concluded that an emphasis on primary care leads to better outcomes for the same level of investment. This simple truth has been called the “Iron Law” of health care systems.

How can the United States get more primary care physicians? One answer is compensation. American primary care doctors routinely earn significantly less than specialists. But it doesn’t have to be that way. When I asked my family doctor in London, Dr. Ahmed Badat, why it is that 62% of British physicians are in family care, he was blunt: “Under the NHS, I make twice as much as a cardiac surgeon.”

If the big payers—government programs and private insurers—beef up fees for primary care (and pay for it by reducing compensation for specialists), more young American med students are likely to choose that route. Repayment plans that forgive the student loans of those in primary care fields also would attract more newly-minted physicians; these programs already are in place in several states.⁹

Continue to: Medical schools also have a role...

Medical schools also have a role to play. It’s no secret that the schools have emphasized specialties, with faculty members often steering their best students into narrow fields. But schools could promote an atmosphere in which primary care is treated as the most desirable destination for new doctors. Actively seeking out, and accepting, applicants who say they want to practice primary care is another key tool the medical schools could employ to deal with this national problem.

More doctors in primary care would mean better health care at lower cost for American patients. It’s long past time to take the steps needed to reach that goal.

In these first decades of the 21st century, the United States is the richest, strongest, most innovative nation on the planet. Americans like to chant “We’re Number 1”—and by many measures, they’re right. But in one crucial area of human endeavor—keeping people healthy—the mighty United States is a third-rate power.

All the other industrialized democracies have significantly better health outcomes than the United States—longer life expectancy, better recovery rates from illness or injury, less infant mortality.¹ Yet these nations spend, on average, half as much as the United States does for health care.¹ And these other rich democracies guarantee health care for everyone—while the United States leaves 29 million people ages <65 years with no health insurance, and another 50 million with deductibles so high that they are effectively uninsured.^2,3

This disgraceful state of affairs is not the fault of the nation’s physicians. Rather, the problems with health care in the United States stem from the system that American providers have to work in.

Health care has become big business. As the physician-turned-reporter Dr. Elisabeth Rosenthal notes in An American Sickness: How Healthcare Became Big Business, profits have come to matter more than patients for much of the $3.3 trillion US health care industry.^4,5 And the financial winners in our system—notably the “Big Four” health insurance giants, the for-profit hospital chains, and “Big Pharma”—fight hard to protect their profits. When the Affordable Care Act (“ObamaCare”) was first proposed, one of its main goals was to cut the administrative costs of health insurance, to force the private insurers to run their business as efficiently as Medicare. The insurance industry didn’t like that; its lobbyists fought back, successfully. As passed, the law allows the insurers to add up to 20% in administrative fees to every doctor and hospital bill—which adds hundreds of billions of dollars to the nation’s total health care spending every year.

Primary care doctors earn significantly less than specialists. But it doesn’t have to be that way.

Then there’s the problem that health-care economists call “specialty distribution imbalance.” In plain English, this means that the United States has too many doctors working in narrow (but highly compensated) subspecialties and not enough in the primary care fields of family medicine, internal medicine, and pediatrics. This is one more area where our country is out of sync with other industrialized democracies.

When I traveled the world studying health care systems, economists and government health ministers regularly told me that an efficient system should have 2 primary care providers for every 1 specialist. That is, primary care should make up about 66% of the overall physician work force.

If a 2:1 ratio of primary care providers to specialists is right, then the United States is upside down.

Most rich countries come close to this desired ratio. In the United Kingdom, family doctors working out of their own offices (it’s called a “surgery”) and treating patients on the local High Street (that is, Main Street), control 70% of the National Health Service (NHS) budget.⁶ “That’s the framework of the NHS, and of course we want to keep it,” John Reid, the UK’s former Minister of Health, told me. “If you just pop into your doctor’s surgery on the high street, that’s often just as effective, but never as expensive, as waiting to see a specialist.”

Continue to: If that 2:1 ratio is the right proportion...

If that 2:1 ratio is the right proportion for an effective health care system, the United States is upside down. For decades now, some two-thirds of new medical graduates have gone into narrower specialties, leaving our country with a serious shortage of primary care physicians.⁷ This situation helps to explain the higher cost and poorer overall outcomes that characterize American health care.

“Health care is often delivered according to a model that concentrates on diseases, high technology, and specialist care,” a report from the World Health Organization noted.⁸ “The results are...higher overall costs, and exclusion of people who cannot pay.” The report concluded that an emphasis on primary care leads to better outcomes for the same level of investment. This simple truth has been called the “Iron Law” of health care systems.

How can the United States get more primary care physicians? One answer is compensation. American primary care doctors routinely earn significantly less than specialists. But it doesn’t have to be that way. When I asked my family doctor in London, Dr. Ahmed Badat, why it is that 62% of British physicians are in family care, he was blunt: “Under the NHS, I make twice as much as a cardiac surgeon.”

If the big payers—government programs and private insurers—beef up fees for primary care (and pay for it by reducing compensation for specialists), more young American med students are likely to choose that route. Repayment plans that forgive the student loans of those in primary care fields also would attract more newly-minted physicians; these programs already are in place in several states.⁹

Continue to: Medical schools also have a role...

Medical schools also have a role to play. It’s no secret that the schools have emphasized specialties, with faculty members often steering their best students into narrow fields. But schools could promote an atmosphere in which primary care is treated as the most desirable destination for new doctors. Actively seeking out, and accepting, applicants who say they want to practice primary care is another key tool the medical schools could employ to deal with this national problem.

More doctors in primary care would mean better health care at lower cost for American patients. It’s long past time to take the steps needed to reach that goal.

In these first decades of the 21st century, the United States is the richest, strongest, most innovative nation on the planet. Americans like to chant “We’re Number 1”—and by many measures, they’re right. But in one crucial area of human endeavor—keeping people healthy—the mighty United States is a third-rate power.

All the other industrialized democracies have significantly better health outcomes than the United States—longer life expectancy, better recovery rates from illness or injury, less infant mortality.¹ Yet these nations spend, on average, half as much as the United States does for health care.¹ And these other rich democracies guarantee health care for everyone—while the United States leaves 29 million people ages <65 years with no health insurance, and another 50 million with deductibles so high that they are effectively uninsured.^2,3

This disgraceful state of affairs is not the fault of the nation’s physicians. Rather, the problems with health care in the United States stem from the system that American providers have to work in.

Health care has become big business. As the physician-turned-reporter Dr. Elisabeth Rosenthal notes in An American Sickness: How Healthcare Became Big Business, profits have come to matter more than patients for much of the $3.3 trillion US health care industry.^4,5 And the financial winners in our system—notably the “Big Four” health insurance giants, the for-profit hospital chains, and “Big Pharma”—fight hard to protect their profits. When the Affordable Care Act (“ObamaCare”) was first proposed, one of its main goals was to cut the administrative costs of health insurance, to force the private insurers to run their business as efficiently as Medicare. The insurance industry didn’t like that; its lobbyists fought back, successfully. As passed, the law allows the insurers to add up to 20% in administrative fees to every doctor and hospital bill—which adds hundreds of billions of dollars to the nation’s total health care spending every year.

Primary care doctors earn significantly less than specialists. But it doesn’t have to be that way.

Then there’s the problem that health-care economists call “specialty distribution imbalance.” In plain English, this means that the United States has too many doctors working in narrow (but highly compensated) subspecialties and not enough in the primary care fields of family medicine, internal medicine, and pediatrics. This is one more area where our country is out of sync with other industrialized democracies.

When I traveled the world studying health care systems, economists and government health ministers regularly told me that an efficient system should have 2 primary care providers for every 1 specialist. That is, primary care should make up about 66% of the overall physician work force.

If a 2:1 ratio of primary care providers to specialists is right, then the United States is upside down.

Most rich countries come close to this desired ratio. In the United Kingdom, family doctors working out of their own offices (it’s called a “surgery”) and treating patients on the local High Street (that is, Main Street), control 70% of the National Health Service (NHS) budget.⁶ “That’s the framework of the NHS, and of course we want to keep it,” John Reid, the UK’s former Minister of Health, told me. “If you just pop into your doctor’s surgery on the high street, that’s often just as effective, but never as expensive, as waiting to see a specialist.”

Continue to: If that 2:1 ratio is the right proportion...

If that 2:1 ratio is the right proportion for an effective health care system, the United States is upside down. For decades now, some two-thirds of new medical graduates have gone into narrower specialties, leaving our country with a serious shortage of primary care physicians.⁷ This situation helps to explain the higher cost and poorer overall outcomes that characterize American health care.

“Health care is often delivered according to a model that concentrates on diseases, high technology, and specialist care,” a report from the World Health Organization noted.⁸ “The results are...higher overall costs, and exclusion of people who cannot pay.” The report concluded that an emphasis on primary care leads to better outcomes for the same level of investment. This simple truth has been called the “Iron Law” of health care systems.

How can the United States get more primary care physicians? One answer is compensation. American primary care doctors routinely earn significantly less than specialists. But it doesn’t have to be that way. When I asked my family doctor in London, Dr. Ahmed Badat, why it is that 62% of British physicians are in family care, he was blunt: “Under the NHS, I make twice as much as a cardiac surgeon.”

If the big payers—government programs and private insurers—beef up fees for primary care (and pay for it by reducing compensation for specialists), more young American med students are likely to choose that route. Repayment plans that forgive the student loans of those in primary care fields also would attract more newly-minted physicians; these programs already are in place in several states.⁹

Continue to: Medical schools also have a role...

Medical schools also have a role to play. It’s no secret that the schools have emphasized specialties, with faculty members often steering their best students into narrow fields. But schools could promote an atmosphere in which primary care is treated as the most desirable destination for new doctors. Actively seeking out, and accepting, applicants who say they want to practice primary care is another key tool the medical schools could employ to deal with this national problem.

More doctors in primary care would mean better health care at lower cost for American patients. It’s long past time to take the steps needed to reach that goal.

A 22-year-old Caucasian man with a history of atopic dermatitis (AD) was referred to our dermatology clinic for evaluation of a diffuse facial rash that had been present for the previous 7 days. The rash initially presented as erythema on the right malar cheek that rapidly spread to the entire face. Initially diagnosed as impetigo, empiric treatment with sulfamethoxazole/trimethoprim (800 mg/160 mg PO BID for 7 days), dicloxacillin (500 mg PO BID for 6 days), cephalexin (500 mg TID for 5 days), and mupirocin (2% topical cream applied TID for 6 days) failed to improve the patient’s symptoms. He reported mild pain associated with facial movements.

The patient had a history of similar (but more limited) rashes, which he described as “recurrent impetigo,” that began during his career as a high school and collegiate wrestler. These rashes were different from the rashes he described as his history of AD, which consisted of pruritic and erythematous skin in his antecubital and popliteal fossae. He denied any history of herpes simplex virus (HSV) infection.

A physical examination revealed numerous monomorphic, 1- to 3-mm, punched-out erosions and ulcers with overlying yellow-brown crust encompassing the patient’s entire face and portions of his anterior neck. Several clustered vesicles on erythematous bases also were noted (FIGUREs 1A and 1B). We used a Dermablade to unroof some of the vesicles and sent the scrapings to the lab for Tzanck, direct fluorescent antibody assay (DFA), and HSV polymerase chain reaction (PCR) testing.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Eczema herpeticum secondary to herpes gladiatorum

The patient’s laboratory results came back and the Tzanck preparation was positive for multinucleated giant cells, and both the DFA and HSV PCR were positive for HSV infection. This, paired with the widely disseminated rash observed on examination and the patient’s history of AD, was consistent with a diagnosis of eczema herpeticum (EH).

Rather than primary impetigo, the patient’s self-described history of recurrent rashes was felt to represent a history of HSV outbreaks. Given his denial of prior oral or genital HSV infection, as well as the coincident onset of these outbreaks during his career as a competitive wrestler, the most likely primary infection source was direct contact with another HSV-infected wrestler.

Herpes gladiatorum refers to a primary cutaneous HSV infection contracted by an athlete through direct skin-to-skin contact with another athlete.¹ It is common in contact sports, such as rugby and wrestling, and particularly common at organized wrestling camps, where mass outbreaks are a frequent occurrence.² Herpes gladiatorum is so common at these camps that many recommend prophylactic valacyclovir treatment for all participants to mitigate the risk of contracting HSV. In a 2016 review, Anderson et al concluded that prophylactic valacyclovir treatment at a 28-day high school wrestling camp effectively reduced outbreak incidence by 89.5%.²

Prophylactic valacyclovir treatment at a 28-day high school wrestling camp reduced outbreak incidence of herpes gladiatorum by 89.5%.

The lesions of herpes gladiatorum are classically limited in distribution and reflective of the areas of direct contact with infected skin, most commonly the face, neck, and arms. Our patient’s history of more limited outbreaks on his face was consistent with this typical presentation. His current outbreak, however, had become much more widely disseminated, which led to the diagnosis of EH secondary to herpes gladiatorum.

Eczema herpeticum: Pathogenesis and diagnosis

Also known as Kaposi’s varicelliform eruption, EH is a rapid, widespread cutaneous dissemination of HSV infection in areas of dermatitis or skin barrier disruption, most commonly caused by HSV-1 infection.³ It is classically associated with AD, but also can occur in patients with impaired epidermal barrier function due to other conditions, such as burns, pemphigus vulgaris, mycosis fungoides, and Darier disease.⁴ It occurs in <3% of patients with AD and is more commonly observed in infants and children with AD than adults.⁵

Continue to: Clinically, the most common manifestations are discrete..

Clinically, the most common manifestations are discrete, monomorphic, 2- to 3-mm, punched-out erosions with hemorrhagic crusts; intact vesicles are less commonly observed.⁴ Involved skin is typically painful and may be pruritic. Clinical diagnosis should be confirmed by laboratory evaluation, typically Tzanck preparation, DFA, and/or HSV PCR.

Complications and the importance of rapid treatment

The most common complication of EH is bacterial superinfection (impetigo), usually by Staphylococcus aureus or group A streptococci. Signs of bacterial superinfection include weeping lesions, pustules, honey-colored/golden crusting, worsening of existing dermatitis, and failure to respond to antiviral treatment. Topical mupirocin 2% cream is generally effective for controlling limited infection. However, systemic antibiotics (cephalosporins or penicillinase-resistant penicillins) may be necessary to control widespread disease.⁴ Clinical improvement should be observed within a single course of an appropriate antibiotic.

In contrast to impetigo, less common but more serious complications of EH can be life threatening. Systemic dissemination of disease is of particular importance in vulnerable populations such as pediatric and immunocompromised patients. Meningoencephalitis, secondary bacteremia, and herpes keratitis can all develop secondary to EH and incur significant morbidity and mortality.¹

Fever, malaise, lymphadenopathy, or eye pain should prompt immediate consideration of inpatient evaluation and treatment for these potentially deadly or debilitating complications. All patients with EH distributed near the eyes should be referred to ophthalmology to rule out ocular involvement.

A diagnosis of eczema herpeticum requires immediate treatment with oral or intravenous antiviral medication.

Immediately treat with antivirals

Due to the potential complications discussed above, a diagnosis of EH necessitates immediate treatment with oral or intravenous antiviral medication. Acyclovir, valacyclovir, or famciclovir may be used, with typical treatment courses ranging from 10 to 14 days or until all mucocutaneous lesions are healed.⁴ Although typically reserved for patients with recurrent genital herpes resulting in 6 or more outbreaks annually, chronic suppressive therapy also may be considered for patients with EH who suffer from frequent or severe recurrent outbreaks.

Continue to: Our patient

Our patient. Given his otherwise excellent health and the absence of symptoms of potentially serious complications, our patient was treated as an outpatient with a 10-day course of valacyclovir 1000 mg PO BID. He was additionally prescribed a 7-day course of cephalexin 500 mg PO TID for coverage of bacterial superinfection. He responded well to treatment.

Ten days after his initial presentation to our clinic, his erosions and vesicles had completely cleared, and the associated erythema had significantly improved (FIGURE 2). Given the severity of his presentation and his history of 2 to 3 outbreaks annually, he opted to continue prophylactic valacyclovir (500 mg/d) for long-term suppression.

CORRESPONDENCE
Jonathan Madden, MD, 221 3rd Street West, JBSA-Randolph, TX 78150, jonathan.f.madden.mil@mail.mil

A 22-year-old Caucasian man with a history of atopic dermatitis (AD) was referred to our dermatology clinic for evaluation of a diffuse facial rash that had been present for the previous 7 days. The rash initially presented as erythema on the right malar cheek that rapidly spread to the entire face. Initially diagnosed as impetigo, empiric treatment with sulfamethoxazole/trimethoprim (800 mg/160 mg PO BID for 7 days), dicloxacillin (500 mg PO BID for 6 days), cephalexin (500 mg TID for 5 days), and mupirocin (2% topical cream applied TID for 6 days) failed to improve the patient’s symptoms. He reported mild pain associated with facial movements.

The patient had a history of similar (but more limited) rashes, which he described as “recurrent impetigo,” that began during his career as a high school and collegiate wrestler. These rashes were different from the rashes he described as his history of AD, which consisted of pruritic and erythematous skin in his antecubital and popliteal fossae. He denied any history of herpes simplex virus (HSV) infection.

A physical examination revealed numerous monomorphic, 1- to 3-mm, punched-out erosions and ulcers with overlying yellow-brown crust encompassing the patient’s entire face and portions of his anterior neck. Several clustered vesicles on erythematous bases also were noted (FIGUREs 1A and 1B). We used a Dermablade to unroof some of the vesicles and sent the scrapings to the lab for Tzanck, direct fluorescent antibody assay (DFA), and HSV polymerase chain reaction (PCR) testing.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Eczema herpeticum secondary to herpes gladiatorum

The patient’s laboratory results came back and the Tzanck preparation was positive for multinucleated giant cells, and both the DFA and HSV PCR were positive for HSV infection. This, paired with the widely disseminated rash observed on examination and the patient’s history of AD, was consistent with a diagnosis of eczema herpeticum (EH).

Rather than primary impetigo, the patient’s self-described history of recurrent rashes was felt to represent a history of HSV outbreaks. Given his denial of prior oral or genital HSV infection, as well as the coincident onset of these outbreaks during his career as a competitive wrestler, the most likely primary infection source was direct contact with another HSV-infected wrestler.

Herpes gladiatorum refers to a primary cutaneous HSV infection contracted by an athlete through direct skin-to-skin contact with another athlete.¹ It is common in contact sports, such as rugby and wrestling, and particularly common at organized wrestling camps, where mass outbreaks are a frequent occurrence.² Herpes gladiatorum is so common at these camps that many recommend prophylactic valacyclovir treatment for all participants to mitigate the risk of contracting HSV. In a 2016 review, Anderson et al concluded that prophylactic valacyclovir treatment at a 28-day high school wrestling camp effectively reduced outbreak incidence by 89.5%.²

Prophylactic valacyclovir treatment at a 28-day high school wrestling camp reduced outbreak incidence of herpes gladiatorum by 89.5%.

The lesions of herpes gladiatorum are classically limited in distribution and reflective of the areas of direct contact with infected skin, most commonly the face, neck, and arms. Our patient’s history of more limited outbreaks on his face was consistent with this typical presentation. His current outbreak, however, had become much more widely disseminated, which led to the diagnosis of EH secondary to herpes gladiatorum.

Eczema herpeticum: Pathogenesis and diagnosis

Also known as Kaposi’s varicelliform eruption, EH is a rapid, widespread cutaneous dissemination of HSV infection in areas of dermatitis or skin barrier disruption, most commonly caused by HSV-1 infection.³ It is classically associated with AD, but also can occur in patients with impaired epidermal barrier function due to other conditions, such as burns, pemphigus vulgaris, mycosis fungoides, and Darier disease.⁴ It occurs in <3% of patients with AD and is more commonly observed in infants and children with AD than adults.⁵

Continue to: Clinically, the most common manifestations are discrete..

Clinically, the most common manifestations are discrete, monomorphic, 2- to 3-mm, punched-out erosions with hemorrhagic crusts; intact vesicles are less commonly observed.⁴ Involved skin is typically painful and may be pruritic. Clinical diagnosis should be confirmed by laboratory evaluation, typically Tzanck preparation, DFA, and/or HSV PCR.

Complications and the importance of rapid treatment

The most common complication of EH is bacterial superinfection (impetigo), usually by Staphylococcus aureus or group A streptococci. Signs of bacterial superinfection include weeping lesions, pustules, honey-colored/golden crusting, worsening of existing dermatitis, and failure to respond to antiviral treatment. Topical mupirocin 2% cream is generally effective for controlling limited infection. However, systemic antibiotics (cephalosporins or penicillinase-resistant penicillins) may be necessary to control widespread disease.⁴ Clinical improvement should be observed within a single course of an appropriate antibiotic.

In contrast to impetigo, less common but more serious complications of EH can be life threatening. Systemic dissemination of disease is of particular importance in vulnerable populations such as pediatric and immunocompromised patients. Meningoencephalitis, secondary bacteremia, and herpes keratitis can all develop secondary to EH and incur significant morbidity and mortality.¹

Fever, malaise, lymphadenopathy, or eye pain should prompt immediate consideration of inpatient evaluation and treatment for these potentially deadly or debilitating complications. All patients with EH distributed near the eyes should be referred to ophthalmology to rule out ocular involvement.

A diagnosis of eczema herpeticum requires immediate treatment with oral or intravenous antiviral medication.

Immediately treat with antivirals

Due to the potential complications discussed above, a diagnosis of EH necessitates immediate treatment with oral or intravenous antiviral medication. Acyclovir, valacyclovir, or famciclovir may be used, with typical treatment courses ranging from 10 to 14 days or until all mucocutaneous lesions are healed.⁴ Although typically reserved for patients with recurrent genital herpes resulting in 6 or more outbreaks annually, chronic suppressive therapy also may be considered for patients with EH who suffer from frequent or severe recurrent outbreaks.

Continue to: Our patient

Our patient. Given his otherwise excellent health and the absence of symptoms of potentially serious complications, our patient was treated as an outpatient with a 10-day course of valacyclovir 1000 mg PO BID. He was additionally prescribed a 7-day course of cephalexin 500 mg PO TID for coverage of bacterial superinfection. He responded well to treatment.

Ten days after his initial presentation to our clinic, his erosions and vesicles had completely cleared, and the associated erythema had significantly improved (FIGURE 2). Given the severity of his presentation and his history of 2 to 3 outbreaks annually, he opted to continue prophylactic valacyclovir (500 mg/d) for long-term suppression.

CORRESPONDENCE
Jonathan Madden, MD, 221 3rd Street West, JBSA-Randolph, TX 78150, jonathan.f.madden.mil@mail.mil

A 22-year-old Caucasian man with a history of atopic dermatitis (AD) was referred to our dermatology clinic for evaluation of a diffuse facial rash that had been present for the previous 7 days. The rash initially presented as erythema on the right malar cheek that rapidly spread to the entire face. Initially diagnosed as impetigo, empiric treatment with sulfamethoxazole/trimethoprim (800 mg/160 mg PO BID for 7 days), dicloxacillin (500 mg PO BID for 6 days), cephalexin (500 mg TID for 5 days), and mupirocin (2% topical cream applied TID for 6 days) failed to improve the patient’s symptoms. He reported mild pain associated with facial movements.

The patient had a history of similar (but more limited) rashes, which he described as “recurrent impetigo,” that began during his career as a high school and collegiate wrestler. These rashes were different from the rashes he described as his history of AD, which consisted of pruritic and erythematous skin in his antecubital and popliteal fossae. He denied any history of herpes simplex virus (HSV) infection.

A physical examination revealed numerous monomorphic, 1- to 3-mm, punched-out erosions and ulcers with overlying yellow-brown crust encompassing the patient’s entire face and portions of his anterior neck. Several clustered vesicles on erythematous bases also were noted (FIGUREs 1A and 1B). We used a Dermablade to unroof some of the vesicles and sent the scrapings to the lab for Tzanck, direct fluorescent antibody assay (DFA), and HSV polymerase chain reaction (PCR) testing.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Eczema herpeticum secondary to herpes gladiatorum

The patient’s laboratory results came back and the Tzanck preparation was positive for multinucleated giant cells, and both the DFA and HSV PCR were positive for HSV infection. This, paired with the widely disseminated rash observed on examination and the patient’s history of AD, was consistent with a diagnosis of eczema herpeticum (EH).

Rather than primary impetigo, the patient’s self-described history of recurrent rashes was felt to represent a history of HSV outbreaks. Given his denial of prior oral or genital HSV infection, as well as the coincident onset of these outbreaks during his career as a competitive wrestler, the most likely primary infection source was direct contact with another HSV-infected wrestler.

Herpes gladiatorum refers to a primary cutaneous HSV infection contracted by an athlete through direct skin-to-skin contact with another athlete.¹ It is common in contact sports, such as rugby and wrestling, and particularly common at organized wrestling camps, where mass outbreaks are a frequent occurrence.² Herpes gladiatorum is so common at these camps that many recommend prophylactic valacyclovir treatment for all participants to mitigate the risk of contracting HSV. In a 2016 review, Anderson et al concluded that prophylactic valacyclovir treatment at a 28-day high school wrestling camp effectively reduced outbreak incidence by 89.5%.²

Prophylactic valacyclovir treatment at a 28-day high school wrestling camp reduced outbreak incidence of herpes gladiatorum by 89.5%.

The lesions of herpes gladiatorum are classically limited in distribution and reflective of the areas of direct contact with infected skin, most commonly the face, neck, and arms. Our patient’s history of more limited outbreaks on his face was consistent with this typical presentation. His current outbreak, however, had become much more widely disseminated, which led to the diagnosis of EH secondary to herpes gladiatorum.

Eczema herpeticum: Pathogenesis and diagnosis

Also known as Kaposi’s varicelliform eruption, EH is a rapid, widespread cutaneous dissemination of HSV infection in areas of dermatitis or skin barrier disruption, most commonly caused by HSV-1 infection.³ It is classically associated with AD, but also can occur in patients with impaired epidermal barrier function due to other conditions, such as burns, pemphigus vulgaris, mycosis fungoides, and Darier disease.⁴ It occurs in <3% of patients with AD and is more commonly observed in infants and children with AD than adults.⁵

Continue to: Clinically, the most common manifestations are discrete..

Clinically, the most common manifestations are discrete, monomorphic, 2- to 3-mm, punched-out erosions with hemorrhagic crusts; intact vesicles are less commonly observed.⁴ Involved skin is typically painful and may be pruritic. Clinical diagnosis should be confirmed by laboratory evaluation, typically Tzanck preparation, DFA, and/or HSV PCR.

Complications and the importance of rapid treatment

The most common complication of EH is bacterial superinfection (impetigo), usually by Staphylococcus aureus or group A streptococci. Signs of bacterial superinfection include weeping lesions, pustules, honey-colored/golden crusting, worsening of existing dermatitis, and failure to respond to antiviral treatment. Topical mupirocin 2% cream is generally effective for controlling limited infection. However, systemic antibiotics (cephalosporins or penicillinase-resistant penicillins) may be necessary to control widespread disease.⁴ Clinical improvement should be observed within a single course of an appropriate antibiotic.

In contrast to impetigo, less common but more serious complications of EH can be life threatening. Systemic dissemination of disease is of particular importance in vulnerable populations such as pediatric and immunocompromised patients. Meningoencephalitis, secondary bacteremia, and herpes keratitis can all develop secondary to EH and incur significant morbidity and mortality.¹

Fever, malaise, lymphadenopathy, or eye pain should prompt immediate consideration of inpatient evaluation and treatment for these potentially deadly or debilitating complications. All patients with EH distributed near the eyes should be referred to ophthalmology to rule out ocular involvement.

A diagnosis of eczema herpeticum requires immediate treatment with oral or intravenous antiviral medication.

Immediately treat with antivirals

Due to the potential complications discussed above, a diagnosis of EH necessitates immediate treatment with oral or intravenous antiviral medication. Acyclovir, valacyclovir, or famciclovir may be used, with typical treatment courses ranging from 10 to 14 days or until all mucocutaneous lesions are healed.⁴ Although typically reserved for patients with recurrent genital herpes resulting in 6 or more outbreaks annually, chronic suppressive therapy also may be considered for patients with EH who suffer from frequent or severe recurrent outbreaks.

Continue to: Our patient

Our patient. Given his otherwise excellent health and the absence of symptoms of potentially serious complications, our patient was treated as an outpatient with a 10-day course of valacyclovir 1000 mg PO BID. He was additionally prescribed a 7-day course of cephalexin 500 mg PO TID for coverage of bacterial superinfection. He responded well to treatment.

Ten days after his initial presentation to our clinic, his erosions and vesicles had completely cleared, and the associated erythema had significantly improved (FIGURE 2). Given the severity of his presentation and his history of 2 to 3 outbreaks annually, he opted to continue prophylactic valacyclovir (500 mg/d) for long-term suppression.

CORRESPONDENCE
Jonathan Madden, MD, 221 3rd Street West, JBSA-Randolph, TX 78150, jonathan.f.madden.mil@mail.mil

ILLUSTRATIVE CASE

A 63-year-old woman with a history of hypertension presents to the emergency department (ED) with acute onset shortness of breath and pleuritic chest pain after traveling across the country for a work conference. She has no history of cancer, liver disease, or renal disease. Her blood pressure is 140/80 mm Hg, and her heart rate is 90 bpm. You diagnose an acute PE in this patient and start anticoagulation. Should you admit her to the hospital to decrease morbidity and mortality?

According to the Centers for Disease Control and Prevention, venous thromboembolism (VTE) affects approximately 900,000 people each year, and approximately 60,000 to 100,000 of these patients die annually.² Pulmonary embolism is the third leading cause of death from cardiovascular disease, following heart attacks and strokes.³ Prompt diagnosis and treatment with systemic anticoagulation improves patient outcomes and decreases the risk of long-term complications.

The 2016 American College of Chest Physicians (CHEST) guideline on antithrombotic therapy for VTE disease recommends home treatment or early discharge over standard discharge (after the first 5 days of treatment) for patients who meet the following clinical criteria: “clinically stable with good cardiopulmonary reserve; no contraindications such as recent bleeding, severe renal or liver disease, or severe thrombocytopenia (ie, <70,000/mm³); expected to be compliant with treatment; and the patient feels well enough to be treated at home.”³

The guideline states that various clinical decision tools, such as the Pulmonary Embolism Severity Index (PESI), can aid in identifying low-risk patients to be considered for treatment at home. The PESI uses age, gender, vital signs, mental status, and a history of cancer, lung, and cardiac disease to stratify patients by risk.⁴

A systematic review of 1 randomized controlled trial (RCT) and 7 observational studies found that in low-risk patients, outpatient treatment was as safe as inpatient treatment.⁵ This more recent study determines the net clinical benefit of hospitalized vs outpatient management in a wider range of patients with acute PE, regardless of initial risk.¹

STUDY SUMMARY

Hospitalization confers no benefit to stable patients with acute PE

This retrospective, propensity-matched cohort study compared rates of adverse events in 1127 patients with acute PE managed in the hospital vs outpatient setting.¹ Patients were classified as outpatients if they were discharged from the ED or discharged from the hospital within 48 hours of admission. Patients were included if a symptomatic acute PE was diagnosed via computed tomography scan or high-probability ventilation-perfusion scan and excluded if they were <19 years of age, diagnosed with a PE during hospitalization, had chronic PE, or were hemodynamically unstable, among other factors. The investigators calculated PESI scores for all patients.

This trial supports guideline recommendations to manage hemodynamically stable patients with acute PE as outpatients.

Propensity scores matched patients on 28 patient characteristics and known risk factors for adverse events to ensure the groups were similar. The primary outcome was rate of adverse events, including recurrent VTE, major bleeding, or death at 14 days. The secondary outcome was rates of the above during the 3-month follow-up period.

Continue to: Of the 1127 eligible patients...

Of the 1127 eligible patients, 1081 were included in the matched cohort, with 576 (53%) treated as hospitalized patients and 505 (47%) treated as outpatients. The mean age of the matched cohorts was 63.2 years for the inpatient group and 63.6 years for the outpatient group. Overall, the cohorts were well matched.

The 14-day rate of adverse events was higher in hospitalized patients than in outpatients (13% vs 3.3%; odds ratio [OR] = 5.07; 95% confidence interval [CI], 1.68-15.28), with each of the adverse events that made up the primary outcome occurring more frequently in the hospitalized group (TABLE). The rate of adverse events at 3 months was also greater for hospitalized patients compared with outpatients (21.7% vs 6.9%; OR = 4.9; 95% CI, 2.62-9.17). The results remained similar for high-risk patients (Class III-V) based on their PESI score.

WHAT’S NEW

A higher rate of AEs in those treated as inpatients vs outpatients

This trial supports the CHEST guideline recommendations³ to manage hemodynamically stable patients with acute PE as outpatients. It adds to the conversation by demonstrating higher rates of adverse events with hospitalization, even in high-risk subgroups (PESI Class III-V).

CAVEATS

A good study, but it wasn’t an RCT

While this is a well-designed cohort study, it is not a randomized controlled trial (RCT). This study defined outpatient management as patients discharged from the ED or hospitalized for <48 hours. However, only 59 of the 544 patients in the outpatient group were early hospital discharges, while the rest were never admitted. Finally, a specialized thrombosis clinic followed up with the patients within 24 hours of discharge, and patients had telephone access to specialized health care professionals; such organization of care contributed to the safe outpatient management of these PE patients.

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

Insurance coverage may present an issue

Medication coverage of direct oral anticoagulants and low molecular weight heparin may present a barrier to patients treated in the outpatient setting who have no insurance or are insured by certain insurance carriers.

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.

ILLUSTRATIVE CASE

A 63-year-old woman with a history of hypertension presents to the emergency department (ED) with acute onset shortness of breath and pleuritic chest pain after traveling across the country for a work conference. She has no history of cancer, liver disease, or renal disease. Her blood pressure is 140/80 mm Hg, and her heart rate is 90 bpm. You diagnose an acute PE in this patient and start anticoagulation. Should you admit her to the hospital to decrease morbidity and mortality?

According to the Centers for Disease Control and Prevention, venous thromboembolism (VTE) affects approximately 900,000 people each year, and approximately 60,000 to 100,000 of these patients die annually.² Pulmonary embolism is the third leading cause of death from cardiovascular disease, following heart attacks and strokes.³ Prompt diagnosis and treatment with systemic anticoagulation improves patient outcomes and decreases the risk of long-term complications.

The 2016 American College of Chest Physicians (CHEST) guideline on antithrombotic therapy for VTE disease recommends home treatment or early discharge over standard discharge (after the first 5 days of treatment) for patients who meet the following clinical criteria: “clinically stable with good cardiopulmonary reserve; no contraindications such as recent bleeding, severe renal or liver disease, or severe thrombocytopenia (ie, <70,000/mm³); expected to be compliant with treatment; and the patient feels well enough to be treated at home.”³

The guideline states that various clinical decision tools, such as the Pulmonary Embolism Severity Index (PESI), can aid in identifying low-risk patients to be considered for treatment at home. The PESI uses age, gender, vital signs, mental status, and a history of cancer, lung, and cardiac disease to stratify patients by risk.⁴

A systematic review of 1 randomized controlled trial (RCT) and 7 observational studies found that in low-risk patients, outpatient treatment was as safe as inpatient treatment.⁵ This more recent study determines the net clinical benefit of hospitalized vs outpatient management in a wider range of patients with acute PE, regardless of initial risk.¹

STUDY SUMMARY

Hospitalization confers no benefit to stable patients with acute PE

This retrospective, propensity-matched cohort study compared rates of adverse events in 1127 patients with acute PE managed in the hospital vs outpatient setting.¹ Patients were classified as outpatients if they were discharged from the ED or discharged from the hospital within 48 hours of admission. Patients were included if a symptomatic acute PE was diagnosed via computed tomography scan or high-probability ventilation-perfusion scan and excluded if they were <19 years of age, diagnosed with a PE during hospitalization, had chronic PE, or were hemodynamically unstable, among other factors. The investigators calculated PESI scores for all patients.

This trial supports guideline recommendations to manage hemodynamically stable patients with acute PE as outpatients.

Propensity scores matched patients on 28 patient characteristics and known risk factors for adverse events to ensure the groups were similar. The primary outcome was rate of adverse events, including recurrent VTE, major bleeding, or death at 14 days. The secondary outcome was rates of the above during the 3-month follow-up period.

Continue to: Of the 1127 eligible patients...

Of the 1127 eligible patients, 1081 were included in the matched cohort, with 576 (53%) treated as hospitalized patients and 505 (47%) treated as outpatients. The mean age of the matched cohorts was 63.2 years for the inpatient group and 63.6 years for the outpatient group. Overall, the cohorts were well matched.

The 14-day rate of adverse events was higher in hospitalized patients than in outpatients (13% vs 3.3%; odds ratio [OR] = 5.07; 95% confidence interval [CI], 1.68-15.28), with each of the adverse events that made up the primary outcome occurring more frequently in the hospitalized group (TABLE). The rate of adverse events at 3 months was also greater for hospitalized patients compared with outpatients (21.7% vs 6.9%; OR = 4.9; 95% CI, 2.62-9.17). The results remained similar for high-risk patients (Class III-V) based on their PESI score.

WHAT’S NEW

A higher rate of AEs in those treated as inpatients vs outpatients

This trial supports the CHEST guideline recommendations³ to manage hemodynamically stable patients with acute PE as outpatients. It adds to the conversation by demonstrating higher rates of adverse events with hospitalization, even in high-risk subgroups (PESI Class III-V).

CAVEATS

A good study, but it wasn’t an RCT

While this is a well-designed cohort study, it is not a randomized controlled trial (RCT). This study defined outpatient management as patients discharged from the ED or hospitalized for <48 hours. However, only 59 of the 544 patients in the outpatient group were early hospital discharges, while the rest were never admitted. Finally, a specialized thrombosis clinic followed up with the patients within 24 hours of discharge, and patients had telephone access to specialized health care professionals; such organization of care contributed to the safe outpatient management of these PE patients.

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

Insurance coverage may present an issue

Medication coverage of direct oral anticoagulants and low molecular weight heparin may present a barrier to patients treated in the outpatient setting who have no insurance or are insured by certain insurance carriers.

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.

ILLUSTRATIVE CASE

A 63-year-old woman with a history of hypertension presents to the emergency department (ED) with acute onset shortness of breath and pleuritic chest pain after traveling across the country for a work conference. She has no history of cancer, liver disease, or renal disease. Her blood pressure is 140/80 mm Hg, and her heart rate is 90 bpm. You diagnose an acute PE in this patient and start anticoagulation. Should you admit her to the hospital to decrease morbidity and mortality?

According to the Centers for Disease Control and Prevention, venous thromboembolism (VTE) affects approximately 900,000 people each year, and approximately 60,000 to 100,000 of these patients die annually.² Pulmonary embolism is the third leading cause of death from cardiovascular disease, following heart attacks and strokes.³ Prompt diagnosis and treatment with systemic anticoagulation improves patient outcomes and decreases the risk of long-term complications.

The 2016 American College of Chest Physicians (CHEST) guideline on antithrombotic therapy for VTE disease recommends home treatment or early discharge over standard discharge (after the first 5 days of treatment) for patients who meet the following clinical criteria: “clinically stable with good cardiopulmonary reserve; no contraindications such as recent bleeding, severe renal or liver disease, or severe thrombocytopenia (ie, <70,000/mm³); expected to be compliant with treatment; and the patient feels well enough to be treated at home.”³

The guideline states that various clinical decision tools, such as the Pulmonary Embolism Severity Index (PESI), can aid in identifying low-risk patients to be considered for treatment at home. The PESI uses age, gender, vital signs, mental status, and a history of cancer, lung, and cardiac disease to stratify patients by risk.⁴

A systematic review of 1 randomized controlled trial (RCT) and 7 observational studies found that in low-risk patients, outpatient treatment was as safe as inpatient treatment.⁵ This more recent study determines the net clinical benefit of hospitalized vs outpatient management in a wider range of patients with acute PE, regardless of initial risk.¹

STUDY SUMMARY

Hospitalization confers no benefit to stable patients with acute PE

This retrospective, propensity-matched cohort study compared rates of adverse events in 1127 patients with acute PE managed in the hospital vs outpatient setting.¹ Patients were classified as outpatients if they were discharged from the ED or discharged from the hospital within 48 hours of admission. Patients were included if a symptomatic acute PE was diagnosed via computed tomography scan or high-probability ventilation-perfusion scan and excluded if they were <19 years of age, diagnosed with a PE during hospitalization, had chronic PE, or were hemodynamically unstable, among other factors. The investigators calculated PESI scores for all patients.

This trial supports guideline recommendations to manage hemodynamically stable patients with acute PE as outpatients.

Propensity scores matched patients on 28 patient characteristics and known risk factors for adverse events to ensure the groups were similar. The primary outcome was rate of adverse events, including recurrent VTE, major bleeding, or death at 14 days. The secondary outcome was rates of the above during the 3-month follow-up period.

Continue to: Of the 1127 eligible patients...

Of the 1127 eligible patients, 1081 were included in the matched cohort, with 576 (53%) treated as hospitalized patients and 505 (47%) treated as outpatients. The mean age of the matched cohorts was 63.2 years for the inpatient group and 63.6 years for the outpatient group. Overall, the cohorts were well matched.

The 14-day rate of adverse events was higher in hospitalized patients than in outpatients (13% vs 3.3%; odds ratio [OR] = 5.07; 95% confidence interval [CI], 1.68-15.28), with each of the adverse events that made up the primary outcome occurring more frequently in the hospitalized group (TABLE). The rate of adverse events at 3 months was also greater for hospitalized patients compared with outpatients (21.7% vs 6.9%; OR = 4.9; 95% CI, 2.62-9.17). The results remained similar for high-risk patients (Class III-V) based on their PESI score.

WHAT’S NEW

A higher rate of AEs in those treated as inpatients vs outpatients

This trial supports the CHEST guideline recommendations³ to manage hemodynamically stable patients with acute PE as outpatients. It adds to the conversation by demonstrating higher rates of adverse events with hospitalization, even in high-risk subgroups (PESI Class III-V).

CAVEATS

A good study, but it wasn’t an RCT

While this is a well-designed cohort study, it is not a randomized controlled trial (RCT). This study defined outpatient management as patients discharged from the ED or hospitalized for <48 hours. However, only 59 of the 544 patients in the outpatient group were early hospital discharges, while the rest were never admitted. Finally, a specialized thrombosis clinic followed up with the patients within 24 hours of discharge, and patients had telephone access to specialized health care professionals; such organization of care contributed to the safe outpatient management of these PE patients.

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

Insurance coverage may present an issue

Medication coverage of direct oral anticoagulants and low molecular weight heparin may present a barrier to patients treated in the outpatient setting who have no insurance or are insured by certain insurance carriers.

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.

ABSTRACT

Purpose Our study examined the efficacy of a primary-care intervention in reducing opioid use among patients who have chronic non-cancer pain (CNCP). We also recorded the intervention’s effect on patients’ decisions to leave (or stay) with the primary-care practice.

Methods A family physician (FP) identified 41 patients in his practice who had CNCP of at least 6 month’s duration and were using opioids. The intervention with each patient involved an initial discussion of ethical principles, evidence-based practice, and current published guidelines. Following the discussion, patients self-selected to participate with their FP in a continuing tapering program or to accept referral to a pain center for management of their opioid medications. Tapering ranged from a 10% reduction per week to a more rapid 25% to 50% reduction every few days. Twenty-seven patients continued tapering with their FP, and 6 months later were retrospectively placed in the Taper Group. Fourteen patients chose not to pursue the tapering option and were referred to a single-modality medical pain clinic (MPC). All patients had the option of staying with the FP for other medical care.

Results At baseline and again at 6 months post-initial intervention, the MPC Group was taking significantly higher daily doses of morphine equivalents than the Taper Group. The Taper Group at 6 months was taking significantly lower average daily narcotic doses in morphine equivalents than at baseline. No significant baseline-to-6 month differences were found in the MPC Group. Contrary to many physicians’ fear of losing patients following candid discussions about opioid use, 40 of the 41 patients continued with the FP for other health needs.

Conclusions FPs can frankly discuss opioid use with their patients based on ethical principles and evidence-based recommendations and employ a tapering protocol consistent with current opioid treatment guidelines without jeopardizing the patient-physician relationship.

[polldaddy:10180698]

Opioid prescriptions for chronic noncancer pain (CNCP) have increased significantly over the past 25 years in the United States.¹ Despite methodologic concerns surrounding research on opioid harms, prescription opioid misuse among CNCP patients is estimated to be 21% to 29% and prescription addiction 8% to 12%.² Tragically, with the overall increase in opioid use for CNCP, substance-related hospital admissions and deaths due to opioid overdose have also risen.³

Increased opioid use began in 1985 when the World Health Organization expanded its ethical mandate for pain relief in dying patients to include relief from all cancer pain.³ Opioid use then accelerated following Portenoy and Foley’s 1986 article⁴ and the 1997 consensus statement by the American Academy of Pain Medicine (AAPM) and the American Pain Society (APS),⁵ with both organizations arguing that opioids have a role in the treatment of CNCP. Increased use of opioids for CNCP continued throughout the 1990s and 2000s, as many states passed legislation removing sanctions on prescribing long-term and high-dose opioid therapy, and pharmaceutical companies aggressively marketed sustained-release opioids.³

A balanced approach to opioids. While acknowledging the serious public health problems of drug abuse, addiction, and diversion of opioids from licit to illicit uses, clinical research and regulation leaders have called for a balanced approach that recognizes the legitimate medical need for opioids for CNCP. In 2009 the APS, in partnership with the AAPM, published evidence-based guidelines on chronic opioid therapy (COT) for adults with CNCP.⁶ In developing these guidelines, a multidisciplinary panel of experts conducted systematic reviews of available evidence and made recommendations on formulating COT for individuals, initiating and titrating therapy, regularly monitoring patients, and managing opioid-related adverse effects. Additional recommendations addressed the use of therapies focusing on psychosocial factors. The APS-AAPM guidelines received the highest rating in a systematic review critically appraising 13 guidelines that address the use of opioids for CNCP.⁷

Continue to: When opioid use is prolonged...

When opioid use is prolonged. Most primary care physicians are aware of the risks of prolonged opioid use, and many have successfully tapered or discontinued opioid medications for patients in acute or pre-chronic stages of pain.⁸ However, many physicians face the challenge of patients who have used COT for a longer time. The APS-AAPM guidelines may help primary care physicians at any stage of treating CNCP patients.

METHODS

Purpose and design. This retrospective study, which reviewed pretest-posttest findings between and within study groups, received an exempt status from Creighton University’s institutional review board. We designed the study to determine the efficacy of an intervention protocol to reduce opioid use by patients with CNCP who had been in a family physician (FP)'s panel for quite some time. Furthermore, because a common fear among primary care providers is that raising concerns with patients about their opioid use may cause those patients to leave their panel,⁹ our study also recorded how many patients stayed with their FP after initiation of the opioid management protocol.

Subjects. This study tracked 41 patients with CNCP in 1 FP’s panel. Inclusion criteria for participation was: 1) presence of CNCP for at least 6 months, 2) current use of opioid medication for CNCP, 3) age of at least 16 years, and 4) ability to read and write English. Two exclusion criteria were the presence of a surgically correctable condition or an organic brain syndrome or psychosis.

Clinical intervention. The FP identified eligible patients in his practice that were taking opioids for CNCP and initiated a discussion with each of them emphasizing his desire to follow the ethical principles of beneficence, nonmaleficence, respect for autonomy, and justice.¹⁰ The FP also presented his reasons for wanting the patient to stop using opioid medication. They included his beliefs that:

1) COT was not safe for the patient based on a growing body of published evidence of harm and death from COT³;
2) long-term use of opioids could lead to misuse, abuse, or addiction²;
3) prolonged opioid use paradoxically increases pain sensitivity that does not resolve with discontinuation of opioid maintenance^11,12 (although pain tolerance does improve after opioid cessation); and
4) the patient’s current pain medications were not in line with published guidelines for use of opioids for CNCP.⁶

Initially, 45 patients were eligible for the study, but 4 declined participation before the intervention discussion and were immediately referred to a single-modality medical pain clinic (MPC). These patients were not included in subsequent analyses. Of the remaining 41 patients, all had a discussion with the MD about ethical principles, practice guidelines, and the importance of opioid tapering. After the discussion, patients decided whether to continue with the plan to taper their opioid therapy or to not taper their therapy and so receive a referral to an MPC.

Continue to: The 27 patients who chose to work with...

The 27 patients who chose to work with their FP started an individually tailored opioid-tapering program and were retrospectively placed in the Taper Group 6 months later. Tapering ranged from a slow 10% reduction in dosage per week to a more rapid 25% to 50% reduction every few days. Although evidence to guide specific recommendations on the rate of reduction is lacking, a slower rate may reduce unpleasant symptoms of opioid withdrawal.⁶ Following the patient-FP discussion, the 14 patients who chose not to pursue the tapering option were referred to an MPC for pain management, but could opt to remain with the FP for all other medical care. At 6 months post-discussion, we retrospectively assigned these 14 patients to the MPC Group.

Measures. We obtained demographic and medical information, including age, gender, race, marital status, and medication level in morphine equivalents, from the electronic health record. Medication level in morphine equivalents was recorded at the beginning of the intervention and again 6 months later. All analyses were conducted using SPSS Version 24 (IBM Corp, Armonk, NY) with P<.05 used to indicate statistical significance.

RESULTS

Between-group differences. The Taper and MPC groups did not differ significantly on demographic variables, with mean ages, respectively, at 57 and 51 years, sex 56% and 50% female, race 74% and 79% white, and marital status 48% and 50% married.

Patients who tapered opioid usage under FP guidance significantly reduced daily morphine equivalents over 6 months.

We found significant differences between the Taper and MPC groups on total daily dose in morphine equivalents at baseline and at 6 months following initial intervention. The Levene’s test for equality of variances was statistically significant, indicating unequal variances between the groups. In our SPSS analyses, we therefore used the option “equal variances not assumed.” TABLE 1 lists resultant means, standard deviations, individual sample t-test scores, and confidence intervals. The MPC Group was taking significantly higher daily doses of morphine equivalents than the Taper Group both at baseline and at 6 months following initial intervention.

Within-group differences. Paired sample t tests indicated significant differences between baseline and 6-month average daily narcotic doses in morphine equivalents for the Taper Group. No significant difference was found between baseline and 6-month daily morphine equivalents for the MPC group. These results indicated that patients who continued opioid tapering with the FP significantly reduced their daily morphine equivalents over the 6 months of the study. Patients in the MPC Group reduced morphine equivalents over the 6 months, but the reduction was not statistically significant. Paired sample t test results are presented in TABLE 2.

Continue to: Patient retention

Patient retention. All but one of the 41 patients in the Tapering and MPC groups continued with the FP for the remainder of their health care needs. Contrary to some physicians’ fears, the patients in this study maintained continuity with their FP.

DISCUSSION

Results of this study indicate that an intervention consisting of a physician-patient discussion of ethical principles and evidence-based practice, followed by individualized opioid tapering per published guidelines, led to a significant reduction in opioid use in patients with CNCP. The Taper Group, which completed the intervention, exhibited significant morphine reductions between baseline and 6-month follow-up. This did not hold true for the MPC Group.

The MPC Group, despite participating in the discussion with the FP, chose not to complete the tapering program and was referred to a single-modality MPC where opioids were managed rather than tapered. While the MPC group reduced daily opioid dose levels, the reduction was not statistically significant. A possible reason for no difference within the MPC Group may be that they had greater dependence on opioids, as their baseline average daily dose was much higher than that in the Taper Group (173 mg vs 31 mg, respectively). Although we did not assess anxiety directly, we speculate that the MPC Group was more anxious about opioid reduction than the Taper Group, and that this anxiety potentially led 4 patients to opt out of the initial FP discussion and 14 patients to self-select out of the tapering program following the discussion.

Of the 14 patients who opted not to participate with their FP in opioid tapering, 13 remained with him for all other care.

The FP intervention was successful for the Taper Group. For MPC patients, an enhanced intervention including behavior health strategies¹³ might have reduced anxiety and increased motivation¹⁴ to continue tapering. Based on moderate-quality evidence, APS-AAPM guidelines strongly recommend that CNCP be viewed as a complex biopsychosocial condition. Therefore, clinicians who prescribe opioids should routinely integrate psychotherapeutic interventions, functional restoration, interdisciplinary therapy, and other adjunctive nonopioid therapies.⁶

Opioid tapering within multidisciplinary rehabilitation programs is possible without significant worsening of pain, mood, and function.¹⁵ Recently, an outpatient opioid-tapering support intervention showed promise for efficacy in reducing prescription opioid doses without resultant increases in pain intensity or pain interference.¹⁶

Continue to: The tapering protocol in our study...

The tapering protocol in our study and the inclusion of behavioral health co-interventions are also recommended by the 2016 guidelines published by the Center for Disease Control and Prevention.¹⁷ More information on the similarities and differences among the various guidelines is available online.^18,19

Caveats with our study. Patients’ entry into the Taper or MPC groups occurred through self-selection rather than random assignment. Thus, caution is recommended in interpreting findings of the FP intervention. And, we did not measure patients’ levels of pain, so differences between groups may have been possible. In addition, the number of patients per group was relatively small, which may have accounted for the lack of significance in the MPC Group findings. Conversely, significant reductions in opioid use in the small tapering sample suggests a relatively robust intervention, despite a lack of random assignment to treatment conditions.

These findings suggest that FPs can have a frank conversation about opioid use with their patients based on ethical principles and evidence-based practice, and employ a tapering protocol consistent with current opioid treatment guidelines. Furthermore, this approach appears not to jeopardize the patient-physician relationship.

CORRESPONDENCE
Thomas P. Guck, PhD, Creighton University School of Medicine, 2412 Cuming Street, Omaha, NE 68131; tpguck@creighton.edu.

ABSTRACT

Purpose Our study examined the efficacy of a primary-care intervention in reducing opioid use among patients who have chronic non-cancer pain (CNCP). We also recorded the intervention’s effect on patients’ decisions to leave (or stay) with the primary-care practice.

Methods A family physician (FP) identified 41 patients in his practice who had CNCP of at least 6 month’s duration and were using opioids. The intervention with each patient involved an initial discussion of ethical principles, evidence-based practice, and current published guidelines. Following the discussion, patients self-selected to participate with their FP in a continuing tapering program or to accept referral to a pain center for management of their opioid medications. Tapering ranged from a 10% reduction per week to a more rapid 25% to 50% reduction every few days. Twenty-seven patients continued tapering with their FP, and 6 months later were retrospectively placed in the Taper Group. Fourteen patients chose not to pursue the tapering option and were referred to a single-modality medical pain clinic (MPC). All patients had the option of staying with the FP for other medical care.

Results At baseline and again at 6 months post-initial intervention, the MPC Group was taking significantly higher daily doses of morphine equivalents than the Taper Group. The Taper Group at 6 months was taking significantly lower average daily narcotic doses in morphine equivalents than at baseline. No significant baseline-to-6 month differences were found in the MPC Group. Contrary to many physicians’ fear of losing patients following candid discussions about opioid use, 40 of the 41 patients continued with the FP for other health needs.

Conclusions FPs can frankly discuss opioid use with their patients based on ethical principles and evidence-based recommendations and employ a tapering protocol consistent with current opioid treatment guidelines without jeopardizing the patient-physician relationship.

[polldaddy:10180698]

Opioid prescriptions for chronic noncancer pain (CNCP) have increased significantly over the past 25 years in the United States.¹ Despite methodologic concerns surrounding research on opioid harms, prescription opioid misuse among CNCP patients is estimated to be 21% to 29% and prescription addiction 8% to 12%.² Tragically, with the overall increase in opioid use for CNCP, substance-related hospital admissions and deaths due to opioid overdose have also risen.³

Increased opioid use began in 1985 when the World Health Organization expanded its ethical mandate for pain relief in dying patients to include relief from all cancer pain.³ Opioid use then accelerated following Portenoy and Foley’s 1986 article⁴ and the 1997 consensus statement by the American Academy of Pain Medicine (AAPM) and the American Pain Society (APS),⁵ with both organizations arguing that opioids have a role in the treatment of CNCP. Increased use of opioids for CNCP continued throughout the 1990s and 2000s, as many states passed legislation removing sanctions on prescribing long-term and high-dose opioid therapy, and pharmaceutical companies aggressively marketed sustained-release opioids.³

A balanced approach to opioids. While acknowledging the serious public health problems of drug abuse, addiction, and diversion of opioids from licit to illicit uses, clinical research and regulation leaders have called for a balanced approach that recognizes the legitimate medical need for opioids for CNCP. In 2009 the APS, in partnership with the AAPM, published evidence-based guidelines on chronic opioid therapy (COT) for adults with CNCP.⁶ In developing these guidelines, a multidisciplinary panel of experts conducted systematic reviews of available evidence and made recommendations on formulating COT for individuals, initiating and titrating therapy, regularly monitoring patients, and managing opioid-related adverse effects. Additional recommendations addressed the use of therapies focusing on psychosocial factors. The APS-AAPM guidelines received the highest rating in a systematic review critically appraising 13 guidelines that address the use of opioids for CNCP.⁷

Continue to: When opioid use is prolonged...

When opioid use is prolonged. Most primary care physicians are aware of the risks of prolonged opioid use, and many have successfully tapered or discontinued opioid medications for patients in acute or pre-chronic stages of pain.⁸ However, many physicians face the challenge of patients who have used COT for a longer time. The APS-AAPM guidelines may help primary care physicians at any stage of treating CNCP patients.

METHODS

Purpose and design. This retrospective study, which reviewed pretest-posttest findings between and within study groups, received an exempt status from Creighton University’s institutional review board. We designed the study to determine the efficacy of an intervention protocol to reduce opioid use by patients with CNCP who had been in a family physician (FP)'s panel for quite some time. Furthermore, because a common fear among primary care providers is that raising concerns with patients about their opioid use may cause those patients to leave their panel,⁹ our study also recorded how many patients stayed with their FP after initiation of the opioid management protocol.

Subjects. This study tracked 41 patients with CNCP in 1 FP’s panel. Inclusion criteria for participation was: 1) presence of CNCP for at least 6 months, 2) current use of opioid medication for CNCP, 3) age of at least 16 years, and 4) ability to read and write English. Two exclusion criteria were the presence of a surgically correctable condition or an organic brain syndrome or psychosis.

Clinical intervention. The FP identified eligible patients in his practice that were taking opioids for CNCP and initiated a discussion with each of them emphasizing his desire to follow the ethical principles of beneficence, nonmaleficence, respect for autonomy, and justice.¹⁰ The FP also presented his reasons for wanting the patient to stop using opioid medication. They included his beliefs that:

1) COT was not safe for the patient based on a growing body of published evidence of harm and death from COT³;
2) long-term use of opioids could lead to misuse, abuse, or addiction²;
3) prolonged opioid use paradoxically increases pain sensitivity that does not resolve with discontinuation of opioid maintenance^11,12 (although pain tolerance does improve after opioid cessation); and
4) the patient’s current pain medications were not in line with published guidelines for use of opioids for CNCP.⁶

Initially, 45 patients were eligible for the study, but 4 declined participation before the intervention discussion and were immediately referred to a single-modality medical pain clinic (MPC). These patients were not included in subsequent analyses. Of the remaining 41 patients, all had a discussion with the MD about ethical principles, practice guidelines, and the importance of opioid tapering. After the discussion, patients decided whether to continue with the plan to taper their opioid therapy or to not taper their therapy and so receive a referral to an MPC.

Continue to: The 27 patients who chose to work with...

The 27 patients who chose to work with their FP started an individually tailored opioid-tapering program and were retrospectively placed in the Taper Group 6 months later. Tapering ranged from a slow 10% reduction in dosage per week to a more rapid 25% to 50% reduction every few days. Although evidence to guide specific recommendations on the rate of reduction is lacking, a slower rate may reduce unpleasant symptoms of opioid withdrawal.⁶ Following the patient-FP discussion, the 14 patients who chose not to pursue the tapering option were referred to an MPC for pain management, but could opt to remain with the FP for all other medical care. At 6 months post-discussion, we retrospectively assigned these 14 patients to the MPC Group.

Measures. We obtained demographic and medical information, including age, gender, race, marital status, and medication level in morphine equivalents, from the electronic health record. Medication level in morphine equivalents was recorded at the beginning of the intervention and again 6 months later. All analyses were conducted using SPSS Version 24 (IBM Corp, Armonk, NY) with P<.05 used to indicate statistical significance.

RESULTS

Between-group differences. The Taper and MPC groups did not differ significantly on demographic variables, with mean ages, respectively, at 57 and 51 years, sex 56% and 50% female, race 74% and 79% white, and marital status 48% and 50% married.

Patients who tapered opioid usage under FP guidance significantly reduced daily morphine equivalents over 6 months.

We found significant differences between the Taper and MPC groups on total daily dose in morphine equivalents at baseline and at 6 months following initial intervention. The Levene’s test for equality of variances was statistically significant, indicating unequal variances between the groups. In our SPSS analyses, we therefore used the option “equal variances not assumed.” TABLE 1 lists resultant means, standard deviations, individual sample t-test scores, and confidence intervals. The MPC Group was taking significantly higher daily doses of morphine equivalents than the Taper Group both at baseline and at 6 months following initial intervention.

Within-group differences. Paired sample t tests indicated significant differences between baseline and 6-month average daily narcotic doses in morphine equivalents for the Taper Group. No significant difference was found between baseline and 6-month daily morphine equivalents for the MPC group. These results indicated that patients who continued opioid tapering with the FP significantly reduced their daily morphine equivalents over the 6 months of the study. Patients in the MPC Group reduced morphine equivalents over the 6 months, but the reduction was not statistically significant. Paired sample t test results are presented in TABLE 2.

Continue to: Patient retention

Patient retention. All but one of the 41 patients in the Tapering and MPC groups continued with the FP for the remainder of their health care needs. Contrary to some physicians’ fears, the patients in this study maintained continuity with their FP.

DISCUSSION

Results of this study indicate that an intervention consisting of a physician-patient discussion of ethical principles and evidence-based practice, followed by individualized opioid tapering per published guidelines, led to a significant reduction in opioid use in patients with CNCP. The Taper Group, which completed the intervention, exhibited significant morphine reductions between baseline and 6-month follow-up. This did not hold true for the MPC Group.

The MPC Group, despite participating in the discussion with the FP, chose not to complete the tapering program and was referred to a single-modality MPC where opioids were managed rather than tapered. While the MPC group reduced daily opioid dose levels, the reduction was not statistically significant. A possible reason for no difference within the MPC Group may be that they had greater dependence on opioids, as their baseline average daily dose was much higher than that in the Taper Group (173 mg vs 31 mg, respectively). Although we did not assess anxiety directly, we speculate that the MPC Group was more anxious about opioid reduction than the Taper Group, and that this anxiety potentially led 4 patients to opt out of the initial FP discussion and 14 patients to self-select out of the tapering program following the discussion.

Of the 14 patients who opted not to participate with their FP in opioid tapering, 13 remained with him for all other care.

The FP intervention was successful for the Taper Group. For MPC patients, an enhanced intervention including behavior health strategies¹³ might have reduced anxiety and increased motivation¹⁴ to continue tapering. Based on moderate-quality evidence, APS-AAPM guidelines strongly recommend that CNCP be viewed as a complex biopsychosocial condition. Therefore, clinicians who prescribe opioids should routinely integrate psychotherapeutic interventions, functional restoration, interdisciplinary therapy, and other adjunctive nonopioid therapies.⁶

Opioid tapering within multidisciplinary rehabilitation programs is possible without significant worsening of pain, mood, and function.¹⁵ Recently, an outpatient opioid-tapering support intervention showed promise for efficacy in reducing prescription opioid doses without resultant increases in pain intensity or pain interference.¹⁶

Continue to: The tapering protocol in our study...

The tapering protocol in our study and the inclusion of behavioral health co-interventions are also recommended by the 2016 guidelines published by the Center for Disease Control and Prevention.¹⁷ More information on the similarities and differences among the various guidelines is available online.^18,19

Caveats with our study. Patients’ entry into the Taper or MPC groups occurred through self-selection rather than random assignment. Thus, caution is recommended in interpreting findings of the FP intervention. And, we did not measure patients’ levels of pain, so differences between groups may have been possible. In addition, the number of patients per group was relatively small, which may have accounted for the lack of significance in the MPC Group findings. Conversely, significant reductions in opioid use in the small tapering sample suggests a relatively robust intervention, despite a lack of random assignment to treatment conditions.

These findings suggest that FPs can have a frank conversation about opioid use with their patients based on ethical principles and evidence-based practice, and employ a tapering protocol consistent with current opioid treatment guidelines. Furthermore, this approach appears not to jeopardize the patient-physician relationship.

CORRESPONDENCE
Thomas P. Guck, PhD, Creighton University School of Medicine, 2412 Cuming Street, Omaha, NE 68131; tpguck@creighton.edu.

ABSTRACT

Purpose Our study examined the efficacy of a primary-care intervention in reducing opioid use among patients who have chronic non-cancer pain (CNCP). We also recorded the intervention’s effect on patients’ decisions to leave (or stay) with the primary-care practice.

Methods A family physician (FP) identified 41 patients in his practice who had CNCP of at least 6 month’s duration and were using opioids. The intervention with each patient involved an initial discussion of ethical principles, evidence-based practice, and current published guidelines. Following the discussion, patients self-selected to participate with their FP in a continuing tapering program or to accept referral to a pain center for management of their opioid medications. Tapering ranged from a 10% reduction per week to a more rapid 25% to 50% reduction every few days. Twenty-seven patients continued tapering with their FP, and 6 months later were retrospectively placed in the Taper Group. Fourteen patients chose not to pursue the tapering option and were referred to a single-modality medical pain clinic (MPC). All patients had the option of staying with the FP for other medical care.

Results At baseline and again at 6 months post-initial intervention, the MPC Group was taking significantly higher daily doses of morphine equivalents than the Taper Group. The Taper Group at 6 months was taking significantly lower average daily narcotic doses in morphine equivalents than at baseline. No significant baseline-to-6 month differences were found in the MPC Group. Contrary to many physicians’ fear of losing patients following candid discussions about opioid use, 40 of the 41 patients continued with the FP for other health needs.

Conclusions FPs can frankly discuss opioid use with their patients based on ethical principles and evidence-based recommendations and employ a tapering protocol consistent with current opioid treatment guidelines without jeopardizing the patient-physician relationship.

[polldaddy:10180698]

Opioid prescriptions for chronic noncancer pain (CNCP) have increased significantly over the past 25 years in the United States.¹ Despite methodologic concerns surrounding research on opioid harms, prescription opioid misuse among CNCP patients is estimated to be 21% to 29% and prescription addiction 8% to 12%.² Tragically, with the overall increase in opioid use for CNCP, substance-related hospital admissions and deaths due to opioid overdose have also risen.³

Increased opioid use began in 1985 when the World Health Organization expanded its ethical mandate for pain relief in dying patients to include relief from all cancer pain.³ Opioid use then accelerated following Portenoy and Foley’s 1986 article⁴ and the 1997 consensus statement by the American Academy of Pain Medicine (AAPM) and the American Pain Society (APS),⁵ with both organizations arguing that opioids have a role in the treatment of CNCP. Increased use of opioids for CNCP continued throughout the 1990s and 2000s, as many states passed legislation removing sanctions on prescribing long-term and high-dose opioid therapy, and pharmaceutical companies aggressively marketed sustained-release opioids.³

A balanced approach to opioids. While acknowledging the serious public health problems of drug abuse, addiction, and diversion of opioids from licit to illicit uses, clinical research and regulation leaders have called for a balanced approach that recognizes the legitimate medical need for opioids for CNCP. In 2009 the APS, in partnership with the AAPM, published evidence-based guidelines on chronic opioid therapy (COT) for adults with CNCP.⁶ In developing these guidelines, a multidisciplinary panel of experts conducted systematic reviews of available evidence and made recommendations on formulating COT for individuals, initiating and titrating therapy, regularly monitoring patients, and managing opioid-related adverse effects. Additional recommendations addressed the use of therapies focusing on psychosocial factors. The APS-AAPM guidelines received the highest rating in a systematic review critically appraising 13 guidelines that address the use of opioids for CNCP.⁷

Continue to: When opioid use is prolonged...

When opioid use is prolonged. Most primary care physicians are aware of the risks of prolonged opioid use, and many have successfully tapered or discontinued opioid medications for patients in acute or pre-chronic stages of pain.⁸ However, many physicians face the challenge of patients who have used COT for a longer time. The APS-AAPM guidelines may help primary care physicians at any stage of treating CNCP patients.

METHODS

Purpose and design. This retrospective study, which reviewed pretest-posttest findings between and within study groups, received an exempt status from Creighton University’s institutional review board. We designed the study to determine the efficacy of an intervention protocol to reduce opioid use by patients with CNCP who had been in a family physician (FP)'s panel for quite some time. Furthermore, because a common fear among primary care providers is that raising concerns with patients about their opioid use may cause those patients to leave their panel,⁹ our study also recorded how many patients stayed with their FP after initiation of the opioid management protocol.

Subjects. This study tracked 41 patients with CNCP in 1 FP’s panel. Inclusion criteria for participation was: 1) presence of CNCP for at least 6 months, 2) current use of opioid medication for CNCP, 3) age of at least 16 years, and 4) ability to read and write English. Two exclusion criteria were the presence of a surgically correctable condition or an organic brain syndrome or psychosis.

Clinical intervention. The FP identified eligible patients in his practice that were taking opioids for CNCP and initiated a discussion with each of them emphasizing his desire to follow the ethical principles of beneficence, nonmaleficence, respect for autonomy, and justice.¹⁰ The FP also presented his reasons for wanting the patient to stop using opioid medication. They included his beliefs that:

1) COT was not safe for the patient based on a growing body of published evidence of harm and death from COT³;
2) long-term use of opioids could lead to misuse, abuse, or addiction²;
3) prolonged opioid use paradoxically increases pain sensitivity that does not resolve with discontinuation of opioid maintenance^11,12 (although pain tolerance does improve after opioid cessation); and
4) the patient’s current pain medications were not in line with published guidelines for use of opioids for CNCP.⁶

Initially, 45 patients were eligible for the study, but 4 declined participation before the intervention discussion and were immediately referred to a single-modality medical pain clinic (MPC). These patients were not included in subsequent analyses. Of the remaining 41 patients, all had a discussion with the MD about ethical principles, practice guidelines, and the importance of opioid tapering. After the discussion, patients decided whether to continue with the plan to taper their opioid therapy or to not taper their therapy and so receive a referral to an MPC.

Continue to: The 27 patients who chose to work with...

The 27 patients who chose to work with their FP started an individually tailored opioid-tapering program and were retrospectively placed in the Taper Group 6 months later. Tapering ranged from a slow 10% reduction in dosage per week to a more rapid 25% to 50% reduction every few days. Although evidence to guide specific recommendations on the rate of reduction is lacking, a slower rate may reduce unpleasant symptoms of opioid withdrawal.⁶ Following the patient-FP discussion, the 14 patients who chose not to pursue the tapering option were referred to an MPC for pain management, but could opt to remain with the FP for all other medical care. At 6 months post-discussion, we retrospectively assigned these 14 patients to the MPC Group.

Measures. We obtained demographic and medical information, including age, gender, race, marital status, and medication level in morphine equivalents, from the electronic health record. Medication level in morphine equivalents was recorded at the beginning of the intervention and again 6 months later. All analyses were conducted using SPSS Version 24 (IBM Corp, Armonk, NY) with P<.05 used to indicate statistical significance.

RESULTS

Between-group differences. The Taper and MPC groups did not differ significantly on demographic variables, with mean ages, respectively, at 57 and 51 years, sex 56% and 50% female, race 74% and 79% white, and marital status 48% and 50% married.

Patients who tapered opioid usage under FP guidance significantly reduced daily morphine equivalents over 6 months.

We found significant differences between the Taper and MPC groups on total daily dose in morphine equivalents at baseline and at 6 months following initial intervention. The Levene’s test for equality of variances was statistically significant, indicating unequal variances between the groups. In our SPSS analyses, we therefore used the option “equal variances not assumed.” TABLE 1 lists resultant means, standard deviations, individual sample t-test scores, and confidence intervals. The MPC Group was taking significantly higher daily doses of morphine equivalents than the Taper Group both at baseline and at 6 months following initial intervention.

Within-group differences. Paired sample t tests indicated significant differences between baseline and 6-month average daily narcotic doses in morphine equivalents for the Taper Group. No significant difference was found between baseline and 6-month daily morphine equivalents for the MPC group. These results indicated that patients who continued opioid tapering with the FP significantly reduced their daily morphine equivalents over the 6 months of the study. Patients in the MPC Group reduced morphine equivalents over the 6 months, but the reduction was not statistically significant. Paired sample t test results are presented in TABLE 2.

Continue to: Patient retention

Patient retention. All but one of the 41 patients in the Tapering and MPC groups continued with the FP for the remainder of their health care needs. Contrary to some physicians’ fears, the patients in this study maintained continuity with their FP.

DISCUSSION

Results of this study indicate that an intervention consisting of a physician-patient discussion of ethical principles and evidence-based practice, followed by individualized opioid tapering per published guidelines, led to a significant reduction in opioid use in patients with CNCP. The Taper Group, which completed the intervention, exhibited significant morphine reductions between baseline and 6-month follow-up. This did not hold true for the MPC Group.

The MPC Group, despite participating in the discussion with the FP, chose not to complete the tapering program and was referred to a single-modality MPC where opioids were managed rather than tapered. While the MPC group reduced daily opioid dose levels, the reduction was not statistically significant. A possible reason for no difference within the MPC Group may be that they had greater dependence on opioids, as their baseline average daily dose was much higher than that in the Taper Group (173 mg vs 31 mg, respectively). Although we did not assess anxiety directly, we speculate that the MPC Group was more anxious about opioid reduction than the Taper Group, and that this anxiety potentially led 4 patients to opt out of the initial FP discussion and 14 patients to self-select out of the tapering program following the discussion.

Of the 14 patients who opted not to participate with their FP in opioid tapering, 13 remained with him for all other care.

The FP intervention was successful for the Taper Group. For MPC patients, an enhanced intervention including behavior health strategies¹³ might have reduced anxiety and increased motivation¹⁴ to continue tapering. Based on moderate-quality evidence, APS-AAPM guidelines strongly recommend that CNCP be viewed as a complex biopsychosocial condition. Therefore, clinicians who prescribe opioids should routinely integrate psychotherapeutic interventions, functional restoration, interdisciplinary therapy, and other adjunctive nonopioid therapies.⁶

Opioid tapering within multidisciplinary rehabilitation programs is possible without significant worsening of pain, mood, and function.¹⁵ Recently, an outpatient opioid-tapering support intervention showed promise for efficacy in reducing prescription opioid doses without resultant increases in pain intensity or pain interference.¹⁶

Continue to: The tapering protocol in our study...

The tapering protocol in our study and the inclusion of behavioral health co-interventions are also recommended by the 2016 guidelines published by the Center for Disease Control and Prevention.¹⁷ More information on the similarities and differences among the various guidelines is available online.^18,19

Caveats with our study. Patients’ entry into the Taper or MPC groups occurred through self-selection rather than random assignment. Thus, caution is recommended in interpreting findings of the FP intervention. And, we did not measure patients’ levels of pain, so differences between groups may have been possible. In addition, the number of patients per group was relatively small, which may have accounted for the lack of significance in the MPC Group findings. Conversely, significant reductions in opioid use in the small tapering sample suggests a relatively robust intervention, despite a lack of random assignment to treatment conditions.

These findings suggest that FPs can have a frank conversation about opioid use with their patients based on ethical principles and evidence-based practice, and employ a tapering protocol consistent with current opioid treatment guidelines. Furthermore, this approach appears not to jeopardize the patient-physician relationship.

CORRESPONDENCE
Thomas P. Guck, PhD, Creighton University School of Medicine, 2412 Cuming Street, Omaha, NE 68131; tpguck@creighton.edu.

THE CASE

A 33-year-old Caucasian woman presented to the emergency department with a 6-day history of fever (103°-104°F) and right groin pain and swelling. Associated symptoms included headache, diarrhea, malaise, weakness, nausea, cough, and anorexia. Upon presentation, she admitted to a recent hike on a bubonic plague–endemic trail in Colorado.

Her vital signs were unremarkable, and the physical examination demonstrated normal findings except for tender, erythematous, nonfluctuant right inguinal lymphadenopathy. The patient was admitted for intractable pain and fever and started on intravenous cefoxitin 2 g IV every 8 hours and oral doxycycline 100 mg every 12 hours for pelvic inflammatory disease vs tick- or flea-borne illness. Due to the patient’s recent trip to a plague-infested area, our suspicion for Yersinia pestis infection was high.

The patient’s work-up included a negative pregnancy test and urinalysis. A complete blood count demonstrated a white blood cell count of 8.6 (4.3-10.5) × 10³/UL with a 3+ left shift and a platelet count of 112 (180-500) × 10³/UL. A complete metabolic panel showed hypokalemia and hyponatremia (potassium 2.8 [3.5-5.1] mmol/L and sodium 134 [137-145] mmol/L). Blood cultures were negative for any bacterial or fungal growth after 48 hours; stool cultures were negative for Salmonella, Shigella, Campylobacter, Giardia, generalized Yersinia, and Escherichia coli O157:H7. Swabs for Gardnerella vaginalis, Trichomonas vaginalis, Candida, Chlamydia trachomatis, and Neisseria gonorrhea also were negative. Lyme, Bartonella henselae, and heterophile antibodies were also negative. Francisella tularensis was not cultured due to low suspicion.

Imaging included a normal chest x-ray and a computed tomography scan of the abdomen and pelvis that showed enlarged right inguinal lymph nodes with fatty stranding, a thicker distal right iliopsoas, hepatosplenomegaly, and an enlarged right adnexa (FIGURE 1). Initial ultrasound of the bubo showed 2 enlarged suprapubic lymph nodes, the largest measuring 3.5 × 1.4 × 2.4 cm³ (FIGURE 2), and 8 enlarged inguinal nodes.

The patient continued to have a low-grade fever, diarrhea, and inguinal lymphadenopathy throughout her first 2 hospitalized days. The cefoxitin was discontinued by Day 3, and the consulting infectious disease physician started oral metronidazole 500 mg every 12 hours due to the patient’s failure to improve. Later that night, the patient experienced increasing erythema and pain in her right inguinal region. A repeat ultrasound showed increased inguinal lymphadenopathy with the largest nodes measuring 2.9 × 1.5 × 2.5 cm³ and 2.7 × 1.3 × 2 cm³ (FIGURE 3).

Although doxycycline is considered an acceptable regimen for Y pestis infection, the infectious disease physician added oral ciprofloxacin 750 mg every 12 hours the following morning, as the patient had not improved.

THE DIAGNOSIS

Although the initial gram stain was negative for Yersinia, clinical suspicion pointed to a diagnosis of bubonic plague. Serology was considered; however, it was not available through the hospital. A definitive diagnosis required bubo aspiration and culture, which was performed but required 48 hours before results would be available.

Continue to: By Day 5, the patient was clinically improved and...

By Day 5, the patient was clinically improved and deemed safe for discharge on empiric treatment with ciprofloxacin 750 mg twice daily and doxycycline 100 mg twice daily to complete a 14-day course of antibiotic therapy for bubonic plague. The bubo culture subsequently grew Y pestis, confirming the diagnosis. The patient made a full recovery and was greatly improved when seen in the outpatient setting by the treating infectious disease physician. Outpatient ultrasound repeated 3 weeks after discharge showed borderline lymphadenopathy, no greater than 1 cm.

DISCUSSION

Between 2000 and 2009, there were 57 cases of Y pestis in the United States; in early 2015, 11 cases were found in 6 Western states.¹ The plague presents in the bubonic form 80% to 95% of the time, and it has never been reported in Michigan (where we treated this patient); however, there was a laboratory case in Illinois. Although rats were traditionally the host for Y pestis, the prairie dog, Cynomys gunnisoni, is a host in the United States.² Rodents are the most important hosts, but more than 200 mammalian species, including domestic pets, have had reported infections. Transmission is primarily via flea bites, but Y pestis also may be transmitted via respiratory secretion, inhalation, or direct handling of contaminated animal tissues. Due to the risk of respiratory spread, the Centers for Disease Control and Prevention must be notified of a diagnosis.^3,4

Y pestis travels from the site of the flea bite to regional lymph nodes, where it reproduces, and the resultant inflammatory reaction creates buboes. The bacteria then circulate in the blood to other organs, although Y pestis bacteria are primarily removed by the liver and spleen. Patients often develop symptoms such as headache, fevers, chills, and gastrointestinal distress. Diagnosis is reached by bubo culture or rapid testing for the F1 antigen. Early intervention with antibiotics is crucial as untreated bubonic plague has a mortality rate of 50% to 90%.^3,4

The differential diagnosis for unilateral inguinal lymphadenopathy with associated constitutional symptoms was broad, in this case, and included pelvic inflammatory disease, bubonic plague, iliopsoas abscess, lymphogranuloma venereum, bartonellosis, infectious mononucleosis, and tick-borne diseases, such as ehrlichiosis, tularemia, Lyme disease, Rocky Mountain spotted fever, and Colorado tick fever.

Although the initial gram stain demonstrated no organisms, a subsequent bubo aspiration and culture grew Y pestis, confirming the diagnosis.

Treatment. Food and Drug Administration–approved treatments include streptomycin (gentamicin 5 mg/kg/day IM or IV for 14 days is more widely utilized), doxycycline 200 mg PO once daily for 10 to 14 days, and fluoroquinolones (ciprofloxacin 500-750 mg every 12 hours for 10-14 days). Trimethoprim-sulfamethoxazole may be used as an alternative, but limitations include potentially incomplete or slowed responses.

Continue to: THE TAKEAWAY

 

 

THE TAKEAWAY

This case points to the importance of a complete, systematic approach to each patient. While bubonic plague is not a diagnosis that would immediately come to mind in a patient visiting an emergency department in Michigan, a thorough history revealed a recent trip to a bubonic plague–endemic area. A thorough physical exam demonstrated unilateral painful inguinal adenopathy—which, when paired with the patient’s history—was consistent with the uncommon diagnosis of bubonic plague.

ACKNOWLEDGEMENTS
The authors thank Brian Waite, MD, and James Addison, MD, for critically revising this report for important intellectual content.

CORRESPONDENCE
Katherine Lazet, DO, 3838 N First Avenue, Evansville, IN 47710; lazetkat@gmail.com

THE CASE

A 33-year-old Caucasian woman presented to the emergency department with a 6-day history of fever (103°-104°F) and right groin pain and swelling. Associated symptoms included headache, diarrhea, malaise, weakness, nausea, cough, and anorexia. Upon presentation, she admitted to a recent hike on a bubonic plague–endemic trail in Colorado.

Her vital signs were unremarkable, and the physical examination demonstrated normal findings except for tender, erythematous, nonfluctuant right inguinal lymphadenopathy. The patient was admitted for intractable pain and fever and started on intravenous cefoxitin 2 g IV every 8 hours and oral doxycycline 100 mg every 12 hours for pelvic inflammatory disease vs tick- or flea-borne illness. Due to the patient’s recent trip to a plague-infested area, our suspicion for Yersinia pestis infection was high.

The patient’s work-up included a negative pregnancy test and urinalysis. A complete blood count demonstrated a white blood cell count of 8.6 (4.3-10.5) × 10³/UL with a 3+ left shift and a platelet count of 112 (180-500) × 10³/UL. A complete metabolic panel showed hypokalemia and hyponatremia (potassium 2.8 [3.5-5.1] mmol/L and sodium 134 [137-145] mmol/L). Blood cultures were negative for any bacterial or fungal growth after 48 hours; stool cultures were negative for Salmonella, Shigella, Campylobacter, Giardia, generalized Yersinia, and Escherichia coli O157:H7. Swabs for Gardnerella vaginalis, Trichomonas vaginalis, Candida, Chlamydia trachomatis, and Neisseria gonorrhea also were negative. Lyme, Bartonella henselae, and heterophile antibodies were also negative. Francisella tularensis was not cultured due to low suspicion.

Imaging included a normal chest x-ray and a computed tomography scan of the abdomen and pelvis that showed enlarged right inguinal lymph nodes with fatty stranding, a thicker distal right iliopsoas, hepatosplenomegaly, and an enlarged right adnexa (FIGURE 1). Initial ultrasound of the bubo showed 2 enlarged suprapubic lymph nodes, the largest measuring 3.5 × 1.4 × 2.4 cm³ (FIGURE 2), and 8 enlarged inguinal nodes.

The patient continued to have a low-grade fever, diarrhea, and inguinal lymphadenopathy throughout her first 2 hospitalized days. The cefoxitin was discontinued by Day 3, and the consulting infectious disease physician started oral metronidazole 500 mg every 12 hours due to the patient’s failure to improve. Later that night, the patient experienced increasing erythema and pain in her right inguinal region. A repeat ultrasound showed increased inguinal lymphadenopathy with the largest nodes measuring 2.9 × 1.5 × 2.5 cm³ and 2.7 × 1.3 × 2 cm³ (FIGURE 3).

Although doxycycline is considered an acceptable regimen for Y pestis infection, the infectious disease physician added oral ciprofloxacin 750 mg every 12 hours the following morning, as the patient had not improved.

THE DIAGNOSIS

Although the initial gram stain was negative for Yersinia, clinical suspicion pointed to a diagnosis of bubonic plague. Serology was considered; however, it was not available through the hospital. A definitive diagnosis required bubo aspiration and culture, which was performed but required 48 hours before results would be available.

Continue to: By Day 5, the patient was clinically improved and...

By Day 5, the patient was clinically improved and deemed safe for discharge on empiric treatment with ciprofloxacin 750 mg twice daily and doxycycline 100 mg twice daily to complete a 14-day course of antibiotic therapy for bubonic plague. The bubo culture subsequently grew Y pestis, confirming the diagnosis. The patient made a full recovery and was greatly improved when seen in the outpatient setting by the treating infectious disease physician. Outpatient ultrasound repeated 3 weeks after discharge showed borderline lymphadenopathy, no greater than 1 cm.

DISCUSSION

Between 2000 and 2009, there were 57 cases of Y pestis in the United States; in early 2015, 11 cases were found in 6 Western states.¹ The plague presents in the bubonic form 80% to 95% of the time, and it has never been reported in Michigan (where we treated this patient); however, there was a laboratory case in Illinois. Although rats were traditionally the host for Y pestis, the prairie dog, Cynomys gunnisoni, is a host in the United States.² Rodents are the most important hosts, but more than 200 mammalian species, including domestic pets, have had reported infections. Transmission is primarily via flea bites, but Y pestis also may be transmitted via respiratory secretion, inhalation, or direct handling of contaminated animal tissues. Due to the risk of respiratory spread, the Centers for Disease Control and Prevention must be notified of a diagnosis.^3,4

Y pestis travels from the site of the flea bite to regional lymph nodes, where it reproduces, and the resultant inflammatory reaction creates buboes. The bacteria then circulate in the blood to other organs, although Y pestis bacteria are primarily removed by the liver and spleen. Patients often develop symptoms such as headache, fevers, chills, and gastrointestinal distress. Diagnosis is reached by bubo culture or rapid testing for the F1 antigen. Early intervention with antibiotics is crucial as untreated bubonic plague has a mortality rate of 50% to 90%.^3,4

The differential diagnosis for unilateral inguinal lymphadenopathy with associated constitutional symptoms was broad, in this case, and included pelvic inflammatory disease, bubonic plague, iliopsoas abscess, lymphogranuloma venereum, bartonellosis, infectious mononucleosis, and tick-borne diseases, such as ehrlichiosis, tularemia, Lyme disease, Rocky Mountain spotted fever, and Colorado tick fever.

Although the initial gram stain demonstrated no organisms, a subsequent bubo aspiration and culture grew Y pestis, confirming the diagnosis.

Treatment. Food and Drug Administration–approved treatments include streptomycin (gentamicin 5 mg/kg/day IM or IV for 14 days is more widely utilized), doxycycline 200 mg PO once daily for 10 to 14 days, and fluoroquinolones (ciprofloxacin 500-750 mg every 12 hours for 10-14 days). Trimethoprim-sulfamethoxazole may be used as an alternative, but limitations include potentially incomplete or slowed responses.

Continue to: THE TAKEAWAY

 

 

THE TAKEAWAY

This case points to the importance of a complete, systematic approach to each patient. While bubonic plague is not a diagnosis that would immediately come to mind in a patient visiting an emergency department in Michigan, a thorough history revealed a recent trip to a bubonic plague–endemic area. A thorough physical exam demonstrated unilateral painful inguinal adenopathy—which, when paired with the patient’s history—was consistent with the uncommon diagnosis of bubonic plague.

ACKNOWLEDGEMENTS
The authors thank Brian Waite, MD, and James Addison, MD, for critically revising this report for important intellectual content.

CORRESPONDENCE
Katherine Lazet, DO, 3838 N First Avenue, Evansville, IN 47710; lazetkat@gmail.com

THE CASE

A 33-year-old Caucasian woman presented to the emergency department with a 6-day history of fever (103°-104°F) and right groin pain and swelling. Associated symptoms included headache, diarrhea, malaise, weakness, nausea, cough, and anorexia. Upon presentation, she admitted to a recent hike on a bubonic plague–endemic trail in Colorado.

Her vital signs were unremarkable, and the physical examination demonstrated normal findings except for tender, erythematous, nonfluctuant right inguinal lymphadenopathy. The patient was admitted for intractable pain and fever and started on intravenous cefoxitin 2 g IV every 8 hours and oral doxycycline 100 mg every 12 hours for pelvic inflammatory disease vs tick- or flea-borne illness. Due to the patient’s recent trip to a plague-infested area, our suspicion for Yersinia pestis infection was high.

The patient’s work-up included a negative pregnancy test and urinalysis. A complete blood count demonstrated a white blood cell count of 8.6 (4.3-10.5) × 10³/UL with a 3+ left shift and a platelet count of 112 (180-500) × 10³/UL. A complete metabolic panel showed hypokalemia and hyponatremia (potassium 2.8 [3.5-5.1] mmol/L and sodium 134 [137-145] mmol/L). Blood cultures were negative for any bacterial or fungal growth after 48 hours; stool cultures were negative for Salmonella, Shigella, Campylobacter, Giardia, generalized Yersinia, and Escherichia coli O157:H7. Swabs for Gardnerella vaginalis, Trichomonas vaginalis, Candida, Chlamydia trachomatis, and Neisseria gonorrhea also were negative. Lyme, Bartonella henselae, and heterophile antibodies were also negative. Francisella tularensis was not cultured due to low suspicion.

Imaging included a normal chest x-ray and a computed tomography scan of the abdomen and pelvis that showed enlarged right inguinal lymph nodes with fatty stranding, a thicker distal right iliopsoas, hepatosplenomegaly, and an enlarged right adnexa (FIGURE 1). Initial ultrasound of the bubo showed 2 enlarged suprapubic lymph nodes, the largest measuring 3.5 × 1.4 × 2.4 cm³ (FIGURE 2), and 8 enlarged inguinal nodes.

The patient continued to have a low-grade fever, diarrhea, and inguinal lymphadenopathy throughout her first 2 hospitalized days. The cefoxitin was discontinued by Day 3, and the consulting infectious disease physician started oral metronidazole 500 mg every 12 hours due to the patient’s failure to improve. Later that night, the patient experienced increasing erythema and pain in her right inguinal region. A repeat ultrasound showed increased inguinal lymphadenopathy with the largest nodes measuring 2.9 × 1.5 × 2.5 cm³ and 2.7 × 1.3 × 2 cm³ (FIGURE 3).

Although doxycycline is considered an acceptable regimen for Y pestis infection, the infectious disease physician added oral ciprofloxacin 750 mg every 12 hours the following morning, as the patient had not improved.

THE DIAGNOSIS

Although the initial gram stain was negative for Yersinia, clinical suspicion pointed to a diagnosis of bubonic plague. Serology was considered; however, it was not available through the hospital. A definitive diagnosis required bubo aspiration and culture, which was performed but required 48 hours before results would be available.

Continue to: By Day 5, the patient was clinically improved and...

By Day 5, the patient was clinically improved and deemed safe for discharge on empiric treatment with ciprofloxacin 750 mg twice daily and doxycycline 100 mg twice daily to complete a 14-day course of antibiotic therapy for bubonic plague. The bubo culture subsequently grew Y pestis, confirming the diagnosis. The patient made a full recovery and was greatly improved when seen in the outpatient setting by the treating infectious disease physician. Outpatient ultrasound repeated 3 weeks after discharge showed borderline lymphadenopathy, no greater than 1 cm.

DISCUSSION

Between 2000 and 2009, there were 57 cases of Y pestis in the United States; in early 2015, 11 cases were found in 6 Western states.¹ The plague presents in the bubonic form 80% to 95% of the time, and it has never been reported in Michigan (where we treated this patient); however, there was a laboratory case in Illinois. Although rats were traditionally the host for Y pestis, the prairie dog, Cynomys gunnisoni, is a host in the United States.² Rodents are the most important hosts, but more than 200 mammalian species, including domestic pets, have had reported infections. Transmission is primarily via flea bites, but Y pestis also may be transmitted via respiratory secretion, inhalation, or direct handling of contaminated animal tissues. Due to the risk of respiratory spread, the Centers for Disease Control and Prevention must be notified of a diagnosis.^3,4

Y pestis travels from the site of the flea bite to regional lymph nodes, where it reproduces, and the resultant inflammatory reaction creates buboes. The bacteria then circulate in the blood to other organs, although Y pestis bacteria are primarily removed by the liver and spleen. Patients often develop symptoms such as headache, fevers, chills, and gastrointestinal distress. Diagnosis is reached by bubo culture or rapid testing for the F1 antigen. Early intervention with antibiotics is crucial as untreated bubonic plague has a mortality rate of 50% to 90%.^3,4

The differential diagnosis for unilateral inguinal lymphadenopathy with associated constitutional symptoms was broad, in this case, and included pelvic inflammatory disease, bubonic plague, iliopsoas abscess, lymphogranuloma venereum, bartonellosis, infectious mononucleosis, and tick-borne diseases, such as ehrlichiosis, tularemia, Lyme disease, Rocky Mountain spotted fever, and Colorado tick fever.

Although the initial gram stain demonstrated no organisms, a subsequent bubo aspiration and culture grew Y pestis, confirming the diagnosis.

Treatment. Food and Drug Administration–approved treatments include streptomycin (gentamicin 5 mg/kg/day IM or IV for 14 days is more widely utilized), doxycycline 200 mg PO once daily for 10 to 14 days, and fluoroquinolones (ciprofloxacin 500-750 mg every 12 hours for 10-14 days). Trimethoprim-sulfamethoxazole may be used as an alternative, but limitations include potentially incomplete or slowed responses.

Continue to: THE TAKEAWAY

 

 

THE TAKEAWAY

This case points to the importance of a complete, systematic approach to each patient. While bubonic plague is not a diagnosis that would immediately come to mind in a patient visiting an emergency department in Michigan, a thorough history revealed a recent trip to a bubonic plague–endemic area. A thorough physical exam demonstrated unilateral painful inguinal adenopathy—which, when paired with the patient’s history—was consistent with the uncommon diagnosis of bubonic plague.

ACKNOWLEDGEMENTS
The authors thank Brian Waite, MD, and James Addison, MD, for critically revising this report for important intellectual content.

CORRESPONDENCE
Katherine Lazet, DO, 3838 N First Avenue, Evansville, IN 47710; lazetkat@gmail.com

An International Antiviral Society-USA Panel recently published an updated set of recommendations on using antiviral drugs to treat and prevent human immunodeficiency virus (HIV) infection¹—a rapidly changing and complex topic. This new guideline updates the society’s 2016 publication.² It contains recommendations on when to start antiretroviral therapy for those who are HIV positive and advice on suitable combinations of antiretroviral drugs. It also details pre- and post-exposure prophylaxis strategies for preventing HIV infection in those at risk.

This Practice Alert highlights the most important recommendations on treating those newly diagnosed as HIV positive and on preventing infection. Physicians who provide care for those who are HIV positive should familiarize themselves with the entire guideline.

Initiating treatment in those newly diagnosed as HIV positive

The panel now recommends starting antiretroviral therapy (ART) as soon as possible after HIV infection is confirmed; immediately if a patient is ready to commit to starting and continuing treatment. Any patient with an opportunistic infection should begin ART within 2 weeks of its diagnosis. Patients being treated for tuberculosis (TB) should begin ART within 2 weeks of starting TB treatment if their CD4 cell count is <50/mcL; those whose count is ≥50/mcL should begin ART within 2 to 8 weeks.

The panel recommends one of 3 ART combinations (TABLE 1¹), all of which contain an integrase strand transfer inhibitor (INSTI). ART started immediately should not include a nonnucleoside reverse transcriptase inhibitor (NNRTI) because of possible viral resistance. The guideline recommends 6 other ART combinations if none of the first 3 options can be used.¹

An initial set of laboratory tests (TABLE 2¹) should be conducted on each individual receiving ART, although treatment can start before the results are returned. Ongoing laboratory monitoring, described in detail in the guideline, depends on the ART regimen chosen and the patient’s response to therapy. The only routinely recommended prophylaxis for opportunistic infections is for Pneumocystis pneumonia if the CD4 count is <200/mcL.

Preventing HIV with prEP

Consider prescribing daily pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (Truvada) for men and women who are at risk from sexual exposure to HIV or who inject illicit drugs. It takes about 1 week for protective tissue levels to be achieved. Testing to rule out HIV infection is recommended before starting PrEP, as is testing for serum creatinine level, estimated glomerular filtration rate, and hepatitis B surface antigen. Tenofovir disoproxil fumarate is not recommended for those with creatinine clearance of less than 60 mL/min/1.73 m². For patients taking PrEP, emphasize other preventive measures such as using condoms to protect against both HIV and other sexually-transmitted diseases (STDs), using clean needles and syringes when injecting drugs, or entering a drug rehabilitation program. After initiating PrEP, schedule the first follow-up visit for 30 days later to repeat the HIV test and to assess adverse reactions and PrEP adherence.

Consider prescribing daily pre-exposure prophylaxis for men and women at risk from sexual exposure to HIV or who inject illicit drugs.

For men who have sex with men (MSM), there is an alternative form of PrEP when sexual exposure is infrequent. “On-demand” or “event-driven” PrEP involves 4 doses of emtricitabine/tenofovir disoproxil fumarate; 2 doses given with food 2 to 24 hours before sex (the closer to 24 the better), one dose 24 hours after the first and one 24 hours after the second. This is referred to as 2-1-1 dosing. This option has only been tested in MSM with sexual exposure. It is not recommended at this time for others at risk for HIV or for MSM with chronic or active hepatitis B infection.

Continue to: Preventing HIV infection with post-exposure prophylaxis

Preventing HIV infection with post-exposure prophylaxis

Post-exposure prophylaxis (PEP) for HIV infection is divided into 2 categories: occupational PEP (oPEP) and non-occupational PEP (nPEP). Recommendations for oPEP are described elsewhere³ and are not covered in this Practice Alert. Summarized below are the recommendations for nPEP after sex, injection drug use, and other nonoccupational exposures, which are also described on the Centers for Disease Control and Prevention (CDC) Web site.⁴

Assess the need for nPEP if high-risk exposure (TABLE 3⁴) occurred ≤72 hours earlier. Before starting nPEP, perform a rapid HIV blood test. If rapid testing is unavailable, start nPEP, which can be discontinued if the patient is later determined to have HIV infection. Repeat HIV testing at 4 to 6 weeks and 3 months following initiation of nPEP. Approved HIV tests are described on the CDC Web site at http://www.cdc.gov/hiv/testing/laboratorytests.html. Oral HIV tests are not recommended for HIV testing before initiating nPEP.

nPEP is not recommended when an individual’s risk of exposure to HIV is not high, or if the exposure occurred more than 72 hours before presentation. An algorithm is available to assist with assessing whether nPEP is recommended (FIGURE⁴).

Specific nPEP regimens. For otherwise healthy adults and adolescents, preferred nPEP consists of a 28-day course of a 3-drug combination: tenofovir disoproxil fumarate 300 mg once daily; emtricitabine 200 mg once daily; and raltegravir, 400 mg twice daily, or dolutegravir 50 mg once daily. Alternative regimens for adults and adolescents are described in the guideline, as are options for children, those with decreased renal function, and pregnant women. Those who receive more than one course of nPEP within a 12-month period should consider PrEP.

Offer immediate post-exposure HIV prophylaxis if high-risk non-occupational contact occurred within the last 72 hours and rapid HIV testing is unavailable.

When additional vaccination is needed. For victims of sexual assault, offer prophylaxis against STD (TABLE 4⁴) and hepatitis B virus (HBV). Those who have not been vaccinated against HBV should receive the first dose at the initial visit. If the exposure source is known to be HBsAg-positive, give the unvaccinated patient both hepatitis B vaccine and hepatitis B immune globulin at the first visit. The full hepatitis B vaccine series should then be completed according to the recommended schedule and the vaccine product used. Those who have completed hepatitis B vaccination but who were not tested with a post-vaccine titer should receive a single dose of hepatitis B vaccine.

Continue to: Victims of sexual assault...

Victims of sexual assault can benefit from referral to professionals with expertise in post-assault counseling. Sexual Assault Nurse Examiner programs are listed at http://www.sane-sart.com.

Financial assistance for patients. Anti-retroviral drugs are expensive, and those who need nPEP may not have a payer source. Many pharmaceutical manufacturers offer medication assistance programs, and processes are set up to handle time-sensitive requests. Information for specific medications can be found at http://www.pparx.org/en/prescription_assistance_programs/list_of_participating_programs. Those who are prescribed nPEP after a sexual assault can receive reimbursement for medications and health care costs through state Crime Victim Compensation Programs funded by the Department of Justice. State-specific contact information is available at http://www.nacvcb.org/index.asp?sid=6.

An International Antiviral Society-USA Panel recently published an updated set of recommendations on using antiviral drugs to treat and prevent human immunodeficiency virus (HIV) infection¹—a rapidly changing and complex topic. This new guideline updates the society’s 2016 publication.² It contains recommendations on when to start antiretroviral therapy for those who are HIV positive and advice on suitable combinations of antiretroviral drugs. It also details pre- and post-exposure prophylaxis strategies for preventing HIV infection in those at risk.

This Practice Alert highlights the most important recommendations on treating those newly diagnosed as HIV positive and on preventing infection. Physicians who provide care for those who are HIV positive should familiarize themselves with the entire guideline.

Initiating treatment in those newly diagnosed as HIV positive

The panel now recommends starting antiretroviral therapy (ART) as soon as possible after HIV infection is confirmed; immediately if a patient is ready to commit to starting and continuing treatment. Any patient with an opportunistic infection should begin ART within 2 weeks of its diagnosis. Patients being treated for tuberculosis (TB) should begin ART within 2 weeks of starting TB treatment if their CD4 cell count is <50/mcL; those whose count is ≥50/mcL should begin ART within 2 to 8 weeks.

The panel recommends one of 3 ART combinations (TABLE 1¹), all of which contain an integrase strand transfer inhibitor (INSTI). ART started immediately should not include a nonnucleoside reverse transcriptase inhibitor (NNRTI) because of possible viral resistance. The guideline recommends 6 other ART combinations if none of the first 3 options can be used.¹

An initial set of laboratory tests (TABLE 2¹) should be conducted on each individual receiving ART, although treatment can start before the results are returned. Ongoing laboratory monitoring, described in detail in the guideline, depends on the ART regimen chosen and the patient’s response to therapy. The only routinely recommended prophylaxis for opportunistic infections is for Pneumocystis pneumonia if the CD4 count is <200/mcL.

Preventing HIV with prEP

Consider prescribing daily pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (Truvada) for men and women who are at risk from sexual exposure to HIV or who inject illicit drugs. It takes about 1 week for protective tissue levels to be achieved. Testing to rule out HIV infection is recommended before starting PrEP, as is testing for serum creatinine level, estimated glomerular filtration rate, and hepatitis B surface antigen. Tenofovir disoproxil fumarate is not recommended for those with creatinine clearance of less than 60 mL/min/1.73 m². For patients taking PrEP, emphasize other preventive measures such as using condoms to protect against both HIV and other sexually-transmitted diseases (STDs), using clean needles and syringes when injecting drugs, or entering a drug rehabilitation program. After initiating PrEP, schedule the first follow-up visit for 30 days later to repeat the HIV test and to assess adverse reactions and PrEP adherence.

Consider prescribing daily pre-exposure prophylaxis for men and women at risk from sexual exposure to HIV or who inject illicit drugs.

For men who have sex with men (MSM), there is an alternative form of PrEP when sexual exposure is infrequent. “On-demand” or “event-driven” PrEP involves 4 doses of emtricitabine/tenofovir disoproxil fumarate; 2 doses given with food 2 to 24 hours before sex (the closer to 24 the better), one dose 24 hours after the first and one 24 hours after the second. This is referred to as 2-1-1 dosing. This option has only been tested in MSM with sexual exposure. It is not recommended at this time for others at risk for HIV or for MSM with chronic or active hepatitis B infection.

Continue to: Preventing HIV infection with post-exposure prophylaxis

Preventing HIV infection with post-exposure prophylaxis

Post-exposure prophylaxis (PEP) for HIV infection is divided into 2 categories: occupational PEP (oPEP) and non-occupational PEP (nPEP). Recommendations for oPEP are described elsewhere³ and are not covered in this Practice Alert. Summarized below are the recommendations for nPEP after sex, injection drug use, and other nonoccupational exposures, which are also described on the Centers for Disease Control and Prevention (CDC) Web site.⁴

Assess the need for nPEP if high-risk exposure (TABLE 3⁴) occurred ≤72 hours earlier. Before starting nPEP, perform a rapid HIV blood test. If rapid testing is unavailable, start nPEP, which can be discontinued if the patient is later determined to have HIV infection. Repeat HIV testing at 4 to 6 weeks and 3 months following initiation of nPEP. Approved HIV tests are described on the CDC Web site at http://www.cdc.gov/hiv/testing/laboratorytests.html. Oral HIV tests are not recommended for HIV testing before initiating nPEP.

nPEP is not recommended when an individual’s risk of exposure to HIV is not high, or if the exposure occurred more than 72 hours before presentation. An algorithm is available to assist with assessing whether nPEP is recommended (FIGURE⁴).

Specific nPEP regimens. For otherwise healthy adults and adolescents, preferred nPEP consists of a 28-day course of a 3-drug combination: tenofovir disoproxil fumarate 300 mg once daily; emtricitabine 200 mg once daily; and raltegravir, 400 mg twice daily, or dolutegravir 50 mg once daily. Alternative regimens for adults and adolescents are described in the guideline, as are options for children, those with decreased renal function, and pregnant women. Those who receive more than one course of nPEP within a 12-month period should consider PrEP.

Offer immediate post-exposure HIV prophylaxis if high-risk non-occupational contact occurred within the last 72 hours and rapid HIV testing is unavailable.

When additional vaccination is needed. For victims of sexual assault, offer prophylaxis against STD (TABLE 4⁴) and hepatitis B virus (HBV). Those who have not been vaccinated against HBV should receive the first dose at the initial visit. If the exposure source is known to be HBsAg-positive, give the unvaccinated patient both hepatitis B vaccine and hepatitis B immune globulin at the first visit. The full hepatitis B vaccine series should then be completed according to the recommended schedule and the vaccine product used. Those who have completed hepatitis B vaccination but who were not tested with a post-vaccine titer should receive a single dose of hepatitis B vaccine.

Continue to: Victims of sexual assault...

Victims of sexual assault can benefit from referral to professionals with expertise in post-assault counseling. Sexual Assault Nurse Examiner programs are listed at http://www.sane-sart.com.

Financial assistance for patients. Anti-retroviral drugs are expensive, and those who need nPEP may not have a payer source. Many pharmaceutical manufacturers offer medication assistance programs, and processes are set up to handle time-sensitive requests. Information for specific medications can be found at http://www.pparx.org/en/prescription_assistance_programs/list_of_participating_programs. Those who are prescribed nPEP after a sexual assault can receive reimbursement for medications and health care costs through state Crime Victim Compensation Programs funded by the Department of Justice. State-specific contact information is available at http://www.nacvcb.org/index.asp?sid=6.

An International Antiviral Society-USA Panel recently published an updated set of recommendations on using antiviral drugs to treat and prevent human immunodeficiency virus (HIV) infection¹—a rapidly changing and complex topic. This new guideline updates the society’s 2016 publication.² It contains recommendations on when to start antiretroviral therapy for those who are HIV positive and advice on suitable combinations of antiretroviral drugs. It also details pre- and post-exposure prophylaxis strategies for preventing HIV infection in those at risk.

This Practice Alert highlights the most important recommendations on treating those newly diagnosed as HIV positive and on preventing infection. Physicians who provide care for those who are HIV positive should familiarize themselves with the entire guideline.

Initiating treatment in those newly diagnosed as HIV positive

The panel now recommends starting antiretroviral therapy (ART) as soon as possible after HIV infection is confirmed; immediately if a patient is ready to commit to starting and continuing treatment. Any patient with an opportunistic infection should begin ART within 2 weeks of its diagnosis. Patients being treated for tuberculosis (TB) should begin ART within 2 weeks of starting TB treatment if their CD4 cell count is <50/mcL; those whose count is ≥50/mcL should begin ART within 2 to 8 weeks.

The panel recommends one of 3 ART combinations (TABLE 1¹), all of which contain an integrase strand transfer inhibitor (INSTI). ART started immediately should not include a nonnucleoside reverse transcriptase inhibitor (NNRTI) because of possible viral resistance. The guideline recommends 6 other ART combinations if none of the first 3 options can be used.¹

An initial set of laboratory tests (TABLE 2¹) should be conducted on each individual receiving ART, although treatment can start before the results are returned. Ongoing laboratory monitoring, described in detail in the guideline, depends on the ART regimen chosen and the patient’s response to therapy. The only routinely recommended prophylaxis for opportunistic infections is for Pneumocystis pneumonia if the CD4 count is <200/mcL.

Preventing HIV with prEP

Consider prescribing daily pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (Truvada) for men and women who are at risk from sexual exposure to HIV or who inject illicit drugs. It takes about 1 week for protective tissue levels to be achieved. Testing to rule out HIV infection is recommended before starting PrEP, as is testing for serum creatinine level, estimated glomerular filtration rate, and hepatitis B surface antigen. Tenofovir disoproxil fumarate is not recommended for those with creatinine clearance of less than 60 mL/min/1.73 m². For patients taking PrEP, emphasize other preventive measures such as using condoms to protect against both HIV and other sexually-transmitted diseases (STDs), using clean needles and syringes when injecting drugs, or entering a drug rehabilitation program. After initiating PrEP, schedule the first follow-up visit for 30 days later to repeat the HIV test and to assess adverse reactions and PrEP adherence.

Consider prescribing daily pre-exposure prophylaxis for men and women at risk from sexual exposure to HIV or who inject illicit drugs.

For men who have sex with men (MSM), there is an alternative form of PrEP when sexual exposure is infrequent. “On-demand” or “event-driven” PrEP involves 4 doses of emtricitabine/tenofovir disoproxil fumarate; 2 doses given with food 2 to 24 hours before sex (the closer to 24 the better), one dose 24 hours after the first and one 24 hours after the second. This is referred to as 2-1-1 dosing. This option has only been tested in MSM with sexual exposure. It is not recommended at this time for others at risk for HIV or for MSM with chronic or active hepatitis B infection.

Continue to: Preventing HIV infection with post-exposure prophylaxis

Preventing HIV infection with post-exposure prophylaxis

Post-exposure prophylaxis (PEP) for HIV infection is divided into 2 categories: occupational PEP (oPEP) and non-occupational PEP (nPEP). Recommendations for oPEP are described elsewhere³ and are not covered in this Practice Alert. Summarized below are the recommendations for nPEP after sex, injection drug use, and other nonoccupational exposures, which are also described on the Centers for Disease Control and Prevention (CDC) Web site.⁴

Assess the need for nPEP if high-risk exposure (TABLE 3⁴) occurred ≤72 hours earlier. Before starting nPEP, perform a rapid HIV blood test. If rapid testing is unavailable, start nPEP, which can be discontinued if the patient is later determined to have HIV infection. Repeat HIV testing at 4 to 6 weeks and 3 months following initiation of nPEP. Approved HIV tests are described on the CDC Web site at http://www.cdc.gov/hiv/testing/laboratorytests.html. Oral HIV tests are not recommended for HIV testing before initiating nPEP.

nPEP is not recommended when an individual’s risk of exposure to HIV is not high, or if the exposure occurred more than 72 hours before presentation. An algorithm is available to assist with assessing whether nPEP is recommended (FIGURE⁴).

Specific nPEP regimens. For otherwise healthy adults and adolescents, preferred nPEP consists of a 28-day course of a 3-drug combination: tenofovir disoproxil fumarate 300 mg once daily; emtricitabine 200 mg once daily; and raltegravir, 400 mg twice daily, or dolutegravir 50 mg once daily. Alternative regimens for adults and adolescents are described in the guideline, as are options for children, those with decreased renal function, and pregnant women. Those who receive more than one course of nPEP within a 12-month period should consider PrEP.

Offer immediate post-exposure HIV prophylaxis if high-risk non-occupational contact occurred within the last 72 hours and rapid HIV testing is unavailable.

When additional vaccination is needed. For victims of sexual assault, offer prophylaxis against STD (TABLE 4⁴) and hepatitis B virus (HBV). Those who have not been vaccinated against HBV should receive the first dose at the initial visit. If the exposure source is known to be HBsAg-positive, give the unvaccinated patient both hepatitis B vaccine and hepatitis B immune globulin at the first visit. The full hepatitis B vaccine series should then be completed according to the recommended schedule and the vaccine product used. Those who have completed hepatitis B vaccination but who were not tested with a post-vaccine titer should receive a single dose of hepatitis B vaccine.

Continue to: Victims of sexual assault...

Victims of sexual assault can benefit from referral to professionals with expertise in post-assault counseling. Sexual Assault Nurse Examiner programs are listed at http://www.sane-sart.com.

Financial assistance for patients. Anti-retroviral drugs are expensive, and those who need nPEP may not have a payer source. Many pharmaceutical manufacturers offer medication assistance programs, and processes are set up to handle time-sensitive requests. Information for specific medications can be found at http://www.pparx.org/en/prescription_assistance_programs/list_of_participating_programs. Those who are prescribed nPEP after a sexual assault can receive reimbursement for medications and health care costs through state Crime Victim Compensation Programs funded by the Department of Justice. State-specific contact information is available at http://www.nacvcb.org/index.asp?sid=6.

In landmark clinical research published in 1996, aspirin (ASA) and the P2Y12 inhibitor ticlopidine used after coronary artery stent implantation was compared to intravenous anticoagulation—at the time, the postprocedure standard of care for preventing thrombosis. What investigators found was a marked reduction in cardiac and hemorrhagic events in patients who were treated with this novel dual antiplatelet therapy (DAPT).¹ Since publication of the results of that trial, the use of ASA plus a P2Y12 inhibitor has expanded to treating acute coronary syndrome (ACS) and stroke.

Over the past 2 decades, much research has been devoted to 1) determining the effectiveness of more potent P2Y12 inhibitors—which block chemoreceptors for adenosine diphosphate—to prevent stent thrombosis and 2) safer regimens to reduce hemorrhagic complications.

When does stent thrombosis occur?

The timing of stent thrombosis is defined as:

• acute (within 24 hours of placement),
• subacute (within 30 days),
• late (within 1 year), or
• very late (after 1 year).

Acute stent thrombosis is almost always related to technical issues surrounding stent implantation. Subacute thrombosis is almost always platelet activation within the stent with thrombus formation—the reason why antiplatelet therapy is beneficial and anticoagulation pathway inhibition is not beneficial.

The delay in healing caused by drug-eluting stents makes it necessary to administer dual antiplatelet therapy for a longer duration—an increase not needed with bare-metal stents.

Late stent complications can be caused by thrombosis, but also might be related to restenosis by 4 to 6 months—ie, tissue overgrowth as the stent becomes part of the body, not clot formation. In several studies, restenosis was a significant issue with balloon dilation alone, occurring in 33% of patients.² Bare-metal stents (BMS) have been shown to reduce the rate of restenosis to approximately 20%; drug-eluting stents (DES) have further decreased restenosis to approximately 5%, in various reports, by impairing endothelial healing, thus limiting tissue overgrowth that leads to restenosis.³ This delay in healing caused by DES makes it necessary to administer DAPT for a longer duration—an increase that is not needed with BMS.

© Myriam and Steve Oh

DAPT has well-defined benefits

As drug-eluting stents were introduced and improved, trials studying optimal duration of DAPT showed that longer duration of treatment reduced stroke incidence and the long-term risk of myocardial infarction (MI) unrelated to stent thrombosis.⁴ Nuances in the treatment of ischemic coronary artery disease (CAD) and secondary prevention of stroke can be perplexing, as can be P2Y12inhibitor selection. Here, we review DAPT agents and discuss current evidence and evidence-based guidelines, thus providing a framework to better understand treatment options and recommendations.

What constitutes DAPT?

Many combinations of antiplatelet therapy are possible but, in the United States, DAPT denotes ASA 81 mg/d plus any of the 3 P2Y12inhibitors: clopidogrel, prasugrel, and ticagrelor. Stimulation of the platelet P2Y12receptor causes stimulation of the platelet glycoprotein IIb/IIIa receptor, which, in turn, enhances platelet degranulation, thromboxane production, and prolonged platelet aggregation. Blocking P2Y12receptors thus impairs the thrombotic processes.⁵

Continue to: ASA, as a component of DAPT...

ASA, as a component of DAPT, is recommended at a dosage of 81 mg/d. In trials of ASA plus clopidogrel, lower ASA dosages had comparable ischemic event rates compared to higher ASA dosages.^6,7 Patients given higher ASA dosages with ticagrelor had poorer outcomes when compared with low-dosage ASA.⁸ Higher dosages of ASA, alone or with DAPT, increase the risk of bleeding complications.^9,10

Clopidogrel is the only P2Y12 inhibitor available as a generic medication in the United States. As a pro-drug, clopidogrel requires 2 metabolic transformations to its active metabolite after being hydrolyzed in the gut, which delays onset of platelet inhibition for several hours after ingestion.¹¹ Furthermore, individual genetic variation in cytochrome P450 (CYP) 2C19 (CYP2C19), one of the hepatic enzymes in this metabolic process, may lead to less alteration of clinical platelet aggregation response, and increased drug interactions.¹² Methods to assess platelet function have shown decreased inhibition of platelet aggregation for some CYP2C19 polymorphisms, although consistent clinical effects of this inhibition have not been identified to date; genetic testing for these polymorphisms is, therefore, not recommended routinely.¹³

Indications for DAPT treatment with clopidogrel are unstable angina or non-ST-segment elevation acute coronary syndrome (NSTE-ACS), whether planned treatment is medical or coronary revascularization. Other indications include acute ST-segment elevation MI (STEMI) with planned medical treatment, and recent MI, stroke, or established peripheral arterial disease.^13,14

Prasugrel has faster onset of action and greater and more consistent P2Y12 inhibition than clopidogrel. After prasugrel is hydrolyzed in the gut, an intermediary metabolite is activated in the liver. Peak serum concentration is reached within 30 minutes.¹² Unlike the case with clopidogrel, genetic variation in the CYP gene does not impart significant impact on forming the active metabolite.¹⁵

Longer duration of DAPT reduces stroke incidence and the long-term risk of myocardial infarction—unrelated to stent thrombosis.

Indication for the use of prasugrel is ACS that is managed with percutaneous coronary intervention (PCI). Dual antiplatelet therapy with prasugrel results in reduced risk of cardiovascular death, nonfatal MI, and stroke, compared with ASA plus clopidogrel, with an increase in bleeding events.¹⁶ Thrombolysis patients and those who have a history of stroke had a greater risk of hemorrhage complications with prasugrel treatment, compared with clopidogrel. Prasugrel offered no benefit to patients older than 75 years or those who weigh <60 kg. If used in patients who weigh <60 kg, however, dosage reduction is recommended.¹⁶

Continue to: Ticagrelor

Ticagrelor. Unlike clopidogrel and prasugrel, ticagrelor is a direct oral, reversible-binding P2Y12 inhibitor. Peak serum concentration is reached within 2 to 3 hours.¹⁷ Indications are ACS or a history of MI, and those with ACS undergoing stent implantation. Ticagrelor was superior to clopidogrel in reducing the risk of death from vascular causes, MI, and stroke, and superior to clopidogrel in reducing the risk of stent thrombosis. There was no increase in the overall major bleeding rate and a decrease in fatal bleeding events compared to clopidogrel. Adverse effects unique to ticagrelor include dyspnea and, in patients with bradydysrhythmias, asymptomatic ventricular pauses. Both effects tend to resolve with continued treatment. This P2Y12 inhibitor should be avoided in patients with severe liver disease.

Loading and maintenance doses of the 3 P2Y12 inhibitors are provided in TABLE 1.^13,14

When—and when not—to initiate DAPT

Treatment recommendations for DAPT originated in the 2016 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with Coronary Artery Disease¹⁴ and in the 2017 European Society of Cardiology (ESC) focused update on dual antiplatelet therapy in coronary artery disease.¹³ Although these guidelines differ slightly, the overall approach they present is similar, with an emphasis on limiting bleeding while preventing stent thrombosis.

Stable ischemic heart disease (SIHD) is defined as confirmed obstructive CAD without either ACS or a history of PCI in the past year.¹⁸ Patients with SIHD but without a history of PCI or recent coronary artery bypass grafting (CABG) receive no benefit from DAPT (Strength of recommendation [SOR]: A).¹⁹ (See TABLE 2 for definitions of SOR and corresponding levels of evidence.)

For patients who have undergone BMS placement, minimum DAPT with clopidogrel is 1 month (SOR: A) and, if there is no significant bleeding on DAPT and no high risk of bleeding (ie, no prior bleeding while taking DAPT, coagulopathy, or oral anticoagulant use), continuation of ASA and clopidogrel beyond 1 month might be reasonable (SOR: B).

Continue to: With a drug-eluting stent...

With a drug-eluting stent, the minimum time for DAPT (using clopidogrel) is 6 months (SOR: A), with a longer duration being reasonable if the patient is not at high risk of bleeding and has had no bleeding complications (SOR: B). For DES patients who have developed a high risk of bleeding, have had significant bleeding, or require a procedure that will place them at high risk of bleeding, DAPT discontinuation can be considered at 3 months (SOR: B).

Updated guidelines allow longer therapy for patients who tolerate DAPT; for them, 12 months of therapy is preferred. In comparing longer and shorter therapy, it has been determined that longer DAPT treatment is superior for reducing the risk of MI and stent thrombosis without increasing the risk of stroke or bleeding complications.²⁰ With increased bleeding, or where there is a need for elective surgery, shortened DAPT is an option.

When treating patients with ACS, including NSTE-ACS or STEMI, DAPT for 1 year is recommended (SOR: A). When medical therapy alone is planned, DAPT is provided with clopidogrel or ticagrelor.

When a patient has been treated with PCI (BMS or DES), DAPT with any of the P2Y12 inhibitors is recommended (SOR: A) unless there is history of stroke or transient ischemic attack (TIA) or the patient is ≥75 years of age, in which case prasugrel is contraindicated (SOR: A: Harm).

Continue to: When lytic interventions are employed in STEMI...

When lytic interventions are employed in STEMI, DAPT with clopidogrel—for a minimum of 14 days and, ideally, for 12 months—should be considered. Without high risk of bleeding, or significant bleeding on DAPT, continuing DAPT for >12 months might be reasonable (SOR: A).

TABLE 3,^13,14 adapted from 2016 ACC/AHA¹⁴ and 2017 ESC¹³ guidelines, provides recommendations about agents and duration of therapy in the management of patients with CAD.

How long should you give DAPT?

Balancing the hemorrhagic complications of DAPT against its benefits is challenging. The use of risk scores to guide duration of DAPT may be considered (SOR: B).

The PRECISE-DAPT score²¹ is used at the time of coronary artery stenting to guide treatment duration. The scoring algorithm incorporates hemoglobin level, leukocyte count, age, creatinine clearance and prior bleeding to create a composite score on a 100-point scale.²² (The algorithm can be found at www.precisedaptscore.com/predapt/webcalculator.html.) If the composite is <25 points, the number needed to treat to prevent an ischemic event is 65, and standard or long-term DAPT (12 to 24 months) is recommended. When the PRECISE-DAPT score is ≥25, the number needed to harm with a hemorrhagic event is 38, and a shorter duration of therapy (3 to 6 months) is recommended.

Ticagrelor should be avoided in patients with severe liver disease.

The DAPT score,²³ available from the American College of Cardiology²⁴ (http://tools.acc.org/DAPTriskapp/#!/content/calculator) is a risk calculator for use after 12 months of DAPT in the absence of complications. Age, cigarette use, diabetes, current or previous MI, presence of congestive heart disease, and type and location of stent all factor into calculating the risk score. DAPT scores range from -2 to 10. A score ≥2 suggests less bleeding risk, with a recommendation to consider longer treatment (≤30 months); a score <2 leads to a recommendation to adhere to standard treatment duration of 12 months.

Continue to: Patients with CAD should...

Patients with CAD should continue ASA treatment when DAPT is discontinued or completed, unless contraindicated.^13,14

Triple therapy: DAPT + anticoagulant

Given that the US population is aging, there are an increasing number of patients with CAD and atrial fibrillation. Stroke is prevented in patients with atrial fibrillation with anticoagulant therapy; when these patients have stent placement for coronary, carotid, vertebral, or intracranial arterial disease, they need DAPT to prevent stent thrombosis. In the immediate post-stenting period, therefore, patients are often placed on an oral anticoagulant as well as DAPT. Vitamin K antagonists (VKAs) should be discontinued after acute stroke, with individualized resumption of a VKA when clinically appropriate.

As we emphasize throughout this article, there is a balance between bleeding risk and the potential benefits of therapy of the selected anticoagulant/DAPT regimen. These complex patients are best managed in close consultation with Cardiology and Neurology because of their potential risk of 3-fold bleeding.²⁵ The findings of a recent study addressing post-stent placement therapy in patients with nonvalvular atrial fibrillation suggests that the direct oral anticoagulant dabigatran may be preferable to warfarin in this setting, because of the lower risk of bleeding with dabigatran without increased thrombotic risk.²⁶ In this study, 3-drug therapy was used for 1 month, followed by discontinuation of ASA and continuation of 2-drug therapy with the direct oral anticoagulant and the P2Y12 inhibitor for the 6- to 12-month time frame post-stenting (SOR: B).

Consider a PPI to reduce the risk of a GI bleed

Proton-pump inhibitors (PPIs) should be considered for patients treated with DAPT if there is a history of gastrointestinal (GI) bleeding (SOR: A). Although a potential interaction between PPIs and P2Y12 inhibition has been identified in laboratory studies, this has not been supported in clinical studies. Therefore, although warnings exist for concomitant use of clopidogrel and PPIs, a PPI is reasonable for patients who are at increased risk of GI hemorrhage, including those taking warfarin, a corticosteroid, or a nonsteroidal anti-inflammatory drug and those of advanced age (SOR: B). Risks and benefits of clopidogrel and PPIs should be discussed with patients. There is no benefit in using PPIs for low-risk patients. (SOR: A: No benefit).^27,28

Perioperative management with DAPT can be thorny

Perioperative management of DAPT patients who have an indwelling coronary stent and require noncardiac surgery is complicated. Stent thrombosis is a calamity, with ≥50% risk of death. Delaying surgery for at least 4 weeks after placement of a BMS and 6 months after placement of a DES reduces the risk of thrombosis.²⁹

Continue to: For emergent surgery...

For emergent surgery, when severe bleeding is not seen or expected, interruption of DAPT can be minimized. After cessation of DAPT components, normal platelet function will return in¹²:

• 7 to 10 days for ASA,
• 5 to 7 days for prasugrel,
• 5 days for clopidogrel, and
• 3 to 5 days for ticagrelor.

If significant bleeding occurs perioperatively, or is expected, platelet transfusion can be helpful, and might need to be repeated because each P2Y12inhibitor has a half-life of between 8 and 12 hours.

For urgent or time-sensitive surgery, discontinuing a P2Y12inhibitor can be considered—while continuing ASA, if possible. DAPT should be restarted as soon as safely possible. If enteral administration is not feasible, ASA can be administered rectally. In this setting, cardiology consultation is strongly encouraged.

Consider giving a proton-pump inhibitor to a patient receiving DAPT who has a history of gastrointestinal bleeding.

Last, elective surgery should be delayed until DAPT is completed, but without discontinuing ASA, if feasible. Spinal, intracranial, prostate, middle-ear, and ophthalmologic surgery while taking ASA can lead to catastrophic complications; consider discontinuing ASA. Cardiology consultation can provide an estimate of thrombosis risk to guide clinical decision-making.³⁰

Can DAPT prevent secondary stroke?

DAPT has brought improvements in the treatment of patients with cardiovascular disease; it has been hypothesized that similar benefits can be seen in patients with ischemic stroke. Knowing the cause of stroke is key to developing a secondary prevention plan; patients with stroke secondary to atherosclerotic disease are most likely to benefit from DAPT.³¹ Conversely, secondary prevention in patients with small-vessel disease and in studies of unselected stroke type has been shown to be harmful.^32,33

Continue to: Clopidogrel and ASA initiated...

Clopidogrel and ASA initiated within 24 hours of a minor stroke (ie, National Institutes of Health Stroke Score/Scale <4 [www.ninds.nih.gov/sites/default/files/NIH_Stroke_Scale_Booklet.pdf]³⁴) or TIA and continued for a total of 21 days of DAPT, followed by clopidogrel alone to complete 90 days of treatment, have been demonstrated to reduce the risk of recurrent ischemic stroke compared to ASA alone without increasing the risk of bleeding (SOR: B).³⁵

In a multinational trial of DAPT, stroke risk was reduced at 90 days after TIA or mild stroke but bleeding risk was higher, compared to ASA alone; continuing DAPT for 90 days might explain the higher risk of bleeding.³⁶

For secondary prevention of stroke in patients with aspirin allergy, monotherapy with clopidogrel is an option, but use of clopidogrel or ticagrelor is not superior to ASA.^37,38 Therefore, there may be benefit, in patients with TIA or minor stroke, to continue DAPT beyond 21 days but at the risk of bleeding complications. (SOR: A: Harm).^33,34

Based on these data, the best duration of DAPT after TIA or mild stroke is likely 21 to 28 days.

When a patient requires VKA therapy, the benefit of using DAPT to further reduce ischemic cerebrovascular or cardiovascular events is unknown (SOR: C). In the setting of atrial fibrillation with unstable angina or CAD stent implantation, however, therapy with DAPT plus a VKA can be considered—but with increased risk of nonfatal and fatal bleeding.³⁹

Continue to: Summing up

Summing up: Key guidance

DAPT has benefits for patients with SIHD and ACS in the setting of medical management or implantation of a coronary artery stent. Balancing the reduction in risk of ongoing ischemic events with hemorrhagic complications presents challenges, as does deciding on duration of therapy. Using a DAPT risk calculator can be helpful to present information to the health care team and the patient, thus encouraging patient-centered treatment decisions.

Unless there is a contraindication, patients with coronary artery disease should continue taking aspirin after DAPT.

Patients at increased risk of ischemia, such those with an ACS presentation, multiple myocardial infarcts, extensive CAD, left-ventricular ejection fraction <40%, chronic kidney disease, or diabetes mellitus might benefit from longer DAPT. Conversely, patients with prior bleeding complications, taking oral anticoagulation, with body weight <60 kg, or on chronic steroids or nonsteroidal medications might benefit from shorter duration of DAPT.

Earlier recommendations about the duration of DAPT continue to be refined by ongoing clinical research. Current-generation DESs have improved over first-generation stents; updated guidelines from the AHA and ESC presented in this review are based on new, improved stents.

ASA should almost always be continued upon completion of DAPT or if P2Y12inhibitors are held for surgery.

Last, in patients with mild ischemic stroke or TIA, DAPT therapy, begun within 24 hours and continued for 21 to 28 days, followed by ASA, 81 mg/d, alone indefinitely, can reduce the risk of recurrent stroke.

CORRESPONDENCE
William J. Curry, MD, MS, Departments of Family and Community Medicine and Public Health Sciences, H154, 500 University Drive, Pennsylvania State University College of Medicine, Hershey, PA 17033; wcurry@pennstatehealth.psu.edu.

In landmark clinical research published in 1996, aspirin (ASA) and the P2Y12 inhibitor ticlopidine used after coronary artery stent implantation was compared to intravenous anticoagulation—at the time, the postprocedure standard of care for preventing thrombosis. What investigators found was a marked reduction in cardiac and hemorrhagic events in patients who were treated with this novel dual antiplatelet therapy (DAPT).¹ Since publication of the results of that trial, the use of ASA plus a P2Y12 inhibitor has expanded to treating acute coronary syndrome (ACS) and stroke.

Over the past 2 decades, much research has been devoted to 1) determining the effectiveness of more potent P2Y12 inhibitors—which block chemoreceptors for adenosine diphosphate—to prevent stent thrombosis and 2) safer regimens to reduce hemorrhagic complications.

When does stent thrombosis occur?

The timing of stent thrombosis is defined as:

• acute (within 24 hours of placement),
• subacute (within 30 days),
• late (within 1 year), or
• very late (after 1 year).

Acute stent thrombosis is almost always related to technical issues surrounding stent implantation. Subacute thrombosis is almost always platelet activation within the stent with thrombus formation—the reason why antiplatelet therapy is beneficial and anticoagulation pathway inhibition is not beneficial.

The delay in healing caused by drug-eluting stents makes it necessary to administer dual antiplatelet therapy for a longer duration—an increase not needed with bare-metal stents.

Late stent complications can be caused by thrombosis, but also might be related to restenosis by 4 to 6 months—ie, tissue overgrowth as the stent becomes part of the body, not clot formation. In several studies, restenosis was a significant issue with balloon dilation alone, occurring in 33% of patients.² Bare-metal stents (BMS) have been shown to reduce the rate of restenosis to approximately 20%; drug-eluting stents (DES) have further decreased restenosis to approximately 5%, in various reports, by impairing endothelial healing, thus limiting tissue overgrowth that leads to restenosis.³ This delay in healing caused by DES makes it necessary to administer DAPT for a longer duration—an increase that is not needed with BMS.

© Myriam and Steve Oh

DAPT has well-defined benefits

As drug-eluting stents were introduced and improved, trials studying optimal duration of DAPT showed that longer duration of treatment reduced stroke incidence and the long-term risk of myocardial infarction (MI) unrelated to stent thrombosis.⁴ Nuances in the treatment of ischemic coronary artery disease (CAD) and secondary prevention of stroke can be perplexing, as can be P2Y12inhibitor selection. Here, we review DAPT agents and discuss current evidence and evidence-based guidelines, thus providing a framework to better understand treatment options and recommendations.

What constitutes DAPT?

Many combinations of antiplatelet therapy are possible but, in the United States, DAPT denotes ASA 81 mg/d plus any of the 3 P2Y12inhibitors: clopidogrel, prasugrel, and ticagrelor. Stimulation of the platelet P2Y12receptor causes stimulation of the platelet glycoprotein IIb/IIIa receptor, which, in turn, enhances platelet degranulation, thromboxane production, and prolonged platelet aggregation. Blocking P2Y12receptors thus impairs the thrombotic processes.⁵

Continue to: ASA, as a component of DAPT...

ASA, as a component of DAPT, is recommended at a dosage of 81 mg/d. In trials of ASA plus clopidogrel, lower ASA dosages had comparable ischemic event rates compared to higher ASA dosages.^6,7 Patients given higher ASA dosages with ticagrelor had poorer outcomes when compared with low-dosage ASA.⁸ Higher dosages of ASA, alone or with DAPT, increase the risk of bleeding complications.^9,10

Clopidogrel is the only P2Y12 inhibitor available as a generic medication in the United States. As a pro-drug, clopidogrel requires 2 metabolic transformations to its active metabolite after being hydrolyzed in the gut, which delays onset of platelet inhibition for several hours after ingestion.¹¹ Furthermore, individual genetic variation in cytochrome P450 (CYP) 2C19 (CYP2C19), one of the hepatic enzymes in this metabolic process, may lead to less alteration of clinical platelet aggregation response, and increased drug interactions.¹² Methods to assess platelet function have shown decreased inhibition of platelet aggregation for some CYP2C19 polymorphisms, although consistent clinical effects of this inhibition have not been identified to date; genetic testing for these polymorphisms is, therefore, not recommended routinely.¹³

Indications for DAPT treatment with clopidogrel are unstable angina or non-ST-segment elevation acute coronary syndrome (NSTE-ACS), whether planned treatment is medical or coronary revascularization. Other indications include acute ST-segment elevation MI (STEMI) with planned medical treatment, and recent MI, stroke, or established peripheral arterial disease.^13,14

Prasugrel has faster onset of action and greater and more consistent P2Y12 inhibition than clopidogrel. After prasugrel is hydrolyzed in the gut, an intermediary metabolite is activated in the liver. Peak serum concentration is reached within 30 minutes.¹² Unlike the case with clopidogrel, genetic variation in the CYP gene does not impart significant impact on forming the active metabolite.¹⁵

Longer duration of DAPT reduces stroke incidence and the long-term risk of myocardial infarction—unrelated to stent thrombosis.

Indication for the use of prasugrel is ACS that is managed with percutaneous coronary intervention (PCI). Dual antiplatelet therapy with prasugrel results in reduced risk of cardiovascular death, nonfatal MI, and stroke, compared with ASA plus clopidogrel, with an increase in bleeding events.¹⁶ Thrombolysis patients and those who have a history of stroke had a greater risk of hemorrhage complications with prasugrel treatment, compared with clopidogrel. Prasugrel offered no benefit to patients older than 75 years or those who weigh <60 kg. If used in patients who weigh <60 kg, however, dosage reduction is recommended.¹⁶

Continue to: Ticagrelor

Ticagrelor. Unlike clopidogrel and prasugrel, ticagrelor is a direct oral, reversible-binding P2Y12 inhibitor. Peak serum concentration is reached within 2 to 3 hours.¹⁷ Indications are ACS or a history of MI, and those with ACS undergoing stent implantation. Ticagrelor was superior to clopidogrel in reducing the risk of death from vascular causes, MI, and stroke, and superior to clopidogrel in reducing the risk of stent thrombosis. There was no increase in the overall major bleeding rate and a decrease in fatal bleeding events compared to clopidogrel. Adverse effects unique to ticagrelor include dyspnea and, in patients with bradydysrhythmias, asymptomatic ventricular pauses. Both effects tend to resolve with continued treatment. This P2Y12 inhibitor should be avoided in patients with severe liver disease.

Loading and maintenance doses of the 3 P2Y12 inhibitors are provided in TABLE 1.^13,14

When—and when not—to initiate DAPT

Treatment recommendations for DAPT originated in the 2016 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with Coronary Artery Disease¹⁴ and in the 2017 European Society of Cardiology (ESC) focused update on dual antiplatelet therapy in coronary artery disease.¹³ Although these guidelines differ slightly, the overall approach they present is similar, with an emphasis on limiting bleeding while preventing stent thrombosis.

Stable ischemic heart disease (SIHD) is defined as confirmed obstructive CAD without either ACS or a history of PCI in the past year.¹⁸ Patients with SIHD but without a history of PCI or recent coronary artery bypass grafting (CABG) receive no benefit from DAPT (Strength of recommendation [SOR]: A).¹⁹ (See TABLE 2 for definitions of SOR and corresponding levels of evidence.)

For patients who have undergone BMS placement, minimum DAPT with clopidogrel is 1 month (SOR: A) and, if there is no significant bleeding on DAPT and no high risk of bleeding (ie, no prior bleeding while taking DAPT, coagulopathy, or oral anticoagulant use), continuation of ASA and clopidogrel beyond 1 month might be reasonable (SOR: B).

Continue to: With a drug-eluting stent...

With a drug-eluting stent, the minimum time for DAPT (using clopidogrel) is 6 months (SOR: A), with a longer duration being reasonable if the patient is not at high risk of bleeding and has had no bleeding complications (SOR: B). For DES patients who have developed a high risk of bleeding, have had significant bleeding, or require a procedure that will place them at high risk of bleeding, DAPT discontinuation can be considered at 3 months (SOR: B).

Updated guidelines allow longer therapy for patients who tolerate DAPT; for them, 12 months of therapy is preferred. In comparing longer and shorter therapy, it has been determined that longer DAPT treatment is superior for reducing the risk of MI and stent thrombosis without increasing the risk of stroke or bleeding complications.²⁰ With increased bleeding, or where there is a need for elective surgery, shortened DAPT is an option.

When treating patients with ACS, including NSTE-ACS or STEMI, DAPT for 1 year is recommended (SOR: A). When medical therapy alone is planned, DAPT is provided with clopidogrel or ticagrelor.

When a patient has been treated with PCI (BMS or DES), DAPT with any of the P2Y12 inhibitors is recommended (SOR: A) unless there is history of stroke or transient ischemic attack (TIA) or the patient is ≥75 years of age, in which case prasugrel is contraindicated (SOR: A: Harm).

Continue to: When lytic interventions are employed in STEMI...

When lytic interventions are employed in STEMI, DAPT with clopidogrel—for a minimum of 14 days and, ideally, for 12 months—should be considered. Without high risk of bleeding, or significant bleeding on DAPT, continuing DAPT for >12 months might be reasonable (SOR: A).

TABLE 3,^13,14 adapted from 2016 ACC/AHA¹⁴ and 2017 ESC¹³ guidelines, provides recommendations about agents and duration of therapy in the management of patients with CAD.

How long should you give DAPT?

Balancing the hemorrhagic complications of DAPT against its benefits is challenging. The use of risk scores to guide duration of DAPT may be considered (SOR: B).

The PRECISE-DAPT score²¹ is used at the time of coronary artery stenting to guide treatment duration. The scoring algorithm incorporates hemoglobin level, leukocyte count, age, creatinine clearance and prior bleeding to create a composite score on a 100-point scale.²² (The algorithm can be found at www.precisedaptscore.com/predapt/webcalculator.html.) If the composite is <25 points, the number needed to treat to prevent an ischemic event is 65, and standard or long-term DAPT (12 to 24 months) is recommended. When the PRECISE-DAPT score is ≥25, the number needed to harm with a hemorrhagic event is 38, and a shorter duration of therapy (3 to 6 months) is recommended.

Ticagrelor should be avoided in patients with severe liver disease.

The DAPT score,²³ available from the American College of Cardiology²⁴ (http://tools.acc.org/DAPTriskapp/#!/content/calculator) is a risk calculator for use after 12 months of DAPT in the absence of complications. Age, cigarette use, diabetes, current or previous MI, presence of congestive heart disease, and type and location of stent all factor into calculating the risk score. DAPT scores range from -2 to 10. A score ≥2 suggests less bleeding risk, with a recommendation to consider longer treatment (≤30 months); a score <2 leads to a recommendation to adhere to standard treatment duration of 12 months.

Continue to: Patients with CAD should...

Patients with CAD should continue ASA treatment when DAPT is discontinued or completed, unless contraindicated.^13,14

Triple therapy: DAPT + anticoagulant

Given that the US population is aging, there are an increasing number of patients with CAD and atrial fibrillation. Stroke is prevented in patients with atrial fibrillation with anticoagulant therapy; when these patients have stent placement for coronary, carotid, vertebral, or intracranial arterial disease, they need DAPT to prevent stent thrombosis. In the immediate post-stenting period, therefore, patients are often placed on an oral anticoagulant as well as DAPT. Vitamin K antagonists (VKAs) should be discontinued after acute stroke, with individualized resumption of a VKA when clinically appropriate.

As we emphasize throughout this article, there is a balance between bleeding risk and the potential benefits of therapy of the selected anticoagulant/DAPT regimen. These complex patients are best managed in close consultation with Cardiology and Neurology because of their potential risk of 3-fold bleeding.²⁵ The findings of a recent study addressing post-stent placement therapy in patients with nonvalvular atrial fibrillation suggests that the direct oral anticoagulant dabigatran may be preferable to warfarin in this setting, because of the lower risk of bleeding with dabigatran without increased thrombotic risk.²⁶ In this study, 3-drug therapy was used for 1 month, followed by discontinuation of ASA and continuation of 2-drug therapy with the direct oral anticoagulant and the P2Y12 inhibitor for the 6- to 12-month time frame post-stenting (SOR: B).

Consider a PPI to reduce the risk of a GI bleed

Proton-pump inhibitors (PPIs) should be considered for patients treated with DAPT if there is a history of gastrointestinal (GI) bleeding (SOR: A). Although a potential interaction between PPIs and P2Y12 inhibition has been identified in laboratory studies, this has not been supported in clinical studies. Therefore, although warnings exist for concomitant use of clopidogrel and PPIs, a PPI is reasonable for patients who are at increased risk of GI hemorrhage, including those taking warfarin, a corticosteroid, or a nonsteroidal anti-inflammatory drug and those of advanced age (SOR: B). Risks and benefits of clopidogrel and PPIs should be discussed with patients. There is no benefit in using PPIs for low-risk patients. (SOR: A: No benefit).^27,28

Perioperative management with DAPT can be thorny

Perioperative management of DAPT patients who have an indwelling coronary stent and require noncardiac surgery is complicated. Stent thrombosis is a calamity, with ≥50% risk of death. Delaying surgery for at least 4 weeks after placement of a BMS and 6 months after placement of a DES reduces the risk of thrombosis.²⁹

Continue to: For emergent surgery...

For emergent surgery, when severe bleeding is not seen or expected, interruption of DAPT can be minimized. After cessation of DAPT components, normal platelet function will return in¹²:

• 7 to 10 days for ASA,
• 5 to 7 days for prasugrel,
• 5 days for clopidogrel, and
• 3 to 5 days for ticagrelor.

If significant bleeding occurs perioperatively, or is expected, platelet transfusion can be helpful, and might need to be repeated because each P2Y12inhibitor has a half-life of between 8 and 12 hours.

For urgent or time-sensitive surgery, discontinuing a P2Y12inhibitor can be considered—while continuing ASA, if possible. DAPT should be restarted as soon as safely possible. If enteral administration is not feasible, ASA can be administered rectally. In this setting, cardiology consultation is strongly encouraged.

Consider giving a proton-pump inhibitor to a patient receiving DAPT who has a history of gastrointestinal bleeding.

Last, elective surgery should be delayed until DAPT is completed, but without discontinuing ASA, if feasible. Spinal, intracranial, prostate, middle-ear, and ophthalmologic surgery while taking ASA can lead to catastrophic complications; consider discontinuing ASA. Cardiology consultation can provide an estimate of thrombosis risk to guide clinical decision-making.³⁰

Can DAPT prevent secondary stroke?

DAPT has brought improvements in the treatment of patients with cardiovascular disease; it has been hypothesized that similar benefits can be seen in patients with ischemic stroke. Knowing the cause of stroke is key to developing a secondary prevention plan; patients with stroke secondary to atherosclerotic disease are most likely to benefit from DAPT.³¹ Conversely, secondary prevention in patients with small-vessel disease and in studies of unselected stroke type has been shown to be harmful.^32,33

Continue to: Clopidogrel and ASA initiated...

Clopidogrel and ASA initiated within 24 hours of a minor stroke (ie, National Institutes of Health Stroke Score/Scale <4 [www.ninds.nih.gov/sites/default/files/NIH_Stroke_Scale_Booklet.pdf]³⁴) or TIA and continued for a total of 21 days of DAPT, followed by clopidogrel alone to complete 90 days of treatment, have been demonstrated to reduce the risk of recurrent ischemic stroke compared to ASA alone without increasing the risk of bleeding (SOR: B).³⁵

In a multinational trial of DAPT, stroke risk was reduced at 90 days after TIA or mild stroke but bleeding risk was higher, compared to ASA alone; continuing DAPT for 90 days might explain the higher risk of bleeding.³⁶

For secondary prevention of stroke in patients with aspirin allergy, monotherapy with clopidogrel is an option, but use of clopidogrel or ticagrelor is not superior to ASA.^37,38 Therefore, there may be benefit, in patients with TIA or minor stroke, to continue DAPT beyond 21 days but at the risk of bleeding complications. (SOR: A: Harm).^33,34

Based on these data, the best duration of DAPT after TIA or mild stroke is likely 21 to 28 days.

When a patient requires VKA therapy, the benefit of using DAPT to further reduce ischemic cerebrovascular or cardiovascular events is unknown (SOR: C). In the setting of atrial fibrillation with unstable angina or CAD stent implantation, however, therapy with DAPT plus a VKA can be considered—but with increased risk of nonfatal and fatal bleeding.³⁹

Continue to: Summing up

Summing up: Key guidance

DAPT has benefits for patients with SIHD and ACS in the setting of medical management or implantation of a coronary artery stent. Balancing the reduction in risk of ongoing ischemic events with hemorrhagic complications presents challenges, as does deciding on duration of therapy. Using a DAPT risk calculator can be helpful to present information to the health care team and the patient, thus encouraging patient-centered treatment decisions.

Unless there is a contraindication, patients with coronary artery disease should continue taking aspirin after DAPT.

Patients at increased risk of ischemia, such those with an ACS presentation, multiple myocardial infarcts, extensive CAD, left-ventricular ejection fraction <40%, chronic kidney disease, or diabetes mellitus might benefit from longer DAPT. Conversely, patients with prior bleeding complications, taking oral anticoagulation, with body weight <60 kg, or on chronic steroids or nonsteroidal medications might benefit from shorter duration of DAPT.

Earlier recommendations about the duration of DAPT continue to be refined by ongoing clinical research. Current-generation DESs have improved over first-generation stents; updated guidelines from the AHA and ESC presented in this review are based on new, improved stents.

ASA should almost always be continued upon completion of DAPT or if P2Y12inhibitors are held for surgery.

Last, in patients with mild ischemic stroke or TIA, DAPT therapy, begun within 24 hours and continued for 21 to 28 days, followed by ASA, 81 mg/d, alone indefinitely, can reduce the risk of recurrent stroke.

CORRESPONDENCE
William J. Curry, MD, MS, Departments of Family and Community Medicine and Public Health Sciences, H154, 500 University Drive, Pennsylvania State University College of Medicine, Hershey, PA 17033; wcurry@pennstatehealth.psu.edu.

In landmark clinical research published in 1996, aspirin (ASA) and the P2Y12 inhibitor ticlopidine used after coronary artery stent implantation was compared to intravenous anticoagulation—at the time, the postprocedure standard of care for preventing thrombosis. What investigators found was a marked reduction in cardiac and hemorrhagic events in patients who were treated with this novel dual antiplatelet therapy (DAPT).¹ Since publication of the results of that trial, the use of ASA plus a P2Y12 inhibitor has expanded to treating acute coronary syndrome (ACS) and stroke.

Over the past 2 decades, much research has been devoted to 1) determining the effectiveness of more potent P2Y12 inhibitors—which block chemoreceptors for adenosine diphosphate—to prevent stent thrombosis and 2) safer regimens to reduce hemorrhagic complications.

When does stent thrombosis occur?

The timing of stent thrombosis is defined as:

• acute (within 24 hours of placement),
• subacute (within 30 days),
• late (within 1 year), or
• very late (after 1 year).

Acute stent thrombosis is almost always related to technical issues surrounding stent implantation. Subacute thrombosis is almost always platelet activation within the stent with thrombus formation—the reason why antiplatelet therapy is beneficial and anticoagulation pathway inhibition is not beneficial.

The delay in healing caused by drug-eluting stents makes it necessary to administer dual antiplatelet therapy for a longer duration—an increase not needed with bare-metal stents.

Late stent complications can be caused by thrombosis, but also might be related to restenosis by 4 to 6 months—ie, tissue overgrowth as the stent becomes part of the body, not clot formation. In several studies, restenosis was a significant issue with balloon dilation alone, occurring in 33% of patients.² Bare-metal stents (BMS) have been shown to reduce the rate of restenosis to approximately 20%; drug-eluting stents (DES) have further decreased restenosis to approximately 5%, in various reports, by impairing endothelial healing, thus limiting tissue overgrowth that leads to restenosis.³ This delay in healing caused by DES makes it necessary to administer DAPT for a longer duration—an increase that is not needed with BMS.

© Myriam and Steve Oh

DAPT has well-defined benefits

As drug-eluting stents were introduced and improved, trials studying optimal duration of DAPT showed that longer duration of treatment reduced stroke incidence and the long-term risk of myocardial infarction (MI) unrelated to stent thrombosis.⁴ Nuances in the treatment of ischemic coronary artery disease (CAD) and secondary prevention of stroke can be perplexing, as can be P2Y12inhibitor selection. Here, we review DAPT agents and discuss current evidence and evidence-based guidelines, thus providing a framework to better understand treatment options and recommendations.

What constitutes DAPT?

Many combinations of antiplatelet therapy are possible but, in the United States, DAPT denotes ASA 81 mg/d plus any of the 3 P2Y12inhibitors: clopidogrel, prasugrel, and ticagrelor. Stimulation of the platelet P2Y12receptor causes stimulation of the platelet glycoprotein IIb/IIIa receptor, which, in turn, enhances platelet degranulation, thromboxane production, and prolonged platelet aggregation. Blocking P2Y12receptors thus impairs the thrombotic processes.⁵

Continue to: ASA, as a component of DAPT...

ASA, as a component of DAPT, is recommended at a dosage of 81 mg/d. In trials of ASA plus clopidogrel, lower ASA dosages had comparable ischemic event rates compared to higher ASA dosages.^6,7 Patients given higher ASA dosages with ticagrelor had poorer outcomes when compared with low-dosage ASA.⁸ Higher dosages of ASA, alone or with DAPT, increase the risk of bleeding complications.^9,10

Clopidogrel is the only P2Y12 inhibitor available as a generic medication in the United States. As a pro-drug, clopidogrel requires 2 metabolic transformations to its active metabolite after being hydrolyzed in the gut, which delays onset of platelet inhibition for several hours after ingestion.¹¹ Furthermore, individual genetic variation in cytochrome P450 (CYP) 2C19 (CYP2C19), one of the hepatic enzymes in this metabolic process, may lead to less alteration of clinical platelet aggregation response, and increased drug interactions.¹² Methods to assess platelet function have shown decreased inhibition of platelet aggregation for some CYP2C19 polymorphisms, although consistent clinical effects of this inhibition have not been identified to date; genetic testing for these polymorphisms is, therefore, not recommended routinely.¹³

Indications for DAPT treatment with clopidogrel are unstable angina or non-ST-segment elevation acute coronary syndrome (NSTE-ACS), whether planned treatment is medical or coronary revascularization. Other indications include acute ST-segment elevation MI (STEMI) with planned medical treatment, and recent MI, stroke, or established peripheral arterial disease.^13,14

Prasugrel has faster onset of action and greater and more consistent P2Y12 inhibition than clopidogrel. After prasugrel is hydrolyzed in the gut, an intermediary metabolite is activated in the liver. Peak serum concentration is reached within 30 minutes.¹² Unlike the case with clopidogrel, genetic variation in the CYP gene does not impart significant impact on forming the active metabolite.¹⁵

Longer duration of DAPT reduces stroke incidence and the long-term risk of myocardial infarction—unrelated to stent thrombosis.

Indication for the use of prasugrel is ACS that is managed with percutaneous coronary intervention (PCI). Dual antiplatelet therapy with prasugrel results in reduced risk of cardiovascular death, nonfatal MI, and stroke, compared with ASA plus clopidogrel, with an increase in bleeding events.¹⁶ Thrombolysis patients and those who have a history of stroke had a greater risk of hemorrhage complications with prasugrel treatment, compared with clopidogrel. Prasugrel offered no benefit to patients older than 75 years or those who weigh <60 kg. If used in patients who weigh <60 kg, however, dosage reduction is recommended.¹⁶

Continue to: Ticagrelor

Ticagrelor. Unlike clopidogrel and prasugrel, ticagrelor is a direct oral, reversible-binding P2Y12 inhibitor. Peak serum concentration is reached within 2 to 3 hours.¹⁷ Indications are ACS or a history of MI, and those with ACS undergoing stent implantation. Ticagrelor was superior to clopidogrel in reducing the risk of death from vascular causes, MI, and stroke, and superior to clopidogrel in reducing the risk of stent thrombosis. There was no increase in the overall major bleeding rate and a decrease in fatal bleeding events compared to clopidogrel. Adverse effects unique to ticagrelor include dyspnea and, in patients with bradydysrhythmias, asymptomatic ventricular pauses. Both effects tend to resolve with continued treatment. This P2Y12 inhibitor should be avoided in patients with severe liver disease.

Loading and maintenance doses of the 3 P2Y12 inhibitors are provided in TABLE 1.^13,14

When—and when not—to initiate DAPT

Treatment recommendations for DAPT originated in the 2016 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with Coronary Artery Disease¹⁴ and in the 2017 European Society of Cardiology (ESC) focused update on dual antiplatelet therapy in coronary artery disease.¹³ Although these guidelines differ slightly, the overall approach they present is similar, with an emphasis on limiting bleeding while preventing stent thrombosis.

Stable ischemic heart disease (SIHD) is defined as confirmed obstructive CAD without either ACS or a history of PCI in the past year.¹⁸ Patients with SIHD but without a history of PCI or recent coronary artery bypass grafting (CABG) receive no benefit from DAPT (Strength of recommendation [SOR]: A).¹⁹ (See TABLE 2 for definitions of SOR and corresponding levels of evidence.)

For patients who have undergone BMS placement, minimum DAPT with clopidogrel is 1 month (SOR: A) and, if there is no significant bleeding on DAPT and no high risk of bleeding (ie, no prior bleeding while taking DAPT, coagulopathy, or oral anticoagulant use), continuation of ASA and clopidogrel beyond 1 month might be reasonable (SOR: B).

Continue to: With a drug-eluting stent...

With a drug-eluting stent, the minimum time for DAPT (using clopidogrel) is 6 months (SOR: A), with a longer duration being reasonable if the patient is not at high risk of bleeding and has had no bleeding complications (SOR: B). For DES patients who have developed a high risk of bleeding, have had significant bleeding, or require a procedure that will place them at high risk of bleeding, DAPT discontinuation can be considered at 3 months (SOR: B).

Updated guidelines allow longer therapy for patients who tolerate DAPT; for them, 12 months of therapy is preferred. In comparing longer and shorter therapy, it has been determined that longer DAPT treatment is superior for reducing the risk of MI and stent thrombosis without increasing the risk of stroke or bleeding complications.²⁰ With increased bleeding, or where there is a need for elective surgery, shortened DAPT is an option.

When treating patients with ACS, including NSTE-ACS or STEMI, DAPT for 1 year is recommended (SOR: A). When medical therapy alone is planned, DAPT is provided with clopidogrel or ticagrelor.

When a patient has been treated with PCI (BMS or DES), DAPT with any of the P2Y12 inhibitors is recommended (SOR: A) unless there is history of stroke or transient ischemic attack (TIA) or the patient is ≥75 years of age, in which case prasugrel is contraindicated (SOR: A: Harm).

Continue to: When lytic interventions are employed in STEMI...

When lytic interventions are employed in STEMI, DAPT with clopidogrel—for a minimum of 14 days and, ideally, for 12 months—should be considered. Without high risk of bleeding, or significant bleeding on DAPT, continuing DAPT for >12 months might be reasonable (SOR: A).

TABLE 3,^13,14 adapted from 2016 ACC/AHA¹⁴ and 2017 ESC¹³ guidelines, provides recommendations about agents and duration of therapy in the management of patients with CAD.

How long should you give DAPT?

Balancing the hemorrhagic complications of DAPT against its benefits is challenging. The use of risk scores to guide duration of DAPT may be considered (SOR: B).

The PRECISE-DAPT score²¹ is used at the time of coronary artery stenting to guide treatment duration. The scoring algorithm incorporates hemoglobin level, leukocyte count, age, creatinine clearance and prior bleeding to create a composite score on a 100-point scale.²² (The algorithm can be found at www.precisedaptscore.com/predapt/webcalculator.html.) If the composite is <25 points, the number needed to treat to prevent an ischemic event is 65, and standard or long-term DAPT (12 to 24 months) is recommended. When the PRECISE-DAPT score is ≥25, the number needed to harm with a hemorrhagic event is 38, and a shorter duration of therapy (3 to 6 months) is recommended.

Ticagrelor should be avoided in patients with severe liver disease.

The DAPT score,²³ available from the American College of Cardiology²⁴ (http://tools.acc.org/DAPTriskapp/#!/content/calculator) is a risk calculator for use after 12 months of DAPT in the absence of complications. Age, cigarette use, diabetes, current or previous MI, presence of congestive heart disease, and type and location of stent all factor into calculating the risk score. DAPT scores range from -2 to 10. A score ≥2 suggests less bleeding risk, with a recommendation to consider longer treatment (≤30 months); a score <2 leads to a recommendation to adhere to standard treatment duration of 12 months.

Continue to: Patients with CAD should...

Patients with CAD should continue ASA treatment when DAPT is discontinued or completed, unless contraindicated.^13,14

Triple therapy: DAPT + anticoagulant

Given that the US population is aging, there are an increasing number of patients with CAD and atrial fibrillation. Stroke is prevented in patients with atrial fibrillation with anticoagulant therapy; when these patients have stent placement for coronary, carotid, vertebral, or intracranial arterial disease, they need DAPT to prevent stent thrombosis. In the immediate post-stenting period, therefore, patients are often placed on an oral anticoagulant as well as DAPT. Vitamin K antagonists (VKAs) should be discontinued after acute stroke, with individualized resumption of a VKA when clinically appropriate.

As we emphasize throughout this article, there is a balance between bleeding risk and the potential benefits of therapy of the selected anticoagulant/DAPT regimen. These complex patients are best managed in close consultation with Cardiology and Neurology because of their potential risk of 3-fold bleeding.²⁵ The findings of a recent study addressing post-stent placement therapy in patients with nonvalvular atrial fibrillation suggests that the direct oral anticoagulant dabigatran may be preferable to warfarin in this setting, because of the lower risk of bleeding with dabigatran without increased thrombotic risk.²⁶ In this study, 3-drug therapy was used for 1 month, followed by discontinuation of ASA and continuation of 2-drug therapy with the direct oral anticoagulant and the P2Y12 inhibitor for the 6- to 12-month time frame post-stenting (SOR: B).

Consider a PPI to reduce the risk of a GI bleed

Proton-pump inhibitors (PPIs) should be considered for patients treated with DAPT if there is a history of gastrointestinal (GI) bleeding (SOR: A). Although a potential interaction between PPIs and P2Y12 inhibition has been identified in laboratory studies, this has not been supported in clinical studies. Therefore, although warnings exist for concomitant use of clopidogrel and PPIs, a PPI is reasonable for patients who are at increased risk of GI hemorrhage, including those taking warfarin, a corticosteroid, or a nonsteroidal anti-inflammatory drug and those of advanced age (SOR: B). Risks and benefits of clopidogrel and PPIs should be discussed with patients. There is no benefit in using PPIs for low-risk patients. (SOR: A: No benefit).^27,28

Perioperative management with DAPT can be thorny

Perioperative management of DAPT patients who have an indwelling coronary stent and require noncardiac surgery is complicated. Stent thrombosis is a calamity, with ≥50% risk of death. Delaying surgery for at least 4 weeks after placement of a BMS and 6 months after placement of a DES reduces the risk of thrombosis.²⁹

Continue to: For emergent surgery...

For emergent surgery, when severe bleeding is not seen or expected, interruption of DAPT can be minimized. After cessation of DAPT components, normal platelet function will return in¹²:

• 7 to 10 days for ASA,
• 5 to 7 days for prasugrel,
• 5 days for clopidogrel, and
• 3 to 5 days for ticagrelor.

If significant bleeding occurs perioperatively, or is expected, platelet transfusion can be helpful, and might need to be repeated because each P2Y12inhibitor has a half-life of between 8 and 12 hours.

For urgent or time-sensitive surgery, discontinuing a P2Y12inhibitor can be considered—while continuing ASA, if possible. DAPT should be restarted as soon as safely possible. If enteral administration is not feasible, ASA can be administered rectally. In this setting, cardiology consultation is strongly encouraged.

Consider giving a proton-pump inhibitor to a patient receiving DAPT who has a history of gastrointestinal bleeding.

Last, elective surgery should be delayed until DAPT is completed, but without discontinuing ASA, if feasible. Spinal, intracranial, prostate, middle-ear, and ophthalmologic surgery while taking ASA can lead to catastrophic complications; consider discontinuing ASA. Cardiology consultation can provide an estimate of thrombosis risk to guide clinical decision-making.³⁰

Can DAPT prevent secondary stroke?

DAPT has brought improvements in the treatment of patients with cardiovascular disease; it has been hypothesized that similar benefits can be seen in patients with ischemic stroke. Knowing the cause of stroke is key to developing a secondary prevention plan; patients with stroke secondary to atherosclerotic disease are most likely to benefit from DAPT.³¹ Conversely, secondary prevention in patients with small-vessel disease and in studies of unselected stroke type has been shown to be harmful.^32,33

Continue to: Clopidogrel and ASA initiated...

Clopidogrel and ASA initiated within 24 hours of a minor stroke (ie, National Institutes of Health Stroke Score/Scale <4 [www.ninds.nih.gov/sites/default/files/NIH_Stroke_Scale_Booklet.pdf]³⁴) or TIA and continued for a total of 21 days of DAPT, followed by clopidogrel alone to complete 90 days of treatment, have been demonstrated to reduce the risk of recurrent ischemic stroke compared to ASA alone without increasing the risk of bleeding (SOR: B).³⁵

In a multinational trial of DAPT, stroke risk was reduced at 90 days after TIA or mild stroke but bleeding risk was higher, compared to ASA alone; continuing DAPT for 90 days might explain the higher risk of bleeding.³⁶

For secondary prevention of stroke in patients with aspirin allergy, monotherapy with clopidogrel is an option, but use of clopidogrel or ticagrelor is not superior to ASA.^37,38 Therefore, there may be benefit, in patients with TIA or minor stroke, to continue DAPT beyond 21 days but at the risk of bleeding complications. (SOR: A: Harm).^33,34

Based on these data, the best duration of DAPT after TIA or mild stroke is likely 21 to 28 days.

When a patient requires VKA therapy, the benefit of using DAPT to further reduce ischemic cerebrovascular or cardiovascular events is unknown (SOR: C). In the setting of atrial fibrillation with unstable angina or CAD stent implantation, however, therapy with DAPT plus a VKA can be considered—but with increased risk of nonfatal and fatal bleeding.³⁹

Continue to: Summing up

Summing up: Key guidance

DAPT has benefits for patients with SIHD and ACS in the setting of medical management or implantation of a coronary artery stent. Balancing the reduction in risk of ongoing ischemic events with hemorrhagic complications presents challenges, as does deciding on duration of therapy. Using a DAPT risk calculator can be helpful to present information to the health care team and the patient, thus encouraging patient-centered treatment decisions.

Unless there is a contraindication, patients with coronary artery disease should continue taking aspirin after DAPT.

Patients at increased risk of ischemia, such those with an ACS presentation, multiple myocardial infarcts, extensive CAD, left-ventricular ejection fraction <40%, chronic kidney disease, or diabetes mellitus might benefit from longer DAPT. Conversely, patients with prior bleeding complications, taking oral anticoagulation, with body weight <60 kg, or on chronic steroids or nonsteroidal medications might benefit from shorter duration of DAPT.

Earlier recommendations about the duration of DAPT continue to be refined by ongoing clinical research. Current-generation DESs have improved over first-generation stents; updated guidelines from the AHA and ESC presented in this review are based on new, improved stents.

ASA should almost always be continued upon completion of DAPT or if P2Y12inhibitors are held for surgery.

Last, in patients with mild ischemic stroke or TIA, DAPT therapy, begun within 24 hours and continued for 21 to 28 days, followed by ASA, 81 mg/d, alone indefinitely, can reduce the risk of recurrent stroke.

CORRESPONDENCE
William J. Curry, MD, MS, Departments of Family and Community Medicine and Public Health Sciences, H154, 500 University Drive, Pennsylvania State University College of Medicine, Hershey, PA 17033; wcurry@pennstatehealth.psu.edu.