The Diagnosis: Milia En Plaque 

Biopsy results revealed a normal epidermis; the dermis showed multiple small cystic structures lined by a stratified squamous epithelium containing eosinophilic keratin surrounded by a mononuclear cell infiltrate and some melanophages (Figure).  

Milia en plaque was first described in 1903 by Balzer and Fouquet.¹ In 1978, Hubler et al² presented 2 cases with an asymptomatic, erythematous, and edematous plaque and white milialike lesions. On histopathology, they showed multiple cystic structures characterized by central laminated keratin and an intense polymorphic inflammatory reaction surrounding the cyst and epidermal appendages. Both patients were treated with topical tretinoin with complete response at 3 months. The authors suggested the term milia en plaque to describe this clinical entity.² 

Milia en plaque is described as an infrequent condition that more often presents on the head, neck, and trunk, as well as the periocular, periauricular, and perinasal areas. It has been reported to occur at any age³ but appears more frequently in middle-aged adults and females. A congenital case also has been reported.⁴ It has been associated with pseudoxanthoma elasticum, lichen planus, trauma, kidney transplant, and cyclosporine use, but it also can present in healthy individuals,³ as in our patient. No clear cause has been identified. 

Pathology is characteristic, with multiple cysts filled with keratin and surrounded by 2 or 3 layers of epithelial cells, associated with a mononuclear, nonlichenoid, mononuclear infiltrate.⁵ Structures similar to follicular infundibular tumors have been described, suggesting a common origin of follicular lesions as milia en plaque.⁶  

Treatment includes surgical excision, cryosurgery, dermabrasion, electrodesiccation, trichloroacetic acid, photodynamic therapy, CO₂ and erbium lasers, topical retinoids, minocycline, and etretinate.⁷ We performed a complete surgical excision in our patient.  

In acneform reactions, erythematous papules and pustules can be found on the cheeks and forehead. Nevus comedonicus appears during childhood and presents with multiple open comedones. Postinflammatory milia is present in chronic inflammatory pathologies such as porphyria cutanea tarda. Histopathologic findings in adnexal tumors show a benign proliferation of any cellular type of a cutaneous annex. 

Milia en plaque is an unusual but benign condition that is distinguished clinically by its characteristic presentation. 

The Diagnosis: Milia En Plaque 

Biopsy results revealed a normal epidermis; the dermis showed multiple small cystic structures lined by a stratified squamous epithelium containing eosinophilic keratin surrounded by a mononuclear cell infiltrate and some melanophages (Figure).  

Milia en plaque was first described in 1903 by Balzer and Fouquet.¹ In 1978, Hubler et al² presented 2 cases with an asymptomatic, erythematous, and edematous plaque and white milialike lesions. On histopathology, they showed multiple cystic structures characterized by central laminated keratin and an intense polymorphic inflammatory reaction surrounding the cyst and epidermal appendages. Both patients were treated with topical tretinoin with complete response at 3 months. The authors suggested the term milia en plaque to describe this clinical entity.² 

Milia en plaque is described as an infrequent condition that more often presents on the head, neck, and trunk, as well as the periocular, periauricular, and perinasal areas. It has been reported to occur at any age³ but appears more frequently in middle-aged adults and females. A congenital case also has been reported.⁴ It has been associated with pseudoxanthoma elasticum, lichen planus, trauma, kidney transplant, and cyclosporine use, but it also can present in healthy individuals,³ as in our patient. No clear cause has been identified. 

Pathology is characteristic, with multiple cysts filled with keratin and surrounded by 2 or 3 layers of epithelial cells, associated with a mononuclear, nonlichenoid, mononuclear infiltrate.⁵ Structures similar to follicular infundibular tumors have been described, suggesting a common origin of follicular lesions as milia en plaque.⁶  

Treatment includes surgical excision, cryosurgery, dermabrasion, electrodesiccation, trichloroacetic acid, photodynamic therapy, CO₂ and erbium lasers, topical retinoids, minocycline, and etretinate.⁷ We performed a complete surgical excision in our patient.  

In acneform reactions, erythematous papules and pustules can be found on the cheeks and forehead. Nevus comedonicus appears during childhood and presents with multiple open comedones. Postinflammatory milia is present in chronic inflammatory pathologies such as porphyria cutanea tarda. Histopathologic findings in adnexal tumors show a benign proliferation of any cellular type of a cutaneous annex. 

Milia en plaque is an unusual but benign condition that is distinguished clinically by its characteristic presentation. 

The Diagnosis: Milia En Plaque 

Biopsy results revealed a normal epidermis; the dermis showed multiple small cystic structures lined by a stratified squamous epithelium containing eosinophilic keratin surrounded by a mononuclear cell infiltrate and some melanophages (Figure).  

Milia en plaque was first described in 1903 by Balzer and Fouquet.¹ In 1978, Hubler et al² presented 2 cases with an asymptomatic, erythematous, and edematous plaque and white milialike lesions. On histopathology, they showed multiple cystic structures characterized by central laminated keratin and an intense polymorphic inflammatory reaction surrounding the cyst and epidermal appendages. Both patients were treated with topical tretinoin with complete response at 3 months. The authors suggested the term milia en plaque to describe this clinical entity.² 

Milia en plaque is described as an infrequent condition that more often presents on the head, neck, and trunk, as well as the periocular, periauricular, and perinasal areas. It has been reported to occur at any age³ but appears more frequently in middle-aged adults and females. A congenital case also has been reported.⁴ It has been associated with pseudoxanthoma elasticum, lichen planus, trauma, kidney transplant, and cyclosporine use, but it also can present in healthy individuals,³ as in our patient. No clear cause has been identified. 

Pathology is characteristic, with multiple cysts filled with keratin and surrounded by 2 or 3 layers of epithelial cells, associated with a mononuclear, nonlichenoid, mononuclear infiltrate.⁵ Structures similar to follicular infundibular tumors have been described, suggesting a common origin of follicular lesions as milia en plaque.⁶  

Treatment includes surgical excision, cryosurgery, dermabrasion, electrodesiccation, trichloroacetic acid, photodynamic therapy, CO₂ and erbium lasers, topical retinoids, minocycline, and etretinate.⁷ We performed a complete surgical excision in our patient.  

In acneform reactions, erythematous papules and pustules can be found on the cheeks and forehead. Nevus comedonicus appears during childhood and presents with multiple open comedones. Postinflammatory milia is present in chronic inflammatory pathologies such as porphyria cutanea tarda. Histopathologic findings in adnexal tumors show a benign proliferation of any cellular type of a cutaneous annex. 

Milia en plaque is an unusual but benign condition that is distinguished clinically by its characteristic presentation. 

A pregnant woman in Wisconsin received prenatal care from a family practitioner. The patient had hypertension, so at about 38 weeks’ gestation, the decision was made to induce labor.

On May 15, 2012, the family practitioner used misoprostol to induce labor. The patient received 100 mcg vaginally at 12:24 pm. The recommended dosage for this indication is 25 mcg.

At 1:28 pm, fetal monitoring was stopped and did not resume until 5 pm. At that time, tachysystole (excessive uterine contractions) was noted, along with fetal heart decelerations. Terbutaline was administered to counteract the contractions, but the uterine activity remained excessive.

Variable late decelerations occurred at 11:36 pm. Prolonged decelerations were noted at 12:08 am on May 16. The cervix was noted to be only 7 cm dilated. At 12:39 am, fetal heart decelerations recurred and bradycardia developed.

Although the family practitioner was present at the bedside at 12:40 am, a fetal scalp monitor was not applied until 1 am. The family practitioner did not have privileges to perform a C-section without supervision, and it was 1:13 am before a physician who could perform a C-section was summoned.

The on-call physician accomplished a vacuum delivery at 1:30 am. Unfortunately, the baby was born with Apgar scores of 1 and 3 and a cord pH of 6.7, indicating severe metabolic acidosis. He was transferred to another hospital for neonatal care, including hypothermia treatments.

The child now has severe cerebral palsy, with gross motor involvement in the arms and legs. He can communicate through augmentative communication devices but cannot actually speak. He will require full-time care for the rest of his life.

Continue to: The defense took the position...

The defense took the position that while the dosage of misoprostol was excessive, the drug was no longer active in the mother’s body, based on its half-life, when the fetal distress occurred.

VERDICT

Four days before trial, the case was settled for $9 ­million.

COMMENTARY

I suspect many of you have made a pot roast—and at least some of you have used the simple, tried-and-true method of putting the meat into the slow cooker with a packet of onion soup mix. It makes a tasty dinner with minimal effort. But onion soup packets are for making onion soup—not seasoning pot roast. Guess what? You just used that soup mix off-label!

As clinicians, we all use medications for clinical indications that haven’t been specifically authorized by the FDA—and we shouldn’t stop. Off-label prescribing is legal, common, and often supported by the standard of care.

But there is a risk: The pill or tablet prepared by the manufacturer is generally aimed at the intended on-label use, not off-label uses. In this case, misoprostol (brand name, Cytotec) is approved by the FDA for prevention and treatment of gastrointestinal ulcers and peptic ulcer disease. The package insert describes dosing as follows:

The recommended adult oral dose of Cytotec for reducing the risk of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this dose cannot be tolerated, a dose of 100 mcg can be used.¹

Continue to: We should not be shocked...

We should not be shocked, then, that Cytotec is supplied as 100- and 200-mcg round white tablets. However, it is frequently used off label for cervical ripening during labor at a dose of “25 mcg inserted into the posterior vaginal fornix.”²

This brings us to the malpractice trap. While off-label use may be appropriate, off-label uses may not neatly “fit” with the substance prepared by the manufacturer. To be properly administered for cervical ripening, the available tablet of misoprostol must be cut with a pill cutter or razor prior to administration.³ Furthermore, dosage is more accurate if the tablet fragments are individually weighed after cutting.³

In this case, the discrepancy between the pill prepared by the manufacturer (100 mcg) and the dosage needed (25 mcg) appears to have caught the defendant family practitioner off guard. So the take-home message is: Use medications as supported by the standard of care—but when using a drug off label, do not assume the product supplied by the manufacturer is appropriate for use as is.

Another interesting aspect of this case is the defense strategy. Most clinicians are aware that the tort of negligence involves (1) duty, (2) breach, (3) causation, and (4) harm. However, it is more logically consistent to think of the elements in this way: (1) duty, (2) breach, (3) harm, and if harm has occurred, (4) examine causation (ie, the logical connection between breach and harm).

In malpractice cases, attorneys frequently focus on one of these specific elements. In this case, the physician’s duty of care and the harm stemming from cerebral palsy are clearly established. Thus, breach and causation take center stage.

Continue to: The defense lawyers...

The defense lawyers acknowledged there was a breach, noting the dosage was “excessive.” However, they argued that this error didn’t matter because the drug was no longer active in the patient’s body. In other words, there was no causal connection between the inappropriately high dose and the resultant uterine tachysystole and fetal distress. This is a difficult road for several reasons.

First, the chief danger of using misoprostol is uterine hyperstimulation and fetal distress. The defense would have to argue the hyperstimulation and fetal distress were coincidental and unrelated to the misoprostol—which carries a black box warning for these very adverse effects. The plaintiff’s attorney is sure to make a big deal out of the black box warning in front of the jury—noting any reasonable clinician practicing obstetrics should be aware of the risks that come with misoprostol’s use. You can almost hear the argument in summation: “It is so important, they drew a warning box around it.”

Furthermore, making the argument that the misoprostol was not in the mother’s system at the time the fetal distress started would entail dueling expert testimony about pharmacokinetics and bioavailability—concepts that are difficult for lay jurors to understand. Misoprostol has a half-life of about 20 to 40 min when administered orally and about 60 min when administered vaginally.⁴ We know the mother received the overdose of misoprostol at 12:24 pm and a little over an hour later, fetal monitoring was discontinued, leaving the patient unmonitored for 3.5 hours. The agent would have been active or at least potentially active when the monitoring was discontinued—but, the defense argued, was the misoprostol biologically active at 5 pm when uterine tachysystole and late decelerations were noted?

The plaintiff’s team might counter with an expert’s explanation that misoprostol’s bioavailability is increased 2- to 3-fold with vaginal versus oral administration. It would also be observed that compared with oral administration, vaginal administration of misoprostol is associated with a slower increase in plasma concentrations but longer elevations (peaking about 1-2 hours after vaginal administration).⁵

At best, the defense expert would be able to argue that the serum level likely peaked 1 to 2 hours after administration (1:24-2:24 pm) and was on its way down when the uterine tachysystole and late decelerations started. During cross-examination, plaintiff’s counsel would secure key expert witness admissions that vaginal absorption is less studied and less certain than oral administration and that “there was no way to be sure” what the patient’s blood level was when the fetal distress was finally detected. The expert would have to acknowledge the black box warning—a concept that is quite easy for a jury to grasp.

Continue to: Most jurors would...

Most jurors would take a skeptical view of the defendant’s argument that the negative outcome in this case was coincidental. Some might even be angered by it. This realization likely prompted the defense to settle this case for $9 million.

IN SUMMARY

Onion soup mix makes great soup, but it’s an even better seasoning for pot roast. Similarly, there are pharmacologic agents that are effective for conditions for which they are not formally indicated. Do not withhold judicious off-label use of medications when appropriate. However, be aware that off-label uses may require extra attention, and dosing and administration may not be consistent with the product you have on hand. Don’t hesitate to seek guidance from pharmacy colleagues when you have questions—they are an underutilized resource and are generally happy to share their expertise.

A pregnant woman in Wisconsin received prenatal care from a family practitioner. The patient had hypertension, so at about 38 weeks’ gestation, the decision was made to induce labor.

On May 15, 2012, the family practitioner used misoprostol to induce labor. The patient received 100 mcg vaginally at 12:24 pm. The recommended dosage for this indication is 25 mcg.

At 1:28 pm, fetal monitoring was stopped and did not resume until 5 pm. At that time, tachysystole (excessive uterine contractions) was noted, along with fetal heart decelerations. Terbutaline was administered to counteract the contractions, but the uterine activity remained excessive.

Variable late decelerations occurred at 11:36 pm. Prolonged decelerations were noted at 12:08 am on May 16. The cervix was noted to be only 7 cm dilated. At 12:39 am, fetal heart decelerations recurred and bradycardia developed.

Although the family practitioner was present at the bedside at 12:40 am, a fetal scalp monitor was not applied until 1 am. The family practitioner did not have privileges to perform a C-section without supervision, and it was 1:13 am before a physician who could perform a C-section was summoned.

The on-call physician accomplished a vacuum delivery at 1:30 am. Unfortunately, the baby was born with Apgar scores of 1 and 3 and a cord pH of 6.7, indicating severe metabolic acidosis. He was transferred to another hospital for neonatal care, including hypothermia treatments.

The child now has severe cerebral palsy, with gross motor involvement in the arms and legs. He can communicate through augmentative communication devices but cannot actually speak. He will require full-time care for the rest of his life.

Continue to: The defense took the position...

The defense took the position that while the dosage of misoprostol was excessive, the drug was no longer active in the mother’s body, based on its half-life, when the fetal distress occurred.

VERDICT

Four days before trial, the case was settled for $9 ­million.

COMMENTARY

I suspect many of you have made a pot roast—and at least some of you have used the simple, tried-and-true method of putting the meat into the slow cooker with a packet of onion soup mix. It makes a tasty dinner with minimal effort. But onion soup packets are for making onion soup—not seasoning pot roast. Guess what? You just used that soup mix off-label!

As clinicians, we all use medications for clinical indications that haven’t been specifically authorized by the FDA—and we shouldn’t stop. Off-label prescribing is legal, common, and often supported by the standard of care.

But there is a risk: The pill or tablet prepared by the manufacturer is generally aimed at the intended on-label use, not off-label uses. In this case, misoprostol (brand name, Cytotec) is approved by the FDA for prevention and treatment of gastrointestinal ulcers and peptic ulcer disease. The package insert describes dosing as follows:

The recommended adult oral dose of Cytotec for reducing the risk of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this dose cannot be tolerated, a dose of 100 mcg can be used.¹

Continue to: We should not be shocked...

We should not be shocked, then, that Cytotec is supplied as 100- and 200-mcg round white tablets. However, it is frequently used off label for cervical ripening during labor at a dose of “25 mcg inserted into the posterior vaginal fornix.”²

This brings us to the malpractice trap. While off-label use may be appropriate, off-label uses may not neatly “fit” with the substance prepared by the manufacturer. To be properly administered for cervical ripening, the available tablet of misoprostol must be cut with a pill cutter or razor prior to administration.³ Furthermore, dosage is more accurate if the tablet fragments are individually weighed after cutting.³

In this case, the discrepancy between the pill prepared by the manufacturer (100 mcg) and the dosage needed (25 mcg) appears to have caught the defendant family practitioner off guard. So the take-home message is: Use medications as supported by the standard of care—but when using a drug off label, do not assume the product supplied by the manufacturer is appropriate for use as is.

Another interesting aspect of this case is the defense strategy. Most clinicians are aware that the tort of negligence involves (1) duty, (2) breach, (3) causation, and (4) harm. However, it is more logically consistent to think of the elements in this way: (1) duty, (2) breach, (3) harm, and if harm has occurred, (4) examine causation (ie, the logical connection between breach and harm).

In malpractice cases, attorneys frequently focus on one of these specific elements. In this case, the physician’s duty of care and the harm stemming from cerebral palsy are clearly established. Thus, breach and causation take center stage.

Continue to: The defense lawyers...

The defense lawyers acknowledged there was a breach, noting the dosage was “excessive.” However, they argued that this error didn’t matter because the drug was no longer active in the patient’s body. In other words, there was no causal connection between the inappropriately high dose and the resultant uterine tachysystole and fetal distress. This is a difficult road for several reasons.

First, the chief danger of using misoprostol is uterine hyperstimulation and fetal distress. The defense would have to argue the hyperstimulation and fetal distress were coincidental and unrelated to the misoprostol—which carries a black box warning for these very adverse effects. The plaintiff’s attorney is sure to make a big deal out of the black box warning in front of the jury—noting any reasonable clinician practicing obstetrics should be aware of the risks that come with misoprostol’s use. You can almost hear the argument in summation: “It is so important, they drew a warning box around it.”

Furthermore, making the argument that the misoprostol was not in the mother’s system at the time the fetal distress started would entail dueling expert testimony about pharmacokinetics and bioavailability—concepts that are difficult for lay jurors to understand. Misoprostol has a half-life of about 20 to 40 min when administered orally and about 60 min when administered vaginally.⁴ We know the mother received the overdose of misoprostol at 12:24 pm and a little over an hour later, fetal monitoring was discontinued, leaving the patient unmonitored for 3.5 hours. The agent would have been active or at least potentially active when the monitoring was discontinued—but, the defense argued, was the misoprostol biologically active at 5 pm when uterine tachysystole and late decelerations were noted?

The plaintiff’s team might counter with an expert’s explanation that misoprostol’s bioavailability is increased 2- to 3-fold with vaginal versus oral administration. It would also be observed that compared with oral administration, vaginal administration of misoprostol is associated with a slower increase in plasma concentrations but longer elevations (peaking about 1-2 hours after vaginal administration).⁵

At best, the defense expert would be able to argue that the serum level likely peaked 1 to 2 hours after administration (1:24-2:24 pm) and was on its way down when the uterine tachysystole and late decelerations started. During cross-examination, plaintiff’s counsel would secure key expert witness admissions that vaginal absorption is less studied and less certain than oral administration and that “there was no way to be sure” what the patient’s blood level was when the fetal distress was finally detected. The expert would have to acknowledge the black box warning—a concept that is quite easy for a jury to grasp.

Continue to: Most jurors would...

Most jurors would take a skeptical view of the defendant’s argument that the negative outcome in this case was coincidental. Some might even be angered by it. This realization likely prompted the defense to settle this case for $9 million.

IN SUMMARY

Onion soup mix makes great soup, but it’s an even better seasoning for pot roast. Similarly, there are pharmacologic agents that are effective for conditions for which they are not formally indicated. Do not withhold judicious off-label use of medications when appropriate. However, be aware that off-label uses may require extra attention, and dosing and administration may not be consistent with the product you have on hand. Don’t hesitate to seek guidance from pharmacy colleagues when you have questions—they are an underutilized resource and are generally happy to share their expertise.

A pregnant woman in Wisconsin received prenatal care from a family practitioner. The patient had hypertension, so at about 38 weeks’ gestation, the decision was made to induce labor.

On May 15, 2012, the family practitioner used misoprostol to induce labor. The patient received 100 mcg vaginally at 12:24 pm. The recommended dosage for this indication is 25 mcg.

At 1:28 pm, fetal monitoring was stopped and did not resume until 5 pm. At that time, tachysystole (excessive uterine contractions) was noted, along with fetal heart decelerations. Terbutaline was administered to counteract the contractions, but the uterine activity remained excessive.

Variable late decelerations occurred at 11:36 pm. Prolonged decelerations were noted at 12:08 am on May 16. The cervix was noted to be only 7 cm dilated. At 12:39 am, fetal heart decelerations recurred and bradycardia developed.

Although the family practitioner was present at the bedside at 12:40 am, a fetal scalp monitor was not applied until 1 am. The family practitioner did not have privileges to perform a C-section without supervision, and it was 1:13 am before a physician who could perform a C-section was summoned.

The on-call physician accomplished a vacuum delivery at 1:30 am. Unfortunately, the baby was born with Apgar scores of 1 and 3 and a cord pH of 6.7, indicating severe metabolic acidosis. He was transferred to another hospital for neonatal care, including hypothermia treatments.

The child now has severe cerebral palsy, with gross motor involvement in the arms and legs. He can communicate through augmentative communication devices but cannot actually speak. He will require full-time care for the rest of his life.

Continue to: The defense took the position...

The defense took the position that while the dosage of misoprostol was excessive, the drug was no longer active in the mother’s body, based on its half-life, when the fetal distress occurred.

VERDICT

Four days before trial, the case was settled for $9 ­million.

COMMENTARY

I suspect many of you have made a pot roast—and at least some of you have used the simple, tried-and-true method of putting the meat into the slow cooker with a packet of onion soup mix. It makes a tasty dinner with minimal effort. But onion soup packets are for making onion soup—not seasoning pot roast. Guess what? You just used that soup mix off-label!

As clinicians, we all use medications for clinical indications that haven’t been specifically authorized by the FDA—and we shouldn’t stop. Off-label prescribing is legal, common, and often supported by the standard of care.

But there is a risk: The pill or tablet prepared by the manufacturer is generally aimed at the intended on-label use, not off-label uses. In this case, misoprostol (brand name, Cytotec) is approved by the FDA for prevention and treatment of gastrointestinal ulcers and peptic ulcer disease. The package insert describes dosing as follows:

The recommended adult oral dose of Cytotec for reducing the risk of NSAID-induced gastric ulcers is 200 mcg four times daily with food. If this dose cannot be tolerated, a dose of 100 mcg can be used.¹

Continue to: We should not be shocked...

We should not be shocked, then, that Cytotec is supplied as 100- and 200-mcg round white tablets. However, it is frequently used off label for cervical ripening during labor at a dose of “25 mcg inserted into the posterior vaginal fornix.”²

This brings us to the malpractice trap. While off-label use may be appropriate, off-label uses may not neatly “fit” with the substance prepared by the manufacturer. To be properly administered for cervical ripening, the available tablet of misoprostol must be cut with a pill cutter or razor prior to administration.³ Furthermore, dosage is more accurate if the tablet fragments are individually weighed after cutting.³

In this case, the discrepancy between the pill prepared by the manufacturer (100 mcg) and the dosage needed (25 mcg) appears to have caught the defendant family practitioner off guard. So the take-home message is: Use medications as supported by the standard of care—but when using a drug off label, do not assume the product supplied by the manufacturer is appropriate for use as is.

Another interesting aspect of this case is the defense strategy. Most clinicians are aware that the tort of negligence involves (1) duty, (2) breach, (3) causation, and (4) harm. However, it is more logically consistent to think of the elements in this way: (1) duty, (2) breach, (3) harm, and if harm has occurred, (4) examine causation (ie, the logical connection between breach and harm).

In malpractice cases, attorneys frequently focus on one of these specific elements. In this case, the physician’s duty of care and the harm stemming from cerebral palsy are clearly established. Thus, breach and causation take center stage.

Continue to: The defense lawyers...

The defense lawyers acknowledged there was a breach, noting the dosage was “excessive.” However, they argued that this error didn’t matter because the drug was no longer active in the patient’s body. In other words, there was no causal connection between the inappropriately high dose and the resultant uterine tachysystole and fetal distress. This is a difficult road for several reasons.

First, the chief danger of using misoprostol is uterine hyperstimulation and fetal distress. The defense would have to argue the hyperstimulation and fetal distress were coincidental and unrelated to the misoprostol—which carries a black box warning for these very adverse effects. The plaintiff’s attorney is sure to make a big deal out of the black box warning in front of the jury—noting any reasonable clinician practicing obstetrics should be aware of the risks that come with misoprostol’s use. You can almost hear the argument in summation: “It is so important, they drew a warning box around it.”

Furthermore, making the argument that the misoprostol was not in the mother’s system at the time the fetal distress started would entail dueling expert testimony about pharmacokinetics and bioavailability—concepts that are difficult for lay jurors to understand. Misoprostol has a half-life of about 20 to 40 min when administered orally and about 60 min when administered vaginally.⁴ We know the mother received the overdose of misoprostol at 12:24 pm and a little over an hour later, fetal monitoring was discontinued, leaving the patient unmonitored for 3.5 hours. The agent would have been active or at least potentially active when the monitoring was discontinued—but, the defense argued, was the misoprostol biologically active at 5 pm when uterine tachysystole and late decelerations were noted?

The plaintiff’s team might counter with an expert’s explanation that misoprostol’s bioavailability is increased 2- to 3-fold with vaginal versus oral administration. It would also be observed that compared with oral administration, vaginal administration of misoprostol is associated with a slower increase in plasma concentrations but longer elevations (peaking about 1-2 hours after vaginal administration).⁵

At best, the defense expert would be able to argue that the serum level likely peaked 1 to 2 hours after administration (1:24-2:24 pm) and was on its way down when the uterine tachysystole and late decelerations started. During cross-examination, plaintiff’s counsel would secure key expert witness admissions that vaginal absorption is less studied and less certain than oral administration and that “there was no way to be sure” what the patient’s blood level was when the fetal distress was finally detected. The expert would have to acknowledge the black box warning—a concept that is quite easy for a jury to grasp.

Continue to: Most jurors would...

Most jurors would take a skeptical view of the defendant’s argument that the negative outcome in this case was coincidental. Some might even be angered by it. This realization likely prompted the defense to settle this case for $9 million.

IN SUMMARY

Onion soup mix makes great soup, but it’s an even better seasoning for pot roast. Similarly, there are pharmacologic agents that are effective for conditions for which they are not formally indicated. Do not withhold judicious off-label use of medications when appropriate. However, be aware that off-label uses may require extra attention, and dosing and administration may not be consistent with the product you have on hand. Don’t hesitate to seek guidance from pharmacy colleagues when you have questions—they are an underutilized resource and are generally happy to share their expertise.

Comparison of the number of major complications of laparoscopic cholecystectomy versus percutaneous catheter drainage in the treatment of acute cholecystitis

This randomized, controlled trial showed that 65% of high-risk patients (APACHE II score of at least 7) with acute cholecystitis experienced major complications after undergoing percutaneous catheter drainage, compared with 12% of patients who underwent laparoscopic cholecystectomy. Major complications included reintervention and recurrent biliary disease. The rate of death was the same in both groups.

Citation: Loozen CS et al. Laparoscopic cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high-risk patients (CHOCOLATE): Multicentre randomised clinical trial. BMJ. 2018 Aug 28;363:k3965.

Food and Drug Administration approves new drug to treat influenza

Two randomized, controlled trials showed that Xofluza (baloxavir marboxil) taken as a single dose decreased symptoms in uncomplicated influenza, compared with placebo. The medication also was associated with a lower viral load on day 1 after administration, compared with both placebo and oseltamivir, the most commonly used medication to treat influenza.

Citation: Hayden FG et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Eng J Med. 2018 Sep 6;379:913-23.
 

Effects of missed hemodialysis treatments

Researchers used a prospective cohort of 8,501 patients from hemodialysis (HD) centers in 20 countries to identify patients who missed one or more HD sessions in 4 months. In the United States, 24% of HD patients missed one or more sessions in 4 months, compared with 10% in Canada and 9% in the United Kingdom. Moreover, 12.2% of U.S. HD patients missed at least one session per month. All-cause mortality was 68% higher in patients who missed one or more sessions in 4 months. Risk factors associated with missing dialysis treatments were travel time of more than 1 hour to the facility, depression, younger age, being on dialysis for a shorter vintage, lower perceived burden of kidney disease, and shorter treatment times.

Citation: Al Salmi I et al. Missed hemodialysis treatments: International variation, predictors, and outcomes in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2018 Nov;72(5)634-43.
 

Do in situ mock codes affect in-hospital cardiac arrest mortality?

This ecological study included multiple hospital systems and showed that hospitals with a higher proportion of in situ mock codes had an in-hospital cardiac arrest survival rate of 42.8% versus 31.8% in hospitals with fewer mock codes (P greater than .0001).

Citation: Josey K et al. Hospitals with more-active participation in conducting standardized in-situ mock codes have improved survival after in-­hospital cardiopulmonary arrest. Resuscitation. 2018 Dec;133:47-52.
 

New oxygen guidelines

In patients admitted with acute stroke or MI, an international expert panel made a strong recommendation against initiating supplemental oxygen when the SpO₂ is greater than 92% and a weak recommendation against initiating supplemental oxygen when the SpO₂ is 90%-92%. In acutely ill medical patients receiving supplemental oxygen, the panel makes a strong recommendation to maintain an upper limit oxygen saturation of less than 96%.

Citation: Siemieniuk RAC et al. Oxygen therapy for acutely ill medical patients: A clinical practice guideline. BMJ. 2018 Oct 24;363:k4169.
 

Comparison of the number of major complications of laparoscopic cholecystectomy versus percutaneous catheter drainage in the treatment of acute cholecystitis

This randomized, controlled trial showed that 65% of high-risk patients (APACHE II score of at least 7) with acute cholecystitis experienced major complications after undergoing percutaneous catheter drainage, compared with 12% of patients who underwent laparoscopic cholecystectomy. Major complications included reintervention and recurrent biliary disease. The rate of death was the same in both groups.

Citation: Loozen CS et al. Laparoscopic cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high-risk patients (CHOCOLATE): Multicentre randomised clinical trial. BMJ. 2018 Aug 28;363:k3965.

Food and Drug Administration approves new drug to treat influenza

Two randomized, controlled trials showed that Xofluza (baloxavir marboxil) taken as a single dose decreased symptoms in uncomplicated influenza, compared with placebo. The medication also was associated with a lower viral load on day 1 after administration, compared with both placebo and oseltamivir, the most commonly used medication to treat influenza.

Citation: Hayden FG et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Eng J Med. 2018 Sep 6;379:913-23.
 

Effects of missed hemodialysis treatments

Researchers used a prospective cohort of 8,501 patients from hemodialysis (HD) centers in 20 countries to identify patients who missed one or more HD sessions in 4 months. In the United States, 24% of HD patients missed one or more sessions in 4 months, compared with 10% in Canada and 9% in the United Kingdom. Moreover, 12.2% of U.S. HD patients missed at least one session per month. All-cause mortality was 68% higher in patients who missed one or more sessions in 4 months. Risk factors associated with missing dialysis treatments were travel time of more than 1 hour to the facility, depression, younger age, being on dialysis for a shorter vintage, lower perceived burden of kidney disease, and shorter treatment times.

Citation: Al Salmi I et al. Missed hemodialysis treatments: International variation, predictors, and outcomes in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2018 Nov;72(5)634-43.
 

Do in situ mock codes affect in-hospital cardiac arrest mortality?

This ecological study included multiple hospital systems and showed that hospitals with a higher proportion of in situ mock codes had an in-hospital cardiac arrest survival rate of 42.8% versus 31.8% in hospitals with fewer mock codes (P greater than .0001).

Citation: Josey K et al. Hospitals with more-active participation in conducting standardized in-situ mock codes have improved survival after in-­hospital cardiopulmonary arrest. Resuscitation. 2018 Dec;133:47-52.
 

New oxygen guidelines

In patients admitted with acute stroke or MI, an international expert panel made a strong recommendation against initiating supplemental oxygen when the SpO₂ is greater than 92% and a weak recommendation against initiating supplemental oxygen when the SpO₂ is 90%-92%. In acutely ill medical patients receiving supplemental oxygen, the panel makes a strong recommendation to maintain an upper limit oxygen saturation of less than 96%.

Citation: Siemieniuk RAC et al. Oxygen therapy for acutely ill medical patients: A clinical practice guideline. BMJ. 2018 Oct 24;363:k4169.
 

Comparison of the number of major complications of laparoscopic cholecystectomy versus percutaneous catheter drainage in the treatment of acute cholecystitis

This randomized, controlled trial showed that 65% of high-risk patients (APACHE II score of at least 7) with acute cholecystitis experienced major complications after undergoing percutaneous catheter drainage, compared with 12% of patients who underwent laparoscopic cholecystectomy. Major complications included reintervention and recurrent biliary disease. The rate of death was the same in both groups.

Citation: Loozen CS et al. Laparoscopic cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high-risk patients (CHOCOLATE): Multicentre randomised clinical trial. BMJ. 2018 Aug 28;363:k3965.

Food and Drug Administration approves new drug to treat influenza

Two randomized, controlled trials showed that Xofluza (baloxavir marboxil) taken as a single dose decreased symptoms in uncomplicated influenza, compared with placebo. The medication also was associated with a lower viral load on day 1 after administration, compared with both placebo and oseltamivir, the most commonly used medication to treat influenza.

Citation: Hayden FG et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Eng J Med. 2018 Sep 6;379:913-23.
 

Effects of missed hemodialysis treatments

Researchers used a prospective cohort of 8,501 patients from hemodialysis (HD) centers in 20 countries to identify patients who missed one or more HD sessions in 4 months. In the United States, 24% of HD patients missed one or more sessions in 4 months, compared with 10% in Canada and 9% in the United Kingdom. Moreover, 12.2% of U.S. HD patients missed at least one session per month. All-cause mortality was 68% higher in patients who missed one or more sessions in 4 months. Risk factors associated with missing dialysis treatments were travel time of more than 1 hour to the facility, depression, younger age, being on dialysis for a shorter vintage, lower perceived burden of kidney disease, and shorter treatment times.

Citation: Al Salmi I et al. Missed hemodialysis treatments: International variation, predictors, and outcomes in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2018 Nov;72(5)634-43.
 

Do in situ mock codes affect in-hospital cardiac arrest mortality?

This ecological study included multiple hospital systems and showed that hospitals with a higher proportion of in situ mock codes had an in-hospital cardiac arrest survival rate of 42.8% versus 31.8% in hospitals with fewer mock codes (P greater than .0001).

Citation: Josey K et al. Hospitals with more-active participation in conducting standardized in-situ mock codes have improved survival after in-­hospital cardiopulmonary arrest. Resuscitation. 2018 Dec;133:47-52.
 

New oxygen guidelines

In patients admitted with acute stroke or MI, an international expert panel made a strong recommendation against initiating supplemental oxygen when the SpO₂ is greater than 92% and a weak recommendation against initiating supplemental oxygen when the SpO₂ is 90%-92%. In acutely ill medical patients receiving supplemental oxygen, the panel makes a strong recommendation to maintain an upper limit oxygen saturation of less than 96%.

Citation: Siemieniuk RAC et al. Oxygen therapy for acutely ill medical patients: A clinical practice guideline. BMJ. 2018 Oct 24;363:k4169.
 

Gastric acid–suppressing medications such as proton pump inhibitors are associated with a significant increase in subsequent antiallergy medication use, particularly in older individuals.

In a population-based study of health insurance data from 8.2 million people, Austrian researchers looked for prescriptions of gastric acid inhibitors, antiallergy drugs, or other commonly prescribed (lipid-modifying and antihypertensive) drugs as controls from 2009-2013.

According to results published in Nature Communications, gastric acid–suppressing drugs were associated with an overall 96% higher rate of subsequent prescriptions for antiallergy medications than among the general population not taking gastric acid–suppressing drugs (P less than .001). Among individuals aged 60 years or older, the rate of allergy medication prescriptions after acid-suppressing treatment was more than five times higher than that in the general population.

The rate of antiallergy medication use after acid-suppressing medication prescription was threefold higher than the rate seen after lipid-modifying or antihypertensive drug prescription.

“Our findings confirm an epidemiological association between gastric acid suppression and development of allergic symptoms, in line with previous mechanistic animal trials and human observational studies,” wrote Galateja Jordakieva, PhD, of the department of physical medicine, rehabilitation, and occupational medicine at the Medical University of Vienna, and coauthors.

All groups of acid-inhibiting medications were associated with a higher rate of subsequent antiallergy medication prescriptions. The only exception was prostaglandin E2 medications, but the authors said that here the numbers were too low to draw conclusions.

The hazard rate for antiallergy medications also increased with increasing numbers of daily doses of acid-suppressing medication, the study showed. The hazard rate for the lowest quartile – up to 20 daily doses per year – was a significant 28% higher than that of the general population, while the third quartile (68-213 daily dose per year) was associated with a 2.67-fold higher hazard. A similar increase was seen for the fourth quartile of acid suppression–medication dosing.

The authors established that just six daily doses of acid-suppressing drugs in a year were associated with significantly earlier prescriptions of antiallergy medication.

Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine, emphasized in an associated commentary that the findings reflect association, not causation. “There are many possible explanations for the observed association ... In fact, the data make other explanations more than likely to be the cause of allergies.”

Coprescriptions of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) are common among PPI users and “are among the drugs that are very well known to increase the risk of an allergic reaction.” The data show that antiallergy medicines are prescribed at a relatively similar rate at all ages, while PPI prescribing increases in the elderly.

“If the rate of prescription of PPIs shows a steep rise with age and they are a significant cause of allergies, then the anti-allergy medicines ... should also show a steep rise with age. The fact that they don’t, either means they show no relation or that any relation has a minimal effect on allergies,” Dr. Evans said. “Nearly all drugs can have very rare allergic reactions, including PPIs, but this paper does not help to show what the true rate is of these very rare reactions, or whether they are caused by PPIs alone. The design and analysis methods in the paper are likely to exaggerate their apparent occurrence.”

The study was supported by Burgenländische Gebietskrankenkasse and the Austrian Science Fund. No conflicts of interest were declared.

SOURCE: Jordakieva G et al. Nat Commun. 2019 Jul 30. doi: 10.1038/s41467-019-10914-6.

Gastric acid–suppressing medications such as proton pump inhibitors are associated with a significant increase in subsequent antiallergy medication use, particularly in older individuals.

In a population-based study of health insurance data from 8.2 million people, Austrian researchers looked for prescriptions of gastric acid inhibitors, antiallergy drugs, or other commonly prescribed (lipid-modifying and antihypertensive) drugs as controls from 2009-2013.

According to results published in Nature Communications, gastric acid–suppressing drugs were associated with an overall 96% higher rate of subsequent prescriptions for antiallergy medications than among the general population not taking gastric acid–suppressing drugs (P less than .001). Among individuals aged 60 years or older, the rate of allergy medication prescriptions after acid-suppressing treatment was more than five times higher than that in the general population.

The rate of antiallergy medication use after acid-suppressing medication prescription was threefold higher than the rate seen after lipid-modifying or antihypertensive drug prescription.

“Our findings confirm an epidemiological association between gastric acid suppression and development of allergic symptoms, in line with previous mechanistic animal trials and human observational studies,” wrote Galateja Jordakieva, PhD, of the department of physical medicine, rehabilitation, and occupational medicine at the Medical University of Vienna, and coauthors.

All groups of acid-inhibiting medications were associated with a higher rate of subsequent antiallergy medication prescriptions. The only exception was prostaglandin E2 medications, but the authors said that here the numbers were too low to draw conclusions.

The hazard rate for antiallergy medications also increased with increasing numbers of daily doses of acid-suppressing medication, the study showed. The hazard rate for the lowest quartile – up to 20 daily doses per year – was a significant 28% higher than that of the general population, while the third quartile (68-213 daily dose per year) was associated with a 2.67-fold higher hazard. A similar increase was seen for the fourth quartile of acid suppression–medication dosing.

The authors established that just six daily doses of acid-suppressing drugs in a year were associated with significantly earlier prescriptions of antiallergy medication.

Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine, emphasized in an associated commentary that the findings reflect association, not causation. “There are many possible explanations for the observed association ... In fact, the data make other explanations more than likely to be the cause of allergies.”

Coprescriptions of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) are common among PPI users and “are among the drugs that are very well known to increase the risk of an allergic reaction.” The data show that antiallergy medicines are prescribed at a relatively similar rate at all ages, while PPI prescribing increases in the elderly.

“If the rate of prescription of PPIs shows a steep rise with age and they are a significant cause of allergies, then the anti-allergy medicines ... should also show a steep rise with age. The fact that they don’t, either means they show no relation or that any relation has a minimal effect on allergies,” Dr. Evans said. “Nearly all drugs can have very rare allergic reactions, including PPIs, but this paper does not help to show what the true rate is of these very rare reactions, or whether they are caused by PPIs alone. The design and analysis methods in the paper are likely to exaggerate their apparent occurrence.”

The study was supported by Burgenländische Gebietskrankenkasse and the Austrian Science Fund. No conflicts of interest were declared.

SOURCE: Jordakieva G et al. Nat Commun. 2019 Jul 30. doi: 10.1038/s41467-019-10914-6.

Gastric acid–suppressing medications such as proton pump inhibitors are associated with a significant increase in subsequent antiallergy medication use, particularly in older individuals.

In a population-based study of health insurance data from 8.2 million people, Austrian researchers looked for prescriptions of gastric acid inhibitors, antiallergy drugs, or other commonly prescribed (lipid-modifying and antihypertensive) drugs as controls from 2009-2013.

According to results published in Nature Communications, gastric acid–suppressing drugs were associated with an overall 96% higher rate of subsequent prescriptions for antiallergy medications than among the general population not taking gastric acid–suppressing drugs (P less than .001). Among individuals aged 60 years or older, the rate of allergy medication prescriptions after acid-suppressing treatment was more than five times higher than that in the general population.

The rate of antiallergy medication use after acid-suppressing medication prescription was threefold higher than the rate seen after lipid-modifying or antihypertensive drug prescription.

“Our findings confirm an epidemiological association between gastric acid suppression and development of allergic symptoms, in line with previous mechanistic animal trials and human observational studies,” wrote Galateja Jordakieva, PhD, of the department of physical medicine, rehabilitation, and occupational medicine at the Medical University of Vienna, and coauthors.

All groups of acid-inhibiting medications were associated with a higher rate of subsequent antiallergy medication prescriptions. The only exception was prostaglandin E2 medications, but the authors said that here the numbers were too low to draw conclusions.

The hazard rate for antiallergy medications also increased with increasing numbers of daily doses of acid-suppressing medication, the study showed. The hazard rate for the lowest quartile – up to 20 daily doses per year – was a significant 28% higher than that of the general population, while the third quartile (68-213 daily dose per year) was associated with a 2.67-fold higher hazard. A similar increase was seen for the fourth quartile of acid suppression–medication dosing.

The authors established that just six daily doses of acid-suppressing drugs in a year were associated with significantly earlier prescriptions of antiallergy medication.

Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine, emphasized in an associated commentary that the findings reflect association, not causation. “There are many possible explanations for the observed association ... In fact, the data make other explanations more than likely to be the cause of allergies.”

Coprescriptions of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) are common among PPI users and “are among the drugs that are very well known to increase the risk of an allergic reaction.” The data show that antiallergy medicines are prescribed at a relatively similar rate at all ages, while PPI prescribing increases in the elderly.

“If the rate of prescription of PPIs shows a steep rise with age and they are a significant cause of allergies, then the anti-allergy medicines ... should also show a steep rise with age. The fact that they don’t, either means they show no relation or that any relation has a minimal effect on allergies,” Dr. Evans said. “Nearly all drugs can have very rare allergic reactions, including PPIs, but this paper does not help to show what the true rate is of these very rare reactions, or whether they are caused by PPIs alone. The design and analysis methods in the paper are likely to exaggerate their apparent occurrence.”

The study was supported by Burgenländische Gebietskrankenkasse and the Austrian Science Fund. No conflicts of interest were declared.

SOURCE: Jordakieva G et al. Nat Commun. 2019 Jul 30. doi: 10.1038/s41467-019-10914-6.

Children who received one or two doses of an MMR-containing vaccine maintained an antibody count well above the seropositivity threshold 10 years after receiving the vaccine, according to Stephane Carryn, PhD, of GlaxoSmithKline and associates.

In a phase 3, observer-blind, randomized study published in Vaccine, 1,887 children aged 12-22 months received two doses of the MMR plus varicella (MMRV) vaccine Priorix-Tetra, one dose of the MMR vaccine Priorix with one dose of the varicella vaccine Varilrix delivered separately, or two doses of the MMR vaccine. Blood samples were collected at baseline and at days 42 and 84, then at year 1, 2, 4, 6, 8, and 10.

Antimeasles and antirubella antibodies declined moderately over the 10-year study period, but seropositivity remained high at 10 years, with about 94.0% of children remaining seropositive for antimeasles antibodies and about 96.6% remaining seropositive for antirubella antibodies. Children who received Priorix-Tetra had antimeasles antibody titers twice as high as those who received Priorix throughout the study. In addition, children who received a second dose of MMR vaccine later in life saw only a transient benefit in antimeasles and antirubella titers.

Antimumps antibody titer levels remained stable over the course of the study, and the seropositivity rate was about 90.0% at 10 years. Children who received a second MMR vaccine later in life saw a boosting effect in seropositivity and antimumps antibody titer levels.

“The responses obtained after receipt of one or two doses of MMR-containing vaccines remain well above the seropositivity thresholds up to 10 years post vaccination, regardless of the vaccine given and the schedule used,” the investigators concluded.

The study was funded and supported by GlaxoSmithKline. The study authors reported being employed by GlaxoSmithKline; two also reported owning shares in the company.

[email protected]

SOURCE: Carryn S et al. Vaccine. 2019 Jul 22. doi: 10.1016/j.vaccine.2019.07.049.

Children who received one or two doses of an MMR-containing vaccine maintained an antibody count well above the seropositivity threshold 10 years after receiving the vaccine, according to Stephane Carryn, PhD, of GlaxoSmithKline and associates.

In a phase 3, observer-blind, randomized study published in Vaccine, 1,887 children aged 12-22 months received two doses of the MMR plus varicella (MMRV) vaccine Priorix-Tetra, one dose of the MMR vaccine Priorix with one dose of the varicella vaccine Varilrix delivered separately, or two doses of the MMR vaccine. Blood samples were collected at baseline and at days 42 and 84, then at year 1, 2, 4, 6, 8, and 10.

Antimeasles and antirubella antibodies declined moderately over the 10-year study period, but seropositivity remained high at 10 years, with about 94.0% of children remaining seropositive for antimeasles antibodies and about 96.6% remaining seropositive for antirubella antibodies. Children who received Priorix-Tetra had antimeasles antibody titers twice as high as those who received Priorix throughout the study. In addition, children who received a second dose of MMR vaccine later in life saw only a transient benefit in antimeasles and antirubella titers.

Antimumps antibody titer levels remained stable over the course of the study, and the seropositivity rate was about 90.0% at 10 years. Children who received a second MMR vaccine later in life saw a boosting effect in seropositivity and antimumps antibody titer levels.

“The responses obtained after receipt of one or two doses of MMR-containing vaccines remain well above the seropositivity thresholds up to 10 years post vaccination, regardless of the vaccine given and the schedule used,” the investigators concluded.

The study was funded and supported by GlaxoSmithKline. The study authors reported being employed by GlaxoSmithKline; two also reported owning shares in the company.

[email protected]

SOURCE: Carryn S et al. Vaccine. 2019 Jul 22. doi: 10.1016/j.vaccine.2019.07.049.

Children who received one or two doses of an MMR-containing vaccine maintained an antibody count well above the seropositivity threshold 10 years after receiving the vaccine, according to Stephane Carryn, PhD, of GlaxoSmithKline and associates.

In a phase 3, observer-blind, randomized study published in Vaccine, 1,887 children aged 12-22 months received two doses of the MMR plus varicella (MMRV) vaccine Priorix-Tetra, one dose of the MMR vaccine Priorix with one dose of the varicella vaccine Varilrix delivered separately, or two doses of the MMR vaccine. Blood samples were collected at baseline and at days 42 and 84, then at year 1, 2, 4, 6, 8, and 10.

Antimeasles and antirubella antibodies declined moderately over the 10-year study period, but seropositivity remained high at 10 years, with about 94.0% of children remaining seropositive for antimeasles antibodies and about 96.6% remaining seropositive for antirubella antibodies. Children who received Priorix-Tetra had antimeasles antibody titers twice as high as those who received Priorix throughout the study. In addition, children who received a second dose of MMR vaccine later in life saw only a transient benefit in antimeasles and antirubella titers.

Antimumps antibody titer levels remained stable over the course of the study, and the seropositivity rate was about 90.0% at 10 years. Children who received a second MMR vaccine later in life saw a boosting effect in seropositivity and antimumps antibody titer levels.

“The responses obtained after receipt of one or two doses of MMR-containing vaccines remain well above the seropositivity thresholds up to 10 years post vaccination, regardless of the vaccine given and the schedule used,” the investigators concluded.

The study was funded and supported by GlaxoSmithKline. The study authors reported being employed by GlaxoSmithKline; two also reported owning shares in the company.

[email protected]

SOURCE: Carryn S et al. Vaccine. 2019 Jul 22. doi: 10.1016/j.vaccine.2019.07.049.

The Centers for Medicare & Medicaid Services is proposing improvements to physician payments and an overhaul of the Merit-based Incentive Payment System (MIPS) track of the Quality Payment Program.

In a separate proposal also released on July 29, the agency proposed that hospitals be required to make more pricing information publicly available.

The Medicare Outpatient Prospective Payment System proposed rule for the 2020 annual update would require hospitals to not only publish their gross charges, but also the negotiated price by specific payer for select services that can be scheduled by a patient in advance.

The proposal states "that hospitals make public their standard changes (both gross charges and payer-specific negotiated charges) for all items and services online in a machine-readable format" which would allow them to be included in price transparency tools and electronic health records.

"Hospitals would be required to post all their payer-specific negotiated rates, which are the prices actually paid by insurers," CMS Administrator Seema Verma said during a July 29 conference call with reporters.

As "deductibles rise and with 29 million uninsured, patients have the right to know the price of health care services so they can shop around for the best deal," she said.

The rule also comes with new enforcement tools so that CMS can ensure hospitals are complying with the rule, should it be finalized.

Hospitals would need to start publishing list prices and payer-specific negotiated prices beginning Jan. 1, 2020.

In a separate proposal to update the physician fee schedule for 2020, CMS is looking to increase Medicare payments in 2021 for evaluation and management (E/M) visits based on recommendations from the American Medical Association's Relative Value Scale Update Committee (AMA-RUC).

With this update, the agency will be "rewarding the time that doctors spend with patients," Administrator Verma said.

The fact sheet on the proposed update to the physician fee schedule also highlights improvements to case management payments, allowing physicians to get paid for case management services if the patient only has one high-risk condition.

"For 2021, we are overhauling the Merit-based Incentive Payment System, or MIPS, to reduce reporting burden, making sure the measures are relevant to clinicians as they move toward value-based care," she said, noting that clinicians would be reporting on fewer, more meaningful measures that are aligned to their specialty or practice area, "making it easier to participate in MIPS."

Look for in depth analysis of both proposals shortly on this website.
 
[email protected]  

The Centers for Medicare & Medicaid Services is proposing improvements to physician payments and an overhaul of the Merit-based Incentive Payment System (MIPS) track of the Quality Payment Program.

In a separate proposal also released on July 29, the agency proposed that hospitals be required to make more pricing information publicly available.

The Medicare Outpatient Prospective Payment System proposed rule for the 2020 annual update would require hospitals to not only publish their gross charges, but also the negotiated price by specific payer for select services that can be scheduled by a patient in advance.

The proposal states "that hospitals make public their standard changes (both gross charges and payer-specific negotiated charges) for all items and services online in a machine-readable format" which would allow them to be included in price transparency tools and electronic health records.

"Hospitals would be required to post all their payer-specific negotiated rates, which are the prices actually paid by insurers," CMS Administrator Seema Verma said during a July 29 conference call with reporters.

As "deductibles rise and with 29 million uninsured, patients have the right to know the price of health care services so they can shop around for the best deal," she said.

The rule also comes with new enforcement tools so that CMS can ensure hospitals are complying with the rule, should it be finalized.

Hospitals would need to start publishing list prices and payer-specific negotiated prices beginning Jan. 1, 2020.

In a separate proposal to update the physician fee schedule for 2020, CMS is looking to increase Medicare payments in 2021 for evaluation and management (E/M) visits based on recommendations from the American Medical Association's Relative Value Scale Update Committee (AMA-RUC).

With this update, the agency will be "rewarding the time that doctors spend with patients," Administrator Verma said.

The fact sheet on the proposed update to the physician fee schedule also highlights improvements to case management payments, allowing physicians to get paid for case management services if the patient only has one high-risk condition.

"For 2021, we are overhauling the Merit-based Incentive Payment System, or MIPS, to reduce reporting burden, making sure the measures are relevant to clinicians as they move toward value-based care," she said, noting that clinicians would be reporting on fewer, more meaningful measures that are aligned to their specialty or practice area, "making it easier to participate in MIPS."

Look for in depth analysis of both proposals shortly on this website.
 
[email protected]  

The Centers for Medicare & Medicaid Services is proposing improvements to physician payments and an overhaul of the Merit-based Incentive Payment System (MIPS) track of the Quality Payment Program.

In a separate proposal also released on July 29, the agency proposed that hospitals be required to make more pricing information publicly available.

The Medicare Outpatient Prospective Payment System proposed rule for the 2020 annual update would require hospitals to not only publish their gross charges, but also the negotiated price by specific payer for select services that can be scheduled by a patient in advance.

The proposal states "that hospitals make public their standard changes (both gross charges and payer-specific negotiated charges) for all items and services online in a machine-readable format" which would allow them to be included in price transparency tools and electronic health records.

"Hospitals would be required to post all their payer-specific negotiated rates, which are the prices actually paid by insurers," CMS Administrator Seema Verma said during a July 29 conference call with reporters.

As "deductibles rise and with 29 million uninsured, patients have the right to know the price of health care services so they can shop around for the best deal," she said.

The rule also comes with new enforcement tools so that CMS can ensure hospitals are complying with the rule, should it be finalized.

Hospitals would need to start publishing list prices and payer-specific negotiated prices beginning Jan. 1, 2020.

In a separate proposal to update the physician fee schedule for 2020, CMS is looking to increase Medicare payments in 2021 for evaluation and management (E/M) visits based on recommendations from the American Medical Association's Relative Value Scale Update Committee (AMA-RUC).

With this update, the agency will be "rewarding the time that doctors spend with patients," Administrator Verma said.

The fact sheet on the proposed update to the physician fee schedule also highlights improvements to case management payments, allowing physicians to get paid for case management services if the patient only has one high-risk condition.

"For 2021, we are overhauling the Merit-based Incentive Payment System, or MIPS, to reduce reporting burden, making sure the measures are relevant to clinicians as they move toward value-based care," she said, noting that clinicians would be reporting on fewer, more meaningful measures that are aligned to their specialty or practice area, "making it easier to participate in MIPS."

Look for in depth analysis of both proposals shortly on this website.
 
[email protected]  

The Centers for Medicare & Medicaid Services is proposing improvements to physician payments and an overhaul of the Merit-based Incentive Payment System (MIPS) track of the Quality Payment Program.

In a separate proposal also released on July 29, the agency proposed that hospitals be required to make more pricing information publicly available.

The Medicare Outpatient Prospective Payment System proposed rule for the 2020 annual update would require hospitals to not only publish their gross charges, but also the negotiated price by specific payer for select services that can be scheduled by a patient in advance.

The proposal states “that hospitals make public their standard changes (both gross charges and payer-specific negotiated charges) for all items and services online in a machine-readable format” which would allow them to be included in price transparency tools and electronic health records.

“Hospitals would be required to post all their payer-specific negotiated rates, which are the prices actually paid by insurers,” CMS Administrator Seema Verma said during a July 29 conference call with reporters.

As “deductibles rise and with 29 million uninsured, patients have the right to know the price of health care services so they can shop around for the best deal,” she said.

The rule also comes with new enforcement tools so that CMS can ensure hospitals are complying with the rule, should it be finalized.

Hospitals would need to start publishing list prices and payer-specific negotiated prices beginning Jan. 1, 2020.

In a separate proposal to update the physician fee schedule for 2020, CMS is looking to increase Medicare payments in 2021 for evaluation and management (E/M) visits based on recommendations from the American Medical Association’s Relative Value Scale Update Committee (AMA-RUC). In fact, CMS is walking back the recently proposed plans to collapse E/M levels. The CPT code changes recommended by the AMA allow clinicians to choose the E/M visit level based on either medical decision making or time.

With this update, the agency will be “rewarding the time that doctors spend with patients,” Administrator Verma said.

In a joint statement, the American Gastroenterological Association, the American College of Gastroenterology and the American Society for Gastrointestinal Endoscopy welcomed the news as the GI societies opposed CMS’ proposal when it was announced last year. “We worked with the AMA and a coalition of specialty societies in an effort to get CMS to rethink collapsing payment for E/M code levels, and subsequently decided to support the AMA’s proposed E/M changes as they moved through the CPT and RUC processes. In the rule, CMS abandons its proposal and adopts the AMA CPT changes and RUC valuation.”

The fact sheet on the proposed update to the physician fee schedule also highlights improvements to case management payments, allowing physicians to get paid for case management services if the patient only has one high-risk condition.

“For 2021, we are overhauling the Merit-based Incentive Payment System, or MIPS, to reduce reporting burden, making sure the measures are relevant to clinicians as they move toward value-based care,” she said, noting that clinicians would be reporting on fewer, more meaningful measures that are aligned to their specialty or practice area, “making it easier to participate in MIPS.” CMS proposed removal of 2 colonoscopy measures from MIPS performance year 2022 because they do not align with MIPS scoring methodology.

The American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy are currently reviewing the details of the proposed rules and will be providing joint comments. CMS will accept comments until Sept. 27, 2019.
 

[email protected]

The Centers for Medicare & Medicaid Services is proposing improvements to physician payments and an overhaul of the Merit-based Incentive Payment System (MIPS) track of the Quality Payment Program.

In a separate proposal also released on July 29, the agency proposed that hospitals be required to make more pricing information publicly available.

The Medicare Outpatient Prospective Payment System proposed rule for the 2020 annual update would require hospitals to not only publish their gross charges, but also the negotiated price by specific payer for select services that can be scheduled by a patient in advance.

The proposal states “that hospitals make public their standard changes (both gross charges and payer-specific negotiated charges) for all items and services online in a machine-readable format” which would allow them to be included in price transparency tools and electronic health records.

“Hospitals would be required to post all their payer-specific negotiated rates, which are the prices actually paid by insurers,” CMS Administrator Seema Verma said during a July 29 conference call with reporters.

As “deductibles rise and with 29 million uninsured, patients have the right to know the price of health care services so they can shop around for the best deal,” she said.

The rule also comes with new enforcement tools so that CMS can ensure hospitals are complying with the rule, should it be finalized.

Hospitals would need to start publishing list prices and payer-specific negotiated prices beginning Jan. 1, 2020.

In a separate proposal to update the physician fee schedule for 2020, CMS is looking to increase Medicare payments in 2021 for evaluation and management (E/M) visits based on recommendations from the American Medical Association’s Relative Value Scale Update Committee (AMA-RUC). In fact, CMS is walking back the recently proposed plans to collapse E/M levels. The CPT code changes recommended by the AMA allow clinicians to choose the E/M visit level based on either medical decision making or time.

With this update, the agency will be “rewarding the time that doctors spend with patients,” Administrator Verma said.

In a joint statement, the American Gastroenterological Association, the American College of Gastroenterology and the American Society for Gastrointestinal Endoscopy welcomed the news as the GI societies opposed CMS’ proposal when it was announced last year. “We worked with the AMA and a coalition of specialty societies in an effort to get CMS to rethink collapsing payment for E/M code levels, and subsequently decided to support the AMA’s proposed E/M changes as they moved through the CPT and RUC processes. In the rule, CMS abandons its proposal and adopts the AMA CPT changes and RUC valuation.”

The fact sheet on the proposed update to the physician fee schedule also highlights improvements to case management payments, allowing physicians to get paid for case management services if the patient only has one high-risk condition.

“For 2021, we are overhauling the Merit-based Incentive Payment System, or MIPS, to reduce reporting burden, making sure the measures are relevant to clinicians as they move toward value-based care,” she said, noting that clinicians would be reporting on fewer, more meaningful measures that are aligned to their specialty or practice area, “making it easier to participate in MIPS.” CMS proposed removal of 2 colonoscopy measures from MIPS performance year 2022 because they do not align with MIPS scoring methodology.

The American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy are currently reviewing the details of the proposed rules and will be providing joint comments. CMS will accept comments until Sept. 27, 2019.
 

[email protected]

The Centers for Medicare & Medicaid Services is proposing improvements to physician payments and an overhaul of the Merit-based Incentive Payment System (MIPS) track of the Quality Payment Program.

In a separate proposal also released on July 29, the agency proposed that hospitals be required to make more pricing information publicly available.

The Medicare Outpatient Prospective Payment System proposed rule for the 2020 annual update would require hospitals to not only publish their gross charges, but also the negotiated price by specific payer for select services that can be scheduled by a patient in advance.

The proposal states “that hospitals make public their standard changes (both gross charges and payer-specific negotiated charges) for all items and services online in a machine-readable format” which would allow them to be included in price transparency tools and electronic health records.

“Hospitals would be required to post all their payer-specific negotiated rates, which are the prices actually paid by insurers,” CMS Administrator Seema Verma said during a July 29 conference call with reporters.

As “deductibles rise and with 29 million uninsured, patients have the right to know the price of health care services so they can shop around for the best deal,” she said.

The rule also comes with new enforcement tools so that CMS can ensure hospitals are complying with the rule, should it be finalized.

Hospitals would need to start publishing list prices and payer-specific negotiated prices beginning Jan. 1, 2020.

In a separate proposal to update the physician fee schedule for 2020, CMS is looking to increase Medicare payments in 2021 for evaluation and management (E/M) visits based on recommendations from the American Medical Association’s Relative Value Scale Update Committee (AMA-RUC). In fact, CMS is walking back the recently proposed plans to collapse E/M levels. The CPT code changes recommended by the AMA allow clinicians to choose the E/M visit level based on either medical decision making or time.

With this update, the agency will be “rewarding the time that doctors spend with patients,” Administrator Verma said.

In a joint statement, the American Gastroenterological Association, the American College of Gastroenterology and the American Society for Gastrointestinal Endoscopy welcomed the news as the GI societies opposed CMS’ proposal when it was announced last year. “We worked with the AMA and a coalition of specialty societies in an effort to get CMS to rethink collapsing payment for E/M code levels, and subsequently decided to support the AMA’s proposed E/M changes as they moved through the CPT and RUC processes. In the rule, CMS abandons its proposal and adopts the AMA CPT changes and RUC valuation.”

The fact sheet on the proposed update to the physician fee schedule also highlights improvements to case management payments, allowing physicians to get paid for case management services if the patient only has one high-risk condition.

“For 2021, we are overhauling the Merit-based Incentive Payment System, or MIPS, to reduce reporting burden, making sure the measures are relevant to clinicians as they move toward value-based care,” she said, noting that clinicians would be reporting on fewer, more meaningful measures that are aligned to their specialty or practice area, “making it easier to participate in MIPS.” CMS proposed removal of 2 colonoscopy measures from MIPS performance year 2022 because they do not align with MIPS scoring methodology.

The American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy are currently reviewing the details of the proposed rules and will be providing joint comments. CMS will accept comments until Sept. 27, 2019.
 

[email protected]

Concurrent or sequential enzyme immunoassays can now be conducted to diagnose Lyme disease, according to the U.S. Food and Drug Administration.

Four previously cleared tests are now approved by the agency for marketing with new indications as part of the revised diagnostic approach. Previously, the two-step diagnostic process consisted of an initial enzyme immunoassay followed by a Western blot test.

“With today’s action, clinicians have a new option to test for Lyme that is easier to interpret by a clinical laboratory due to the streamlined method of conducting the test. These tests may improve confidence in diagnosing a patient for a condition that requires the earliest possible treatment to ensure the best outcome for patients,” Tim Stenzel, MD, PhD, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiologic Health, said in a press release announcing the newly approved approach.

The modified two-tier enzyme immunoassay approach was found to be as accurate for assessing exposure to Borrelia burgdorferi as the standard immunoassay followed by Western blot test in an FDA review of data from clinical studies using the following ZEUS Scientific ELISA Test Systems: Borrelia VlsE1/pepC10 IgG/IgM; Borrelia burgdorferi IgG/IgM; Borrelia burgdorferi IgM; and Borrelia burgdorferi IgG.

The recommendations of the Centers for Disease Control and Prevention should be followed for the diagnosis of Lyme disease and for determining when laboratory tests are appropriate, the FDA statement said. In 2017, the last year for which the CDC published data, a total of 42,743 confirmed and probable cases of Lyme disease were reported, an increase of 17% from 2016.

The FDA granted clearance of the ZEUS ELISA enzyme immunoassay tests to ZEUS Scientific.

[email protected]

Concurrent or sequential enzyme immunoassays can now be conducted to diagnose Lyme disease, according to the U.S. Food and Drug Administration.

Four previously cleared tests are now approved by the agency for marketing with new indications as part of the revised diagnostic approach. Previously, the two-step diagnostic process consisted of an initial enzyme immunoassay followed by a Western blot test.

“With today’s action, clinicians have a new option to test for Lyme that is easier to interpret by a clinical laboratory due to the streamlined method of conducting the test. These tests may improve confidence in diagnosing a patient for a condition that requires the earliest possible treatment to ensure the best outcome for patients,” Tim Stenzel, MD, PhD, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiologic Health, said in a press release announcing the newly approved approach.

The modified two-tier enzyme immunoassay approach was found to be as accurate for assessing exposure to Borrelia burgdorferi as the standard immunoassay followed by Western blot test in an FDA review of data from clinical studies using the following ZEUS Scientific ELISA Test Systems: Borrelia VlsE1/pepC10 IgG/IgM; Borrelia burgdorferi IgG/IgM; Borrelia burgdorferi IgM; and Borrelia burgdorferi IgG.

The recommendations of the Centers for Disease Control and Prevention should be followed for the diagnosis of Lyme disease and for determining when laboratory tests are appropriate, the FDA statement said. In 2017, the last year for which the CDC published data, a total of 42,743 confirmed and probable cases of Lyme disease were reported, an increase of 17% from 2016.

The FDA granted clearance of the ZEUS ELISA enzyme immunoassay tests to ZEUS Scientific.

[email protected]

Concurrent or sequential enzyme immunoassays can now be conducted to diagnose Lyme disease, according to the U.S. Food and Drug Administration.

Four previously cleared tests are now approved by the agency for marketing with new indications as part of the revised diagnostic approach. Previously, the two-step diagnostic process consisted of an initial enzyme immunoassay followed by a Western blot test.

“With today’s action, clinicians have a new option to test for Lyme that is easier to interpret by a clinical laboratory due to the streamlined method of conducting the test. These tests may improve confidence in diagnosing a patient for a condition that requires the earliest possible treatment to ensure the best outcome for patients,” Tim Stenzel, MD, PhD, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiologic Health, said in a press release announcing the newly approved approach.

The modified two-tier enzyme immunoassay approach was found to be as accurate for assessing exposure to Borrelia burgdorferi as the standard immunoassay followed by Western blot test in an FDA review of data from clinical studies using the following ZEUS Scientific ELISA Test Systems: Borrelia VlsE1/pepC10 IgG/IgM; Borrelia burgdorferi IgG/IgM; Borrelia burgdorferi IgM; and Borrelia burgdorferi IgG.

The recommendations of the Centers for Disease Control and Prevention should be followed for the diagnosis of Lyme disease and for determining when laboratory tests are appropriate, the FDA statement said. In 2017, the last year for which the CDC published data, a total of 42,743 confirmed and probable cases of Lyme disease were reported, an increase of 17% from 2016.

The FDA granted clearance of the ZEUS ELISA enzyme immunoassay tests to ZEUS Scientific.

[email protected]

Aside from a possible increased risk of enteric infections, long-term use of the proton pump inhibitor (PPI) pantoprazole appears safe in patients with stable atherosclerotic vascular disease, according to a prospective trial involving more than 17,000 participants.

In contrast with published observational studies, the present trial found no associations between long-term PPI use and previously reported risks such as pneumonia, fracture, or cerebrovascular events, according to lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Ont., and colleagues.

“To our knowledge, this is the largest PPI trial for any indication and the first prospective randomized trial to evaluate the many long-term safety concerns related to PPI therapy,” the investigators wrote in Gastroenterology. “It is reassuring that there was no evidence for harm for most of these events other than an excess of enteric infections.”

“Given how commonly acid suppressive medications are used, it is important to ensure that this class of drugs is safe,” the investigators wrote. They noted that patients are often alarmed by “sensational headlines” about PPI safety. “There are balancing articles that more carefully discuss the risks and benefits of taking PPI therapy but these receive less media attention,” the investigators added.

The present, prospective trial, COMPASS, involved 17,598 participants from 33 countries with stable peripheral artery disease and cardiovascular disease. “We use the term participants, rather than patients, as not all of those taking part in this research would have been patients throughout the trial but all participated in the randomized controlled trial,” the investigators wrote.

In addition to evaluating the safety of pantoprazole, the study was initially designed to measure the efficacy of pantoprazole for preventing upper gastrointestinal events in participants taking rivaroxaban and/or aspirin, which, in combination, were recently shown to reduce cardiovascular outcomes among patients with stable cardiovascular conditions. As such, participants in the trial were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or 2.5-mg rivaroxaban twice daily combined with 100-mg aspirin once daily. The primary efficacy outcomes for these three groups were stroke, myocardial infarction, and cardiovascular death. This portion of the trial was discontinued early because of evidence that showed the superiority of combination therapy over aspirin alone; however, the pantoprazole component of the trial continued, as planned, for 3 years.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. Pantoprazole safety outcomes centered on those previously reported by observational studies, including dementia, chronic kidney disease, gastric atrophy, fracture, cancer, pneumonia, diabetes mellitus, chronic obstructive lung disease, Clostrididoides difficile infection, and other enteric infections. Hospitalization rates for noncardiovascular and cardiovascular events were also reported. Data were gathered via questionnaires, which were conducted every 6 months.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking an NSAID (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis of cardiovascular outcomes revealed no significant differences between placebo and pantoprazole groups. Of all the evaluated safety measures, only enteric infections differed significantly between groups, occurring at a higher rate in the pantoprazole group than in the placebo group (1.4% vs. 1.0%; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). Although C. difficile infection was more common among pantoprazole users, only 13 such events occurred, precluding statistical significance.

According to the investigators, these findings should offer reassurance to PPI prescribers and users; they noted that previous findings from observational studies warrant skepticism. “A significant proportion of patients are prescribed PPI therapy inappropriately, and in these cases, it is reasonable to advocate strategies to discontinue acid suppression. However, when there is a clinical need for PPI therapy, these data suggest that the benefits are likely to outweigh any putative risks.”

In regard to the possible increased risk of enteric infection, the investigators again urged a conservative interpretation, as the increased rate of enteric infection among PPI users was still lower than rates reported by systematic reviews. “The data in the current randomized trial were not adjusted for multiple testing so this result should be interpreted with caution,” the investigators wrote. Although acid suppression may allow for increased ingestion of pathogenic organisms, which could theoretically increase the risk of enteric infection, the investigators stated that the benefits of PPIs likely outweigh their risks.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Bayer, Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 29. doi: 10.1053/j.gastro.2019.05.056.

Aside from a possible increased risk of enteric infections, long-term use of the proton pump inhibitor (PPI) pantoprazole appears safe in patients with stable atherosclerotic vascular disease, according to a prospective trial involving more than 17,000 participants.

In contrast with published observational studies, the present trial found no associations between long-term PPI use and previously reported risks such as pneumonia, fracture, or cerebrovascular events, according to lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Ont., and colleagues.

“To our knowledge, this is the largest PPI trial for any indication and the first prospective randomized trial to evaluate the many long-term safety concerns related to PPI therapy,” the investigators wrote in Gastroenterology. “It is reassuring that there was no evidence for harm for most of these events other than an excess of enteric infections.”

“Given how commonly acid suppressive medications are used, it is important to ensure that this class of drugs is safe,” the investigators wrote. They noted that patients are often alarmed by “sensational headlines” about PPI safety. “There are balancing articles that more carefully discuss the risks and benefits of taking PPI therapy but these receive less media attention,” the investigators added.

The present, prospective trial, COMPASS, involved 17,598 participants from 33 countries with stable peripheral artery disease and cardiovascular disease. “We use the term participants, rather than patients, as not all of those taking part in this research would have been patients throughout the trial but all participated in the randomized controlled trial,” the investigators wrote.

In addition to evaluating the safety of pantoprazole, the study was initially designed to measure the efficacy of pantoprazole for preventing upper gastrointestinal events in participants taking rivaroxaban and/or aspirin, which, in combination, were recently shown to reduce cardiovascular outcomes among patients with stable cardiovascular conditions. As such, participants in the trial were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or 2.5-mg rivaroxaban twice daily combined with 100-mg aspirin once daily. The primary efficacy outcomes for these three groups were stroke, myocardial infarction, and cardiovascular death. This portion of the trial was discontinued early because of evidence that showed the superiority of combination therapy over aspirin alone; however, the pantoprazole component of the trial continued, as planned, for 3 years.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. Pantoprazole safety outcomes centered on those previously reported by observational studies, including dementia, chronic kidney disease, gastric atrophy, fracture, cancer, pneumonia, diabetes mellitus, chronic obstructive lung disease, Clostrididoides difficile infection, and other enteric infections. Hospitalization rates for noncardiovascular and cardiovascular events were also reported. Data were gathered via questionnaires, which were conducted every 6 months.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking an NSAID (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis of cardiovascular outcomes revealed no significant differences between placebo and pantoprazole groups. Of all the evaluated safety measures, only enteric infections differed significantly between groups, occurring at a higher rate in the pantoprazole group than in the placebo group (1.4% vs. 1.0%; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). Although C. difficile infection was more common among pantoprazole users, only 13 such events occurred, precluding statistical significance.

According to the investigators, these findings should offer reassurance to PPI prescribers and users; they noted that previous findings from observational studies warrant skepticism. “A significant proportion of patients are prescribed PPI therapy inappropriately, and in these cases, it is reasonable to advocate strategies to discontinue acid suppression. However, when there is a clinical need for PPI therapy, these data suggest that the benefits are likely to outweigh any putative risks.”

In regard to the possible increased risk of enteric infection, the investigators again urged a conservative interpretation, as the increased rate of enteric infection among PPI users was still lower than rates reported by systematic reviews. “The data in the current randomized trial were not adjusted for multiple testing so this result should be interpreted with caution,” the investigators wrote. Although acid suppression may allow for increased ingestion of pathogenic organisms, which could theoretically increase the risk of enteric infection, the investigators stated that the benefits of PPIs likely outweigh their risks.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Bayer, Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 29. doi: 10.1053/j.gastro.2019.05.056.

Aside from a possible increased risk of enteric infections, long-term use of the proton pump inhibitor (PPI) pantoprazole appears safe in patients with stable atherosclerotic vascular disease, according to a prospective trial involving more than 17,000 participants.

In contrast with published observational studies, the present trial found no associations between long-term PPI use and previously reported risks such as pneumonia, fracture, or cerebrovascular events, according to lead author Paul Moayyedi, MB ChB, PhD, of McMaster University in Hamilton, Ont., and colleagues.

“To our knowledge, this is the largest PPI trial for any indication and the first prospective randomized trial to evaluate the many long-term safety concerns related to PPI therapy,” the investigators wrote in Gastroenterology. “It is reassuring that there was no evidence for harm for most of these events other than an excess of enteric infections.”

“Given how commonly acid suppressive medications are used, it is important to ensure that this class of drugs is safe,” the investigators wrote. They noted that patients are often alarmed by “sensational headlines” about PPI safety. “There are balancing articles that more carefully discuss the risks and benefits of taking PPI therapy but these receive less media attention,” the investigators added.

The present, prospective trial, COMPASS, involved 17,598 participants from 33 countries with stable peripheral artery disease and cardiovascular disease. “We use the term participants, rather than patients, as not all of those taking part in this research would have been patients throughout the trial but all participated in the randomized controlled trial,” the investigators wrote.

In addition to evaluating the safety of pantoprazole, the study was initially designed to measure the efficacy of pantoprazole for preventing upper gastrointestinal events in participants taking rivaroxaban and/or aspirin, which, in combination, were recently shown to reduce cardiovascular outcomes among patients with stable cardiovascular conditions. As such, participants in the trial were randomized to one of three groups: 100-mg aspirin once daily, 5-mg rivaroxaban twice daily, or 2.5-mg rivaroxaban twice daily combined with 100-mg aspirin once daily. The primary efficacy outcomes for these three groups were stroke, myocardial infarction, and cardiovascular death. This portion of the trial was discontinued early because of evidence that showed the superiority of combination therapy over aspirin alone; however, the pantoprazole component of the trial continued, as planned, for 3 years.

At baseline, about two-thirds of participants (64%) were not taking a PPI, requiring randomization to either 40-mg pantoprazole once daily or matching placebo. Pantoprazole safety outcomes centered on those previously reported by observational studies, including dementia, chronic kidney disease, gastric atrophy, fracture, cancer, pneumonia, diabetes mellitus, chronic obstructive lung disease, Clostrididoides difficile infection, and other enteric infections. Hospitalization rates for noncardiovascular and cardiovascular events were also reported. Data were gathered via questionnaires, which were conducted every 6 months.

Most patients in the trial (78%) were male, and 23% were current smokers. Smaller proportions of the population were taking an NSAID (5%) and/or had a history of peptic ulcer disease (2.6%). The median follow-up was 3.01 years, ranging from 2.49 to 3.59 years. Permanent discontinuations occurred at approximately equal rates in the pantoprazole (21%) and placebo (22%) group after a median of 11 months (338 days). In both groups, more than 96% of participants who continued treatment took their medications as prescribed at least 80% of the time.

Analysis of cardiovascular outcomes revealed no significant differences between placebo and pantoprazole groups. Of all the evaluated safety measures, only enteric infections differed significantly between groups, occurring at a higher rate in the pantoprazole group than in the placebo group (1.4% vs. 1.0%; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). Although C. difficile infection was more common among pantoprazole users, only 13 such events occurred, precluding statistical significance.

According to the investigators, these findings should offer reassurance to PPI prescribers and users; they noted that previous findings from observational studies warrant skepticism. “A significant proportion of patients are prescribed PPI therapy inappropriately, and in these cases, it is reasonable to advocate strategies to discontinue acid suppression. However, when there is a clinical need for PPI therapy, these data suggest that the benefits are likely to outweigh any putative risks.”

In regard to the possible increased risk of enteric infection, the investigators again urged a conservative interpretation, as the increased rate of enteric infection among PPI users was still lower than rates reported by systematic reviews. “The data in the current randomized trial were not adjusted for multiple testing so this result should be interpreted with caution,” the investigators wrote. Although acid suppression may allow for increased ingestion of pathogenic organisms, which could theoretically increase the risk of enteric infection, the investigators stated that the benefits of PPIs likely outweigh their risks.

The COMPASS trial was funded by Bayer AG. The investigators disclosed additional relationships with Bayer, Allergan, Takeda, Janssen, and others.

SOURCE: Moayyedi P et al. Gastro. 2019 May 29. doi: 10.1053/j.gastro.2019.05.056.

Clopidogrel appears to reduce the risk of colorectal cancer (CRC) as much as low-dose aspirin, based on a case-control study involving more than 15,000 cases.

Source: American Gastroenterological Association

Risk of CRC was reduced by 20%-30% when clopidogrel was given alone or in combination with aspirin, reported lead author Antonio Rodríguez-Miguel of Príncipe de Asturias University Hospital in Madrid and colleagues. This finding adds support to the hypothesis that low-dose aspirin is chemoprotective primarily because of its antiplatelet properties, they noted.

“The mechanism of action of low-dose aspirin to explain its protective effect is subject to debate,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Although aspirin is a nonsteroidal anti-inflammatory drug (NSAID) and these drugs are known to prevent CRC through the inhibition of cyclooxygenase (COX)-2 in epithelial and stromal cells in the large bowel, at low doses (75-300 mg/d) aspirin has only transient effects on this isozyme, while permanently inactivating platelet COX-1 and suppressing thromboxane A₂ production. The apparent lack of dose-dependence of the chemoprotective effect of aspirin, as well as the potential role of locally activated platelets in upregulating COX-2 expression in adjacent nucleated cells of the intestinal mucosa, have led [to] the postulation that low-dose aspirin could exert its chemoprotective effect via its antiplatelet action.”

Although previous studies have explored the chemoprotective potential of other antiplatelet agents, such as clopidogrel, the resultant body of evidence remains small. In 2017, for example, Avi Leader, MD, and colleagues reported that the chemoprotective effect of dual-antiplatelet therapy (DAPT) with clopidogrel and aspirin was superior to aspirin monotherapy, based on an additional 8% risk reduction. The present study aimed to build on such findings with evaluation of a Mediterranean cohort, which could reduce confounding lifestyle factors, owing to a lower rate of cardiovascular morbidity than other populations.

The nested, case-control study involved 15,491 cases of CRC and 60,000 controls who were randomly selected and frequency matched by sex, age, and year of indexing. Data were drawn from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish medical record database with more than 7 million patients. Records of patients involved in the present study were screened for prescription of three antiplatelet agents: low-dose aspirin, clopidogrel, and triflusal. Additional categorization identified current users, recent users, past users, and nonusers. The effects of clopidogrel and aspirin were evaluated separately, as monotherapies, and together, as DAPT.

Demographically, the mean age of the entire study population was 68.6 years, with a slight male predominance (59%). Median follow-up was similar between cases and controls, at approximately 3 years, ranging from about 1.5 to 6 years. Cases showed higher rates of gout, alcohol abuse, acute digestive diseases, and peripheral artery disease, whereas controls were more likely to have histories involving stroke, acute myocardial infarction, chronic digestive diseases, and constipation.

Controls were more likely to be current aspirin users than patients diagnosed with CRC (12.8% vs. 12.2%), giving an associated adjusted odds ratio (AOR) of 0.83. Risk reduction became statistically apparent after 180 days of aspirin usage, with an AOR of 0.79, and more prominent in the 1- to 3-year range, with an AOR of 0.73. This chemoprotective effect faded rapidly with discontinuation.

Current clopidogrel usage led to a comparable level of risk reduction, with an AOR of 0.80. It wasn’t until a year of continuous clopidogrel monotherapy that risk reduction became statistically significant, with an AOR of 0.65, which dropped to 0.57 between years 1 and 3.

Turning to a matched comparison of aspirin or clopidogrel monotherapy versus DAPT, the investigators found similar rates of chemoprotection. Current aspirin usage of any duration offered an adjusted risk reduction of 17%, compared with 25% for clopidogrel, and 29% for DAPT. Beyond 1 year of continuous and current usage, the superiority of DAPT was called into question, as clopidogrel monotherapy offered the greatest risk reduction, at 37%, compared with 22% for aspirin, and 22% for DAPT. Risk analyses involving triflusal lacked statistical significance.

“The results of the present study are compatible with a chemoprotective effect of clopidogrel against CRC, equivalent in magnitude to the one observed for low-dose aspirin,” the investigators wrote. “This finding indirectly supports the hypothesis that the chemoprotective effect of low-dose aspirin is mediated mostly through the permanent inactivation of platelet COX-1.”

The investigators pointed out that the chemoprotective effects of antiplatelet therapy begin to appear early in treatment, independently from lifestyle factors, but risk reduction depends on current usage. Although short-term usage of either aspirin or clopidogrel was associated with an increased risk of CRC, the investigators suggested that this was more likely a perceived risk rather than an actual one. “In our view, this observation could be explained in part by a detection bias, owing to an increased risk of GI bleeding induced by antiplatelet agents that could lead to a greater number of colonoscopies, and, as a result, an early cancer diagnosis,” they wrote.

The study was funded by the Fundación Instituto Teófilo Hernando. Dr. García-Rodríguez disclosed a relationship with CEIFE, which has received funding from Bayer and AstraZeneca.

SOURCE: Rodríguez-Miguel et al. Clin Gastrenterol Hepatol. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.012.

Clopidogrel appears to reduce the risk of colorectal cancer (CRC) as much as low-dose aspirin, based on a case-control study involving more than 15,000 cases.

Source: American Gastroenterological Association

Risk of CRC was reduced by 20%-30% when clopidogrel was given alone or in combination with aspirin, reported lead author Antonio Rodríguez-Miguel of Príncipe de Asturias University Hospital in Madrid and colleagues. This finding adds support to the hypothesis that low-dose aspirin is chemoprotective primarily because of its antiplatelet properties, they noted.

“The mechanism of action of low-dose aspirin to explain its protective effect is subject to debate,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Although aspirin is a nonsteroidal anti-inflammatory drug (NSAID) and these drugs are known to prevent CRC through the inhibition of cyclooxygenase (COX)-2 in epithelial and stromal cells in the large bowel, at low doses (75-300 mg/d) aspirin has only transient effects on this isozyme, while permanently inactivating platelet COX-1 and suppressing thromboxane A₂ production. The apparent lack of dose-dependence of the chemoprotective effect of aspirin, as well as the potential role of locally activated platelets in upregulating COX-2 expression in adjacent nucleated cells of the intestinal mucosa, have led [to] the postulation that low-dose aspirin could exert its chemoprotective effect via its antiplatelet action.”

Although previous studies have explored the chemoprotective potential of other antiplatelet agents, such as clopidogrel, the resultant body of evidence remains small. In 2017, for example, Avi Leader, MD, and colleagues reported that the chemoprotective effect of dual-antiplatelet therapy (DAPT) with clopidogrel and aspirin was superior to aspirin monotherapy, based on an additional 8% risk reduction. The present study aimed to build on such findings with evaluation of a Mediterranean cohort, which could reduce confounding lifestyle factors, owing to a lower rate of cardiovascular morbidity than other populations.

The nested, case-control study involved 15,491 cases of CRC and 60,000 controls who were randomly selected and frequency matched by sex, age, and year of indexing. Data were drawn from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish medical record database with more than 7 million patients. Records of patients involved in the present study were screened for prescription of three antiplatelet agents: low-dose aspirin, clopidogrel, and triflusal. Additional categorization identified current users, recent users, past users, and nonusers. The effects of clopidogrel and aspirin were evaluated separately, as monotherapies, and together, as DAPT.

Demographically, the mean age of the entire study population was 68.6 years, with a slight male predominance (59%). Median follow-up was similar between cases and controls, at approximately 3 years, ranging from about 1.5 to 6 years. Cases showed higher rates of gout, alcohol abuse, acute digestive diseases, and peripheral artery disease, whereas controls were more likely to have histories involving stroke, acute myocardial infarction, chronic digestive diseases, and constipation.

Controls were more likely to be current aspirin users than patients diagnosed with CRC (12.8% vs. 12.2%), giving an associated adjusted odds ratio (AOR) of 0.83. Risk reduction became statistically apparent after 180 days of aspirin usage, with an AOR of 0.79, and more prominent in the 1- to 3-year range, with an AOR of 0.73. This chemoprotective effect faded rapidly with discontinuation.

Current clopidogrel usage led to a comparable level of risk reduction, with an AOR of 0.80. It wasn’t until a year of continuous clopidogrel monotherapy that risk reduction became statistically significant, with an AOR of 0.65, which dropped to 0.57 between years 1 and 3.

Turning to a matched comparison of aspirin or clopidogrel monotherapy versus DAPT, the investigators found similar rates of chemoprotection. Current aspirin usage of any duration offered an adjusted risk reduction of 17%, compared with 25% for clopidogrel, and 29% for DAPT. Beyond 1 year of continuous and current usage, the superiority of DAPT was called into question, as clopidogrel monotherapy offered the greatest risk reduction, at 37%, compared with 22% for aspirin, and 22% for DAPT. Risk analyses involving triflusal lacked statistical significance.

“The results of the present study are compatible with a chemoprotective effect of clopidogrel against CRC, equivalent in magnitude to the one observed for low-dose aspirin,” the investigators wrote. “This finding indirectly supports the hypothesis that the chemoprotective effect of low-dose aspirin is mediated mostly through the permanent inactivation of platelet COX-1.”

The investigators pointed out that the chemoprotective effects of antiplatelet therapy begin to appear early in treatment, independently from lifestyle factors, but risk reduction depends on current usage. Although short-term usage of either aspirin or clopidogrel was associated with an increased risk of CRC, the investigators suggested that this was more likely a perceived risk rather than an actual one. “In our view, this observation could be explained in part by a detection bias, owing to an increased risk of GI bleeding induced by antiplatelet agents that could lead to a greater number of colonoscopies, and, as a result, an early cancer diagnosis,” they wrote.

The study was funded by the Fundación Instituto Teófilo Hernando. Dr. García-Rodríguez disclosed a relationship with CEIFE, which has received funding from Bayer and AstraZeneca.

SOURCE: Rodríguez-Miguel et al. Clin Gastrenterol Hepatol. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.012.

Clopidogrel appears to reduce the risk of colorectal cancer (CRC) as much as low-dose aspirin, based on a case-control study involving more than 15,000 cases.

Source: American Gastroenterological Association

Risk of CRC was reduced by 20%-30% when clopidogrel was given alone or in combination with aspirin, reported lead author Antonio Rodríguez-Miguel of Príncipe de Asturias University Hospital in Madrid and colleagues. This finding adds support to the hypothesis that low-dose aspirin is chemoprotective primarily because of its antiplatelet properties, they noted.

“The mechanism of action of low-dose aspirin to explain its protective effect is subject to debate,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Although aspirin is a nonsteroidal anti-inflammatory drug (NSAID) and these drugs are known to prevent CRC through the inhibition of cyclooxygenase (COX)-2 in epithelial and stromal cells in the large bowel, at low doses (75-300 mg/d) aspirin has only transient effects on this isozyme, while permanently inactivating platelet COX-1 and suppressing thromboxane A₂ production. The apparent lack of dose-dependence of the chemoprotective effect of aspirin, as well as the potential role of locally activated platelets in upregulating COX-2 expression in adjacent nucleated cells of the intestinal mucosa, have led [to] the postulation that low-dose aspirin could exert its chemoprotective effect via its antiplatelet action.”

Although previous studies have explored the chemoprotective potential of other antiplatelet agents, such as clopidogrel, the resultant body of evidence remains small. In 2017, for example, Avi Leader, MD, and colleagues reported that the chemoprotective effect of dual-antiplatelet therapy (DAPT) with clopidogrel and aspirin was superior to aspirin monotherapy, based on an additional 8% risk reduction. The present study aimed to build on such findings with evaluation of a Mediterranean cohort, which could reduce confounding lifestyle factors, owing to a lower rate of cardiovascular morbidity than other populations.

The nested, case-control study involved 15,491 cases of CRC and 60,000 controls who were randomly selected and frequency matched by sex, age, and year of indexing. Data were drawn from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish medical record database with more than 7 million patients. Records of patients involved in the present study were screened for prescription of three antiplatelet agents: low-dose aspirin, clopidogrel, and triflusal. Additional categorization identified current users, recent users, past users, and nonusers. The effects of clopidogrel and aspirin were evaluated separately, as monotherapies, and together, as DAPT.

Demographically, the mean age of the entire study population was 68.6 years, with a slight male predominance (59%). Median follow-up was similar between cases and controls, at approximately 3 years, ranging from about 1.5 to 6 years. Cases showed higher rates of gout, alcohol abuse, acute digestive diseases, and peripheral artery disease, whereas controls were more likely to have histories involving stroke, acute myocardial infarction, chronic digestive diseases, and constipation.

Controls were more likely to be current aspirin users than patients diagnosed with CRC (12.8% vs. 12.2%), giving an associated adjusted odds ratio (AOR) of 0.83. Risk reduction became statistically apparent after 180 days of aspirin usage, with an AOR of 0.79, and more prominent in the 1- to 3-year range, with an AOR of 0.73. This chemoprotective effect faded rapidly with discontinuation.

Current clopidogrel usage led to a comparable level of risk reduction, with an AOR of 0.80. It wasn’t until a year of continuous clopidogrel monotherapy that risk reduction became statistically significant, with an AOR of 0.65, which dropped to 0.57 between years 1 and 3.

Turning to a matched comparison of aspirin or clopidogrel monotherapy versus DAPT, the investigators found similar rates of chemoprotection. Current aspirin usage of any duration offered an adjusted risk reduction of 17%, compared with 25% for clopidogrel, and 29% for DAPT. Beyond 1 year of continuous and current usage, the superiority of DAPT was called into question, as clopidogrel monotherapy offered the greatest risk reduction, at 37%, compared with 22% for aspirin, and 22% for DAPT. Risk analyses involving triflusal lacked statistical significance.

“The results of the present study are compatible with a chemoprotective effect of clopidogrel against CRC, equivalent in magnitude to the one observed for low-dose aspirin,” the investigators wrote. “This finding indirectly supports the hypothesis that the chemoprotective effect of low-dose aspirin is mediated mostly through the permanent inactivation of platelet COX-1.”

The investigators pointed out that the chemoprotective effects of antiplatelet therapy begin to appear early in treatment, independently from lifestyle factors, but risk reduction depends on current usage. Although short-term usage of either aspirin or clopidogrel was associated with an increased risk of CRC, the investigators suggested that this was more likely a perceived risk rather than an actual one. “In our view, this observation could be explained in part by a detection bias, owing to an increased risk of GI bleeding induced by antiplatelet agents that could lead to a greater number of colonoscopies, and, as a result, an early cancer diagnosis,” they wrote.

The study was funded by the Fundación Instituto Teófilo Hernando. Dr. García-Rodríguez disclosed a relationship with CEIFE, which has received funding from Bayer and AstraZeneca.

SOURCE: Rodríguez-Miguel et al. Clin Gastrenterol Hepatol. 2018 Dec 20. doi: 10.1016/j.cgh.2018.12.012.