Click here to read the supplement. 

Learn about the latest research on the development of the skin microbiome in infancy (including the neonatal period), the essential role of a healthy skin microbiome, and practical advice for patients.

Click here to read the supplement. 

Learn about the latest research on the development of the skin microbiome in infancy (including the neonatal period), the essential role of a healthy skin microbiome, and practical advice for patients.

Click here to read the supplement. 

Learn about the latest research on the development of the skin microbiome in infancy (including the neonatal period), the essential role of a healthy skin microbiome, and practical advice for patients.

CASE Patient with early pregnancy failure opts for surgical management

A 36-year-old woman (G3P2) at 9 weeks from her last menstrual period presents for an initial obstetric examination. On transvaginal ultrasound, her ObGyn notes an embryo measuring 9 weeks without cardiac activity. The ObGyn informs her of the early pregnancy failure diagnosis and offers bereavement support, and then reviews the available options: expectant management with follow-up in 2 weeks, medical management with mifepristone and misoprostol, and surgical management with a dilation and curettage (D&C). The patient is interested in expedited treatment and thus selects D&C, and the staff books the next available operating room (OR) slot for her the subsequent week. Over the weekend, the patient calls to report heavy bleeding and passage of clots, and the ObGyn’s practice partner takes her to the OR for a D&C for incomplete abortion.

Early pregnancy failure occurs in about 1 in 5 pregnancies. Treatment options include expectant, medical, or surgical management. Surgical management is classically offered in the OR via D&C. With the advent of manual vacuum aspiration (MVA) using a 60-mL handheld syringe aspirator, office-based treatment of pregnancy failure has become more widely available.

In this article we make the case for why, in appropriate clinical situations, office-based uterine aspiration, compared with uterine aspiration in the OR, should be the standard for surgical management of early pregnancy failure, for these reasons:

1. equivalent safety profile

2. reduced costs, and 

3. patient-centered characteristics.

1 Office-based procedures are safe

Suction curettage is one of the most common surgical procedures for a woman to undergo during her lifetime, and it has an excellent safety profile. Authors of a recent systematic review found that major surgical complications, including transfusion and uterine perforation requiring repair, occurred in less than 0.1% of all uterine aspiration procedures.¹ Importantly, this complication rate did not differ by inpatient or outpatient site of procedure.

Anesthesia-related complications at the time of aspiration also are extremely rare, and they are less likely to occur in the office setting than in surgical centers or hospital-based clinics (<0.2% and <0.5%, respectively).¹ This may be a result of the types of anesthesia offered at varying locations, given that local analgesia or moderate sedation is likely used in office-based procedures while deep sedation or general anesthesia may be employed at other practice locations.

Studies specifically designed to determine the safety of suction aspiration by practice location have yielded similar results. Researchers who conducted a systematic review comparing the safety of procedures done at ambulatory surgical centers with office-based procedures found no difference in safety between procedures performed in these 2 settings.² These findings were confirmed by results from a large retrospective cohort study that reviewed more than 50,000 aspiration procedures performed in ambulatory surgical centers versus private offices.³ In that study, only 0.32% of women had any major adverse event, and there were no statistically significant differences in complication rates between settings.³

Complication rates based on procedure type are similar for MVA and electric suction aspiration. Early studies revealed no difference in the need for reaspiration or other complications for MVA compared with electric suction.⁴ This was later confirmed by a systematic review that found no significant differences in safety by type of suction overall, and a possible trend toward fewer uterine perforations with MVA.⁵ When procedures were assessed by gestational age, additional trends toward the safety of MVA emerged. For example, in procedures performed at less than 50 days’ gestational age, estimated blood loss and severe pain occurred less commonly during procedures performed using MVA.⁵

Continue to: 2 Office-based procedures are less expensive

2 Office-based procedures are less expensive

There has been a trend in recent decades to obtain cost savings by moving appropriately selected gynecologic procedures from the operative suite to the outpatient setting. Because of MVA’s minimal up-front and ongoing costs, office-based suction aspiration is one of the most cost-effective procedures performed in the outpatient setting.

Dalton and colleagues, for example, demonstrated that in women diagnosed with early pregnancy failure, suction curettage is 50% less expensive when performed in the office as compared to in the operating suite.⁶ Likewise, in a cohort of patients who presented to the emergency department with an incomplete abortion, Blumenthal and colleagues showed a 41% procedural cost reduction by offering D&C in the outpatient setting instead of the OR.⁷ Waiting times and mean procedure times also were reduced by nearly half.

Recent studies have broadened cost analyses beyond the comparison of inpatient versus outpatient procedures. A multicenter trial of women with first-trimester pregnancy failure compared the costs of medication management with those of surgical procedures; as expected, the cost of D&C in the OR was significantly more expensive than medication management.⁸ However, MVA in the office was less expensive than medication management, due largely to the increased cost of managing medication failures.

In addition, a recent, well-designed decision model study demonstrated that offering women with early pregnancy failure a greater array of management options decreases costs.⁹ The study compared the costs when women were offered the most common options, expectant management or uterine evacuation in the OR, versus the costs when additional options were also offered. When options were expanded to include medication management and MVA in the office, costs decreased by nearly 20% overall.⁹

3 Office-based procedures are more patient centered

The benefits of surgical management of an early pregnancy failure include very high success rates (98%) and convenient timing. Among women who elect surgical management, a desire to expedite the process in a predictable fashion is a common factor in their decision.^10,11 It is unsurprising then that 68% of patients will select an office-based procedure if they do not perceive that the clinician has a setting preference.⁶

When surgical management is performed in the OR, scheduling delays are common. Such delays can be clinically important: Women progressing to a miscarriage while awaiting surgical treatment may be at risk for urgent, unplanned interval procedures for incomplete abortion, and they may be dissatisfied with the inability to access the desired management. While women are highly satisfied after treatment for early pregnancy failure in general,⁶ OR treatment can cause dissatisfaction because patients miss more work days or need assistance at home.¹² In a cross-sectional study, patients who elected office-based aspiration reported less delay to treatment (less than 2 hours) compared with women who elected OR procedures (more than 12 hours), and shorter time to procedure initiation was a satisfier.¹³

Women also note fear of the hospital setting and general anesthesia, and they tend to see hospital-based services as more invasive.¹¹ Clinicians can offer anesthesia in the outpatient setting with nonsteroidal anti-inflammatory medications and a paracervical block, oral sedation with an anxiolytic, or in some cases intravenous (IV) sedation with conscious sedation.

Continue to: Our process for office-based uterine aspiration

Our process for office-based uterine aspiration

We follow the step-by-step process outlined below for performing office-based uterine aspiration. Clinicians should review their clinic’s protocols prior to implementing such a plan.

Review the patient history and pregnancy dating. Patients with serious medical conditions, such as history of postabortion hemorrhage or a bleeding disorder, may not be appropriate candidates for an office-based procedure. We perform bedside ultrasonography to confirm pregnancy dating and diagnosis of pregnancy failure.

Review consent for the procedure and sedation. Risks of office-based uterine aspiration are the same as those for D&C: bleeding, uterine perforation, and failure to fully evacuate the uterus. Benefits include rapid, safe evacuation of the pregnancy. Alternative treatments include expectant or medical management.

For pain management, we start by discussing expectations with the patient. Providing general anesthesia in the outpatient setting is not safe; many women are satisfied, however, with local anesthesia with or without sedation.

Local anesthesia may be given using a paracervical block with 2 mL of 1% lidocaine at the tenaculum site followed by 18 mL divided between the 4 and 8 o’clock positions. In our practice, we are trained providers of conscious sedation, so additionally we offer IV fentanyl 100 μg and IV midazolam 2 mg given prior to the procedure.

Provide antibiotic prophylaxis. The American College of Obstetricians and Gynecologists and the Society for Family Planning recommend doxycycline 200 mg orally as a preoperative prophylaxis for office-based uterine aspiration.^14,15 Metronidazole is an acceptable alternative for patients who have medication allergies.

Prepare the surgical field. To complete this procedure, you will need the following equipment:

• one MVA kit that includes an aspirator, curettes, and dilators (FIGURE)
• 20 mL 1% lidocaine, divided into two 10-mL syringes with a 22-gauge 3.5-inch spinal needle
• speculum
• cervical antiseptic prep
• single-tooth tenaculum
• ring forceps.

Perform the MVA procedure. A full description of how to perform the MVA procedure using the Ipas MVA Plus Aspirator device is available online at http://provideaccess.org/wp-content/uploads/2012/09/4Performing-MVA-Us ing-the-Ipas-MVA-Plus.pdf.

A good option for many women

A D&C in the OR remains an appropriate option for patients who are clinically unstable due to heavy vaginal bleeding. With highly sensitive home urine pregnancy tests, pregnancies often are diagnosed before clinically apparent miscarriage. In fact, many such patients are diagnosed with pregnancy failure in the office, as was our patient in the case scenario. For such women, office-based management of early pregnancy failure is preferred because it is safe, cost-effective, and patient centered.

CASE Patient with early pregnancy failure opts for surgical management

A 36-year-old woman (G3P2) at 9 weeks from her last menstrual period presents for an initial obstetric examination. On transvaginal ultrasound, her ObGyn notes an embryo measuring 9 weeks without cardiac activity. The ObGyn informs her of the early pregnancy failure diagnosis and offers bereavement support, and then reviews the available options: expectant management with follow-up in 2 weeks, medical management with mifepristone and misoprostol, and surgical management with a dilation and curettage (D&C). The patient is interested in expedited treatment and thus selects D&C, and the staff books the next available operating room (OR) slot for her the subsequent week. Over the weekend, the patient calls to report heavy bleeding and passage of clots, and the ObGyn’s practice partner takes her to the OR for a D&C for incomplete abortion.

Early pregnancy failure occurs in about 1 in 5 pregnancies. Treatment options include expectant, medical, or surgical management. Surgical management is classically offered in the OR via D&C. With the advent of manual vacuum aspiration (MVA) using a 60-mL handheld syringe aspirator, office-based treatment of pregnancy failure has become more widely available.

In this article we make the case for why, in appropriate clinical situations, office-based uterine aspiration, compared with uterine aspiration in the OR, should be the standard for surgical management of early pregnancy failure, for these reasons:

1. equivalent safety profile

2. reduced costs, and 

3. patient-centered characteristics.

1 Office-based procedures are safe

Suction curettage is one of the most common surgical procedures for a woman to undergo during her lifetime, and it has an excellent safety profile. Authors of a recent systematic review found that major surgical complications, including transfusion and uterine perforation requiring repair, occurred in less than 0.1% of all uterine aspiration procedures.¹ Importantly, this complication rate did not differ by inpatient or outpatient site of procedure.

Anesthesia-related complications at the time of aspiration also are extremely rare, and they are less likely to occur in the office setting than in surgical centers or hospital-based clinics (<0.2% and <0.5%, respectively).¹ This may be a result of the types of anesthesia offered at varying locations, given that local analgesia or moderate sedation is likely used in office-based procedures while deep sedation or general anesthesia may be employed at other practice locations.

Studies specifically designed to determine the safety of suction aspiration by practice location have yielded similar results. Researchers who conducted a systematic review comparing the safety of procedures done at ambulatory surgical centers with office-based procedures found no difference in safety between procedures performed in these 2 settings.² These findings were confirmed by results from a large retrospective cohort study that reviewed more than 50,000 aspiration procedures performed in ambulatory surgical centers versus private offices.³ In that study, only 0.32% of women had any major adverse event, and there were no statistically significant differences in complication rates between settings.³

Complication rates based on procedure type are similar for MVA and electric suction aspiration. Early studies revealed no difference in the need for reaspiration or other complications for MVA compared with electric suction.⁴ This was later confirmed by a systematic review that found no significant differences in safety by type of suction overall, and a possible trend toward fewer uterine perforations with MVA.⁵ When procedures were assessed by gestational age, additional trends toward the safety of MVA emerged. For example, in procedures performed at less than 50 days’ gestational age, estimated blood loss and severe pain occurred less commonly during procedures performed using MVA.⁵

Continue to: 2 Office-based procedures are less expensive

2 Office-based procedures are less expensive

There has been a trend in recent decades to obtain cost savings by moving appropriately selected gynecologic procedures from the operative suite to the outpatient setting. Because of MVA’s minimal up-front and ongoing costs, office-based suction aspiration is one of the most cost-effective procedures performed in the outpatient setting.

Dalton and colleagues, for example, demonstrated that in women diagnosed with early pregnancy failure, suction curettage is 50% less expensive when performed in the office as compared to in the operating suite.⁶ Likewise, in a cohort of patients who presented to the emergency department with an incomplete abortion, Blumenthal and colleagues showed a 41% procedural cost reduction by offering D&C in the outpatient setting instead of the OR.⁷ Waiting times and mean procedure times also were reduced by nearly half.

Recent studies have broadened cost analyses beyond the comparison of inpatient versus outpatient procedures. A multicenter trial of women with first-trimester pregnancy failure compared the costs of medication management with those of surgical procedures; as expected, the cost of D&C in the OR was significantly more expensive than medication management.⁸ However, MVA in the office was less expensive than medication management, due largely to the increased cost of managing medication failures.

In addition, a recent, well-designed decision model study demonstrated that offering women with early pregnancy failure a greater array of management options decreases costs.⁹ The study compared the costs when women were offered the most common options, expectant management or uterine evacuation in the OR, versus the costs when additional options were also offered. When options were expanded to include medication management and MVA in the office, costs decreased by nearly 20% overall.⁹

3 Office-based procedures are more patient centered

The benefits of surgical management of an early pregnancy failure include very high success rates (98%) and convenient timing. Among women who elect surgical management, a desire to expedite the process in a predictable fashion is a common factor in their decision.^10,11 It is unsurprising then that 68% of patients will select an office-based procedure if they do not perceive that the clinician has a setting preference.⁶

When surgical management is performed in the OR, scheduling delays are common. Such delays can be clinically important: Women progressing to a miscarriage while awaiting surgical treatment may be at risk for urgent, unplanned interval procedures for incomplete abortion, and they may be dissatisfied with the inability to access the desired management. While women are highly satisfied after treatment for early pregnancy failure in general,⁶ OR treatment can cause dissatisfaction because patients miss more work days or need assistance at home.¹² In a cross-sectional study, patients who elected office-based aspiration reported less delay to treatment (less than 2 hours) compared with women who elected OR procedures (more than 12 hours), and shorter time to procedure initiation was a satisfier.¹³

Women also note fear of the hospital setting and general anesthesia, and they tend to see hospital-based services as more invasive.¹¹ Clinicians can offer anesthesia in the outpatient setting with nonsteroidal anti-inflammatory medications and a paracervical block, oral sedation with an anxiolytic, or in some cases intravenous (IV) sedation with conscious sedation.

Continue to: Our process for office-based uterine aspiration

Our process for office-based uterine aspiration

We follow the step-by-step process outlined below for performing office-based uterine aspiration. Clinicians should review their clinic’s protocols prior to implementing such a plan.

Review the patient history and pregnancy dating. Patients with serious medical conditions, such as history of postabortion hemorrhage or a bleeding disorder, may not be appropriate candidates for an office-based procedure. We perform bedside ultrasonography to confirm pregnancy dating and diagnosis of pregnancy failure.

Review consent for the procedure and sedation. Risks of office-based uterine aspiration are the same as those for D&C: bleeding, uterine perforation, and failure to fully evacuate the uterus. Benefits include rapid, safe evacuation of the pregnancy. Alternative treatments include expectant or medical management.

For pain management, we start by discussing expectations with the patient. Providing general anesthesia in the outpatient setting is not safe; many women are satisfied, however, with local anesthesia with or without sedation.

Local anesthesia may be given using a paracervical block with 2 mL of 1% lidocaine at the tenaculum site followed by 18 mL divided between the 4 and 8 o’clock positions. In our practice, we are trained providers of conscious sedation, so additionally we offer IV fentanyl 100 μg and IV midazolam 2 mg given prior to the procedure.

Provide antibiotic prophylaxis. The American College of Obstetricians and Gynecologists and the Society for Family Planning recommend doxycycline 200 mg orally as a preoperative prophylaxis for office-based uterine aspiration.^14,15 Metronidazole is an acceptable alternative for patients who have medication allergies.

Prepare the surgical field. To complete this procedure, you will need the following equipment:

• one MVA kit that includes an aspirator, curettes, and dilators (FIGURE)
• 20 mL 1% lidocaine, divided into two 10-mL syringes with a 22-gauge 3.5-inch spinal needle
• speculum
• cervical antiseptic prep
• single-tooth tenaculum
• ring forceps.

Perform the MVA procedure. A full description of how to perform the MVA procedure using the Ipas MVA Plus Aspirator device is available online at http://provideaccess.org/wp-content/uploads/2012/09/4Performing-MVA-Us ing-the-Ipas-MVA-Plus.pdf.

A good option for many women

A D&C in the OR remains an appropriate option for patients who are clinically unstable due to heavy vaginal bleeding. With highly sensitive home urine pregnancy tests, pregnancies often are diagnosed before clinically apparent miscarriage. In fact, many such patients are diagnosed with pregnancy failure in the office, as was our patient in the case scenario. For such women, office-based management of early pregnancy failure is preferred because it is safe, cost-effective, and patient centered.

CASE Patient with early pregnancy failure opts for surgical management

A 36-year-old woman (G3P2) at 9 weeks from her last menstrual period presents for an initial obstetric examination. On transvaginal ultrasound, her ObGyn notes an embryo measuring 9 weeks without cardiac activity. The ObGyn informs her of the early pregnancy failure diagnosis and offers bereavement support, and then reviews the available options: expectant management with follow-up in 2 weeks, medical management with mifepristone and misoprostol, and surgical management with a dilation and curettage (D&C). The patient is interested in expedited treatment and thus selects D&C, and the staff books the next available operating room (OR) slot for her the subsequent week. Over the weekend, the patient calls to report heavy bleeding and passage of clots, and the ObGyn’s practice partner takes her to the OR for a D&C for incomplete abortion.

Early pregnancy failure occurs in about 1 in 5 pregnancies. Treatment options include expectant, medical, or surgical management. Surgical management is classically offered in the OR via D&C. With the advent of manual vacuum aspiration (MVA) using a 60-mL handheld syringe aspirator, office-based treatment of pregnancy failure has become more widely available.

In this article we make the case for why, in appropriate clinical situations, office-based uterine aspiration, compared with uterine aspiration in the OR, should be the standard for surgical management of early pregnancy failure, for these reasons:

1. equivalent safety profile

2. reduced costs, and 

3. patient-centered characteristics.

1 Office-based procedures are safe

Suction curettage is one of the most common surgical procedures for a woman to undergo during her lifetime, and it has an excellent safety profile. Authors of a recent systematic review found that major surgical complications, including transfusion and uterine perforation requiring repair, occurred in less than 0.1% of all uterine aspiration procedures.¹ Importantly, this complication rate did not differ by inpatient or outpatient site of procedure.

Anesthesia-related complications at the time of aspiration also are extremely rare, and they are less likely to occur in the office setting than in surgical centers or hospital-based clinics (<0.2% and <0.5%, respectively).¹ This may be a result of the types of anesthesia offered at varying locations, given that local analgesia or moderate sedation is likely used in office-based procedures while deep sedation or general anesthesia may be employed at other practice locations.

Studies specifically designed to determine the safety of suction aspiration by practice location have yielded similar results. Researchers who conducted a systematic review comparing the safety of procedures done at ambulatory surgical centers with office-based procedures found no difference in safety between procedures performed in these 2 settings.² These findings were confirmed by results from a large retrospective cohort study that reviewed more than 50,000 aspiration procedures performed in ambulatory surgical centers versus private offices.³ In that study, only 0.32% of women had any major adverse event, and there were no statistically significant differences in complication rates between settings.³

Complication rates based on procedure type are similar for MVA and electric suction aspiration. Early studies revealed no difference in the need for reaspiration or other complications for MVA compared with electric suction.⁴ This was later confirmed by a systematic review that found no significant differences in safety by type of suction overall, and a possible trend toward fewer uterine perforations with MVA.⁵ When procedures were assessed by gestational age, additional trends toward the safety of MVA emerged. For example, in procedures performed at less than 50 days’ gestational age, estimated blood loss and severe pain occurred less commonly during procedures performed using MVA.⁵

Continue to: 2 Office-based procedures are less expensive

2 Office-based procedures are less expensive

There has been a trend in recent decades to obtain cost savings by moving appropriately selected gynecologic procedures from the operative suite to the outpatient setting. Because of MVA’s minimal up-front and ongoing costs, office-based suction aspiration is one of the most cost-effective procedures performed in the outpatient setting.

Dalton and colleagues, for example, demonstrated that in women diagnosed with early pregnancy failure, suction curettage is 50% less expensive when performed in the office as compared to in the operating suite.⁶ Likewise, in a cohort of patients who presented to the emergency department with an incomplete abortion, Blumenthal and colleagues showed a 41% procedural cost reduction by offering D&C in the outpatient setting instead of the OR.⁷ Waiting times and mean procedure times also were reduced by nearly half.

Recent studies have broadened cost analyses beyond the comparison of inpatient versus outpatient procedures. A multicenter trial of women with first-trimester pregnancy failure compared the costs of medication management with those of surgical procedures; as expected, the cost of D&C in the OR was significantly more expensive than medication management.⁸ However, MVA in the office was less expensive than medication management, due largely to the increased cost of managing medication failures.

In addition, a recent, well-designed decision model study demonstrated that offering women with early pregnancy failure a greater array of management options decreases costs.⁹ The study compared the costs when women were offered the most common options, expectant management or uterine evacuation in the OR, versus the costs when additional options were also offered. When options were expanded to include medication management and MVA in the office, costs decreased by nearly 20% overall.⁹

3 Office-based procedures are more patient centered

The benefits of surgical management of an early pregnancy failure include very high success rates (98%) and convenient timing. Among women who elect surgical management, a desire to expedite the process in a predictable fashion is a common factor in their decision.^10,11 It is unsurprising then that 68% of patients will select an office-based procedure if they do not perceive that the clinician has a setting preference.⁶

When surgical management is performed in the OR, scheduling delays are common. Such delays can be clinically important: Women progressing to a miscarriage while awaiting surgical treatment may be at risk for urgent, unplanned interval procedures for incomplete abortion, and they may be dissatisfied with the inability to access the desired management. While women are highly satisfied after treatment for early pregnancy failure in general,⁶ OR treatment can cause dissatisfaction because patients miss more work days or need assistance at home.¹² In a cross-sectional study, patients who elected office-based aspiration reported less delay to treatment (less than 2 hours) compared with women who elected OR procedures (more than 12 hours), and shorter time to procedure initiation was a satisfier.¹³

Women also note fear of the hospital setting and general anesthesia, and they tend to see hospital-based services as more invasive.¹¹ Clinicians can offer anesthesia in the outpatient setting with nonsteroidal anti-inflammatory medications and a paracervical block, oral sedation with an anxiolytic, or in some cases intravenous (IV) sedation with conscious sedation.

Continue to: Our process for office-based uterine aspiration

Our process for office-based uterine aspiration

We follow the step-by-step process outlined below for performing office-based uterine aspiration. Clinicians should review their clinic’s protocols prior to implementing such a plan.

Review the patient history and pregnancy dating. Patients with serious medical conditions, such as history of postabortion hemorrhage or a bleeding disorder, may not be appropriate candidates for an office-based procedure. We perform bedside ultrasonography to confirm pregnancy dating and diagnosis of pregnancy failure.

Review consent for the procedure and sedation. Risks of office-based uterine aspiration are the same as those for D&C: bleeding, uterine perforation, and failure to fully evacuate the uterus. Benefits include rapid, safe evacuation of the pregnancy. Alternative treatments include expectant or medical management.

For pain management, we start by discussing expectations with the patient. Providing general anesthesia in the outpatient setting is not safe; many women are satisfied, however, with local anesthesia with or without sedation.

Local anesthesia may be given using a paracervical block with 2 mL of 1% lidocaine at the tenaculum site followed by 18 mL divided between the 4 and 8 o’clock positions. In our practice, we are trained providers of conscious sedation, so additionally we offer IV fentanyl 100 μg and IV midazolam 2 mg given prior to the procedure.

Provide antibiotic prophylaxis. The American College of Obstetricians and Gynecologists and the Society for Family Planning recommend doxycycline 200 mg orally as a preoperative prophylaxis for office-based uterine aspiration.^14,15 Metronidazole is an acceptable alternative for patients who have medication allergies.

Prepare the surgical field. To complete this procedure, you will need the following equipment:

• one MVA kit that includes an aspirator, curettes, and dilators (FIGURE)
• 20 mL 1% lidocaine, divided into two 10-mL syringes with a 22-gauge 3.5-inch spinal needle
• speculum
• cervical antiseptic prep
• single-tooth tenaculum
• ring forceps.

Perform the MVA procedure. A full description of how to perform the MVA procedure using the Ipas MVA Plus Aspirator device is available online at http://provideaccess.org/wp-content/uploads/2012/09/4Performing-MVA-Us ing-the-Ipas-MVA-Plus.pdf.

A good option for many women

A D&C in the OR remains an appropriate option for patients who are clinically unstable due to heavy vaginal bleeding. With highly sensitive home urine pregnancy tests, pregnancies often are diagnosed before clinically apparent miscarriage. In fact, many such patients are diagnosed with pregnancy failure in the office, as was our patient in the case scenario. For such women, office-based management of early pregnancy failure is preferred because it is safe, cost-effective, and patient centered.

Most people know that preterm birth is a major contributor to perinatal morbidity and mortality. Consequently, strict guidelines have been enforced to prevent non–medically indicated scheduled deliveries before 39 weeks’ gestation. Fewer people recognize that late-term birth is also an important and avoidable contributor to perinatal morbidity. To improve pregnancy outcomes, we may need enhanced guidelines about minimizing expectant management of pregnancy beyond 41 weeks’ gestation.

For the fetus, what is the optimal duration of a healthy pregnancy?

When pregnancy progresses past the date of the confinement, the risk of fetal or newborn injury or death increases, especially after 41 weeks’ gestation. Analysis of this risk, day by day, suggests that after 40 weeks’ and 3 days’ gestation there is no medical benefit to the fetus to remain in utero because, compared with induced delivery, expectant management of the pregnancy is associated with a greater rate of fetal and newborn morbidity and mortality.¹

The fetal and newborn benefits of delivery, rather than expectant management, at term include: a decrease in stillbirth and perinatal death rates, a decrease in admissions to the neonatal intensive care unit (NICU), a decrease in meconium-stained amniotic fluid and meconium aspiration syndrome, a decrease in low Apgar scores, and a decrease in problems related to uteroplacental insufficiency, including oligohydramnios.² In a comprehensive meta-analysis, induction of labor at or beyond term reduced the risk of perinatal death or stillbirth by 67%, the risk of a 5-minute Apgar score below 7 by 30%, and the risk of NICU admission by 12%.² The number of women that would need to be induced to prevent 1 perinatal death was estimated to be 426.²

Maternal benefits of avoiding late-term pregnancy

The maternal benefits of avoiding continuing a pregnancy past 41 weeks’ gestation include a reduction in labor dystocia and the risk of cesarean delivery (CD).^2,3 In one clinical trial, 3,407 women with low-risk pregnancy were randomly assigned to induction of labor at 41 weeks’ gestation or expectant management, awaiting the onset of labor with serial antenatal monitoring (nonstress tests and assessment of amniotic fluid volume).⁴ The CD rate was lower among the women randomized to induction of labor at 41 weeks’ (21.2% vs 24.5% in the expectant management group, P = .03). The rate of meconium-stained fluid was lower in the induction of labor group (25.0% vs 28.7%, P = .009). The rate of CD due to fetal distress also was lower in the induction of labor group (5.7% vs 8.3%, P = .003). The risks of maternal postpartum hemorrhage, sepsis, and endometritis did not differ between the groups. There were 2 stillbirths in the expectant management group (2/1,706) and none in the induction of labor group (0/1,701). There were no neonatal deaths in this study.⁴

Obstetric management, including accurate dating of pregnancy and membrane sweeping at term, can help to reduce the risk that a pregnancy will progress beyond 41 weeks’ gestation.⁵

Continue to: Routinely use ultrasound to accurately establish gestational age

Routinely use ultrasound to accurately establish gestational age

First trimester ultrasound should be offered to all pregnant women because it is a more accurate assessment of gestational age and will result in fewer pregnancies that are thought to be at or beyond 41 weeks’ gestation.⁵ In a meta-analysis of 8 studies, including 25,516 women, early ultrasonography reduced the rate of intervention for postterm pregnancy by 42% (31/1,000 to 18/1,000 pregnant women).⁶

Membrane sweeping (or stripping)

Membrane sweeping, which causes the release of prostaglandins, has been reported to reduce the risk of late-term and postterm induction of labor.^7,8 In the most recent Cochrane review on the topic, sweeping membranes reduced the rate of induction of labor at 41 weeks by 41% and at 42 weeks by 72%.⁷ To avoid one induction of labor for late-term or postterm pregnancy, sweeping of membranes would need to be performed on 8 women. In a recent meta-analysis, membrane sweeping reduced the rate of induction of labor for postmaturity by 48%.⁹

Membrane sweeping is associated with pain and an increased rate of vaginal bleeding.¹⁰ It does not increase the rate of maternal or neonatal infection, however. It also does not reduce the CD rate. In the United Kingdom, the National Institute for Health and Clinical Excellence recommends that all clinicians have a discussion of membrane sweeping with their patients at 38 weeks’ gestation and offer membrane stripping at 40 weeks to increase the rate of timely spontaneous labor and to avoid the risks of prolonged pregnancy.¹¹ Of note, in one randomized study of women planning a trial of labor after CD, membrane sweeping did not impact the duration of pregnancy, onset of spontaneous labor, or the CD rate.¹²

Steps from an expert. A skillfull midwife practicing in the United Kingdom provides the following guidance on how to perform membrane sweeping.¹³

1. Prepare the patient. Explain the procedure, have the patient empty her bladder, and encourage relaxed breathing if the vaginal examination causes pain.
2. Abdominal exam. Assess uterine size, fetal lie and presentation, and fetal heart tones.
3. Vaginal exam. Ascertain cervical dilation, effacement, and position. If the cervix is closed a sweep may not be possible. In this case, massaging the vaginal fornices may help to release prostaglandins and stimulate uterine contractions. If the cervix is closed but soft, massage of the cervix may permit the insertion of a finger. If the cervix is favorable for sweeping, insert one finger in the cervix and rotate the finger in a circle to separate the amnion from the cervix.
4. After the procedure. Provide the woman with a sanitary pad and recommend acetaminophen and a warm bath if she has discomfort or painful contractions. Advise her to come to the maternity unit in the following situations: severe pain, significant bleeding, or spontaneous rupture of the membranes.

Membrane sweeping can be performed as frequently as every 3 days. Formal cervical ripening and induction of labor may need to be planned if membrane sweeping does not result in the initiation of regular contractions.

Continue to: Collaborative decision making

Collaborative decision making

All clinicians recognize the primacy of patient autonomy.¹⁴ Competent patients have the right to select the course of care that they believe is optimal. When a patient decides to continue her pregnancy past 41 weeks, it is helpful to endorse respect for the decision and inquire about the patient’s reasons for continuing the pregnancy. Understanding the patient’s concerns may begin a conversation that will result in the patient accepting a plan for induction near 41 weeks’ gestation. If the patient insists on expectant management well beyond 41 weeks, the medical record should contain a summary of the clinician recommendation to induce labor at or before 41 weeks’ gestation and the patient’s preference for expectant management and her understanding of the decision’s risks.

Obstetricians and midwives constantly face the challenge of balancing the desire to avoid meddlesome interference in a pregnancy with the need to act to prevent adverse pregnancy outcomes. The challenge is daunting. A comprehensive meta-analysis of the benefit of induction of labor at or beyond term, estimated that 426 inductions would need to be initiated to prevent one perinatal death.² From one perspective it is meddlesome to intervene on more than 400 women to prevent one perinatal death. However, substantial data indicate that expectant management of a well-dated pregnancy at 41 weeks’ gestation will result in adverse outcomes that likely could be prevented by induction of labor. If you ran an airline and could take an action to prevent one airplane crash for every 400 flights, you would likely move heaven and earth to try to prevent that disaster. Unless the patient strongly prefers expectant management, well-managed induction of labor at or before 41 weeks’ gestation is likely to reduce the rate of adverse pregnancy events and, hence, is warranted.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Most people know that preterm birth is a major contributor to perinatal morbidity and mortality. Consequently, strict guidelines have been enforced to prevent non–medically indicated scheduled deliveries before 39 weeks’ gestation. Fewer people recognize that late-term birth is also an important and avoidable contributor to perinatal morbidity. To improve pregnancy outcomes, we may need enhanced guidelines about minimizing expectant management of pregnancy beyond 41 weeks’ gestation.

For the fetus, what is the optimal duration of a healthy pregnancy?

When pregnancy progresses past the date of the confinement, the risk of fetal or newborn injury or death increases, especially after 41 weeks’ gestation. Analysis of this risk, day by day, suggests that after 40 weeks’ and 3 days’ gestation there is no medical benefit to the fetus to remain in utero because, compared with induced delivery, expectant management of the pregnancy is associated with a greater rate of fetal and newborn morbidity and mortality.¹

The fetal and newborn benefits of delivery, rather than expectant management, at term include: a decrease in stillbirth and perinatal death rates, a decrease in admissions to the neonatal intensive care unit (NICU), a decrease in meconium-stained amniotic fluid and meconium aspiration syndrome, a decrease in low Apgar scores, and a decrease in problems related to uteroplacental insufficiency, including oligohydramnios.² In a comprehensive meta-analysis, induction of labor at or beyond term reduced the risk of perinatal death or stillbirth by 67%, the risk of a 5-minute Apgar score below 7 by 30%, and the risk of NICU admission by 12%.² The number of women that would need to be induced to prevent 1 perinatal death was estimated to be 426.²

Maternal benefits of avoiding late-term pregnancy

The maternal benefits of avoiding continuing a pregnancy past 41 weeks’ gestation include a reduction in labor dystocia and the risk of cesarean delivery (CD).^2,3 In one clinical trial, 3,407 women with low-risk pregnancy were randomly assigned to induction of labor at 41 weeks’ gestation or expectant management, awaiting the onset of labor with serial antenatal monitoring (nonstress tests and assessment of amniotic fluid volume).⁴ The CD rate was lower among the women randomized to induction of labor at 41 weeks’ (21.2% vs 24.5% in the expectant management group, P = .03). The rate of meconium-stained fluid was lower in the induction of labor group (25.0% vs 28.7%, P = .009). The rate of CD due to fetal distress also was lower in the induction of labor group (5.7% vs 8.3%, P = .003). The risks of maternal postpartum hemorrhage, sepsis, and endometritis did not differ between the groups. There were 2 stillbirths in the expectant management group (2/1,706) and none in the induction of labor group (0/1,701). There were no neonatal deaths in this study.⁴

Obstetric management, including accurate dating of pregnancy and membrane sweeping at term, can help to reduce the risk that a pregnancy will progress beyond 41 weeks’ gestation.⁵

Continue to: Routinely use ultrasound to accurately establish gestational age

Routinely use ultrasound to accurately establish gestational age

First trimester ultrasound should be offered to all pregnant women because it is a more accurate assessment of gestational age and will result in fewer pregnancies that are thought to be at or beyond 41 weeks’ gestation.⁵ In a meta-analysis of 8 studies, including 25,516 women, early ultrasonography reduced the rate of intervention for postterm pregnancy by 42% (31/1,000 to 18/1,000 pregnant women).⁶

Membrane sweeping (or stripping)

Membrane sweeping, which causes the release of prostaglandins, has been reported to reduce the risk of late-term and postterm induction of labor.^7,8 In the most recent Cochrane review on the topic, sweeping membranes reduced the rate of induction of labor at 41 weeks by 41% and at 42 weeks by 72%.⁷ To avoid one induction of labor for late-term or postterm pregnancy, sweeping of membranes would need to be performed on 8 women. In a recent meta-analysis, membrane sweeping reduced the rate of induction of labor for postmaturity by 48%.⁹

Membrane sweeping is associated with pain and an increased rate of vaginal bleeding.¹⁰ It does not increase the rate of maternal or neonatal infection, however. It also does not reduce the CD rate. In the United Kingdom, the National Institute for Health and Clinical Excellence recommends that all clinicians have a discussion of membrane sweeping with their patients at 38 weeks’ gestation and offer membrane stripping at 40 weeks to increase the rate of timely spontaneous labor and to avoid the risks of prolonged pregnancy.¹¹ Of note, in one randomized study of women planning a trial of labor after CD, membrane sweeping did not impact the duration of pregnancy, onset of spontaneous labor, or the CD rate.¹²

Steps from an expert. A skillfull midwife practicing in the United Kingdom provides the following guidance on how to perform membrane sweeping.¹³

1. Prepare the patient. Explain the procedure, have the patient empty her bladder, and encourage relaxed breathing if the vaginal examination causes pain.
2. Abdominal exam. Assess uterine size, fetal lie and presentation, and fetal heart tones.
3. Vaginal exam. Ascertain cervical dilation, effacement, and position. If the cervix is closed a sweep may not be possible. In this case, massaging the vaginal fornices may help to release prostaglandins and stimulate uterine contractions. If the cervix is closed but soft, massage of the cervix may permit the insertion of a finger. If the cervix is favorable for sweeping, insert one finger in the cervix and rotate the finger in a circle to separate the amnion from the cervix.
4. After the procedure. Provide the woman with a sanitary pad and recommend acetaminophen and a warm bath if she has discomfort or painful contractions. Advise her to come to the maternity unit in the following situations: severe pain, significant bleeding, or spontaneous rupture of the membranes.

Membrane sweeping can be performed as frequently as every 3 days. Formal cervical ripening and induction of labor may need to be planned if membrane sweeping does not result in the initiation of regular contractions.

Continue to: Collaborative decision making

Collaborative decision making

All clinicians recognize the primacy of patient autonomy.¹⁴ Competent patients have the right to select the course of care that they believe is optimal. When a patient decides to continue her pregnancy past 41 weeks, it is helpful to endorse respect for the decision and inquire about the patient’s reasons for continuing the pregnancy. Understanding the patient’s concerns may begin a conversation that will result in the patient accepting a plan for induction near 41 weeks’ gestation. If the patient insists on expectant management well beyond 41 weeks, the medical record should contain a summary of the clinician recommendation to induce labor at or before 41 weeks’ gestation and the patient’s preference for expectant management and her understanding of the decision’s risks.

Obstetricians and midwives constantly face the challenge of balancing the desire to avoid meddlesome interference in a pregnancy with the need to act to prevent adverse pregnancy outcomes. The challenge is daunting. A comprehensive meta-analysis of the benefit of induction of labor at or beyond term, estimated that 426 inductions would need to be initiated to prevent one perinatal death.² From one perspective it is meddlesome to intervene on more than 400 women to prevent one perinatal death. However, substantial data indicate that expectant management of a well-dated pregnancy at 41 weeks’ gestation will result in adverse outcomes that likely could be prevented by induction of labor. If you ran an airline and could take an action to prevent one airplane crash for every 400 flights, you would likely move heaven and earth to try to prevent that disaster. Unless the patient strongly prefers expectant management, well-managed induction of labor at or before 41 weeks’ gestation is likely to reduce the rate of adverse pregnancy events and, hence, is warranted.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Most people know that preterm birth is a major contributor to perinatal morbidity and mortality. Consequently, strict guidelines have been enforced to prevent non–medically indicated scheduled deliveries before 39 weeks’ gestation. Fewer people recognize that late-term birth is also an important and avoidable contributor to perinatal morbidity. To improve pregnancy outcomes, we may need enhanced guidelines about minimizing expectant management of pregnancy beyond 41 weeks’ gestation.

For the fetus, what is the optimal duration of a healthy pregnancy?

When pregnancy progresses past the date of the confinement, the risk of fetal or newborn injury or death increases, especially after 41 weeks’ gestation. Analysis of this risk, day by day, suggests that after 40 weeks’ and 3 days’ gestation there is no medical benefit to the fetus to remain in utero because, compared with induced delivery, expectant management of the pregnancy is associated with a greater rate of fetal and newborn morbidity and mortality.¹

The fetal and newborn benefits of delivery, rather than expectant management, at term include: a decrease in stillbirth and perinatal death rates, a decrease in admissions to the neonatal intensive care unit (NICU), a decrease in meconium-stained amniotic fluid and meconium aspiration syndrome, a decrease in low Apgar scores, and a decrease in problems related to uteroplacental insufficiency, including oligohydramnios.² In a comprehensive meta-analysis, induction of labor at or beyond term reduced the risk of perinatal death or stillbirth by 67%, the risk of a 5-minute Apgar score below 7 by 30%, and the risk of NICU admission by 12%.² The number of women that would need to be induced to prevent 1 perinatal death was estimated to be 426.²

Maternal benefits of avoiding late-term pregnancy

The maternal benefits of avoiding continuing a pregnancy past 41 weeks’ gestation include a reduction in labor dystocia and the risk of cesarean delivery (CD).^2,3 In one clinical trial, 3,407 women with low-risk pregnancy were randomly assigned to induction of labor at 41 weeks’ gestation or expectant management, awaiting the onset of labor with serial antenatal monitoring (nonstress tests and assessment of amniotic fluid volume).⁴ The CD rate was lower among the women randomized to induction of labor at 41 weeks’ (21.2% vs 24.5% in the expectant management group, P = .03). The rate of meconium-stained fluid was lower in the induction of labor group (25.0% vs 28.7%, P = .009). The rate of CD due to fetal distress also was lower in the induction of labor group (5.7% vs 8.3%, P = .003). The risks of maternal postpartum hemorrhage, sepsis, and endometritis did not differ between the groups. There were 2 stillbirths in the expectant management group (2/1,706) and none in the induction of labor group (0/1,701). There were no neonatal deaths in this study.⁴

Obstetric management, including accurate dating of pregnancy and membrane sweeping at term, can help to reduce the risk that a pregnancy will progress beyond 41 weeks’ gestation.⁵

Continue to: Routinely use ultrasound to accurately establish gestational age

Routinely use ultrasound to accurately establish gestational age

First trimester ultrasound should be offered to all pregnant women because it is a more accurate assessment of gestational age and will result in fewer pregnancies that are thought to be at or beyond 41 weeks’ gestation.⁵ In a meta-analysis of 8 studies, including 25,516 women, early ultrasonography reduced the rate of intervention for postterm pregnancy by 42% (31/1,000 to 18/1,000 pregnant women).⁶

Membrane sweeping (or stripping)

Membrane sweeping, which causes the release of prostaglandins, has been reported to reduce the risk of late-term and postterm induction of labor.^7,8 In the most recent Cochrane review on the topic, sweeping membranes reduced the rate of induction of labor at 41 weeks by 41% and at 42 weeks by 72%.⁷ To avoid one induction of labor for late-term or postterm pregnancy, sweeping of membranes would need to be performed on 8 women. In a recent meta-analysis, membrane sweeping reduced the rate of induction of labor for postmaturity by 48%.⁹

Membrane sweeping is associated with pain and an increased rate of vaginal bleeding.¹⁰ It does not increase the rate of maternal or neonatal infection, however. It also does not reduce the CD rate. In the United Kingdom, the National Institute for Health and Clinical Excellence recommends that all clinicians have a discussion of membrane sweeping with their patients at 38 weeks’ gestation and offer membrane stripping at 40 weeks to increase the rate of timely spontaneous labor and to avoid the risks of prolonged pregnancy.¹¹ Of note, in one randomized study of women planning a trial of labor after CD, membrane sweeping did not impact the duration of pregnancy, onset of spontaneous labor, or the CD rate.¹²

Steps from an expert. A skillfull midwife practicing in the United Kingdom provides the following guidance on how to perform membrane sweeping.¹³

1. Prepare the patient. Explain the procedure, have the patient empty her bladder, and encourage relaxed breathing if the vaginal examination causes pain.
2. Abdominal exam. Assess uterine size, fetal lie and presentation, and fetal heart tones.
3. Vaginal exam. Ascertain cervical dilation, effacement, and position. If the cervix is closed a sweep may not be possible. In this case, massaging the vaginal fornices may help to release prostaglandins and stimulate uterine contractions. If the cervix is closed but soft, massage of the cervix may permit the insertion of a finger. If the cervix is favorable for sweeping, insert one finger in the cervix and rotate the finger in a circle to separate the amnion from the cervix.
4. After the procedure. Provide the woman with a sanitary pad and recommend acetaminophen and a warm bath if she has discomfort or painful contractions. Advise her to come to the maternity unit in the following situations: severe pain, significant bleeding, or spontaneous rupture of the membranes.

Membrane sweeping can be performed as frequently as every 3 days. Formal cervical ripening and induction of labor may need to be planned if membrane sweeping does not result in the initiation of regular contractions.

Continue to: Collaborative decision making

Collaborative decision making

All clinicians recognize the primacy of patient autonomy.¹⁴ Competent patients have the right to select the course of care that they believe is optimal. When a patient decides to continue her pregnancy past 41 weeks, it is helpful to endorse respect for the decision and inquire about the patient’s reasons for continuing the pregnancy. Understanding the patient’s concerns may begin a conversation that will result in the patient accepting a plan for induction near 41 weeks’ gestation. If the patient insists on expectant management well beyond 41 weeks, the medical record should contain a summary of the clinician recommendation to induce labor at or before 41 weeks’ gestation and the patient’s preference for expectant management and her understanding of the decision’s risks.

Obstetricians and midwives constantly face the challenge of balancing the desire to avoid meddlesome interference in a pregnancy with the need to act to prevent adverse pregnancy outcomes. The challenge is daunting. A comprehensive meta-analysis of the benefit of induction of labor at or beyond term, estimated that 426 inductions would need to be initiated to prevent one perinatal death.² From one perspective it is meddlesome to intervene on more than 400 women to prevent one perinatal death. However, substantial data indicate that expectant management of a well-dated pregnancy at 41 weeks’ gestation will result in adverse outcomes that likely could be prevented by induction of labor. If you ran an airline and could take an action to prevent one airplane crash for every 400 flights, you would likely move heaven and earth to try to prevent that disaster. Unless the patient strongly prefers expectant management, well-managed induction of labor at or before 41 weeks’ gestation is likely to reduce the rate of adverse pregnancy events and, hence, is warranted.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Department of Medicine, Massachusetts General Hospital, Boston

Case

A 75 year-old woman with a history of hypertension, diabetes mellitus, heart failure and nonvalvular atrial fibrillation (CHA₂DS₂-VASc score, 8) on anticoagulation is admitted with weakness and dysarthria. Exam is notable for hypertension and right-sided hemiparesis. CT of the head shows an intraparenchymal hemorrhage in the left putamen. Her anticoagulation is reversed and blood pressure well controlled. She is discharged 12 days later.

Brief overview of the issue

Intracranial hemorrhage (ICH) is the second most common cause of stroke and is associated with high morbidity and mortality.¹ It is estimated that 10%-15% of spontaneous ICH cases occur in patients on therapeutic anticoagulation for atrial fibrillation.² As our population ages and more people develop atrial fibrillation, anticoagulation for primary or secondary prevention of embolic stroke also will likely increase, placing more people at risk for ICH. Even stringently controlled therapeutic international normalized ratios (INRs) between 2 and 3 may double the risk of ICH.³

Patients with ICH require close monitoring and treatment, including blood pressure control, reversal of anticoagulation, reduction of intracranial pressure and, at times, neurosurgery.⁴ Although anticoagulation is discontinued and reversed at the onset of ICH, no clear consensus exists as to when it is safe to resume it. Although anticoagulation decreases the risk of stroke/thromboembolism, it may also increase the amount of bleeding associated with the initial ICH or lead to its recurrence.

Factors that may contribute to rebleeding include uncontrolled hypertension, advanced age, time to resumption of anticoagulation, and lobar location of ICH (i.e., in cerebral cortex and/or underlying white matter).⁵ Traditionally, lobar ICH has high incidence of cerebral amyloid angiopathy and has been associated with higher bleeding rates than has deep ICH (i.e., involving the thalami, basal ganglia, cerebellum, or brainstem) where cerebral amyloid angiopathy is rare and ICH is usually from hypertensive vessel disease. However, in patients with active thromboembolic disease, high-risk atrial fibrillation, and mechanical valves, withholding anticoagulation could place them at high risk of stroke.

Two questions should be addressed in the case presented: Is it safe to restart therapeutic anticoagulation; and if so, what is the optimal time interval between ICH and reinitiation of anticoagulation?

Overview of the data

There is limited guidance from major professional societies regarding the reinitiation of anticoagulation and the optimal timing of safely resuming anticoagulation in patients with prior ICH.

Current European Stroke Organization guidelines provide no specific recommendations for anticoagulation resumption after ICH.⁷ The American Heart Association/American Stroke Association guideline has a class IIA (weak) recommendation to avoid anticoagulation in spontaneous lobar ICH and a class IIB (very weak) recommendation to consider resuming anticoagulation in nonlobar ICH on a case-by-case basis.⁴

Two recent meta-analyses have examined outcomes of resuming anticoagulation after ICH. In a meta-analysis of 5,300 patients with nonlobar ICH involving eight retrospective studies, Murthy et al. evaluated the risk of thromboembolic events (described as a composite outcome of MI and stroke) and the risk of recurrent ICH.⁸ They reported that resumption of therapeutic anticoagulation was associated with a decrease in the rate of thromboembolic events (6.7% vs. 17.6%; risk ratio, 0.35; 95% confidence interval, 0.25-0.45) with no significant change in the rate of repeat ICH (8.7% vs. 7.8%).

A second meta-analysis of three retrospective trials conducted by Biffi et al. examined anticoagulation resumption in 1,012 patients with ICH solely in the setting of thromboprophylaxis for nonvalvular atrial fibrillation.⁹ Reinitiation of anticoagulation after ICH was associated with decreased mortality (hazard ratio, 0.27; 95% CI, 0.19-0.40; P less than .0001), improved functional outcome (HR, 4.15; 95% CI, 2.92-5.90; P less than .0001), and reduction in all-cause stroke recurrence (HR 0.47; 95% CI, 0.36-0.64; P less than .0001). There was no significant difference in the rate of recurrent ICH when anticoagulation was resumed. Despite the notion that patients with cerebral amyloid angiopathy are at high risk of rebleeding, this positive association still held irrespective of lobar vs. nonlobar location of ICH.

Collectively, these studies suggest that resumption of anticoagulation may be effective in decreasing the rates of thromboembolism, as well as provide a functional and mortality benefit without increasing the risk of rebleeding, irrespective of the location of the bleed.

Less is known about the optimal timing of resumption of therapeutic anticoagulation, with data ranging from 72 hours to 30 weeks.¹⁰ The American Heart Association/American Stroke Association has a class IIB (very weak) recommendation to avoid anticoagulation for at least 4 weeks in patients without mechanical heart valves.⁴ The median time to resumption of therapeutic anticoagulation in aforementioned meta-analyses ranged from 10 to 44 days.^8,9

A recent observational study of 2,619 ICH survivors explored the relationship between the timing of reinitiation of anticoagulation and the incidence of thrombotic events (defined as ischemic stroke or death because of MI or systemic arterial thromboembolism) and hemorrhagic events (defined as recurrent ICH or bleeding event leading to death) occurring at least 28 days after initial ICH in patients with atrial fibrillation.¹¹

A decrease in thrombotic events was demonstrated if anticoagulation was started 4-16 weeks after ICH. However, when anticoagulation was started more than 16 weeks after ICH, no benefit was seen. Additionally, there was no significant difference in hemorrhagic events between men and women who resumed anticoagulation. In patients with high venous thromboembolism risk based on CHA₂DS₂-VASc score, resumption of anticoagulation was associated with a decreased predicted incidence of vascular death and nonfatal stroke, with the greatest benefit observed when anticoagulation was started at 7-8 weeks after ICH.

Unfortunately, published literature to date on anticoagulation after ICH is based entirely on retrospective studies – not randomized, controlled studies – making it more likely that anticoagulation would have been resumed in healthier patients, not those left debilitated by the ICH.

Furthermore, information on the location and size of the hemorrhages – which may serve as another confounding factor – often has not been reported. This is important since patients with smaller hemorrhages in less precarious areas also may be more likely to have resumption of anticoagulation. Another limitation of the current literature is that warfarin is the most common anticoagulant studied, with few studies involving the increasingly prescribed newer direct oral anticoagulants. It is also important to stress that a causal relationship between use of anticoagulants and certain outcomes or adverse effects following ICH may be more difficult to invoke in the absence of randomized controlled study designs.

Application of the data to our patient

Resumption of anticoagulation in our patient with ICH requires balancing the risk of hemorrhage expansion and recurrent ICH with the risk of thromboembolic disease.

Our patient is at higher risk of bleeding because of her advanced age, but adequate control of her blood pressure and nonlobar location of her ICH in the basal ganglia also may decrease her risk of recurrent ICH. Her high CHA₂DS₂-VASc score places her at high risk of thromboembolic event and stroke, making it more likely for reinitiation of anticoagulation to confer a mortality benefit.

Based on AHA guidelines,⁴ we should wait at least 4 weeks, or possibly wait until weeks 7-8 after ICH when the greatest benefit may be expected based on prediction models.¹¹

Bottom line

It would likely be safe to resume anticoagulation 4-8 weeks after ICH in our patient.

Dr. Gibson, Dr. Restrepo, Dr. Sasidhara, and Dr. Manian are hospitalists at Massachusetts General Hospital, Boston.

References

1. An SJ et al. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update. J Stroke. 2017 Jan;19:3-10.

2. Horstmann S et al. Intracerebral hemorrhage during anticoagulation with vitamin K antagonists: a consecutive observational study. J Neurol. 2013 Aug;260:2046-51.

3. Rosand J et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004 Apr 26;164:880-4.

4. Hemphill JC et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015 Jul;46:2032-60.

5. Aguillar MI et al. Update in intracerebral hemorrhage. Neurohospitalist. 2011;1:148-59.

6. Hill MD et al. Rate of stroke recurrence in patients with primary intracerebral hemorrhage. Stroke. 2000;31:123-7.

7. Steiner T et al. European Stroke Organization (ESO) guidelines for the management of spontaneous cerebral hemorrhage. Int J Stroke. 2014;9:840-55.

8. Murthy SB et al. Restarting anticoagulation therapy after intracranial hemorrhage: A systematic review and meta-analysis. Stroke. 2017 Jun;48:1594-600.

9. Biffi A et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol. 2017 Nov;82:755-65.

10. Witt DM. What to do after the bleed: Resuming anticoagulation after major bleeding. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;206:620-4.

11. Pennlert J et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017 Feb;48:314-20.

Key Points

• Robust scientific data on when to resume anticoagulation after ICH does not exist.
• Retrospective studies have shown that anticoagulation resumption after 4-8 weeks decreases the risk of thromboembolic events, decreases mortality, and improves functional status following ICH with no significant change in the risk of its recurrence.
• Prospective, randomized controlled trials are needed to explore risks/benefits of anticoagulation resumption and better define its optimal timing in relation to ICH.

Quiz

Which of the following is false regarding ICH?

A. Lobar ICHs are usually associated with cerebral amyloid angiopathy which are prone to bleeding.

B. Randomized, controlled studies have helped guide the decision as to when to resume anticoagulation in patients with ICH.

C. Current guidelines suggest deferring therapeutic anticoagulation for at least 4 weeks following ICH.

D. Resumption of anticoagulation after 4-8 weeks does not lead to increased risk of rebleeding in patients with prior ICH.



The false answer is B: Current recommendations regarding resumption of anticoagulation in patients with ICH are based solely on retrospective observational studies; there are no randomized, control trials to date.

A is true: In contrast to hypertensive vessel disease associated with deep ICH, lobar hemorrhages are usually associated with cerebral amyloid angiopathy, which are more prone to bleeding.

C is true: The AHA/ASA has a class IIB recommendation to avoid anticoagulation for at least 4 weeks after ICH in patients without mechanical heart valves.

D is true: Several studies have shown that resumption of anticoagulation 4-8 weeks after ICH does not increase the risk of rebleeding.




 

Department of Medicine, Massachusetts General Hospital, Boston

Case

A 75 year-old woman with a history of hypertension, diabetes mellitus, heart failure and nonvalvular atrial fibrillation (CHA₂DS₂-VASc score, 8) on anticoagulation is admitted with weakness and dysarthria. Exam is notable for hypertension and right-sided hemiparesis. CT of the head shows an intraparenchymal hemorrhage in the left putamen. Her anticoagulation is reversed and blood pressure well controlled. She is discharged 12 days later.

Brief overview of the issue

Intracranial hemorrhage (ICH) is the second most common cause of stroke and is associated with high morbidity and mortality.¹ It is estimated that 10%-15% of spontaneous ICH cases occur in patients on therapeutic anticoagulation for atrial fibrillation.² As our population ages and more people develop atrial fibrillation, anticoagulation for primary or secondary prevention of embolic stroke also will likely increase, placing more people at risk for ICH. Even stringently controlled therapeutic international normalized ratios (INRs) between 2 and 3 may double the risk of ICH.³

Patients with ICH require close monitoring and treatment, including blood pressure control, reversal of anticoagulation, reduction of intracranial pressure and, at times, neurosurgery.⁴ Although anticoagulation is discontinued and reversed at the onset of ICH, no clear consensus exists as to when it is safe to resume it. Although anticoagulation decreases the risk of stroke/thromboembolism, it may also increase the amount of bleeding associated with the initial ICH or lead to its recurrence.

Factors that may contribute to rebleeding include uncontrolled hypertension, advanced age, time to resumption of anticoagulation, and lobar location of ICH (i.e., in cerebral cortex and/or underlying white matter).⁵ Traditionally, lobar ICH has high incidence of cerebral amyloid angiopathy and has been associated with higher bleeding rates than has deep ICH (i.e., involving the thalami, basal ganglia, cerebellum, or brainstem) where cerebral amyloid angiopathy is rare and ICH is usually from hypertensive vessel disease. However, in patients with active thromboembolic disease, high-risk atrial fibrillation, and mechanical valves, withholding anticoagulation could place them at high risk of stroke.

Two questions should be addressed in the case presented: Is it safe to restart therapeutic anticoagulation; and if so, what is the optimal time interval between ICH and reinitiation of anticoagulation?

Overview of the data

There is limited guidance from major professional societies regarding the reinitiation of anticoagulation and the optimal timing of safely resuming anticoagulation in patients with prior ICH.

Current European Stroke Organization guidelines provide no specific recommendations for anticoagulation resumption after ICH.⁷ The American Heart Association/American Stroke Association guideline has a class IIA (weak) recommendation to avoid anticoagulation in spontaneous lobar ICH and a class IIB (very weak) recommendation to consider resuming anticoagulation in nonlobar ICH on a case-by-case basis.⁴

Two recent meta-analyses have examined outcomes of resuming anticoagulation after ICH. In a meta-analysis of 5,300 patients with nonlobar ICH involving eight retrospective studies, Murthy et al. evaluated the risk of thromboembolic events (described as a composite outcome of MI and stroke) and the risk of recurrent ICH.⁸ They reported that resumption of therapeutic anticoagulation was associated with a decrease in the rate of thromboembolic events (6.7% vs. 17.6%; risk ratio, 0.35; 95% confidence interval, 0.25-0.45) with no significant change in the rate of repeat ICH (8.7% vs. 7.8%).

A second meta-analysis of three retrospective trials conducted by Biffi et al. examined anticoagulation resumption in 1,012 patients with ICH solely in the setting of thromboprophylaxis for nonvalvular atrial fibrillation.⁹ Reinitiation of anticoagulation after ICH was associated with decreased mortality (hazard ratio, 0.27; 95% CI, 0.19-0.40; P less than .0001), improved functional outcome (HR, 4.15; 95% CI, 2.92-5.90; P less than .0001), and reduction in all-cause stroke recurrence (HR 0.47; 95% CI, 0.36-0.64; P less than .0001). There was no significant difference in the rate of recurrent ICH when anticoagulation was resumed. Despite the notion that patients with cerebral amyloid angiopathy are at high risk of rebleeding, this positive association still held irrespective of lobar vs. nonlobar location of ICH.

Collectively, these studies suggest that resumption of anticoagulation may be effective in decreasing the rates of thromboembolism, as well as provide a functional and mortality benefit without increasing the risk of rebleeding, irrespective of the location of the bleed.

Less is known about the optimal timing of resumption of therapeutic anticoagulation, with data ranging from 72 hours to 30 weeks.¹⁰ The American Heart Association/American Stroke Association has a class IIB (very weak) recommendation to avoid anticoagulation for at least 4 weeks in patients without mechanical heart valves.⁴ The median time to resumption of therapeutic anticoagulation in aforementioned meta-analyses ranged from 10 to 44 days.^8,9

A recent observational study of 2,619 ICH survivors explored the relationship between the timing of reinitiation of anticoagulation and the incidence of thrombotic events (defined as ischemic stroke or death because of MI or systemic arterial thromboembolism) and hemorrhagic events (defined as recurrent ICH or bleeding event leading to death) occurring at least 28 days after initial ICH in patients with atrial fibrillation.¹¹

A decrease in thrombotic events was demonstrated if anticoagulation was started 4-16 weeks after ICH. However, when anticoagulation was started more than 16 weeks after ICH, no benefit was seen. Additionally, there was no significant difference in hemorrhagic events between men and women who resumed anticoagulation. In patients with high venous thromboembolism risk based on CHA₂DS₂-VASc score, resumption of anticoagulation was associated with a decreased predicted incidence of vascular death and nonfatal stroke, with the greatest benefit observed when anticoagulation was started at 7-8 weeks after ICH.

Unfortunately, published literature to date on anticoagulation after ICH is based entirely on retrospective studies – not randomized, controlled studies – making it more likely that anticoagulation would have been resumed in healthier patients, not those left debilitated by the ICH.

Furthermore, information on the location and size of the hemorrhages – which may serve as another confounding factor – often has not been reported. This is important since patients with smaller hemorrhages in less precarious areas also may be more likely to have resumption of anticoagulation. Another limitation of the current literature is that warfarin is the most common anticoagulant studied, with few studies involving the increasingly prescribed newer direct oral anticoagulants. It is also important to stress that a causal relationship between use of anticoagulants and certain outcomes or adverse effects following ICH may be more difficult to invoke in the absence of randomized controlled study designs.

Application of the data to our patient

Resumption of anticoagulation in our patient with ICH requires balancing the risk of hemorrhage expansion and recurrent ICH with the risk of thromboembolic disease.

Our patient is at higher risk of bleeding because of her advanced age, but adequate control of her blood pressure and nonlobar location of her ICH in the basal ganglia also may decrease her risk of recurrent ICH. Her high CHA₂DS₂-VASc score places her at high risk of thromboembolic event and stroke, making it more likely for reinitiation of anticoagulation to confer a mortality benefit.

Based on AHA guidelines,⁴ we should wait at least 4 weeks, or possibly wait until weeks 7-8 after ICH when the greatest benefit may be expected based on prediction models.¹¹

Bottom line

It would likely be safe to resume anticoagulation 4-8 weeks after ICH in our patient.

Dr. Gibson, Dr. Restrepo, Dr. Sasidhara, and Dr. Manian are hospitalists at Massachusetts General Hospital, Boston.

References

1. An SJ et al. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update. J Stroke. 2017 Jan;19:3-10.

2. Horstmann S et al. Intracerebral hemorrhage during anticoagulation with vitamin K antagonists: a consecutive observational study. J Neurol. 2013 Aug;260:2046-51.

3. Rosand J et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004 Apr 26;164:880-4.

4. Hemphill JC et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015 Jul;46:2032-60.

5. Aguillar MI et al. Update in intracerebral hemorrhage. Neurohospitalist. 2011;1:148-59.

6. Hill MD et al. Rate of stroke recurrence in patients with primary intracerebral hemorrhage. Stroke. 2000;31:123-7.

7. Steiner T et al. European Stroke Organization (ESO) guidelines for the management of spontaneous cerebral hemorrhage. Int J Stroke. 2014;9:840-55.

8. Murthy SB et al. Restarting anticoagulation therapy after intracranial hemorrhage: A systematic review and meta-analysis. Stroke. 2017 Jun;48:1594-600.

9. Biffi A et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol. 2017 Nov;82:755-65.

10. Witt DM. What to do after the bleed: Resuming anticoagulation after major bleeding. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;206:620-4.

11. Pennlert J et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017 Feb;48:314-20.

Key Points

• Robust scientific data on when to resume anticoagulation after ICH does not exist.
• Retrospective studies have shown that anticoagulation resumption after 4-8 weeks decreases the risk of thromboembolic events, decreases mortality, and improves functional status following ICH with no significant change in the risk of its recurrence.
• Prospective, randomized controlled trials are needed to explore risks/benefits of anticoagulation resumption and better define its optimal timing in relation to ICH.

Quiz

Which of the following is false regarding ICH?

A. Lobar ICHs are usually associated with cerebral amyloid angiopathy which are prone to bleeding.

B. Randomized, controlled studies have helped guide the decision as to when to resume anticoagulation in patients with ICH.

C. Current guidelines suggest deferring therapeutic anticoagulation for at least 4 weeks following ICH.

D. Resumption of anticoagulation after 4-8 weeks does not lead to increased risk of rebleeding in patients with prior ICH.



The false answer is B: Current recommendations regarding resumption of anticoagulation in patients with ICH are based solely on retrospective observational studies; there are no randomized, control trials to date.

A is true: In contrast to hypertensive vessel disease associated with deep ICH, lobar hemorrhages are usually associated with cerebral amyloid angiopathy, which are more prone to bleeding.

C is true: The AHA/ASA has a class IIB recommendation to avoid anticoagulation for at least 4 weeks after ICH in patients without mechanical heart valves.

D is true: Several studies have shown that resumption of anticoagulation 4-8 weeks after ICH does not increase the risk of rebleeding.




 

Department of Medicine, Massachusetts General Hospital, Boston

Case

A 75 year-old woman with a history of hypertension, diabetes mellitus, heart failure and nonvalvular atrial fibrillation (CHA₂DS₂-VASc score, 8) on anticoagulation is admitted with weakness and dysarthria. Exam is notable for hypertension and right-sided hemiparesis. CT of the head shows an intraparenchymal hemorrhage in the left putamen. Her anticoagulation is reversed and blood pressure well controlled. She is discharged 12 days later.

Brief overview of the issue

Intracranial hemorrhage (ICH) is the second most common cause of stroke and is associated with high morbidity and mortality.¹ It is estimated that 10%-15% of spontaneous ICH cases occur in patients on therapeutic anticoagulation for atrial fibrillation.² As our population ages and more people develop atrial fibrillation, anticoagulation for primary or secondary prevention of embolic stroke also will likely increase, placing more people at risk for ICH. Even stringently controlled therapeutic international normalized ratios (INRs) between 2 and 3 may double the risk of ICH.³

Patients with ICH require close monitoring and treatment, including blood pressure control, reversal of anticoagulation, reduction of intracranial pressure and, at times, neurosurgery.⁴ Although anticoagulation is discontinued and reversed at the onset of ICH, no clear consensus exists as to when it is safe to resume it. Although anticoagulation decreases the risk of stroke/thromboembolism, it may also increase the amount of bleeding associated with the initial ICH or lead to its recurrence.

Factors that may contribute to rebleeding include uncontrolled hypertension, advanced age, time to resumption of anticoagulation, and lobar location of ICH (i.e., in cerebral cortex and/or underlying white matter).⁵ Traditionally, lobar ICH has high incidence of cerebral amyloid angiopathy and has been associated with higher bleeding rates than has deep ICH (i.e., involving the thalami, basal ganglia, cerebellum, or brainstem) where cerebral amyloid angiopathy is rare and ICH is usually from hypertensive vessel disease. However, in patients with active thromboembolic disease, high-risk atrial fibrillation, and mechanical valves, withholding anticoagulation could place them at high risk of stroke.

Two questions should be addressed in the case presented: Is it safe to restart therapeutic anticoagulation; and if so, what is the optimal time interval between ICH and reinitiation of anticoagulation?

Overview of the data

There is limited guidance from major professional societies regarding the reinitiation of anticoagulation and the optimal timing of safely resuming anticoagulation in patients with prior ICH.

Current European Stroke Organization guidelines provide no specific recommendations for anticoagulation resumption after ICH.⁷ The American Heart Association/American Stroke Association guideline has a class IIA (weak) recommendation to avoid anticoagulation in spontaneous lobar ICH and a class IIB (very weak) recommendation to consider resuming anticoagulation in nonlobar ICH on a case-by-case basis.⁴

Two recent meta-analyses have examined outcomes of resuming anticoagulation after ICH. In a meta-analysis of 5,300 patients with nonlobar ICH involving eight retrospective studies, Murthy et al. evaluated the risk of thromboembolic events (described as a composite outcome of MI and stroke) and the risk of recurrent ICH.⁸ They reported that resumption of therapeutic anticoagulation was associated with a decrease in the rate of thromboembolic events (6.7% vs. 17.6%; risk ratio, 0.35; 95% confidence interval, 0.25-0.45) with no significant change in the rate of repeat ICH (8.7% vs. 7.8%).

A second meta-analysis of three retrospective trials conducted by Biffi et al. examined anticoagulation resumption in 1,012 patients with ICH solely in the setting of thromboprophylaxis for nonvalvular atrial fibrillation.⁹ Reinitiation of anticoagulation after ICH was associated with decreased mortality (hazard ratio, 0.27; 95% CI, 0.19-0.40; P less than .0001), improved functional outcome (HR, 4.15; 95% CI, 2.92-5.90; P less than .0001), and reduction in all-cause stroke recurrence (HR 0.47; 95% CI, 0.36-0.64; P less than .0001). There was no significant difference in the rate of recurrent ICH when anticoagulation was resumed. Despite the notion that patients with cerebral amyloid angiopathy are at high risk of rebleeding, this positive association still held irrespective of lobar vs. nonlobar location of ICH.

Collectively, these studies suggest that resumption of anticoagulation may be effective in decreasing the rates of thromboembolism, as well as provide a functional and mortality benefit without increasing the risk of rebleeding, irrespective of the location of the bleed.

Less is known about the optimal timing of resumption of therapeutic anticoagulation, with data ranging from 72 hours to 30 weeks.¹⁰ The American Heart Association/American Stroke Association has a class IIB (very weak) recommendation to avoid anticoagulation for at least 4 weeks in patients without mechanical heart valves.⁴ The median time to resumption of therapeutic anticoagulation in aforementioned meta-analyses ranged from 10 to 44 days.^8,9

A recent observational study of 2,619 ICH survivors explored the relationship between the timing of reinitiation of anticoagulation and the incidence of thrombotic events (defined as ischemic stroke or death because of MI or systemic arterial thromboembolism) and hemorrhagic events (defined as recurrent ICH or bleeding event leading to death) occurring at least 28 days after initial ICH in patients with atrial fibrillation.¹¹

A decrease in thrombotic events was demonstrated if anticoagulation was started 4-16 weeks after ICH. However, when anticoagulation was started more than 16 weeks after ICH, no benefit was seen. Additionally, there was no significant difference in hemorrhagic events between men and women who resumed anticoagulation. In patients with high venous thromboembolism risk based on CHA₂DS₂-VASc score, resumption of anticoagulation was associated with a decreased predicted incidence of vascular death and nonfatal stroke, with the greatest benefit observed when anticoagulation was started at 7-8 weeks after ICH.

Unfortunately, published literature to date on anticoagulation after ICH is based entirely on retrospective studies – not randomized, controlled studies – making it more likely that anticoagulation would have been resumed in healthier patients, not those left debilitated by the ICH.

Furthermore, information on the location and size of the hemorrhages – which may serve as another confounding factor – often has not been reported. This is important since patients with smaller hemorrhages in less precarious areas also may be more likely to have resumption of anticoagulation. Another limitation of the current literature is that warfarin is the most common anticoagulant studied, with few studies involving the increasingly prescribed newer direct oral anticoagulants. It is also important to stress that a causal relationship between use of anticoagulants and certain outcomes or adverse effects following ICH may be more difficult to invoke in the absence of randomized controlled study designs.

Application of the data to our patient

Resumption of anticoagulation in our patient with ICH requires balancing the risk of hemorrhage expansion and recurrent ICH with the risk of thromboembolic disease.

Our patient is at higher risk of bleeding because of her advanced age, but adequate control of her blood pressure and nonlobar location of her ICH in the basal ganglia also may decrease her risk of recurrent ICH. Her high CHA₂DS₂-VASc score places her at high risk of thromboembolic event and stroke, making it more likely for reinitiation of anticoagulation to confer a mortality benefit.

Based on AHA guidelines,⁴ we should wait at least 4 weeks, or possibly wait until weeks 7-8 after ICH when the greatest benefit may be expected based on prediction models.¹¹

Bottom line

It would likely be safe to resume anticoagulation 4-8 weeks after ICH in our patient.

Dr. Gibson, Dr. Restrepo, Dr. Sasidhara, and Dr. Manian are hospitalists at Massachusetts General Hospital, Boston.

References

1. An SJ et al. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update. J Stroke. 2017 Jan;19:3-10.

2. Horstmann S et al. Intracerebral hemorrhage during anticoagulation with vitamin K antagonists: a consecutive observational study. J Neurol. 2013 Aug;260:2046-51.

3. Rosand J et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004 Apr 26;164:880-4.

4. Hemphill JC et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015 Jul;46:2032-60.

5. Aguillar MI et al. Update in intracerebral hemorrhage. Neurohospitalist. 2011;1:148-59.

6. Hill MD et al. Rate of stroke recurrence in patients with primary intracerebral hemorrhage. Stroke. 2000;31:123-7.

7. Steiner T et al. European Stroke Organization (ESO) guidelines for the management of spontaneous cerebral hemorrhage. Int J Stroke. 2014;9:840-55.

8. Murthy SB et al. Restarting anticoagulation therapy after intracranial hemorrhage: A systematic review and meta-analysis. Stroke. 2017 Jun;48:1594-600.

9. Biffi A et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol. 2017 Nov;82:755-65.

10. Witt DM. What to do after the bleed: Resuming anticoagulation after major bleeding. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;206:620-4.

11. Pennlert J et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017 Feb;48:314-20.

Key Points

• Robust scientific data on when to resume anticoagulation after ICH does not exist.
• Retrospective studies have shown that anticoagulation resumption after 4-8 weeks decreases the risk of thromboembolic events, decreases mortality, and improves functional status following ICH with no significant change in the risk of its recurrence.
• Prospective, randomized controlled trials are needed to explore risks/benefits of anticoagulation resumption and better define its optimal timing in relation to ICH.

Quiz

Which of the following is false regarding ICH?

A. Lobar ICHs are usually associated with cerebral amyloid angiopathy which are prone to bleeding.

B. Randomized, controlled studies have helped guide the decision as to when to resume anticoagulation in patients with ICH.

C. Current guidelines suggest deferring therapeutic anticoagulation for at least 4 weeks following ICH.

D. Resumption of anticoagulation after 4-8 weeks does not lead to increased risk of rebleeding in patients with prior ICH.



The false answer is B: Current recommendations regarding resumption of anticoagulation in patients with ICH are based solely on retrospective observational studies; there are no randomized, control trials to date.

A is true: In contrast to hypertensive vessel disease associated with deep ICH, lobar hemorrhages are usually associated with cerebral amyloid angiopathy, which are more prone to bleeding.

C is true: The AHA/ASA has a class IIB recommendation to avoid anticoagulation for at least 4 weeks after ICH in patients without mechanical heart valves.

D is true: Several studies have shown that resumption of anticoagulation 4-8 weeks after ICH does not increase the risk of rebleeding.




 

BOSTON – Patients with atrial fibrillation who present to emergency departments, despite being asymptomatic, often go based on of their understanding of advice they had previously received from their physicians, according to results from a prospective study of 356 Canadian atrial arrhythmia patients seen in emergency settings.

Mitchel L. Zoler/MDedge News

One way to deal with potentially inappropriate emergency department use is to have concerned patients with atrial fibrillation (AF) record their heart rhythm data with a handheld device or watch, transfer the records to their smartphones, and transmit the information to a remote physician for interpretation and advice, Benedict M. Glover, MD, said at the annual International AF Symposium.

Dr. Glover and his associates are in the process of developing a prototype system of this design to address the need they identified in a recent registry of 356 patients with a primary diagnosis of AF who sought care in the emergency department (ED) of any of seven participating Canadian medical centers, including five academic centers and two community hospitals. The survey results showed that 71% of the patients were symptomatic and 29% were asymptomatic then they first presented to an emergency department.


Case reviews of the 356 patients showed that 152 (43%) came to the EDs for what were classified as inappropriate reasons. The most common cause by far of an inappropriate emergency presentation was prior medical advice the patient had received, cited in 62% of the inappropriate cases, compared with 9% of the appropriate cases, said Dr. Glover, an electrophysiologist at Sunnybrook Health Sciences Centre in Toronto.

The inappropriate ED use by AF patients could be addressed in at least two ways, he said. One solution might be to give patients an alternative destination, so that instead of going to an emergency department they could go to an outpatient AF clinic. A second solution is to give patients a way to have their heart rhythm assessed remotely at the time of their concern. Dr. Glover said that his center had the staff capacity to deal with the potential influx of rhythm data from a pilot-sized program of remote heart-rhythm monitoring, but he conceded that scaling up to deal with the data that could come from the entire panel of AF patients managed by Sunnybrook physicians would be a huge challenge.

“The issue is what do we do with the data after we get it,” Dr. Glover said. “It’s a lot of information.”

Dr. Glover had no disclosures.

[email protected]

BOSTON – Patients with atrial fibrillation who present to emergency departments, despite being asymptomatic, often go based on of their understanding of advice they had previously received from their physicians, according to results from a prospective study of 356 Canadian atrial arrhythmia patients seen in emergency settings.

Mitchel L. Zoler/MDedge News

One way to deal with potentially inappropriate emergency department use is to have concerned patients with atrial fibrillation (AF) record their heart rhythm data with a handheld device or watch, transfer the records to their smartphones, and transmit the information to a remote physician for interpretation and advice, Benedict M. Glover, MD, said at the annual International AF Symposium.

Dr. Glover and his associates are in the process of developing a prototype system of this design to address the need they identified in a recent registry of 356 patients with a primary diagnosis of AF who sought care in the emergency department (ED) of any of seven participating Canadian medical centers, including five academic centers and two community hospitals. The survey results showed that 71% of the patients were symptomatic and 29% were asymptomatic then they first presented to an emergency department.


Case reviews of the 356 patients showed that 152 (43%) came to the EDs for what were classified as inappropriate reasons. The most common cause by far of an inappropriate emergency presentation was prior medical advice the patient had received, cited in 62% of the inappropriate cases, compared with 9% of the appropriate cases, said Dr. Glover, an electrophysiologist at Sunnybrook Health Sciences Centre in Toronto.

The inappropriate ED use by AF patients could be addressed in at least two ways, he said. One solution might be to give patients an alternative destination, so that instead of going to an emergency department they could go to an outpatient AF clinic. A second solution is to give patients a way to have their heart rhythm assessed remotely at the time of their concern. Dr. Glover said that his center had the staff capacity to deal with the potential influx of rhythm data from a pilot-sized program of remote heart-rhythm monitoring, but he conceded that scaling up to deal with the data that could come from the entire panel of AF patients managed by Sunnybrook physicians would be a huge challenge.

“The issue is what do we do with the data after we get it,” Dr. Glover said. “It’s a lot of information.”

Dr. Glover had no disclosures.

[email protected]

BOSTON – Patients with atrial fibrillation who present to emergency departments, despite being asymptomatic, often go based on of their understanding of advice they had previously received from their physicians, according to results from a prospective study of 356 Canadian atrial arrhythmia patients seen in emergency settings.

Mitchel L. Zoler/MDedge News

One way to deal with potentially inappropriate emergency department use is to have concerned patients with atrial fibrillation (AF) record their heart rhythm data with a handheld device or watch, transfer the records to their smartphones, and transmit the information to a remote physician for interpretation and advice, Benedict M. Glover, MD, said at the annual International AF Symposium.

Dr. Glover and his associates are in the process of developing a prototype system of this design to address the need they identified in a recent registry of 356 patients with a primary diagnosis of AF who sought care in the emergency department (ED) of any of seven participating Canadian medical centers, including five academic centers and two community hospitals. The survey results showed that 71% of the patients were symptomatic and 29% were asymptomatic then they first presented to an emergency department.


Case reviews of the 356 patients showed that 152 (43%) came to the EDs for what were classified as inappropriate reasons. The most common cause by far of an inappropriate emergency presentation was prior medical advice the patient had received, cited in 62% of the inappropriate cases, compared with 9% of the appropriate cases, said Dr. Glover, an electrophysiologist at Sunnybrook Health Sciences Centre in Toronto.

The inappropriate ED use by AF patients could be addressed in at least two ways, he said. One solution might be to give patients an alternative destination, so that instead of going to an emergency department they could go to an outpatient AF clinic. A second solution is to give patients a way to have their heart rhythm assessed remotely at the time of their concern. Dr. Glover said that his center had the staff capacity to deal with the potential influx of rhythm data from a pilot-sized program of remote heart-rhythm monitoring, but he conceded that scaling up to deal with the data that could come from the entire panel of AF patients managed by Sunnybrook physicians would be a huge challenge.

“The issue is what do we do with the data after we get it,” Dr. Glover said. “It’s a lot of information.”

Dr. Glover had no disclosures.

[email protected]

Terrific Care and Medex are recalling CoaguChek XS PT test strips they distributed between Dec. 27, 2017, and Dec. 15, 2018. According to a release, the Food and Drug Administration has identified this recall as Class I, which is the most serious type of recall and indicates that “use of these devices may cause serious injuries or death.”

These strips are used by patients taking warfarin to help determine the patients’ international normalized ratio, which doctors and patients then use to decide whether the dose is appropriate. Roche Diagnostics, the strips’ manufacturer, issued a recall in September 2018; the test strips distributed by Terrific Care and Medex, however, were not labeled or authorized for sale in the United States and were therefore not included in that original recall. According to the release, the strips in this recall, which was initiated Dec. 21, 2018, were purchased by Terrific Care and Medex from an unknown source and then distributed in the United States. On Jan. 28, 2019, Terrific Care sent an Urgent Medical Device Recall Notification Letter to customers.

The full recall is described on the FDA website.
 

[email protected]

Terrific Care and Medex are recalling CoaguChek XS PT test strips they distributed between Dec. 27, 2017, and Dec. 15, 2018. According to a release, the Food and Drug Administration has identified this recall as Class I, which is the most serious type of recall and indicates that “use of these devices may cause serious injuries or death.”

These strips are used by patients taking warfarin to help determine the patients’ international normalized ratio, which doctors and patients then use to decide whether the dose is appropriate. Roche Diagnostics, the strips’ manufacturer, issued a recall in September 2018; the test strips distributed by Terrific Care and Medex, however, were not labeled or authorized for sale in the United States and were therefore not included in that original recall. According to the release, the strips in this recall, which was initiated Dec. 21, 2018, were purchased by Terrific Care and Medex from an unknown source and then distributed in the United States. On Jan. 28, 2019, Terrific Care sent an Urgent Medical Device Recall Notification Letter to customers.

The full recall is described on the FDA website.
 

[email protected]

Terrific Care and Medex are recalling CoaguChek XS PT test strips they distributed between Dec. 27, 2017, and Dec. 15, 2018. According to a release, the Food and Drug Administration has identified this recall as Class I, which is the most serious type of recall and indicates that “use of these devices may cause serious injuries or death.”

These strips are used by patients taking warfarin to help determine the patients’ international normalized ratio, which doctors and patients then use to decide whether the dose is appropriate. Roche Diagnostics, the strips’ manufacturer, issued a recall in September 2018; the test strips distributed by Terrific Care and Medex, however, were not labeled or authorized for sale in the United States and were therefore not included in that original recall. According to the release, the strips in this recall, which was initiated Dec. 21, 2018, were purchased by Terrific Care and Medex from an unknown source and then distributed in the United States. On Jan. 28, 2019, Terrific Care sent an Urgent Medical Device Recall Notification Letter to customers.

The full recall is described on the FDA website.
 

[email protected]

LA JOLLA, CALIF. – The combination of duvelisib and romidepsin is active and can provide a bridge to transplant in relapsed or refractory peripheral T-cell lymphoma (PTCL), according to researchers.

Vidyard Video

In a phase 1 trial, duvelisib plus romidepsin produced an overall response rate (ORR) of 59% in patients with PTCL. Sixteen patients achieved a response, nine had a complete response (CR), and six complete responders went on to transplant.

“So we think that you can achieve remission deep enough to then move on to a potentially curative approach,” said study investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.

She and her colleagues evaluated romidepsin plus duvelisib, as well as bortezomib plus duvelisib, in a phase 1 trial (NCT02783625) of patients with relapsed or refractory PTCL or cutaneous T-cell lymphoma (CTCL).

Dr. Mehta-Shah presented the results at the annual T-cell Lymphoma Forum.

She reported results in 80 patients­ – 51 with PTCL and 29 with CTCL. The patients’ median age was 64 years (range, 28-83), and 57% of the study population were men. Patients had received a median of 3 (range, 1-16) prior therapies, and 16% had received a prior transplant.
 

Treatment

Dr. Mehta-Shah noted that patients and providers could choose whether patients would receive romidepsin or bortezomib.

Patients in the romidepsin arm received romidepsin at 10 mg/m² on days 1, 8, and 15 of each 28-day cycle. Patients in the bortezomib arm received bortezomib at 1 mg/m² on days 1, 4, 8, and 11 of each cycle.

Duvelisib dosing was escalated, so patients received duvelisib at 25 mg, 50 mg, or 75 mg twice daily.

In the bortezomib arm, there was one dose-limiting toxicity – grade 3 neutropenia – in a patient who received duvelisib at the 25-mg dose. There were no dose-limiting toxicities in the romidepsin arm.

The researchers determined that the maximum tolerated dose (MTD) of duvelisib was 75 mg twice daily in the romidepsin arm and 25 mg twice daily in the bortezomib arm.
 

Lead-in phase

The study also had a lead-in phase during which patients could receive single-agent duvelisib.

“Because the original phase 1 study of duvelisib did not collect as many prospective tumor biopsies or on-treatment biopsies, we built into this study a lead-in phase so that we could characterize on-treatment biopsies to better understand mechanisms of response or resistance,” Dr. Mehta-Shah said.

Patients and providers could choose to be part of the lead-in phase, she noted. Patients who did not achieve a CR during this phase went on to receive either combination therapy, which was predetermined before the monotherapy began.

There were 14 patients who received duvelisib monotherapy at 75 mg twice daily. Four of them achieved a CR, and three had a partial response (PR). Ten patients went on to receive romidepsin as well. One of them achieved a CR, and three had a PR.

There were 12 patients who received duvelisib monotherapy at 25 mg twice daily. Three of them achieved a CR, and two had a PR. Nine patients went on to receive bortezomib as well. This combination produced one CR and two PRs.
 

 

 

Efficacy with romidepsin

Among all evaluable PTCL patients in the romidepsin arm, the ORR was 59% (16/27), and the CR rate was 33% (9/27).

Responses occurred in seven patients with PTCL not otherwise specified (NOS), six with angioimmunoblastic T-cell lymphoma (AITL), one with hepatosplenic T-cell lymphoma, one with aggressive epidermotropic CD8+ T-cell lymphoma, and one with primary cutaneous PTCL.

CRs occurred in five patients with AITL and four with PTCL-NOS. Six patients who achieved a CR went on to transplant.

Among evaluable CTCL patients in the romidepsin arm, the ORR was 45% (5/11), and there were no CRs. Responses occurred in three patients with mycosis fungoides and two with Sézary syndrome.

The median progression-free survival was 5.41 months in CTCL patients and 6.72 months in PTCL patients.

Efficacy with bortezomib

Among evaluable PTCL patients in the bortezomib arm, the ORR was 44% (7/16), and the CR rate was 25% (4/16).

Responses occurred in three patients with AITL and four with PTCL-NOS. CRs occurred in two patients with each subtype.

Among evaluable CTCL patients in the bortezomib arm, the ORR was 27% (4/15), and there were no CRs. Responses occurred in one patient with mycosis fungoides and three with Sézary syndrome. One CTCL patient went on to transplant.

The median progression-free survival was 4.56 months among CTCL patients and 4.39 months in PTCL patients.
 

Safety

Dr. Mehta-Shah said both combinations were considered safe and well tolerated. However, there was a grade 5 adverse event (AE) – Stevens-Johnson syndrome – that occurred in the bortezomib arm and was considered possibly related to treatment.

Grade 3/4 AEs observed in the 31 patients treated at the MTD in the romidepsin arm were transaminase increase (n = 7), diarrhea (n = 6), hyponatremia (n = 4), neutrophil count decrease (n = 10), and platelet count decrease (n = 3).

Grade 3/4 AEs observed in the 23 patients treated at the MTD in the bortezomib arm were transaminase increase (n = 2) and neutrophil count decrease (n = 5).

Grade 3/4 transaminitis seemed to be more common among patients who received duvelisib alone during the lead-in phase, Dr. Mehta-Shah said.

Among patients treated at the MTD in the romidepsin arm, grade 3/4 transaminitis occurred in four patients treated during the lead-in phase and three who began receiving romidepsin and duvelisib together. In the bortezomib arm, grade 3/4 transaminitis occurred in two patients treated at the MTD, both of whom received duvelisib alone during the lead-in phase.

Based on these results, Dr. Mehta-Shah and her colleagues are planning to expand the romidepsin arm to an additional 25 patients. By testing the combination in more patients, the researchers hope to better understand the occurrence of transaminitis and assess the durability of response.

This study is supported by Verastem. Dr. Shah reported relationships with Celgene, Kyowa Kirin, Bristol-Myers Squibb, Verastem, and Genentech.

The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]

LA JOLLA, CALIF. – The combination of duvelisib and romidepsin is active and can provide a bridge to transplant in relapsed or refractory peripheral T-cell lymphoma (PTCL), according to researchers.

Vidyard Video

In a phase 1 trial, duvelisib plus romidepsin produced an overall response rate (ORR) of 59% in patients with PTCL. Sixteen patients achieved a response, nine had a complete response (CR), and six complete responders went on to transplant.

“So we think that you can achieve remission deep enough to then move on to a potentially curative approach,” said study investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.

She and her colleagues evaluated romidepsin plus duvelisib, as well as bortezomib plus duvelisib, in a phase 1 trial (NCT02783625) of patients with relapsed or refractory PTCL or cutaneous T-cell lymphoma (CTCL).

Dr. Mehta-Shah presented the results at the annual T-cell Lymphoma Forum.

She reported results in 80 patients­ – 51 with PTCL and 29 with CTCL. The patients’ median age was 64 years (range, 28-83), and 57% of the study population were men. Patients had received a median of 3 (range, 1-16) prior therapies, and 16% had received a prior transplant.
 

Treatment

Dr. Mehta-Shah noted that patients and providers could choose whether patients would receive romidepsin or bortezomib.

Patients in the romidepsin arm received romidepsin at 10 mg/m² on days 1, 8, and 15 of each 28-day cycle. Patients in the bortezomib arm received bortezomib at 1 mg/m² on days 1, 4, 8, and 11 of each cycle.

Duvelisib dosing was escalated, so patients received duvelisib at 25 mg, 50 mg, or 75 mg twice daily.

In the bortezomib arm, there was one dose-limiting toxicity – grade 3 neutropenia – in a patient who received duvelisib at the 25-mg dose. There were no dose-limiting toxicities in the romidepsin arm.

The researchers determined that the maximum tolerated dose (MTD) of duvelisib was 75 mg twice daily in the romidepsin arm and 25 mg twice daily in the bortezomib arm.
 

Lead-in phase

The study also had a lead-in phase during which patients could receive single-agent duvelisib.

“Because the original phase 1 study of duvelisib did not collect as many prospective tumor biopsies or on-treatment biopsies, we built into this study a lead-in phase so that we could characterize on-treatment biopsies to better understand mechanisms of response or resistance,” Dr. Mehta-Shah said.

Patients and providers could choose to be part of the lead-in phase, she noted. Patients who did not achieve a CR during this phase went on to receive either combination therapy, which was predetermined before the monotherapy began.

There were 14 patients who received duvelisib monotherapy at 75 mg twice daily. Four of them achieved a CR, and three had a partial response (PR). Ten patients went on to receive romidepsin as well. One of them achieved a CR, and three had a PR.

There were 12 patients who received duvelisib monotherapy at 25 mg twice daily. Three of them achieved a CR, and two had a PR. Nine patients went on to receive bortezomib as well. This combination produced one CR and two PRs.
 

 

 

Efficacy with romidepsin

Among all evaluable PTCL patients in the romidepsin arm, the ORR was 59% (16/27), and the CR rate was 33% (9/27).

Responses occurred in seven patients with PTCL not otherwise specified (NOS), six with angioimmunoblastic T-cell lymphoma (AITL), one with hepatosplenic T-cell lymphoma, one with aggressive epidermotropic CD8+ T-cell lymphoma, and one with primary cutaneous PTCL.

CRs occurred in five patients with AITL and four with PTCL-NOS. Six patients who achieved a CR went on to transplant.

Among evaluable CTCL patients in the romidepsin arm, the ORR was 45% (5/11), and there were no CRs. Responses occurred in three patients with mycosis fungoides and two with Sézary syndrome.

The median progression-free survival was 5.41 months in CTCL patients and 6.72 months in PTCL patients.

Efficacy with bortezomib

Among evaluable PTCL patients in the bortezomib arm, the ORR was 44% (7/16), and the CR rate was 25% (4/16).

Responses occurred in three patients with AITL and four with PTCL-NOS. CRs occurred in two patients with each subtype.

Among evaluable CTCL patients in the bortezomib arm, the ORR was 27% (4/15), and there were no CRs. Responses occurred in one patient with mycosis fungoides and three with Sézary syndrome. One CTCL patient went on to transplant.

The median progression-free survival was 4.56 months among CTCL patients and 4.39 months in PTCL patients.
 

Safety

Dr. Mehta-Shah said both combinations were considered safe and well tolerated. However, there was a grade 5 adverse event (AE) – Stevens-Johnson syndrome – that occurred in the bortezomib arm and was considered possibly related to treatment.

Grade 3/4 AEs observed in the 31 patients treated at the MTD in the romidepsin arm were transaminase increase (n = 7), diarrhea (n = 6), hyponatremia (n = 4), neutrophil count decrease (n = 10), and platelet count decrease (n = 3).

Grade 3/4 AEs observed in the 23 patients treated at the MTD in the bortezomib arm were transaminase increase (n = 2) and neutrophil count decrease (n = 5).

Grade 3/4 transaminitis seemed to be more common among patients who received duvelisib alone during the lead-in phase, Dr. Mehta-Shah said.

Among patients treated at the MTD in the romidepsin arm, grade 3/4 transaminitis occurred in four patients treated during the lead-in phase and three who began receiving romidepsin and duvelisib together. In the bortezomib arm, grade 3/4 transaminitis occurred in two patients treated at the MTD, both of whom received duvelisib alone during the lead-in phase.

Based on these results, Dr. Mehta-Shah and her colleagues are planning to expand the romidepsin arm to an additional 25 patients. By testing the combination in more patients, the researchers hope to better understand the occurrence of transaminitis and assess the durability of response.

This study is supported by Verastem. Dr. Shah reported relationships with Celgene, Kyowa Kirin, Bristol-Myers Squibb, Verastem, and Genentech.

The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]

LA JOLLA, CALIF. – The combination of duvelisib and romidepsin is active and can provide a bridge to transplant in relapsed or refractory peripheral T-cell lymphoma (PTCL), according to researchers.

Vidyard Video

In a phase 1 trial, duvelisib plus romidepsin produced an overall response rate (ORR) of 59% in patients with PTCL. Sixteen patients achieved a response, nine had a complete response (CR), and six complete responders went on to transplant.

“So we think that you can achieve remission deep enough to then move on to a potentially curative approach,” said study investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.

She and her colleagues evaluated romidepsin plus duvelisib, as well as bortezomib plus duvelisib, in a phase 1 trial (NCT02783625) of patients with relapsed or refractory PTCL or cutaneous T-cell lymphoma (CTCL).

Dr. Mehta-Shah presented the results at the annual T-cell Lymphoma Forum.

She reported results in 80 patients­ – 51 with PTCL and 29 with CTCL. The patients’ median age was 64 years (range, 28-83), and 57% of the study population were men. Patients had received a median of 3 (range, 1-16) prior therapies, and 16% had received a prior transplant.
 

Treatment

Dr. Mehta-Shah noted that patients and providers could choose whether patients would receive romidepsin or bortezomib.

Patients in the romidepsin arm received romidepsin at 10 mg/m² on days 1, 8, and 15 of each 28-day cycle. Patients in the bortezomib arm received bortezomib at 1 mg/m² on days 1, 4, 8, and 11 of each cycle.

Duvelisib dosing was escalated, so patients received duvelisib at 25 mg, 50 mg, or 75 mg twice daily.

In the bortezomib arm, there was one dose-limiting toxicity – grade 3 neutropenia – in a patient who received duvelisib at the 25-mg dose. There were no dose-limiting toxicities in the romidepsin arm.

The researchers determined that the maximum tolerated dose (MTD) of duvelisib was 75 mg twice daily in the romidepsin arm and 25 mg twice daily in the bortezomib arm.
 

Lead-in phase

The study also had a lead-in phase during which patients could receive single-agent duvelisib.

“Because the original phase 1 study of duvelisib did not collect as many prospective tumor biopsies or on-treatment biopsies, we built into this study a lead-in phase so that we could characterize on-treatment biopsies to better understand mechanisms of response or resistance,” Dr. Mehta-Shah said.

Patients and providers could choose to be part of the lead-in phase, she noted. Patients who did not achieve a CR during this phase went on to receive either combination therapy, which was predetermined before the monotherapy began.

There were 14 patients who received duvelisib monotherapy at 75 mg twice daily. Four of them achieved a CR, and three had a partial response (PR). Ten patients went on to receive romidepsin as well. One of them achieved a CR, and three had a PR.

There were 12 patients who received duvelisib monotherapy at 25 mg twice daily. Three of them achieved a CR, and two had a PR. Nine patients went on to receive bortezomib as well. This combination produced one CR and two PRs.
 

 

 

Efficacy with romidepsin

Among all evaluable PTCL patients in the romidepsin arm, the ORR was 59% (16/27), and the CR rate was 33% (9/27).

Responses occurred in seven patients with PTCL not otherwise specified (NOS), six with angioimmunoblastic T-cell lymphoma (AITL), one with hepatosplenic T-cell lymphoma, one with aggressive epidermotropic CD8+ T-cell lymphoma, and one with primary cutaneous PTCL.

CRs occurred in five patients with AITL and four with PTCL-NOS. Six patients who achieved a CR went on to transplant.

Among evaluable CTCL patients in the romidepsin arm, the ORR was 45% (5/11), and there were no CRs. Responses occurred in three patients with mycosis fungoides and two with Sézary syndrome.

The median progression-free survival was 5.41 months in CTCL patients and 6.72 months in PTCL patients.

Efficacy with bortezomib

Among evaluable PTCL patients in the bortezomib arm, the ORR was 44% (7/16), and the CR rate was 25% (4/16).

Responses occurred in three patients with AITL and four with PTCL-NOS. CRs occurred in two patients with each subtype.

Among evaluable CTCL patients in the bortezomib arm, the ORR was 27% (4/15), and there were no CRs. Responses occurred in one patient with mycosis fungoides and three with Sézary syndrome. One CTCL patient went on to transplant.

The median progression-free survival was 4.56 months among CTCL patients and 4.39 months in PTCL patients.
 

Safety

Dr. Mehta-Shah said both combinations were considered safe and well tolerated. However, there was a grade 5 adverse event (AE) – Stevens-Johnson syndrome – that occurred in the bortezomib arm and was considered possibly related to treatment.

Grade 3/4 AEs observed in the 31 patients treated at the MTD in the romidepsin arm were transaminase increase (n = 7), diarrhea (n = 6), hyponatremia (n = 4), neutrophil count decrease (n = 10), and platelet count decrease (n = 3).

Grade 3/4 AEs observed in the 23 patients treated at the MTD in the bortezomib arm were transaminase increase (n = 2) and neutrophil count decrease (n = 5).

Grade 3/4 transaminitis seemed to be more common among patients who received duvelisib alone during the lead-in phase, Dr. Mehta-Shah said.

Among patients treated at the MTD in the romidepsin arm, grade 3/4 transaminitis occurred in four patients treated during the lead-in phase and three who began receiving romidepsin and duvelisib together. In the bortezomib arm, grade 3/4 transaminitis occurred in two patients treated at the MTD, both of whom received duvelisib alone during the lead-in phase.

Based on these results, Dr. Mehta-Shah and her colleagues are planning to expand the romidepsin arm to an additional 25 patients. By testing the combination in more patients, the researchers hope to better understand the occurrence of transaminitis and assess the durability of response.

This study is supported by Verastem. Dr. Shah reported relationships with Celgene, Kyowa Kirin, Bristol-Myers Squibb, Verastem, and Genentech.

The T-cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]

Rural families that live far from their child’s cancer center face unique challenges, particularly lost work and missed family activities, because of long drives and inadequate emergency care at local hospitals, a small study has found.

Lead author Emily B. Walling, MD, of the University of Michigan, Ann Arbor, and her colleagues interviewed 18 caregivers with children who received treatment at St. Louis (Mo.) Children’s Hospital, an urban pediatric hospital. The caregivers lived in a rural area 2 or more hours’ driving distance from the hospital, and their children had received six or more treatments of chemotherapy and/or radiation at the cancer center. To be eligible, families had to have sought emergency care related to their child’s cancer diagnosis at least once in their local community. A total of 18 caregivers (12 mothers and 6 fathers) from 16 families were identified. The families answered questions focused on how the distance between home and hospital affected their child’s cancer treatment.

From the 18 interviews, investigators determined that top problems encountered by the rural families included poor emergent care at local hospitals, strain on family members because of extended travel time, and challenges in managing and coping with a pediatric diagnosis, according to the study published in the Journal of Oncology Practice.

In regards to emergency care, the families reported frustration with local emergency care providers who they felt did not take their concerns seriously. Parents also noted a lack of resources and training related to specialized care at local hospitals. Because of inadequacies at local hospitals, the caregivers reported delays in care, poor symptom management, incorrect procedures, inability to access central lines, and underappreciation of the child’s immunocompromised state, according to the study. The parents also reported that local hospital providers sometimes failed to follow the recommendations of oncology specialists at St. Louis Children’s Hospital and that other times there was redundant care between both health care centers.

Interviewees also described disruption to family members and guilt about missing important activities of other children because of long drives to the urban cancer center. Caregivers worried about missed school for children and separation from siblings. Families also reported financial burdens from missed work and increased costs associated with food, gas, and housing while away from home. In addition, inclement weather increased travel stress, as did treatment-related problems during the drive not easily managed in a vehicle.

Based on the interviews, investigators recommended steps to improve the care of rural pediatric cancer patients, including improved guidance to caregivers about unexpected trips to local hospitals, more outreach to local hospitals, and better medical visit coordination. If local hospitals are identified at diagnosis, communication between the local hospital and cancer center could be established early, study authors wrote. If deficiencies in care are discovered, local hospitals may be prompted to “stock materials or parents could be redirected to other hospitals at which they are routinely available,” authors suggested.

“This would foster collaboration between local physicians and specialists at the cancer-treating hospital, and thereby lower levels of frustration and increase parent’s trust of local providers,” authors wrote.

[email protected]

SOURCE: Walling EB et al. J Oncol Pract. 2019 Jan 31. doi: 10.1200/JOP.18.00115.

Rural families that live far from their child’s cancer center face unique challenges, particularly lost work and missed family activities, because of long drives and inadequate emergency care at local hospitals, a small study has found.

Lead author Emily B. Walling, MD, of the University of Michigan, Ann Arbor, and her colleagues interviewed 18 caregivers with children who received treatment at St. Louis (Mo.) Children’s Hospital, an urban pediatric hospital. The caregivers lived in a rural area 2 or more hours’ driving distance from the hospital, and their children had received six or more treatments of chemotherapy and/or radiation at the cancer center. To be eligible, families had to have sought emergency care related to their child’s cancer diagnosis at least once in their local community. A total of 18 caregivers (12 mothers and 6 fathers) from 16 families were identified. The families answered questions focused on how the distance between home and hospital affected their child’s cancer treatment.

From the 18 interviews, investigators determined that top problems encountered by the rural families included poor emergent care at local hospitals, strain on family members because of extended travel time, and challenges in managing and coping with a pediatric diagnosis, according to the study published in the Journal of Oncology Practice.

In regards to emergency care, the families reported frustration with local emergency care providers who they felt did not take their concerns seriously. Parents also noted a lack of resources and training related to specialized care at local hospitals. Because of inadequacies at local hospitals, the caregivers reported delays in care, poor symptom management, incorrect procedures, inability to access central lines, and underappreciation of the child’s immunocompromised state, according to the study. The parents also reported that local hospital providers sometimes failed to follow the recommendations of oncology specialists at St. Louis Children’s Hospital and that other times there was redundant care between both health care centers.

Interviewees also described disruption to family members and guilt about missing important activities of other children because of long drives to the urban cancer center. Caregivers worried about missed school for children and separation from siblings. Families also reported financial burdens from missed work and increased costs associated with food, gas, and housing while away from home. In addition, inclement weather increased travel stress, as did treatment-related problems during the drive not easily managed in a vehicle.

Based on the interviews, investigators recommended steps to improve the care of rural pediatric cancer patients, including improved guidance to caregivers about unexpected trips to local hospitals, more outreach to local hospitals, and better medical visit coordination. If local hospitals are identified at diagnosis, communication between the local hospital and cancer center could be established early, study authors wrote. If deficiencies in care are discovered, local hospitals may be prompted to “stock materials or parents could be redirected to other hospitals at which they are routinely available,” authors suggested.

“This would foster collaboration between local physicians and specialists at the cancer-treating hospital, and thereby lower levels of frustration and increase parent’s trust of local providers,” authors wrote.

[email protected]

SOURCE: Walling EB et al. J Oncol Pract. 2019 Jan 31. doi: 10.1200/JOP.18.00115.

Rural families that live far from their child’s cancer center face unique challenges, particularly lost work and missed family activities, because of long drives and inadequate emergency care at local hospitals, a small study has found.

Lead author Emily B. Walling, MD, of the University of Michigan, Ann Arbor, and her colleagues interviewed 18 caregivers with children who received treatment at St. Louis (Mo.) Children’s Hospital, an urban pediatric hospital. The caregivers lived in a rural area 2 or more hours’ driving distance from the hospital, and their children had received six or more treatments of chemotherapy and/or radiation at the cancer center. To be eligible, families had to have sought emergency care related to their child’s cancer diagnosis at least once in their local community. A total of 18 caregivers (12 mothers and 6 fathers) from 16 families were identified. The families answered questions focused on how the distance between home and hospital affected their child’s cancer treatment.

From the 18 interviews, investigators determined that top problems encountered by the rural families included poor emergent care at local hospitals, strain on family members because of extended travel time, and challenges in managing and coping with a pediatric diagnosis, according to the study published in the Journal of Oncology Practice.

In regards to emergency care, the families reported frustration with local emergency care providers who they felt did not take their concerns seriously. Parents also noted a lack of resources and training related to specialized care at local hospitals. Because of inadequacies at local hospitals, the caregivers reported delays in care, poor symptom management, incorrect procedures, inability to access central lines, and underappreciation of the child’s immunocompromised state, according to the study. The parents also reported that local hospital providers sometimes failed to follow the recommendations of oncology specialists at St. Louis Children’s Hospital and that other times there was redundant care between both health care centers.

Interviewees also described disruption to family members and guilt about missing important activities of other children because of long drives to the urban cancer center. Caregivers worried about missed school for children and separation from siblings. Families also reported financial burdens from missed work and increased costs associated with food, gas, and housing while away from home. In addition, inclement weather increased travel stress, as did treatment-related problems during the drive not easily managed in a vehicle.

Based on the interviews, investigators recommended steps to improve the care of rural pediatric cancer patients, including improved guidance to caregivers about unexpected trips to local hospitals, more outreach to local hospitals, and better medical visit coordination. If local hospitals are identified at diagnosis, communication between the local hospital and cancer center could be established early, study authors wrote. If deficiencies in care are discovered, local hospitals may be prompted to “stock materials or parents could be redirected to other hospitals at which they are routinely available,” authors suggested.

“This would foster collaboration between local physicians and specialists at the cancer-treating hospital, and thereby lower levels of frustration and increase parent’s trust of local providers,” authors wrote.

[email protected]

SOURCE: Walling EB et al. J Oncol Pract. 2019 Jan 31. doi: 10.1200/JOP.18.00115.

EXPERT COMMENTARY

Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019;364:k4810.

The Women’s Health Initiative trials, in which menopausal women were randomly assigned to treatment with oral CEE or placebo, found that statistically the largest risk associated with menopausal hormone therapy (HT) was increased VTE.¹ Recently, investigators in the United Kingdom (UK) published results of their research aimed at determining the association between the risk of VTE and the use of different types of HT.²

Details of the study

Vinogradova and colleagues used 2 UK primary care research databases, QResearch and Clinical Practice Research Datalink, to identify cases of incident VTE in general practice records, hospital admissions, and mortality records. They identified 80,396 women (aged 40 to 79 years) diagnosed with VTE between 1998 and 2017 and 391,494 control women matched by age and general practice. The mean age of the case and control women was approximately 64 years; the great majority of women were white. Analyses were adjusted for smoking, body mass index (BMI), family history of VTE, and comorbidities associated with VTE.

Types of HT used. The investigators found that 5,795 (7.2%) women with VTE and 21,670 (5.5%) controls were exposed to HT in the 90 days before the index date (the first date of VTE diagnosis for cases became the index date for matched controls). In those exposed to HT:

• 4,915 (85%) cases and 16,938 (78%) controls used oral preparations (including 102 [1.8%] cases and 312 [1.4%] controls who also had transdermal preparations)
• 880 (14%) cases and 4,731 (19%) controls used transdermal HT only.

Association of VTE with HT. Risk of VTE was increased with all oral HT formulations, including combined (estrogen plus progestogen) and estrogen-only preparations. Use of oral CEE (odds ratio [OR], 1.49) and estradiol (OR, 1.27) were both associated with an elevated risk of VTE (P<.05 for both comparisons). In contrast, use of transdermal estradiol (the great majority of which was administered by patch) was not associated with an elevated risk of VTE (OR, 0.96).

Direct comparison of oral estradiol and CEE found that the lower VTE risk with oral estradiol achieved statistical significance (P = .005). Direct comparison of oral and transdermal estrogen revealed an OR of 1.7 for the oral route of administration (P<.001)

Continue to: Study strengths and weaknesses

Study strengths and weaknesses

This study used data from the 2 largest primary care databases in the United Kingdom. Analyses were adjusted for numerous confounding factors, including acute and chronic conditions, lifestyle factors, and social deprivation. Additional sensitivity analyses were conducted and yielded results similar to those of the main analysis.

Several limitations could have resulted in some residual confounding bias. For example, drug exposure information was based on HT prescriptions and not actual use; data on some factors were not available, such as indications for HT, age at menopause, and education level; and for a small proportion of women, some data (smoking status, alcohol consumption, BMI) were missing and had to be imputed for analysis.

EXPERT COMMENTARY

Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019;364:k4810.

The Women’s Health Initiative trials, in which menopausal women were randomly assigned to treatment with oral CEE or placebo, found that statistically the largest risk associated with menopausal hormone therapy (HT) was increased VTE.¹ Recently, investigators in the United Kingdom (UK) published results of their research aimed at determining the association between the risk of VTE and the use of different types of HT.²

Details of the study

Vinogradova and colleagues used 2 UK primary care research databases, QResearch and Clinical Practice Research Datalink, to identify cases of incident VTE in general practice records, hospital admissions, and mortality records. They identified 80,396 women (aged 40 to 79 years) diagnosed with VTE between 1998 and 2017 and 391,494 control women matched by age and general practice. The mean age of the case and control women was approximately 64 years; the great majority of women were white. Analyses were adjusted for smoking, body mass index (BMI), family history of VTE, and comorbidities associated with VTE.

Types of HT used. The investigators found that 5,795 (7.2%) women with VTE and 21,670 (5.5%) controls were exposed to HT in the 90 days before the index date (the first date of VTE diagnosis for cases became the index date for matched controls). In those exposed to HT:

• 4,915 (85%) cases and 16,938 (78%) controls used oral preparations (including 102 [1.8%] cases and 312 [1.4%] controls who also had transdermal preparations)
• 880 (14%) cases and 4,731 (19%) controls used transdermal HT only.

Association of VTE with HT. Risk of VTE was increased with all oral HT formulations, including combined (estrogen plus progestogen) and estrogen-only preparations. Use of oral CEE (odds ratio [OR], 1.49) and estradiol (OR, 1.27) were both associated with an elevated risk of VTE (P<.05 for both comparisons). In contrast, use of transdermal estradiol (the great majority of which was administered by patch) was not associated with an elevated risk of VTE (OR, 0.96).

Direct comparison of oral estradiol and CEE found that the lower VTE risk with oral estradiol achieved statistical significance (P = .005). Direct comparison of oral and transdermal estrogen revealed an OR of 1.7 for the oral route of administration (P<.001)

Continue to: Study strengths and weaknesses

Study strengths and weaknesses

This study used data from the 2 largest primary care databases in the United Kingdom. Analyses were adjusted for numerous confounding factors, including acute and chronic conditions, lifestyle factors, and social deprivation. Additional sensitivity analyses were conducted and yielded results similar to those of the main analysis.

Several limitations could have resulted in some residual confounding bias. For example, drug exposure information was based on HT prescriptions and not actual use; data on some factors were not available, such as indications for HT, age at menopause, and education level; and for a small proportion of women, some data (smoking status, alcohol consumption, BMI) were missing and had to be imputed for analysis.

EXPERT COMMENTARY

Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019;364:k4810.

The Women’s Health Initiative trials, in which menopausal women were randomly assigned to treatment with oral CEE or placebo, found that statistically the largest risk associated with menopausal hormone therapy (HT) was increased VTE.¹ Recently, investigators in the United Kingdom (UK) published results of their research aimed at determining the association between the risk of VTE and the use of different types of HT.²

Details of the study

Vinogradova and colleagues used 2 UK primary care research databases, QResearch and Clinical Practice Research Datalink, to identify cases of incident VTE in general practice records, hospital admissions, and mortality records. They identified 80,396 women (aged 40 to 79 years) diagnosed with VTE between 1998 and 2017 and 391,494 control women matched by age and general practice. The mean age of the case and control women was approximately 64 years; the great majority of women were white. Analyses were adjusted for smoking, body mass index (BMI), family history of VTE, and comorbidities associated with VTE.

Types of HT used. The investigators found that 5,795 (7.2%) women with VTE and 21,670 (5.5%) controls were exposed to HT in the 90 days before the index date (the first date of VTE diagnosis for cases became the index date for matched controls). In those exposed to HT:

• 4,915 (85%) cases and 16,938 (78%) controls used oral preparations (including 102 [1.8%] cases and 312 [1.4%] controls who also had transdermal preparations)
• 880 (14%) cases and 4,731 (19%) controls used transdermal HT only.

Association of VTE with HT. Risk of VTE was increased with all oral HT formulations, including combined (estrogen plus progestogen) and estrogen-only preparations. Use of oral CEE (odds ratio [OR], 1.49) and estradiol (OR, 1.27) were both associated with an elevated risk of VTE (P<.05 for both comparisons). In contrast, use of transdermal estradiol (the great majority of which was administered by patch) was not associated with an elevated risk of VTE (OR, 0.96).

Direct comparison of oral estradiol and CEE found that the lower VTE risk with oral estradiol achieved statistical significance (P = .005). Direct comparison of oral and transdermal estrogen revealed an OR of 1.7 for the oral route of administration (P<.001)

Continue to: Study strengths and weaknesses

Study strengths and weaknesses

This study used data from the 2 largest primary care databases in the United Kingdom. Analyses were adjusted for numerous confounding factors, including acute and chronic conditions, lifestyle factors, and social deprivation. Additional sensitivity analyses were conducted and yielded results similar to those of the main analysis.

Several limitations could have resulted in some residual confounding bias. For example, drug exposure information was based on HT prescriptions and not actual use; data on some factors were not available, such as indications for HT, age at menopause, and education level; and for a small proportion of women, some data (smoking status, alcohol consumption, BMI) were missing and had to be imputed for analysis.

Patients with RA in clinical remission who received an MRI-based treat-to-target strategy did not achieve superior disease activity remission rates (85% vs. 88%) or reduced radiographic progression (66% vs. 62%), compared with a conventional treat-to-target strategy, according to results of the Danish, 2-year, investigator-initiated, randomized, multicenter IMAGINE-RA trial published in JAMA (2019 Feb 5. doi: 10.1001/jama.2018.21362).

We covered this study at the 2018 European Congress of Rheumatology before it was published in the journal. Read the story at the link above.

[email protected]

Patients with RA in clinical remission who received an MRI-based treat-to-target strategy did not achieve superior disease activity remission rates (85% vs. 88%) or reduced radiographic progression (66% vs. 62%), compared with a conventional treat-to-target strategy, according to results of the Danish, 2-year, investigator-initiated, randomized, multicenter IMAGINE-RA trial published in JAMA (2019 Feb 5. doi: 10.1001/jama.2018.21362).

We covered this study at the 2018 European Congress of Rheumatology before it was published in the journal. Read the story at the link above.

[email protected]

Patients with RA in clinical remission who received an MRI-based treat-to-target strategy did not achieve superior disease activity remission rates (85% vs. 88%) or reduced radiographic progression (66% vs. 62%), compared with a conventional treat-to-target strategy, according to results of the Danish, 2-year, investigator-initiated, randomized, multicenter IMAGINE-RA trial published in JAMA (2019 Feb 5. doi: 10.1001/jama.2018.21362).

We covered this study at the 2018 European Congress of Rheumatology before it was published in the journal. Read the story at the link above.

[email protected]