Red blood cell culture showing

Staphylococcus infection

Credit: Bill Branson

A computerized safety checklist that pulls information from patients’ electronic medical records can reduce the incidence of central line-associated bloodstream infections (CLABSIs), according to a study published in Pediatrics.

The study was conducted among children admitted to the pediatric intensive care unit at Lucile Packard Children’s Hospital Stanford in California.

Researchers found the safety checklist increased overall staff compliance with best practices for CLABSI prevention and resulted in a 3-fold reduction in CLABSI incidence.

The automated checklist, and a dashboard-style interface used to interact with it, was designed to help caregivers follow national guidelines for CLABSI prevention. The system combed through data in a patient’s electronic medical record and pushed alerts to physicians and nurses when a patient’s central line was due for care.

The dashboard interface displayed real-time alerts on a large LCD screen in the nurses’ station. Alerts—shown as red, yellow, or green dots beside patients’ names—were generated if, for example, the dressing on a patient’s central line was due to be changed, or if it was time for caregivers to re-evaluate whether medications given in the central line could be switched to oral formulations instead.

“The information was visible and easy to digest,” said study author Deborah Franzon, MD. “We improved compliance with best-care practices and pulled information that otherwise would have been difficult to look for. It reduced busy work and made it possible for the healthcare team to perform their jobs more efficiently and effectively.”

The system was implemented on May 1, 2011, but the researchers considered the rollout period to extend to August 31, 2011. So this period was not included in the analysis.

The team compared data on CLABSI rates, compliance with bundle elements, and staff perceptions/knowledge before the intervention began—from June 1, 2009, to April 30, 2011—and after the system was fully implemented—September 1, 2011, to December 31, 2012.

CLABSI rates decreased from 2.6 per 1000 line-days before the intervention to 0.7 per 1000 line-days afterward (P=0.02). There were a total of 19 CLABSIs per 7322 line-days pre-intervention and 7 CLABSIs per 6155 line-days post-intervention.

The researchers estimated that the intervention saved approximately $260,000 per year in healthcare costs. Treating a single CLABSI costs approximately $39,000.

The team also found that daily documentation of line necessity increased from 30% before the intervention to 73% after (P<0.001). Compliance with dressing changes increased from 87% to 90% (P=0.003).

Compliance with cap changes increased from 87% to 93% (P<0.001). And compliance with port needle changes increased from 69% to 95% (P<0.001). However, compliance with insertion bundle documentation decreased from 67% to 62% (P=0.001).

After the system was implemented, there was a significant increase in staff perception that the medical team addressed central line necessity during rounds (P=0.02). But there was no significant difference in communication among team members (P=0.73) or knowledge regarding the components of the maintenance bundle (P=0.39).

Nevertheless, the researchers concluded that their system promotes compliance with best practices for CLABSI prevention, thereby reducing the risk of harm to patients.

The team hopes to use the system in other ways, such as monitoring the recovery of children who have received organ transplants.

“[The system] lets physicians focus on taking care of the patient while automating some of the background safety checks,” said study author Natalie Pageler, MD. “The nice thing about this tool is that it’s integrated into the electronic medical record, which we use every single day.”

Red blood cell culture showing

Staphylococcus infection

Credit: Bill Branson

A computerized safety checklist that pulls information from patients’ electronic medical records can reduce the incidence of central line-associated bloodstream infections (CLABSIs), according to a study published in Pediatrics.

The study was conducted among children admitted to the pediatric intensive care unit at Lucile Packard Children’s Hospital Stanford in California.

Researchers found the safety checklist increased overall staff compliance with best practices for CLABSI prevention and resulted in a 3-fold reduction in CLABSI incidence.

The automated checklist, and a dashboard-style interface used to interact with it, was designed to help caregivers follow national guidelines for CLABSI prevention. The system combed through data in a patient’s electronic medical record and pushed alerts to physicians and nurses when a patient’s central line was due for care.

The dashboard interface displayed real-time alerts on a large LCD screen in the nurses’ station. Alerts—shown as red, yellow, or green dots beside patients’ names—were generated if, for example, the dressing on a patient’s central line was due to be changed, or if it was time for caregivers to re-evaluate whether medications given in the central line could be switched to oral formulations instead.

“The information was visible and easy to digest,” said study author Deborah Franzon, MD. “We improved compliance with best-care practices and pulled information that otherwise would have been difficult to look for. It reduced busy work and made it possible for the healthcare team to perform their jobs more efficiently and effectively.”

The system was implemented on May 1, 2011, but the researchers considered the rollout period to extend to August 31, 2011. So this period was not included in the analysis.

The team compared data on CLABSI rates, compliance with bundle elements, and staff perceptions/knowledge before the intervention began—from June 1, 2009, to April 30, 2011—and after the system was fully implemented—September 1, 2011, to December 31, 2012.

CLABSI rates decreased from 2.6 per 1000 line-days before the intervention to 0.7 per 1000 line-days afterward (P=0.02). There were a total of 19 CLABSIs per 7322 line-days pre-intervention and 7 CLABSIs per 6155 line-days post-intervention.

The researchers estimated that the intervention saved approximately $260,000 per year in healthcare costs. Treating a single CLABSI costs approximately $39,000.

The team also found that daily documentation of line necessity increased from 30% before the intervention to 73% after (P<0.001). Compliance with dressing changes increased from 87% to 90% (P=0.003).

Compliance with cap changes increased from 87% to 93% (P<0.001). And compliance with port needle changes increased from 69% to 95% (P<0.001). However, compliance with insertion bundle documentation decreased from 67% to 62% (P=0.001).

After the system was implemented, there was a significant increase in staff perception that the medical team addressed central line necessity during rounds (P=0.02). But there was no significant difference in communication among team members (P=0.73) or knowledge regarding the components of the maintenance bundle (P=0.39).

Nevertheless, the researchers concluded that their system promotes compliance with best practices for CLABSI prevention, thereby reducing the risk of harm to patients.

The team hopes to use the system in other ways, such as monitoring the recovery of children who have received organ transplants.

“[The system] lets physicians focus on taking care of the patient while automating some of the background safety checks,” said study author Natalie Pageler, MD. “The nice thing about this tool is that it’s integrated into the electronic medical record, which we use every single day.”

Red blood cell culture showing

Staphylococcus infection

Credit: Bill Branson

A computerized safety checklist that pulls information from patients’ electronic medical records can reduce the incidence of central line-associated bloodstream infections (CLABSIs), according to a study published in Pediatrics.

The study was conducted among children admitted to the pediatric intensive care unit at Lucile Packard Children’s Hospital Stanford in California.

Researchers found the safety checklist increased overall staff compliance with best practices for CLABSI prevention and resulted in a 3-fold reduction in CLABSI incidence.

The automated checklist, and a dashboard-style interface used to interact with it, was designed to help caregivers follow national guidelines for CLABSI prevention. The system combed through data in a patient’s electronic medical record and pushed alerts to physicians and nurses when a patient’s central line was due for care.

The dashboard interface displayed real-time alerts on a large LCD screen in the nurses’ station. Alerts—shown as red, yellow, or green dots beside patients’ names—were generated if, for example, the dressing on a patient’s central line was due to be changed, or if it was time for caregivers to re-evaluate whether medications given in the central line could be switched to oral formulations instead.

“The information was visible and easy to digest,” said study author Deborah Franzon, MD. “We improved compliance with best-care practices and pulled information that otherwise would have been difficult to look for. It reduced busy work and made it possible for the healthcare team to perform their jobs more efficiently and effectively.”

The system was implemented on May 1, 2011, but the researchers considered the rollout period to extend to August 31, 2011. So this period was not included in the analysis.

The team compared data on CLABSI rates, compliance with bundle elements, and staff perceptions/knowledge before the intervention began—from June 1, 2009, to April 30, 2011—and after the system was fully implemented—September 1, 2011, to December 31, 2012.

CLABSI rates decreased from 2.6 per 1000 line-days before the intervention to 0.7 per 1000 line-days afterward (P=0.02). There were a total of 19 CLABSIs per 7322 line-days pre-intervention and 7 CLABSIs per 6155 line-days post-intervention.

The researchers estimated that the intervention saved approximately $260,000 per year in healthcare costs. Treating a single CLABSI costs approximately $39,000.

The team also found that daily documentation of line necessity increased from 30% before the intervention to 73% after (P<0.001). Compliance with dressing changes increased from 87% to 90% (P=0.003).

Compliance with cap changes increased from 87% to 93% (P<0.001). And compliance with port needle changes increased from 69% to 95% (P<0.001). However, compliance with insertion bundle documentation decreased from 67% to 62% (P=0.001).

After the system was implemented, there was a significant increase in staff perception that the medical team addressed central line necessity during rounds (P=0.02). But there was no significant difference in communication among team members (P=0.73) or knowledge regarding the components of the maintenance bundle (P=0.39).

Nevertheless, the researchers concluded that their system promotes compliance with best practices for CLABSI prevention, thereby reducing the risk of harm to patients.

The team hopes to use the system in other ways, such as monitoring the recovery of children who have received organ transplants.

“[The system] lets physicians focus on taking care of the patient while automating some of the background safety checks,” said study author Natalie Pageler, MD. “The nice thing about this tool is that it’s integrated into the electronic medical record, which we use every single day.”

Blood for transfusion

Credit: UAB Hospital

In a large study, patients who received red blood cell (RBC) transfusions after percutaneous coronary intervention (PCI) had a higher risk of in-hospital heart attack, stroke, and death than their non-transfused peers.

The retrospective study included data on nearly 2 million patients who underwent a PCI at hospitals across the US.

The research revealed considerable variation in transfusion practices for this patient population, although the overall rate of transfusion was low.

This makes sense, as giving RBC transfusions to patients with coronary artery disease is controversial, according to the study authors.

They said there is a growing body of evidence suggesting that transfusion in the setting of acute coronary syndromes (ACS) and in hospitalized patients with a history of coronary artery disease may be associated with an increased risk of heart attack and death.

Furthermore, current guideline statements are cautious about recommending transfusion in hospitalized patients with a history of coronary artery disease and make no recommendation on transfusion in the setting of ACS, citing an absence of definitive evidence.

With this in mind, Matthew W. Sherwood, MD, of Duke Clinical Research Institute in Durham, North Carolina, and his colleagues examined transfusion practice patterns and outcomes in 1,967,218 patients (2,258,711 visits) who underwent PCI from July 2009 to March 2013 at 1431 US hospitals.

The team reported their findings in JAMA.

Overall, 2.1% of patients had a transfusion. However, transfusion practices varied among the hospitals. The unadjusted transfusion rates ranged from 0% to 13%. Overall, 96.3% of hospitals transfused less than 5% of patients, and 3.7% of hospitals transfused 5% of patients or more.

Risk-standardized rates of transfusion by hospital ranged from 0.3% to 9.3%. The risk was adjusted for factors such as age, sex, body mass index, ACS presentation, PCI status, history of congestive heart failure, etc.

Compared to no transfusion, receiving an RBC transfusion was associated with a greater risk of heart attack (4.5% vs 1.8%), stroke (2.0% vs 0.2%), and in-hospital death (12.5% vs 1.2%), irrespective of bleeding complications.

Patients were more likely to receive a transfusion if they were older, female, and had hypertension, diabetes, advanced renal dysfunction, and prior heart attack or heart failure.

The researchers speculated that the variation in transfusion practice patterns observed in this study may be related to several factors, including previously held beliefs about the benefit of transfusion and recently published data indicating the lack of benefit and potential hazard associated with transfusion.

The team said these data highlight the need for randomized trials of transfusion strategies to guide practice in patients undergoing PCI. And until these trials provide more definitive answers, clinicians should try to reduce the risk of bleeding and, therefore, the need for transfusion in patients undergoing PCI.

Blood for transfusion

Credit: UAB Hospital

In a large study, patients who received red blood cell (RBC) transfusions after percutaneous coronary intervention (PCI) had a higher risk of in-hospital heart attack, stroke, and death than their non-transfused peers.

The retrospective study included data on nearly 2 million patients who underwent a PCI at hospitals across the US.

The research revealed considerable variation in transfusion practices for this patient population, although the overall rate of transfusion was low.

This makes sense, as giving RBC transfusions to patients with coronary artery disease is controversial, according to the study authors.

They said there is a growing body of evidence suggesting that transfusion in the setting of acute coronary syndromes (ACS) and in hospitalized patients with a history of coronary artery disease may be associated with an increased risk of heart attack and death.

Furthermore, current guideline statements are cautious about recommending transfusion in hospitalized patients with a history of coronary artery disease and make no recommendation on transfusion in the setting of ACS, citing an absence of definitive evidence.

With this in mind, Matthew W. Sherwood, MD, of Duke Clinical Research Institute in Durham, North Carolina, and his colleagues examined transfusion practice patterns and outcomes in 1,967,218 patients (2,258,711 visits) who underwent PCI from July 2009 to March 2013 at 1431 US hospitals.

The team reported their findings in JAMA.

Overall, 2.1% of patients had a transfusion. However, transfusion practices varied among the hospitals. The unadjusted transfusion rates ranged from 0% to 13%. Overall, 96.3% of hospitals transfused less than 5% of patients, and 3.7% of hospitals transfused 5% of patients or more.

Risk-standardized rates of transfusion by hospital ranged from 0.3% to 9.3%. The risk was adjusted for factors such as age, sex, body mass index, ACS presentation, PCI status, history of congestive heart failure, etc.

Compared to no transfusion, receiving an RBC transfusion was associated with a greater risk of heart attack (4.5% vs 1.8%), stroke (2.0% vs 0.2%), and in-hospital death (12.5% vs 1.2%), irrespective of bleeding complications.

Patients were more likely to receive a transfusion if they were older, female, and had hypertension, diabetes, advanced renal dysfunction, and prior heart attack or heart failure.

The researchers speculated that the variation in transfusion practice patterns observed in this study may be related to several factors, including previously held beliefs about the benefit of transfusion and recently published data indicating the lack of benefit and potential hazard associated with transfusion.

The team said these data highlight the need for randomized trials of transfusion strategies to guide practice in patients undergoing PCI. And until these trials provide more definitive answers, clinicians should try to reduce the risk of bleeding and, therefore, the need for transfusion in patients undergoing PCI.

Blood for transfusion

Credit: UAB Hospital

In a large study, patients who received red blood cell (RBC) transfusions after percutaneous coronary intervention (PCI) had a higher risk of in-hospital heart attack, stroke, and death than their non-transfused peers.

The retrospective study included data on nearly 2 million patients who underwent a PCI at hospitals across the US.

The research revealed considerable variation in transfusion practices for this patient population, although the overall rate of transfusion was low.

This makes sense, as giving RBC transfusions to patients with coronary artery disease is controversial, according to the study authors.

They said there is a growing body of evidence suggesting that transfusion in the setting of acute coronary syndromes (ACS) and in hospitalized patients with a history of coronary artery disease may be associated with an increased risk of heart attack and death.

Furthermore, current guideline statements are cautious about recommending transfusion in hospitalized patients with a history of coronary artery disease and make no recommendation on transfusion in the setting of ACS, citing an absence of definitive evidence.

With this in mind, Matthew W. Sherwood, MD, of Duke Clinical Research Institute in Durham, North Carolina, and his colleagues examined transfusion practice patterns and outcomes in 1,967,218 patients (2,258,711 visits) who underwent PCI from July 2009 to March 2013 at 1431 US hospitals.

The team reported their findings in JAMA.

Overall, 2.1% of patients had a transfusion. However, transfusion practices varied among the hospitals. The unadjusted transfusion rates ranged from 0% to 13%. Overall, 96.3% of hospitals transfused less than 5% of patients, and 3.7% of hospitals transfused 5% of patients or more.

Risk-standardized rates of transfusion by hospital ranged from 0.3% to 9.3%. The risk was adjusted for factors such as age, sex, body mass index, ACS presentation, PCI status, history of congestive heart failure, etc.

Compared to no transfusion, receiving an RBC transfusion was associated with a greater risk of heart attack (4.5% vs 1.8%), stroke (2.0% vs 0.2%), and in-hospital death (12.5% vs 1.2%), irrespective of bleeding complications.

Patients were more likely to receive a transfusion if they were older, female, and had hypertension, diabetes, advanced renal dysfunction, and prior heart attack or heart failure.

The researchers speculated that the variation in transfusion practice patterns observed in this study may be related to several factors, including previously held beliefs about the benefit of transfusion and recently published data indicating the lack of benefit and potential hazard associated with transfusion.

The team said these data highlight the need for randomized trials of transfusion strategies to guide practice in patients undergoing PCI. And until these trials provide more definitive answers, clinicians should try to reduce the risk of bleeding and, therefore, the need for transfusion in patients undergoing PCI.

Clinical question

Can therapeutic hypothermia improve functional outcomes in comatose patients with severe bacterial meningitis?

Bottom line

For critically ill patients with severe bacterial meningitis, induced hypothermia using intravascular cooling or other cooling techniques does not improve outcomes and may lead to increased mortality. This trial was stopped early and thus lacked the statistical power to make definitive conclusions about the potential harmful effects of this intervention. (LOE = 1b-)

Reference

Mourvillier B, Tubach F, van de Beek D, et al. Induced hypothermia in severe bacterial meningitis: A randomized clinical trial. JAMA 2013;310(20):2174-2183.

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Adult patients with suspected or confirmed bacterial meningitis who had a Glasgow Coma Scale (GCS) score of less than 8 for fewer than 12 hours were randomized, using concealed allocation, into the induced hypothermia group or to usual care. All patients received appropriate antimicrobial therapy. In the hypothermia group, intravascular cooling was achieved by a loading dose of 1500 mL 40C saline over 30 minutes, and additional 500 mL boluses over 10 minutes as needed, to achieve a temperature of 33.50C or lower. Other cooling techniques, including ice packs, cooling air, and cooling pads, were also used. Temperatures were maintained between 32C and 34C for 48 hours, and the rewarming phase was passive. Baseline characteristics in the intervention group and control group were similar: mean age was 59 years, median GCS score was 7, all patients were mechanically ventilated, and the causative organism was identified as Streptococcus pneumoniae in the majority of patients. Analysis was by intention to treat. The primary outcome was the score on the Glasgow Outcome Scale. A favorable outcome was a score of 5, indicating mild or no disability; an unfavorable outcome was any score 1 through 4, with 1 indicating death. At 3 months, there was a trend toward unfavorable outcomes in the hypothermia group (86% vs 73% in the control group; relative risk = 1.17; 0.95-1.43; P = .13), as well as a trend toward increased mortality (hazard ratio = 1.76; 0.89-3.45; P = .10). The trial was stopped early because of the higher mortality in the hypothermia group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Can therapeutic hypothermia improve functional outcomes in comatose patients with severe bacterial meningitis?

Bottom line

For critically ill patients with severe bacterial meningitis, induced hypothermia using intravascular cooling or other cooling techniques does not improve outcomes and may lead to increased mortality. This trial was stopped early and thus lacked the statistical power to make definitive conclusions about the potential harmful effects of this intervention. (LOE = 1b-)

Reference

Mourvillier B, Tubach F, van de Beek D, et al. Induced hypothermia in severe bacterial meningitis: A randomized clinical trial. JAMA 2013;310(20):2174-2183.

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Adult patients with suspected or confirmed bacterial meningitis who had a Glasgow Coma Scale (GCS) score of less than 8 for fewer than 12 hours were randomized, using concealed allocation, into the induced hypothermia group or to usual care. All patients received appropriate antimicrobial therapy. In the hypothermia group, intravascular cooling was achieved by a loading dose of 1500 mL 40C saline over 30 minutes, and additional 500 mL boluses over 10 minutes as needed, to achieve a temperature of 33.50C or lower. Other cooling techniques, including ice packs, cooling air, and cooling pads, were also used. Temperatures were maintained between 32C and 34C for 48 hours, and the rewarming phase was passive. Baseline characteristics in the intervention group and control group were similar: mean age was 59 years, median GCS score was 7, all patients were mechanically ventilated, and the causative organism was identified as Streptococcus pneumoniae in the majority of patients. Analysis was by intention to treat. The primary outcome was the score on the Glasgow Outcome Scale. A favorable outcome was a score of 5, indicating mild or no disability; an unfavorable outcome was any score 1 through 4, with 1 indicating death. At 3 months, there was a trend toward unfavorable outcomes in the hypothermia group (86% vs 73% in the control group; relative risk = 1.17; 0.95-1.43; P = .13), as well as a trend toward increased mortality (hazard ratio = 1.76; 0.89-3.45; P = .10). The trial was stopped early because of the higher mortality in the hypothermia group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Can therapeutic hypothermia improve functional outcomes in comatose patients with severe bacterial meningitis?

Bottom line

For critically ill patients with severe bacterial meningitis, induced hypothermia using intravascular cooling or other cooling techniques does not improve outcomes and may lead to increased mortality. This trial was stopped early and thus lacked the statistical power to make definitive conclusions about the potential harmful effects of this intervention. (LOE = 1b-)

Reference

Mourvillier B, Tubach F, van de Beek D, et al. Induced hypothermia in severe bacterial meningitis: A randomized clinical trial. JAMA 2013;310(20):2174-2183.

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Adult patients with suspected or confirmed bacterial meningitis who had a Glasgow Coma Scale (GCS) score of less than 8 for fewer than 12 hours were randomized, using concealed allocation, into the induced hypothermia group or to usual care. All patients received appropriate antimicrobial therapy. In the hypothermia group, intravascular cooling was achieved by a loading dose of 1500 mL 40C saline over 30 minutes, and additional 500 mL boluses over 10 minutes as needed, to achieve a temperature of 33.50C or lower. Other cooling techniques, including ice packs, cooling air, and cooling pads, were also used. Temperatures were maintained between 32C and 34C for 48 hours, and the rewarming phase was passive. Baseline characteristics in the intervention group and control group were similar: mean age was 59 years, median GCS score was 7, all patients were mechanically ventilated, and the causative organism was identified as Streptococcus pneumoniae in the majority of patients. Analysis was by intention to treat. The primary outcome was the score on the Glasgow Outcome Scale. A favorable outcome was a score of 5, indicating mild or no disability; an unfavorable outcome was any score 1 through 4, with 1 indicating death. At 3 months, there was a trend toward unfavorable outcomes in the hypothermia group (86% vs 73% in the control group; relative risk = 1.17; 0.95-1.43; P = .13), as well as a trend toward increased mortality (hazard ratio = 1.76; 0.89-3.45; P = .10). The trial was stopped early because of the higher mortality in the hypothermia group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

How should anemia and iron deficiency be treated in adults with heart disease?

Bottom line

For hospitalized patients with anemia and coronary heart disease, the American College of Physicians recommends a restrictive transfusion strategy and a trigger hemoglobin of 7 g/dL to 8 g/dL. Furthermore, erythropoiesis-stimulating agents (ESAs) should be avoided in patients with coronary heart disease or congestive heart failure and mild to moderate anemia. Evidence regarding intravenous iron for this patient population is inconclusive. (LOE = 1a)

Reference

Kansagara D, Dyer E, Englander H, Fu R, Freeman M, Kagen D. Treatment of anemia in patients with heart disease: A systematic review. Ann Intern Med 2013;159(11):746-757. Qaseem A, Humphrey LL, Fitterman N, Starkey M, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Treatment of anemia in patients with heart disease: A clinical practice guideline from the American College of Physicians. Ann Intern Med 2013;159(11):770-779.

Study design

Practice guideline

Funding source

Government

Allocation

Uncertain

Setting

Various (meta-analysis)

Synopsis

The American College of Physicians developed this guideline based on a systematic review of the literature that evaluated the benefits and harms of anemia treatment in adults with heart disease. The authors searched multiple databases including MEDLINE and the Cochrane Library, to identify trials that studied the effects of blood transfusions, ESAs, and iron in patients with anemia and congestive heart failure or coronary heart disease. Observational transfusion studies were also included. Two reviewers independently assessed studies for inclusion, extracted data, and assessed study quality. Data was combined for meta-analysis when possible. Although it was low-quality evidence, liberal transfusion strategies as compared with restrictive strategies in treating anemia showed no effect on mortality for patients with heart disease. Moderate-strength to high-strength evidence from the ESA studies also showed no benefit, but did show a potential for harm, including an increased risk of venous thromboembolism. Finally, although few studies evaluated intravenous iron therapy, one good-quality study showed that it increased short-term exercise tolerance and quality of life in patients with heart failure. Based on these findings, the American College of Physicians guideline committee makes the following recommendations: (1) Use a restrictive red blood cell transfusion strategy with a hemoglobin threshold of 7 g/dL to 8 g/dL in hospitalized patients with coronary heart disease; and (2) avoid ESAs in patients with mild to moderate anemia and congestive heart failure or coronary heart disease. Because of lack of evidence regarding long-term outcomes and possible harms, as well as limited overall data, there was no recommendation made regarding the use of intravenous iron.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

How should anemia and iron deficiency be treated in adults with heart disease?

Bottom line

For hospitalized patients with anemia and coronary heart disease, the American College of Physicians recommends a restrictive transfusion strategy and a trigger hemoglobin of 7 g/dL to 8 g/dL. Furthermore, erythropoiesis-stimulating agents (ESAs) should be avoided in patients with coronary heart disease or congestive heart failure and mild to moderate anemia. Evidence regarding intravenous iron for this patient population is inconclusive. (LOE = 1a)

Reference

Kansagara D, Dyer E, Englander H, Fu R, Freeman M, Kagen D. Treatment of anemia in patients with heart disease: A systematic review. Ann Intern Med 2013;159(11):746-757. Qaseem A, Humphrey LL, Fitterman N, Starkey M, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Treatment of anemia in patients with heart disease: A clinical practice guideline from the American College of Physicians. Ann Intern Med 2013;159(11):770-779.

Study design

Practice guideline

Funding source

Government

Allocation

Uncertain

Setting

Various (meta-analysis)

Synopsis

The American College of Physicians developed this guideline based on a systematic review of the literature that evaluated the benefits and harms of anemia treatment in adults with heart disease. The authors searched multiple databases including MEDLINE and the Cochrane Library, to identify trials that studied the effects of blood transfusions, ESAs, and iron in patients with anemia and congestive heart failure or coronary heart disease. Observational transfusion studies were also included. Two reviewers independently assessed studies for inclusion, extracted data, and assessed study quality. Data was combined for meta-analysis when possible. Although it was low-quality evidence, liberal transfusion strategies as compared with restrictive strategies in treating anemia showed no effect on mortality for patients with heart disease. Moderate-strength to high-strength evidence from the ESA studies also showed no benefit, but did show a potential for harm, including an increased risk of venous thromboembolism. Finally, although few studies evaluated intravenous iron therapy, one good-quality study showed that it increased short-term exercise tolerance and quality of life in patients with heart failure. Based on these findings, the American College of Physicians guideline committee makes the following recommendations: (1) Use a restrictive red blood cell transfusion strategy with a hemoglobin threshold of 7 g/dL to 8 g/dL in hospitalized patients with coronary heart disease; and (2) avoid ESAs in patients with mild to moderate anemia and congestive heart failure or coronary heart disease. Because of lack of evidence regarding long-term outcomes and possible harms, as well as limited overall data, there was no recommendation made regarding the use of intravenous iron.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

How should anemia and iron deficiency be treated in adults with heart disease?

Bottom line

For hospitalized patients with anemia and coronary heart disease, the American College of Physicians recommends a restrictive transfusion strategy and a trigger hemoglobin of 7 g/dL to 8 g/dL. Furthermore, erythropoiesis-stimulating agents (ESAs) should be avoided in patients with coronary heart disease or congestive heart failure and mild to moderate anemia. Evidence regarding intravenous iron for this patient population is inconclusive. (LOE = 1a)

Reference

Kansagara D, Dyer E, Englander H, Fu R, Freeman M, Kagen D. Treatment of anemia in patients with heart disease: A systematic review. Ann Intern Med 2013;159(11):746-757. Qaseem A, Humphrey LL, Fitterman N, Starkey M, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Treatment of anemia in patients with heart disease: A clinical practice guideline from the American College of Physicians. Ann Intern Med 2013;159(11):770-779.

Study design

Practice guideline

Funding source

Government

Allocation

Uncertain

Setting

Various (meta-analysis)

Synopsis

The American College of Physicians developed this guideline based on a systematic review of the literature that evaluated the benefits and harms of anemia treatment in adults with heart disease. The authors searched multiple databases including MEDLINE and the Cochrane Library, to identify trials that studied the effects of blood transfusions, ESAs, and iron in patients with anemia and congestive heart failure or coronary heart disease. Observational transfusion studies were also included. Two reviewers independently assessed studies for inclusion, extracted data, and assessed study quality. Data was combined for meta-analysis when possible. Although it was low-quality evidence, liberal transfusion strategies as compared with restrictive strategies in treating anemia showed no effect on mortality for patients with heart disease. Moderate-strength to high-strength evidence from the ESA studies also showed no benefit, but did show a potential for harm, including an increased risk of venous thromboembolism. Finally, although few studies evaluated intravenous iron therapy, one good-quality study showed that it increased short-term exercise tolerance and quality of life in patients with heart failure. Based on these findings, the American College of Physicians guideline committee makes the following recommendations: (1) Use a restrictive red blood cell transfusion strategy with a hemoglobin threshold of 7 g/dL to 8 g/dL in hospitalized patients with coronary heart disease; and (2) avoid ESAs in patients with mild to moderate anemia and congestive heart failure or coronary heart disease. Because of lack of evidence regarding long-term outcomes and possible harms, as well as limited overall data, there was no recommendation made regarding the use of intravenous iron.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

As recently defined by the International Federation of Gynecology and Obstetrics (FIGO)—and endorsed by the American College of Obstetricians and Gynecologists—the term “abnormal uterine bleeding” (AUB) now describes any departure from normal menstrual bleeding.¹ To determine the most appropriate intervention for this widespread problem, FIGO proposed that clinicians consider potential contributors to the clinical problem by investigating and categorizing patients according to the following system:

• Polyp
• Adenomyosis
• Leiomyoma
• Malignancy and hyperplasia
• Coagulopathy
• Ovulatory disorders
• Endometrial dysfunction
• Iatrogenic
• Not otherwise classified.

A given individual may be found to have one or more of these features, but not all of the features may contribute to the AUB. To facilitate their use, these nine causes are more commonly identified using the acronym PALM-COEIN.

In this article, I focus on three of these categories, presenting recent data on AUB associated with leiomyomata (AUB-L) or adenomyosis (AUB-A), and AUB of an iatrogenic nature (AUB-I).

AUB-L: SATISFACTION RATES ARE SIMILAR 5 YEARS AFTER FIBROID TREATMENT BY SURGERY OR UTERINE ARTERY EMBOLIZATION

Gupta JK, Sinha A, Lumsden MA, Hickey M. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2012;5:CD005073. doi:10.1002/14651858.CD005073.pub3.

Women who undergo uterine artery embolization (UAE) for the treatment of symptomatic uterine fibroids are just as satisfied with the outcome as women treated with hysterectomy or myomectomy, according to this 2012 review from the Cochrane Database.

Gupta and colleagues found similar patient-satisfaction rates at 5 years (odds ratio [OR] 0.9; 95% confidence interval [CI], 0.45–1.8), although women undergoing UAE were more likely to require additional interventions within 2 years (56 additional interventions per 1,000 women for surgery vs 250 per 1,000 women for UAE; OR, 5.64).

Details and general findings
Gupta and colleagues selected randomized, controlled trials comparing UAE with surgery:

• three trials of UAE versus abdominal hysterectomy (n = 291)
• one trial of UAE versus hysterectomy or myomectomy (the specific surgery was determined by patient preference) (n = 157)
• one trial of UAE versus myomectomy in women desiring future childbearing (n = 121).

In these trials, UAE was bilateral and involved the use of permanent embolic material.

Among the findings:

• Costs were lower with UAE, as assessed by measuring the duration of the procedure, length of hospitalization, and time to resumption of normal activities.
• Ovarian-failure rates were comparable between women in the UAE and surgery groups. Ovarian function was assessed by measuring follicle-stimulating hormone (FSH), although FSH thresholds varied in some of the studies.
• Pregnancy was less likely after UAE than after myomectomy. In the trial comparing UAE with myomectomy, 26 women later tried to conceive after UAE versus 40 after myomectomy. Significantly fewer women became pregnant after UAE (OR, 0.29; 95% CI, 0.10–0.85).

Related Article: Update on Fertility  G. David Adamson, MD; Mary E. Abusief, MD (February 2014)

Bleeding outcomes were not measured
Strengths of this systematic review are its inclusion of high-quality, randomized, controlled trials and its assessment of ovarian-failure rates. However, a major weakness is the fact that its design does not allow for discrete evaluation of bleeding outcomes. Nor can its findings be broken down by the type of leiomyoma being treated.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This review demonstrates that women are satisfied with outcomes five years after UAE and that ovarian failure is not more common after UAE than after surgery. Although the available evidence demonstrates that pregnancy following UAE is possible, women requiring a surgical procedure for AUB-L who are uncertain about their childbearing plans or who are hoping to conceive should be encouraged to select myomectomy as their intervention of choice.

AUB-A: FOR ADENOMYOSIS-ASSOCIATED AUB, CONSIDER THE LNG-IUS AS AN ALTERNATIVE TO HYSTERECTOMY

Ozdegirmenci O, Kayikcioglu F, Akgul MA, et al. Comparison of levonorgestrel intrauterine system versus hysterectomy on efficacy and quality of life in patients with adenomyosis. Fertil Steril. 2011;95(2):497–502.

In a small randomized, controlled trial of the levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena) versus hysterectomy for adenomyosis-associated AUB, women allocated to the LNG-IUS experienced a reduction in bleeding and comparable gains in hemoglobin values during the first year of use. Both the LNG-IUS and hysterectomy improved health-related quality of life, but the LNG-IUS was associated with superior improvements in measures of psychological and social functioning.

Related Article: Update: Minimally invasive gynecology  Amy Garcia, MD (April 2013)

Details and general findings of the trial
Eighty-six women were enrolled in the trial after exclusion of endometrial pathology as a cause of their heavy menstrual bleeding and after transvaginal ultrasound and magnetic resonance imaging findings were consistent with the diagnosis of adenomyosis. Participants then were randomly assigned to undergo hysterectomy or insertion of an LNG-IUS (43 women in each group). At baseline, the mean (SD) age was 44.28 (4.36) years among women in the LNG-IUS group versus 46.38 (3.76) years among women undergoing hysterectomy (P = .032), a statistical difference that I suspect is not clinically significant.

Menstrual bleeding, hemoglobin levels, and quality of life were assessed prior to insertion or surgery, and again at 6- and 12-month follow-up. Eleven women in the hysterectomy group were lost to follow-up.

General findings of the trial include:

• Women in the LNG-IUS group had a mean reduction in the volume of menstrual bleeding—as measured by the number of pads used—from two pads to one pad at 6 months, remaining at that level until 12 months. Serum hemoglobin levels increased from a median of just over
  11 g/dL at the time of insertion to 13 g/dL at 6 months and slightly higher at 12 months. In the five self-reported quality-of-life domains assessed (physical, psychological, social, environmental, and a national environmental domain), women using the LNG-IUS demonstrated improvement in all five.
• Women in the hysterectomy group were treated using an abdominal surgical approach, with one patient experiencing postoperative wound infection that required secondary suture. Postoperative pathologic analysis found that 21 of these women (65.6%) had adenomyosis, six women (18.8%) had myomas, three women (9.4%) had both adenomyosis and a myoma, and two women (6.2%) had a normal uterus. Serum hemoglobin levels increased from a median of roughly 10.5 g/dL at the time of treatment to 13 g/dL at 6 months and slightly higher at 12 months. (There were no statistically significant differences in hemoglobin values between the LNG-IUS and hysterectomy groups at any point in the study.) Quality of life improved in three of the five domains assessed (physical and both environmental domains).

Although 11 women were lost to follow-up, this trial appeared to have an adequate sample size to examine the selected outcomes, and the population was well defined.

Two weaknesses were the limited follow-up (only 12 months) and the use of quality-of-life measures designed for a Turkish population (the trial was conducted in Turkey), which may or may not be fully applicable to a US population.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
The relationship of adenomyosis to gynecologic symptoms, including heavy menstrual bleeding and dysmenorrhea, needs further study. However, this trial confirmed that transvaginal ultrasound is helpful in the nonsurgical diagnosis of adenomyosis and suggests that the LNG-IUS may be as effective at 1 year as hysterectomy for the treatment of adenomyosis-associated heavy menstrual bleeding (AUB-A).
Clinicians who perform office-based ultrasound to assess AUB should familiarize themselves with the criteria for ultrasonic diagnosis of adenomyosis. These criteria include the presence of heterogeneous myometrial echogenicity, a loss of clarity of the endo-myometrial interface, typically radially oriented linear striations, the appearance of myometrial cysts, and an overall globular enlarged uterus characterized by asymmetric thickening of the myometrium.²
In patients with heavy menstrual bleeding who have these findings, particularly if there is coexistent dysmenorrhea and uterine tenderness, it behooves the clinician to consider the LNG-IUS as first-line therapy, especially for women who wish to preserve fertility, but also for women for whom fertility is not an issue.
There is some evidence that the therapeutic effect of the LNG-IUS containing 20 µg of levonorgestrel may start to fade at 2 or 3 years, a possibility that should be shared with patients.³ Other features, such as cavity size, thickness of the myometrium, and the coexistence of clinically relevant leiomyomas, have not been evaluated but may have an impact on the clinical response.

AUB-I: LOW-DOSE DOXYCYCLINE REDUCES THE TIME TO AMENORRHEA IN USERS OF CONTINUOUS ORAL CONTRACEPTIVES

Kaneshiro B, Edelman A, Carlson NE, Nichols M, Forbes MM, Jensen J. A randomized controlled trial of subantimicrobial-dose doxycycline to prevent unscheduled bleeding with continuous oral contraceptive pill use. Contraception. 2012;85(4):351–358.

Unscheduled bleeding is the most common complaint among women who use continuous combination oral contraceptives (OCs). Because unscheduled bleeding has been correlated with the upregulation of matrix metalloprotineases (MMPs), Kaneshiro and colleagues conducted a randomized, controlled trial of doxycycline (an MMP inhibitor) versus placebo among users of continuous OCs. The addition of doxycycline to the OC regimen did not significantly reduce unscheduled bleeding during the first 84 days of use, but it did shorten the time required to achieve amenorrhea (mean of 61.7 days for doxycycline vs 85.2 days for placebo; standard error [SE], 7.7 vs 6.7, respectively; P = .03).

Related Article: Big step forward and downward: An OC with 10 μg of estrogen  Robert L. Barbieri, MD (Editorial, May 2011)

Details and general findings of the trial
Participants (n = 65) were healthy women aged 18 to 45 years who had no contraindications to continuous use of combination OCs. Prior to enrollment, they all had used cyclic combination contraception (pill, patch, or ring) without unscheduled bleeding, thereby avoiding the “transition bleeding” that often occurs when continuous OCs are initiated.

All women in the trial were started on continuous OCs (20 µg ethinyl estradiol with 100 µg levonorgestrel; Aviane) and then randomly assigned to receive one of the following for 84 days in addition to the OC:

• doxycycline 40 mg daily (controlled-release Oracea), a subantimicrobial dose
• placebo.

After 84 days, doxycycline was discontinued, and participants were observed for an additional 28 days on the OC regimen alone for the documentation of bleeding patterns.

General findings:

• The number of bleeding and spotting days decreased in both groups over the course of the study.
• During the first 84 days of the trial, bleeding and spotting occurred among a median of 11 and 17 women in the doxycycline and placebo groups, respectively, and bleeding alone (without spotting) occurred in a median 3 and 4 women in the doxycycline and placebo groups, respectively.
• During the 28-day observation period, bleeding and spotting occurred among a median of 0 and 6 women in the doxycycline and placebo groups, respectively. Bleeding alone (without spotting) was absent in both groups.
• Women in the doxycycline group were significantly less likely to report side effects such as headache, depressed mood, and abdominal cramping. However, they were more likely to prefer continuous OCs without doxycycline, compared with women receiving placebo (16.1% vs 10.7%).

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This trial increases our insight into AUB associated with the use of progestins and suggests that concomitant doxycycline may reduce unscheduled bleeding and spotting in women using continuous combination OCs. The trial was of adequate sample size for the primary outcomes, lending credence to its findings, although longer-term data would be helpful.
I have included this trial for two reasons:
It offers useful information regarding the mechanisms and potential prevention or reduction of AUB-I in users of continuous combined estrogen-progestin contraception.
Doxycycline is one of the agents covered in a Cochrane review of high-quality research into AUB-I in women using progestin-only products, including injectables, implantables, intrauterine systems, and oral agents.4 Estrogens have been shown to have some value in reducing breakthrough bleeding associated with depot medroxyprogesterone acetate, and individual use of tranexamic acid or doxycycline has shown value in terminating an episode of breakthrough bleeding in women using progestin-only contraceptives.

TELL US WHAT YOU THINK!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice. We will consider publishing your letter and in a future issue.
Send your letter to: [email protected] Please include the city and state in which you practice.
Stay in touch! Your feedback is important to us!

As recently defined by the International Federation of Gynecology and Obstetrics (FIGO)—and endorsed by the American College of Obstetricians and Gynecologists—the term “abnormal uterine bleeding” (AUB) now describes any departure from normal menstrual bleeding.¹ To determine the most appropriate intervention for this widespread problem, FIGO proposed that clinicians consider potential contributors to the clinical problem by investigating and categorizing patients according to the following system:

• Polyp
• Adenomyosis
• Leiomyoma
• Malignancy and hyperplasia
• Coagulopathy
• Ovulatory disorders
• Endometrial dysfunction
• Iatrogenic
• Not otherwise classified.

A given individual may be found to have one or more of these features, but not all of the features may contribute to the AUB. To facilitate their use, these nine causes are more commonly identified using the acronym PALM-COEIN.

In this article, I focus on three of these categories, presenting recent data on AUB associated with leiomyomata (AUB-L) or adenomyosis (AUB-A), and AUB of an iatrogenic nature (AUB-I).

AUB-L: SATISFACTION RATES ARE SIMILAR 5 YEARS AFTER FIBROID TREATMENT BY SURGERY OR UTERINE ARTERY EMBOLIZATION

Gupta JK, Sinha A, Lumsden MA, Hickey M. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2012;5:CD005073. doi:10.1002/14651858.CD005073.pub3.

Women who undergo uterine artery embolization (UAE) for the treatment of symptomatic uterine fibroids are just as satisfied with the outcome as women treated with hysterectomy or myomectomy, according to this 2012 review from the Cochrane Database.

Gupta and colleagues found similar patient-satisfaction rates at 5 years (odds ratio [OR] 0.9; 95% confidence interval [CI], 0.45–1.8), although women undergoing UAE were more likely to require additional interventions within 2 years (56 additional interventions per 1,000 women for surgery vs 250 per 1,000 women for UAE; OR, 5.64).

Details and general findings
Gupta and colleagues selected randomized, controlled trials comparing UAE with surgery:

• three trials of UAE versus abdominal hysterectomy (n = 291)
• one trial of UAE versus hysterectomy or myomectomy (the specific surgery was determined by patient preference) (n = 157)
• one trial of UAE versus myomectomy in women desiring future childbearing (n = 121).

In these trials, UAE was bilateral and involved the use of permanent embolic material.

Among the findings:

• Costs were lower with UAE, as assessed by measuring the duration of the procedure, length of hospitalization, and time to resumption of normal activities.
• Ovarian-failure rates were comparable between women in the UAE and surgery groups. Ovarian function was assessed by measuring follicle-stimulating hormone (FSH), although FSH thresholds varied in some of the studies.
• Pregnancy was less likely after UAE than after myomectomy. In the trial comparing UAE with myomectomy, 26 women later tried to conceive after UAE versus 40 after myomectomy. Significantly fewer women became pregnant after UAE (OR, 0.29; 95% CI, 0.10–0.85).

Related Article: Update on Fertility  G. David Adamson, MD; Mary E. Abusief, MD (February 2014)

Bleeding outcomes were not measured
Strengths of this systematic review are its inclusion of high-quality, randomized, controlled trials and its assessment of ovarian-failure rates. However, a major weakness is the fact that its design does not allow for discrete evaluation of bleeding outcomes. Nor can its findings be broken down by the type of leiomyoma being treated.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This review demonstrates that women are satisfied with outcomes five years after UAE and that ovarian failure is not more common after UAE than after surgery. Although the available evidence demonstrates that pregnancy following UAE is possible, women requiring a surgical procedure for AUB-L who are uncertain about their childbearing plans or who are hoping to conceive should be encouraged to select myomectomy as their intervention of choice.

AUB-A: FOR ADENOMYOSIS-ASSOCIATED AUB, CONSIDER THE LNG-IUS AS AN ALTERNATIVE TO HYSTERECTOMY

Ozdegirmenci O, Kayikcioglu F, Akgul MA, et al. Comparison of levonorgestrel intrauterine system versus hysterectomy on efficacy and quality of life in patients with adenomyosis. Fertil Steril. 2011;95(2):497–502.

In a small randomized, controlled trial of the levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena) versus hysterectomy for adenomyosis-associated AUB, women allocated to the LNG-IUS experienced a reduction in bleeding and comparable gains in hemoglobin values during the first year of use. Both the LNG-IUS and hysterectomy improved health-related quality of life, but the LNG-IUS was associated with superior improvements in measures of psychological and social functioning.

Related Article: Update: Minimally invasive gynecology  Amy Garcia, MD (April 2013)

Details and general findings of the trial
Eighty-six women were enrolled in the trial after exclusion of endometrial pathology as a cause of their heavy menstrual bleeding and after transvaginal ultrasound and magnetic resonance imaging findings were consistent with the diagnosis of adenomyosis. Participants then were randomly assigned to undergo hysterectomy or insertion of an LNG-IUS (43 women in each group). At baseline, the mean (SD) age was 44.28 (4.36) years among women in the LNG-IUS group versus 46.38 (3.76) years among women undergoing hysterectomy (P = .032), a statistical difference that I suspect is not clinically significant.

Menstrual bleeding, hemoglobin levels, and quality of life were assessed prior to insertion or surgery, and again at 6- and 12-month follow-up. Eleven women in the hysterectomy group were lost to follow-up.

General findings of the trial include:

• Women in the LNG-IUS group had a mean reduction in the volume of menstrual bleeding—as measured by the number of pads used—from two pads to one pad at 6 months, remaining at that level until 12 months. Serum hemoglobin levels increased from a median of just over
  11 g/dL at the time of insertion to 13 g/dL at 6 months and slightly higher at 12 months. In the five self-reported quality-of-life domains assessed (physical, psychological, social, environmental, and a national environmental domain), women using the LNG-IUS demonstrated improvement in all five.
• Women in the hysterectomy group were treated using an abdominal surgical approach, with one patient experiencing postoperative wound infection that required secondary suture. Postoperative pathologic analysis found that 21 of these women (65.6%) had adenomyosis, six women (18.8%) had myomas, three women (9.4%) had both adenomyosis and a myoma, and two women (6.2%) had a normal uterus. Serum hemoglobin levels increased from a median of roughly 10.5 g/dL at the time of treatment to 13 g/dL at 6 months and slightly higher at 12 months. (There were no statistically significant differences in hemoglobin values between the LNG-IUS and hysterectomy groups at any point in the study.) Quality of life improved in three of the five domains assessed (physical and both environmental domains).

Although 11 women were lost to follow-up, this trial appeared to have an adequate sample size to examine the selected outcomes, and the population was well defined.

Two weaknesses were the limited follow-up (only 12 months) and the use of quality-of-life measures designed for a Turkish population (the trial was conducted in Turkey), which may or may not be fully applicable to a US population.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
The relationship of adenomyosis to gynecologic symptoms, including heavy menstrual bleeding and dysmenorrhea, needs further study. However, this trial confirmed that transvaginal ultrasound is helpful in the nonsurgical diagnosis of adenomyosis and suggests that the LNG-IUS may be as effective at 1 year as hysterectomy for the treatment of adenomyosis-associated heavy menstrual bleeding (AUB-A).
Clinicians who perform office-based ultrasound to assess AUB should familiarize themselves with the criteria for ultrasonic diagnosis of adenomyosis. These criteria include the presence of heterogeneous myometrial echogenicity, a loss of clarity of the endo-myometrial interface, typically radially oriented linear striations, the appearance of myometrial cysts, and an overall globular enlarged uterus characterized by asymmetric thickening of the myometrium.²
In patients with heavy menstrual bleeding who have these findings, particularly if there is coexistent dysmenorrhea and uterine tenderness, it behooves the clinician to consider the LNG-IUS as first-line therapy, especially for women who wish to preserve fertility, but also for women for whom fertility is not an issue.
There is some evidence that the therapeutic effect of the LNG-IUS containing 20 µg of levonorgestrel may start to fade at 2 or 3 years, a possibility that should be shared with patients.³ Other features, such as cavity size, thickness of the myometrium, and the coexistence of clinically relevant leiomyomas, have not been evaluated but may have an impact on the clinical response.

AUB-I: LOW-DOSE DOXYCYCLINE REDUCES THE TIME TO AMENORRHEA IN USERS OF CONTINUOUS ORAL CONTRACEPTIVES

Kaneshiro B, Edelman A, Carlson NE, Nichols M, Forbes MM, Jensen J. A randomized controlled trial of subantimicrobial-dose doxycycline to prevent unscheduled bleeding with continuous oral contraceptive pill use. Contraception. 2012;85(4):351–358.

Unscheduled bleeding is the most common complaint among women who use continuous combination oral contraceptives (OCs). Because unscheduled bleeding has been correlated with the upregulation of matrix metalloprotineases (MMPs), Kaneshiro and colleagues conducted a randomized, controlled trial of doxycycline (an MMP inhibitor) versus placebo among users of continuous OCs. The addition of doxycycline to the OC regimen did not significantly reduce unscheduled bleeding during the first 84 days of use, but it did shorten the time required to achieve amenorrhea (mean of 61.7 days for doxycycline vs 85.2 days for placebo; standard error [SE], 7.7 vs 6.7, respectively; P = .03).

Related Article: Big step forward and downward: An OC with 10 μg of estrogen  Robert L. Barbieri, MD (Editorial, May 2011)

Details and general findings of the trial
Participants (n = 65) were healthy women aged 18 to 45 years who had no contraindications to continuous use of combination OCs. Prior to enrollment, they all had used cyclic combination contraception (pill, patch, or ring) without unscheduled bleeding, thereby avoiding the “transition bleeding” that often occurs when continuous OCs are initiated.

All women in the trial were started on continuous OCs (20 µg ethinyl estradiol with 100 µg levonorgestrel; Aviane) and then randomly assigned to receive one of the following for 84 days in addition to the OC:

• doxycycline 40 mg daily (controlled-release Oracea), a subantimicrobial dose
• placebo.

After 84 days, doxycycline was discontinued, and participants were observed for an additional 28 days on the OC regimen alone for the documentation of bleeding patterns.

General findings:

• The number of bleeding and spotting days decreased in both groups over the course of the study.
• During the first 84 days of the trial, bleeding and spotting occurred among a median of 11 and 17 women in the doxycycline and placebo groups, respectively, and bleeding alone (without spotting) occurred in a median 3 and 4 women in the doxycycline and placebo groups, respectively.
• During the 28-day observation period, bleeding and spotting occurred among a median of 0 and 6 women in the doxycycline and placebo groups, respectively. Bleeding alone (without spotting) was absent in both groups.
• Women in the doxycycline group were significantly less likely to report side effects such as headache, depressed mood, and abdominal cramping. However, they were more likely to prefer continuous OCs without doxycycline, compared with women receiving placebo (16.1% vs 10.7%).

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This trial increases our insight into AUB associated with the use of progestins and suggests that concomitant doxycycline may reduce unscheduled bleeding and spotting in women using continuous combination OCs. The trial was of adequate sample size for the primary outcomes, lending credence to its findings, although longer-term data would be helpful.
I have included this trial for two reasons:
It offers useful information regarding the mechanisms and potential prevention or reduction of AUB-I in users of continuous combined estrogen-progestin contraception.
Doxycycline is one of the agents covered in a Cochrane review of high-quality research into AUB-I in women using progestin-only products, including injectables, implantables, intrauterine systems, and oral agents.4 Estrogens have been shown to have some value in reducing breakthrough bleeding associated with depot medroxyprogesterone acetate, and individual use of tranexamic acid or doxycycline has shown value in terminating an episode of breakthrough bleeding in women using progestin-only contraceptives.

TELL US WHAT YOU THINK!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice. We will consider publishing your letter and in a future issue.
Send your letter to: [email protected] Please include the city and state in which you practice.
Stay in touch! Your feedback is important to us!

As recently defined by the International Federation of Gynecology and Obstetrics (FIGO)—and endorsed by the American College of Obstetricians and Gynecologists—the term “abnormal uterine bleeding” (AUB) now describes any departure from normal menstrual bleeding.¹ To determine the most appropriate intervention for this widespread problem, FIGO proposed that clinicians consider potential contributors to the clinical problem by investigating and categorizing patients according to the following system:

• Polyp
• Adenomyosis
• Leiomyoma
• Malignancy and hyperplasia
• Coagulopathy
• Ovulatory disorders
• Endometrial dysfunction
• Iatrogenic
• Not otherwise classified.

A given individual may be found to have one or more of these features, but not all of the features may contribute to the AUB. To facilitate their use, these nine causes are more commonly identified using the acronym PALM-COEIN.

In this article, I focus on three of these categories, presenting recent data on AUB associated with leiomyomata (AUB-L) or adenomyosis (AUB-A), and AUB of an iatrogenic nature (AUB-I).

AUB-L: SATISFACTION RATES ARE SIMILAR 5 YEARS AFTER FIBROID TREATMENT BY SURGERY OR UTERINE ARTERY EMBOLIZATION

Gupta JK, Sinha A, Lumsden MA, Hickey M. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2012;5:CD005073. doi:10.1002/14651858.CD005073.pub3.

Women who undergo uterine artery embolization (UAE) for the treatment of symptomatic uterine fibroids are just as satisfied with the outcome as women treated with hysterectomy or myomectomy, according to this 2012 review from the Cochrane Database.

Gupta and colleagues found similar patient-satisfaction rates at 5 years (odds ratio [OR] 0.9; 95% confidence interval [CI], 0.45–1.8), although women undergoing UAE were more likely to require additional interventions within 2 years (56 additional interventions per 1,000 women for surgery vs 250 per 1,000 women for UAE; OR, 5.64).

Details and general findings
Gupta and colleagues selected randomized, controlled trials comparing UAE with surgery:

• three trials of UAE versus abdominal hysterectomy (n = 291)
• one trial of UAE versus hysterectomy or myomectomy (the specific surgery was determined by patient preference) (n = 157)
• one trial of UAE versus myomectomy in women desiring future childbearing (n = 121).

In these trials, UAE was bilateral and involved the use of permanent embolic material.

Among the findings:

• Costs were lower with UAE, as assessed by measuring the duration of the procedure, length of hospitalization, and time to resumption of normal activities.
• Ovarian-failure rates were comparable between women in the UAE and surgery groups. Ovarian function was assessed by measuring follicle-stimulating hormone (FSH), although FSH thresholds varied in some of the studies.
• Pregnancy was less likely after UAE than after myomectomy. In the trial comparing UAE with myomectomy, 26 women later tried to conceive after UAE versus 40 after myomectomy. Significantly fewer women became pregnant after UAE (OR, 0.29; 95% CI, 0.10–0.85).

Related Article: Update on Fertility  G. David Adamson, MD; Mary E. Abusief, MD (February 2014)

Bleeding outcomes were not measured
Strengths of this systematic review are its inclusion of high-quality, randomized, controlled trials and its assessment of ovarian-failure rates. However, a major weakness is the fact that its design does not allow for discrete evaluation of bleeding outcomes. Nor can its findings be broken down by the type of leiomyoma being treated.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This review demonstrates that women are satisfied with outcomes five years after UAE and that ovarian failure is not more common after UAE than after surgery. Although the available evidence demonstrates that pregnancy following UAE is possible, women requiring a surgical procedure for AUB-L who are uncertain about their childbearing plans or who are hoping to conceive should be encouraged to select myomectomy as their intervention of choice.

AUB-A: FOR ADENOMYOSIS-ASSOCIATED AUB, CONSIDER THE LNG-IUS AS AN ALTERNATIVE TO HYSTERECTOMY

Ozdegirmenci O, Kayikcioglu F, Akgul MA, et al. Comparison of levonorgestrel intrauterine system versus hysterectomy on efficacy and quality of life in patients with adenomyosis. Fertil Steril. 2011;95(2):497–502.

In a small randomized, controlled trial of the levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena) versus hysterectomy for adenomyosis-associated AUB, women allocated to the LNG-IUS experienced a reduction in bleeding and comparable gains in hemoglobin values during the first year of use. Both the LNG-IUS and hysterectomy improved health-related quality of life, but the LNG-IUS was associated with superior improvements in measures of psychological and social functioning.

Related Article: Update: Minimally invasive gynecology  Amy Garcia, MD (April 2013)

Details and general findings of the trial
Eighty-six women were enrolled in the trial after exclusion of endometrial pathology as a cause of their heavy menstrual bleeding and after transvaginal ultrasound and magnetic resonance imaging findings were consistent with the diagnosis of adenomyosis. Participants then were randomly assigned to undergo hysterectomy or insertion of an LNG-IUS (43 women in each group). At baseline, the mean (SD) age was 44.28 (4.36) years among women in the LNG-IUS group versus 46.38 (3.76) years among women undergoing hysterectomy (P = .032), a statistical difference that I suspect is not clinically significant.

Menstrual bleeding, hemoglobin levels, and quality of life were assessed prior to insertion or surgery, and again at 6- and 12-month follow-up. Eleven women in the hysterectomy group were lost to follow-up.

General findings of the trial include:

• Women in the LNG-IUS group had a mean reduction in the volume of menstrual bleeding—as measured by the number of pads used—from two pads to one pad at 6 months, remaining at that level until 12 months. Serum hemoglobin levels increased from a median of just over
  11 g/dL at the time of insertion to 13 g/dL at 6 months and slightly higher at 12 months. In the five self-reported quality-of-life domains assessed (physical, psychological, social, environmental, and a national environmental domain), women using the LNG-IUS demonstrated improvement in all five.
• Women in the hysterectomy group were treated using an abdominal surgical approach, with one patient experiencing postoperative wound infection that required secondary suture. Postoperative pathologic analysis found that 21 of these women (65.6%) had adenomyosis, six women (18.8%) had myomas, three women (9.4%) had both adenomyosis and a myoma, and two women (6.2%) had a normal uterus. Serum hemoglobin levels increased from a median of roughly 10.5 g/dL at the time of treatment to 13 g/dL at 6 months and slightly higher at 12 months. (There were no statistically significant differences in hemoglobin values between the LNG-IUS and hysterectomy groups at any point in the study.) Quality of life improved in three of the five domains assessed (physical and both environmental domains).

Although 11 women were lost to follow-up, this trial appeared to have an adequate sample size to examine the selected outcomes, and the population was well defined.

Two weaknesses were the limited follow-up (only 12 months) and the use of quality-of-life measures designed for a Turkish population (the trial was conducted in Turkey), which may or may not be fully applicable to a US population.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
The relationship of adenomyosis to gynecologic symptoms, including heavy menstrual bleeding and dysmenorrhea, needs further study. However, this trial confirmed that transvaginal ultrasound is helpful in the nonsurgical diagnosis of adenomyosis and suggests that the LNG-IUS may be as effective at 1 year as hysterectomy for the treatment of adenomyosis-associated heavy menstrual bleeding (AUB-A).
Clinicians who perform office-based ultrasound to assess AUB should familiarize themselves with the criteria for ultrasonic diagnosis of adenomyosis. These criteria include the presence of heterogeneous myometrial echogenicity, a loss of clarity of the endo-myometrial interface, typically radially oriented linear striations, the appearance of myometrial cysts, and an overall globular enlarged uterus characterized by asymmetric thickening of the myometrium.²
In patients with heavy menstrual bleeding who have these findings, particularly if there is coexistent dysmenorrhea and uterine tenderness, it behooves the clinician to consider the LNG-IUS as first-line therapy, especially for women who wish to preserve fertility, but also for women for whom fertility is not an issue.
There is some evidence that the therapeutic effect of the LNG-IUS containing 20 µg of levonorgestrel may start to fade at 2 or 3 years, a possibility that should be shared with patients.³ Other features, such as cavity size, thickness of the myometrium, and the coexistence of clinically relevant leiomyomas, have not been evaluated but may have an impact on the clinical response.

AUB-I: LOW-DOSE DOXYCYCLINE REDUCES THE TIME TO AMENORRHEA IN USERS OF CONTINUOUS ORAL CONTRACEPTIVES

Kaneshiro B, Edelman A, Carlson NE, Nichols M, Forbes MM, Jensen J. A randomized controlled trial of subantimicrobial-dose doxycycline to prevent unscheduled bleeding with continuous oral contraceptive pill use. Contraception. 2012;85(4):351–358.

Unscheduled bleeding is the most common complaint among women who use continuous combination oral contraceptives (OCs). Because unscheduled bleeding has been correlated with the upregulation of matrix metalloprotineases (MMPs), Kaneshiro and colleagues conducted a randomized, controlled trial of doxycycline (an MMP inhibitor) versus placebo among users of continuous OCs. The addition of doxycycline to the OC regimen did not significantly reduce unscheduled bleeding during the first 84 days of use, but it did shorten the time required to achieve amenorrhea (mean of 61.7 days for doxycycline vs 85.2 days for placebo; standard error [SE], 7.7 vs 6.7, respectively; P = .03).

Related Article: Big step forward and downward: An OC with 10 μg of estrogen  Robert L. Barbieri, MD (Editorial, May 2011)

Details and general findings of the trial
Participants (n = 65) were healthy women aged 18 to 45 years who had no contraindications to continuous use of combination OCs. Prior to enrollment, they all had used cyclic combination contraception (pill, patch, or ring) without unscheduled bleeding, thereby avoiding the “transition bleeding” that often occurs when continuous OCs are initiated.

All women in the trial were started on continuous OCs (20 µg ethinyl estradiol with 100 µg levonorgestrel; Aviane) and then randomly assigned to receive one of the following for 84 days in addition to the OC:

• doxycycline 40 mg daily (controlled-release Oracea), a subantimicrobial dose
• placebo.

After 84 days, doxycycline was discontinued, and participants were observed for an additional 28 days on the OC regimen alone for the documentation of bleeding patterns.

General findings:

• The number of bleeding and spotting days decreased in both groups over the course of the study.
• During the first 84 days of the trial, bleeding and spotting occurred among a median of 11 and 17 women in the doxycycline and placebo groups, respectively, and bleeding alone (without spotting) occurred in a median 3 and 4 women in the doxycycline and placebo groups, respectively.
• During the 28-day observation period, bleeding and spotting occurred among a median of 0 and 6 women in the doxycycline and placebo groups, respectively. Bleeding alone (without spotting) was absent in both groups.
• Women in the doxycycline group were significantly less likely to report side effects such as headache, depressed mood, and abdominal cramping. However, they were more likely to prefer continuous OCs without doxycycline, compared with women receiving placebo (16.1% vs 10.7%).

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This trial increases our insight into AUB associated with the use of progestins and suggests that concomitant doxycycline may reduce unscheduled bleeding and spotting in women using continuous combination OCs. The trial was of adequate sample size for the primary outcomes, lending credence to its findings, although longer-term data would be helpful.
I have included this trial for two reasons:
It offers useful information regarding the mechanisms and potential prevention or reduction of AUB-I in users of continuous combined estrogen-progestin contraception.
Doxycycline is one of the agents covered in a Cochrane review of high-quality research into AUB-I in women using progestin-only products, including injectables, implantables, intrauterine systems, and oral agents.4 Estrogens have been shown to have some value in reducing breakthrough bleeding associated with depot medroxyprogesterone acetate, and individual use of tranexamic acid or doxycycline has shown value in terminating an episode of breakthrough bleeding in women using progestin-only contraceptives.

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ALL in the bone marrow

Inhibiting two biosynthesis pathways can override treatment resistance in acute lymphoblastic leukemia (ALL), preclinical research suggests.

Researchers found that inhibiting only one pathway did not effectively kill ALL cells. The cells simply used another pathway to replicate their DNA and continue dividing.

But inhibiting both pathways induced apoptosis in human leukemia cells and reduced tumor burden in mouse models of T- and B-cell ALL.

“This new, dual-targeting approach shows that we can overcome the redundancy in DNA synthesis in ALL cells and identifies a potential target for metabolic intervention in ALL, and possibly in other hematological cancers,” said study author Caius Radu, MD, of the University of California, Los Angeles.

He and his colleagues described this approach in The Journal of Experimental Medicine.

The research began with the knowledge that deoxyribonucleotide triphosphates, including deoxycytidine triphosphate (dCTP), are required for DNA replication, which is necessary for cell division. And dCTP can be produced by the de novo pathway or the nucleoside salvage pathway.

Dr Radu and his colleagues discovered that inhibiting the de novo pathway with the compound thymidine caused leukemia cells to switch to the nucleoside salvage pathway for dCTP production.

However, inhibiting both the de novo and nucleoside salvage pathways prevented dCTP production and proved lethal for leukemia cells.

A number of experiments elicited these results. In one, the researchers knocked down the deoxycytidine kinase (dCK) in human T-ALL cells to inhibit the nucleoside salvage pathway. Then, they administered thymidine to inhibit the de novo pathway. This resulted in dCTP depletion, stalled DNA replication, replication stress, DNA damage, and apoptosis.

The researchers also used the small-molecule inhibitor DI-39 to target dCK. They found that co-administration of DI-39 and thymidine induced replication stress and apoptosis in several leukemia cell lines: CEM, Jurkat, MOLT-4, NALM-6 and RS4;116.

The team then tested DI-39 and thymidine in mice bearing CEM tumors. They found the combination reduced tumor growth in mice bearing established, subcutaneous CEM xenografts and in mice with systemic T-ALL.

In the systemic T-ALL model, treatment with thymidine alone resulted in a 7-fold reduction in tumor burden compared to vehicle control or DI-39 alone. But when thymidine and DI-39 were administered together, mice saw a 100-fold reduction in tumor burden compared to thymidine alone.

The thymidine-DI-39 combination also proved effective against B-ALL cells and in a mouse model of B-ALL. However, the effects were not as great as those observed in T-ALL.

Finally, the researchers evaluated the effects of thymidine and DI-39 in hematopoietic progenitor cells. They looked at the Lineage^- Sca-1⁺ c-Kit⁺ hematopoietic stem cell population, as well as short-term, long-term, and multipotent progenitor hematopoietic progenitor cells.

There was a minor decrease in the percentage of Lineage^- Sca-1⁺ c-Kit⁺ cells after thymidine treatment. However, there were no other significant changes in progenitor cells between the treatment and control groups. Why leukemic cells and normal hematopoietic progenitors respond so differently to this treatment requires further investigation, the researchers said.

But they also noted that this study advances our understanding of DNA synthesis in leukemic cells and suggests that targeted metabolic intervention could be a new therapeutic approach in ALL.

ALL in the bone marrow

Inhibiting two biosynthesis pathways can override treatment resistance in acute lymphoblastic leukemia (ALL), preclinical research suggests.

Researchers found that inhibiting only one pathway did not effectively kill ALL cells. The cells simply used another pathway to replicate their DNA and continue dividing.

But inhibiting both pathways induced apoptosis in human leukemia cells and reduced tumor burden in mouse models of T- and B-cell ALL.

“This new, dual-targeting approach shows that we can overcome the redundancy in DNA synthesis in ALL cells and identifies a potential target for metabolic intervention in ALL, and possibly in other hematological cancers,” said study author Caius Radu, MD, of the University of California, Los Angeles.

He and his colleagues described this approach in The Journal of Experimental Medicine.

The research began with the knowledge that deoxyribonucleotide triphosphates, including deoxycytidine triphosphate (dCTP), are required for DNA replication, which is necessary for cell division. And dCTP can be produced by the de novo pathway or the nucleoside salvage pathway.

Dr Radu and his colleagues discovered that inhibiting the de novo pathway with the compound thymidine caused leukemia cells to switch to the nucleoside salvage pathway for dCTP production.

However, inhibiting both the de novo and nucleoside salvage pathways prevented dCTP production and proved lethal for leukemia cells.

A number of experiments elicited these results. In one, the researchers knocked down the deoxycytidine kinase (dCK) in human T-ALL cells to inhibit the nucleoside salvage pathway. Then, they administered thymidine to inhibit the de novo pathway. This resulted in dCTP depletion, stalled DNA replication, replication stress, DNA damage, and apoptosis.

The researchers also used the small-molecule inhibitor DI-39 to target dCK. They found that co-administration of DI-39 and thymidine induced replication stress and apoptosis in several leukemia cell lines: CEM, Jurkat, MOLT-4, NALM-6 and RS4;116.

The team then tested DI-39 and thymidine in mice bearing CEM tumors. They found the combination reduced tumor growth in mice bearing established, subcutaneous CEM xenografts and in mice with systemic T-ALL.

In the systemic T-ALL model, treatment with thymidine alone resulted in a 7-fold reduction in tumor burden compared to vehicle control or DI-39 alone. But when thymidine and DI-39 were administered together, mice saw a 100-fold reduction in tumor burden compared to thymidine alone.

The thymidine-DI-39 combination also proved effective against B-ALL cells and in a mouse model of B-ALL. However, the effects were not as great as those observed in T-ALL.

Finally, the researchers evaluated the effects of thymidine and DI-39 in hematopoietic progenitor cells. They looked at the Lineage^- Sca-1⁺ c-Kit⁺ hematopoietic stem cell population, as well as short-term, long-term, and multipotent progenitor hematopoietic progenitor cells.

There was a minor decrease in the percentage of Lineage^- Sca-1⁺ c-Kit⁺ cells after thymidine treatment. However, there were no other significant changes in progenitor cells between the treatment and control groups. Why leukemic cells and normal hematopoietic progenitors respond so differently to this treatment requires further investigation, the researchers said.

But they also noted that this study advances our understanding of DNA synthesis in leukemic cells and suggests that targeted metabolic intervention could be a new therapeutic approach in ALL.

ALL in the bone marrow

Inhibiting two biosynthesis pathways can override treatment resistance in acute lymphoblastic leukemia (ALL), preclinical research suggests.

Researchers found that inhibiting only one pathway did not effectively kill ALL cells. The cells simply used another pathway to replicate their DNA and continue dividing.

But inhibiting both pathways induced apoptosis in human leukemia cells and reduced tumor burden in mouse models of T- and B-cell ALL.

“This new, dual-targeting approach shows that we can overcome the redundancy in DNA synthesis in ALL cells and identifies a potential target for metabolic intervention in ALL, and possibly in other hematological cancers,” said study author Caius Radu, MD, of the University of California, Los Angeles.

He and his colleagues described this approach in The Journal of Experimental Medicine.

The research began with the knowledge that deoxyribonucleotide triphosphates, including deoxycytidine triphosphate (dCTP), are required for DNA replication, which is necessary for cell division. And dCTP can be produced by the de novo pathway or the nucleoside salvage pathway.

Dr Radu and his colleagues discovered that inhibiting the de novo pathway with the compound thymidine caused leukemia cells to switch to the nucleoside salvage pathway for dCTP production.

However, inhibiting both the de novo and nucleoside salvage pathways prevented dCTP production and proved lethal for leukemia cells.

A number of experiments elicited these results. In one, the researchers knocked down the deoxycytidine kinase (dCK) in human T-ALL cells to inhibit the nucleoside salvage pathway. Then, they administered thymidine to inhibit the de novo pathway. This resulted in dCTP depletion, stalled DNA replication, replication stress, DNA damage, and apoptosis.

The researchers also used the small-molecule inhibitor DI-39 to target dCK. They found that co-administration of DI-39 and thymidine induced replication stress and apoptosis in several leukemia cell lines: CEM, Jurkat, MOLT-4, NALM-6 and RS4;116.

The team then tested DI-39 and thymidine in mice bearing CEM tumors. They found the combination reduced tumor growth in mice bearing established, subcutaneous CEM xenografts and in mice with systemic T-ALL.

In the systemic T-ALL model, treatment with thymidine alone resulted in a 7-fold reduction in tumor burden compared to vehicle control or DI-39 alone. But when thymidine and DI-39 were administered together, mice saw a 100-fold reduction in tumor burden compared to thymidine alone.

The thymidine-DI-39 combination also proved effective against B-ALL cells and in a mouse model of B-ALL. However, the effects were not as great as those observed in T-ALL.

Finally, the researchers evaluated the effects of thymidine and DI-39 in hematopoietic progenitor cells. They looked at the Lineage^- Sca-1⁺ c-Kit⁺ hematopoietic stem cell population, as well as short-term, long-term, and multipotent progenitor hematopoietic progenitor cells.

There was a minor decrease in the percentage of Lineage^- Sca-1⁺ c-Kit⁺ cells after thymidine treatment. However, there were no other significant changes in progenitor cells between the treatment and control groups. Why leukemic cells and normal hematopoietic progenitors respond so differently to this treatment requires further investigation, the researchers said.

But they also noted that this study advances our understanding of DNA synthesis in leukemic cells and suggests that targeted metabolic intervention could be a new therapeutic approach in ALL.

Adult chimpanzee
David Morgan & Crickette Sanz

Investigators have found evidence suggesting the malaria parasite Plasmodium vivax originated in Africa.

Until recently, the closest genetic relatives of human P vivax were found only in Asian macaques, leading researchers to believe that P vivax originated in Asia.

The current study, published in Nature Communications, showed that wild apes in central Africa are widely infected with parasites that are, genetically, nearly identical to human P vivax.

This finding overturns the dogma that P vivax originated in Asia, despite being most prevalent in humans there now, and also solves other questions about P vivax infection.

For example, it explains why the Duffy-null phenotype, which confers resistance to P vivax, is common among people indigenous to Africa. And it explains how travelers returning from regions where most people are Duffy-negative can be infected with P vivax.

Paul Sharp, PhD, of the University of Edinburgh in the UK, and his colleagues conducted this research, testing more than 5000 ape fecal samples from dozens of field stations and sanctuaries in Africa for P vivax DNA.

They found P vivax-like sequences in chimpanzees, western gorillas, and eastern gorillas, but not in bonobos. Ape P vivax was highly prevalent in wild communities, exhibiting infection rates consistent with stable transmission of the parasite within the wild apes.

To examine the evolutionary relationships between ape and human parasites, the researchers generated parasite DNA sequences from wild and sanctuary apes, as well as from a global sampling of human P vivax infections.

They constructed a family tree of the sequences and found that ape and human parasites were very closely related. But ape parasites were more diverse than the human parasites and did not group according to their host species. The human parasites formed a single lineage that fell within the branches of ape parasite sequences.

From these evolutionary relationships, the investigators concluded that P vivax is of African—not Asian—origin and that all existing human P vivax parasites evolved from a single ancestor that spread out of Africa.

The high prevalence of P vivax in wild apes, along with the recent finding of ape P vivax in a European traveler, indicates the existence of a substantial natural reservoir of P vivax in Africa.

Resolving the Duffy-negative paradox

Of the 5 Plasmodium species known to cause malaria in humans, P vivax is the most widespread. Although highly prevalent in Asia and Latin America, P vivax was thought to be absent from west and central Africa due to a mutation that causes the Duffy-negative phenotype in most indigenous African people.

P vivax parasites enter human red blood cells via the Duffy protein receptor. Because the absence of the receptor on the surface of these cells confers protection against P vivax malaria, this parasite has long been suspected to be the agent that selected for this mutation. However, this hypothesis had been difficult to reconcile with the belief that P vivax originated in Asia.

“Our finding that wild-living apes in central Africa show widespread infection with diverse strains of P vivax provides new insight into the evolutionary history of human P vivax and resolves the paradox that a mutation conferring resistance to P vivax occurs with high frequency in the very region where this parasite is absent in humans,” said study author Beatrice Hahn, MD, of the University of Pennsylvania in Philadelphia.

“One interpretation of the relationships that we observed is that a single host switch from apes gave rise to human P vivax, analogous to the origin of human P falciparum,” Dr Sharp added. “However, this seems unlikely in this case, since ape P vivax does not divide into gorilla- and chimpanzee-specific lineages.”

A more plausible scenario, according to the researchers, is that an ancestral P vivax stock was able to infect humans, gorillas, and chimpanzees in Africa until the Duffy-negative mutation started to spread—around 30,000 years ago—and eliminated P vivax from humans there.

Under this scenario, existing human-infecting P vivax is a parasite that survived after spreading out of Africa.

“The existence of a P vivax reservoir within the forests of central Africa has public health implications,” said study author Martine Peeters, PhD, of the Institut de Recherche pour le Développement and the University of Montpellier in France.

“First, it solves the mystery of P vivax infections in travelers returning from regions where 99% of the human population is Duffy-negative. It also raises the possibility that Duffy-positive humans whose work may bring them in close proximity to chimpanzees and gorillas may become infected by ape P vivax. This has already happened once and may happen again, with unknown consequences.”

The investigators are also concerned about the possibility that ape P vivax may spread via international travel to countries where human P vivax is actively transmitted. Since ape P vivax is more genetically diverse than human P vivax, it may have more versatility to escape treatment and prevention measures, especially if human and ape parasites were able to recombine.

Given what biologists know about P vivax’s ability to switch hosts, the researchers suggest it is important to screen Duffy-positive and Duffy-negative humans in west central Africa, as well as transmitting mosquito vectors, for the presence of ape P vivax. The team believes this information is necessary to inform malaria control and eradication efforts of the propensity of ape P vivax to cross over to humans.

The investigators are also planning to compare and contrast the molecular and biological properties of human and ape parasites to identify host-specific interactions and transmission requirements, thereby uncovering vulnerabilities that can be exploited to combat human malaria.

Adult chimpanzee
David Morgan & Crickette Sanz

Investigators have found evidence suggesting the malaria parasite Plasmodium vivax originated in Africa.

Until recently, the closest genetic relatives of human P vivax were found only in Asian macaques, leading researchers to believe that P vivax originated in Asia.

The current study, published in Nature Communications, showed that wild apes in central Africa are widely infected with parasites that are, genetically, nearly identical to human P vivax.

This finding overturns the dogma that P vivax originated in Asia, despite being most prevalent in humans there now, and also solves other questions about P vivax infection.

For example, it explains why the Duffy-null phenotype, which confers resistance to P vivax, is common among people indigenous to Africa. And it explains how travelers returning from regions where most people are Duffy-negative can be infected with P vivax.

Paul Sharp, PhD, of the University of Edinburgh in the UK, and his colleagues conducted this research, testing more than 5000 ape fecal samples from dozens of field stations and sanctuaries in Africa for P vivax DNA.

They found P vivax-like sequences in chimpanzees, western gorillas, and eastern gorillas, but not in bonobos. Ape P vivax was highly prevalent in wild communities, exhibiting infection rates consistent with stable transmission of the parasite within the wild apes.

To examine the evolutionary relationships between ape and human parasites, the researchers generated parasite DNA sequences from wild and sanctuary apes, as well as from a global sampling of human P vivax infections.

They constructed a family tree of the sequences and found that ape and human parasites were very closely related. But ape parasites were more diverse than the human parasites and did not group according to their host species. The human parasites formed a single lineage that fell within the branches of ape parasite sequences.

From these evolutionary relationships, the investigators concluded that P vivax is of African—not Asian—origin and that all existing human P vivax parasites evolved from a single ancestor that spread out of Africa.

The high prevalence of P vivax in wild apes, along with the recent finding of ape P vivax in a European traveler, indicates the existence of a substantial natural reservoir of P vivax in Africa.

Resolving the Duffy-negative paradox

Of the 5 Plasmodium species known to cause malaria in humans, P vivax is the most widespread. Although highly prevalent in Asia and Latin America, P vivax was thought to be absent from west and central Africa due to a mutation that causes the Duffy-negative phenotype in most indigenous African people.

P vivax parasites enter human red blood cells via the Duffy protein receptor. Because the absence of the receptor on the surface of these cells confers protection against P vivax malaria, this parasite has long been suspected to be the agent that selected for this mutation. However, this hypothesis had been difficult to reconcile with the belief that P vivax originated in Asia.

“Our finding that wild-living apes in central Africa show widespread infection with diverse strains of P vivax provides new insight into the evolutionary history of human P vivax and resolves the paradox that a mutation conferring resistance to P vivax occurs with high frequency in the very region where this parasite is absent in humans,” said study author Beatrice Hahn, MD, of the University of Pennsylvania in Philadelphia.

“One interpretation of the relationships that we observed is that a single host switch from apes gave rise to human P vivax, analogous to the origin of human P falciparum,” Dr Sharp added. “However, this seems unlikely in this case, since ape P vivax does not divide into gorilla- and chimpanzee-specific lineages.”

A more plausible scenario, according to the researchers, is that an ancestral P vivax stock was able to infect humans, gorillas, and chimpanzees in Africa until the Duffy-negative mutation started to spread—around 30,000 years ago—and eliminated P vivax from humans there.

Under this scenario, existing human-infecting P vivax is a parasite that survived after spreading out of Africa.

“The existence of a P vivax reservoir within the forests of central Africa has public health implications,” said study author Martine Peeters, PhD, of the Institut de Recherche pour le Développement and the University of Montpellier in France.

“First, it solves the mystery of P vivax infections in travelers returning from regions where 99% of the human population is Duffy-negative. It also raises the possibility that Duffy-positive humans whose work may bring them in close proximity to chimpanzees and gorillas may become infected by ape P vivax. This has already happened once and may happen again, with unknown consequences.”

The investigators are also concerned about the possibility that ape P vivax may spread via international travel to countries where human P vivax is actively transmitted. Since ape P vivax is more genetically diverse than human P vivax, it may have more versatility to escape treatment and prevention measures, especially if human and ape parasites were able to recombine.

Given what biologists know about P vivax’s ability to switch hosts, the researchers suggest it is important to screen Duffy-positive and Duffy-negative humans in west central Africa, as well as transmitting mosquito vectors, for the presence of ape P vivax. The team believes this information is necessary to inform malaria control and eradication efforts of the propensity of ape P vivax to cross over to humans.

The investigators are also planning to compare and contrast the molecular and biological properties of human and ape parasites to identify host-specific interactions and transmission requirements, thereby uncovering vulnerabilities that can be exploited to combat human malaria.

Adult chimpanzee
David Morgan & Crickette Sanz

Investigators have found evidence suggesting the malaria parasite Plasmodium vivax originated in Africa.

Until recently, the closest genetic relatives of human P vivax were found only in Asian macaques, leading researchers to believe that P vivax originated in Asia.

The current study, published in Nature Communications, showed that wild apes in central Africa are widely infected with parasites that are, genetically, nearly identical to human P vivax.

This finding overturns the dogma that P vivax originated in Asia, despite being most prevalent in humans there now, and also solves other questions about P vivax infection.

For example, it explains why the Duffy-null phenotype, which confers resistance to P vivax, is common among people indigenous to Africa. And it explains how travelers returning from regions where most people are Duffy-negative can be infected with P vivax.

Paul Sharp, PhD, of the University of Edinburgh in the UK, and his colleagues conducted this research, testing more than 5000 ape fecal samples from dozens of field stations and sanctuaries in Africa for P vivax DNA.

They found P vivax-like sequences in chimpanzees, western gorillas, and eastern gorillas, but not in bonobos. Ape P vivax was highly prevalent in wild communities, exhibiting infection rates consistent with stable transmission of the parasite within the wild apes.

To examine the evolutionary relationships between ape and human parasites, the researchers generated parasite DNA sequences from wild and sanctuary apes, as well as from a global sampling of human P vivax infections.

They constructed a family tree of the sequences and found that ape and human parasites were very closely related. But ape parasites were more diverse than the human parasites and did not group according to their host species. The human parasites formed a single lineage that fell within the branches of ape parasite sequences.

From these evolutionary relationships, the investigators concluded that P vivax is of African—not Asian—origin and that all existing human P vivax parasites evolved from a single ancestor that spread out of Africa.

The high prevalence of P vivax in wild apes, along with the recent finding of ape P vivax in a European traveler, indicates the existence of a substantial natural reservoir of P vivax in Africa.

Resolving the Duffy-negative paradox

Of the 5 Plasmodium species known to cause malaria in humans, P vivax is the most widespread. Although highly prevalent in Asia and Latin America, P vivax was thought to be absent from west and central Africa due to a mutation that causes the Duffy-negative phenotype in most indigenous African people.

P vivax parasites enter human red blood cells via the Duffy protein receptor. Because the absence of the receptor on the surface of these cells confers protection against P vivax malaria, this parasite has long been suspected to be the agent that selected for this mutation. However, this hypothesis had been difficult to reconcile with the belief that P vivax originated in Asia.

“Our finding that wild-living apes in central Africa show widespread infection with diverse strains of P vivax provides new insight into the evolutionary history of human P vivax and resolves the paradox that a mutation conferring resistance to P vivax occurs with high frequency in the very region where this parasite is absent in humans,” said study author Beatrice Hahn, MD, of the University of Pennsylvania in Philadelphia.

“One interpretation of the relationships that we observed is that a single host switch from apes gave rise to human P vivax, analogous to the origin of human P falciparum,” Dr Sharp added. “However, this seems unlikely in this case, since ape P vivax does not divide into gorilla- and chimpanzee-specific lineages.”

A more plausible scenario, according to the researchers, is that an ancestral P vivax stock was able to infect humans, gorillas, and chimpanzees in Africa until the Duffy-negative mutation started to spread—around 30,000 years ago—and eliminated P vivax from humans there.

Under this scenario, existing human-infecting P vivax is a parasite that survived after spreading out of Africa.

“The existence of a P vivax reservoir within the forests of central Africa has public health implications,” said study author Martine Peeters, PhD, of the Institut de Recherche pour le Développement and the University of Montpellier in France.

“First, it solves the mystery of P vivax infections in travelers returning from regions where 99% of the human population is Duffy-negative. It also raises the possibility that Duffy-positive humans whose work may bring them in close proximity to chimpanzees and gorillas may become infected by ape P vivax. This has already happened once and may happen again, with unknown consequences.”

The investigators are also concerned about the possibility that ape P vivax may spread via international travel to countries where human P vivax is actively transmitted. Since ape P vivax is more genetically diverse than human P vivax, it may have more versatility to escape treatment and prevention measures, especially if human and ape parasites were able to recombine.

Given what biologists know about P vivax’s ability to switch hosts, the researchers suggest it is important to screen Duffy-positive and Duffy-negative humans in west central Africa, as well as transmitting mosquito vectors, for the presence of ape P vivax. The team believes this information is necessary to inform malaria control and eradication efforts of the propensity of ape P vivax to cross over to humans.

The investigators are also planning to compare and contrast the molecular and biological properties of human and ape parasites to identify host-specific interactions and transmission requirements, thereby uncovering vulnerabilities that can be exploited to combat human malaria.