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.

A new evidence-based guideline on how to identify and treat patients with nonvalvular atrial fibrillation to prevent cardioembolic stroke from the American Academy of Neurology suggests when to conduct cardiac rhythm monitoring and offer anticoagulation, including newer agents in place of warfarin.

But the guideline might already be outdated in not considering the results of the recent CRYSTAL-AF study, in which long-term cardiac rhythm monitoring of patients with a previous cryptogenic stroke detected asymptomatic patients at a significantly higher rate than did standard monitoring methods.

The guideline also extends the routine use of anticoagulation for patients with nonvalvular atrial fibrillation (NVAF) who are generally undertreated or whose health was thought a possible barrier to their use, such as those aged 75 years or older, those with mild dementia, and those at moderate risk of falls.

"Cognizant of the global reach of the AAN [American Academy of Neurology], the guideline also examines the evidence base for a treatment alternative to warfarin or its analogues for patients in developing countries who may not have access to the new oral anticoagulants," said lead author Dr. Antonio Culebras in an interview.

"The World Health Organization has determined that atrial fibrillation has reached near-epidemic proportions," observed Dr. Culebras of the State University of New York, Syracuse. "Approximately 1 in 20 individuals with AF will have a stroke unless treated appropriately."

The risk for stroke among patients with NVAF is highest in those with a history of transient ischemic attack (TIA) or prior stroke, at an absolute value of around 10% per year. Patients with "lone NVAF," meaning they have no additional risk factors, have less than a 2% increased risk of stroke per year.

The AAN issued a practice parameter on this topic in 1998 (Neurology 1998;51:671-3). At the time, warfarin, adjusted to an international normalized ratio (INR) of 2.0, was, and largely remains, the recommended standard for patients at risk for cardioembolic stroke. Aspirin was the only recommended alterative for those unable to receive the vitamin K antagonist or who were deemed to be at low risk of stroke, although the evidence was scanty.

Since then, several new oral anticoagulant agents have become available, including the direct thrombin inhibitor dabigatran (Pradaxa), and two factor Xa inhibitors – rivaroxaban (Xarelto) and apixaban (Eliquis) – which have been shown to be at least as effective as, if not more effective than, warfarin. Cardiac rhythm monitoring via a variety of methods has also been introduced as a means to try to detect NVAF in asymptomatic patients.

The aim of the AAN guideline (Neurology 2014;82:716-24) was therefore to look at the latest evidence on the detection of AF using new technologies, as well as the use of treatments to reduce the risk of stroke without increasing the risk of hemorrhage versus the long-standing standard of therapy, warfarin. Data published from 1998 to March 2013 were considered in the preparation of the guideline.

Cardiac rhythm monitoring for NVAF

Seventeen studies were found that examined the use of cardiac monitoring technologies to detect new cases of NVAF. The most common methods used were 24-hour Holter monitoring and serial electrocardiograms, but some emerging evidence on newer technologies was included. The proportion of patients identified with NVAF ranged from 0% to 23%, with the average detection rate 10.7% in all of the studies included.

"The guideline addresses the question of long-term monitoring of patients with NVAF," Dr. Culebras said. "It recommends that clinicians ‘might’ [level C evidence] obtain outpatient cardiac rhythm studies in patients with cryptogenic stroke without known NVAF to identify patients with occult NVAF." He added that the guideline also recommends that monitoring might be needed for prolonged periods of 1 or more weeks rather than for shorter periods, such as 24 hours.

However, at the time the guideline was being prepared, recent data from the CRYSTAL-AF study were not available, and this means the guideline is already outdated, Dr. Richard A. Bernstein, professor of neurology at Northwestern University, Chicago, said in an interview. He was not a guideline author.

Dr. Bernstein was on the steering committee for the CRYSTAL-AF trial, which assessed the performance of Medtronic’s Reveal XT Insertable Cardiac Monitor and found that the implanted device could detect NVAF better than serial ECGs or Holter monitoring (8.6% vs. 1.4%; P = .0006); most (74%) cases of NVAF found were asymptomatic.*

"CRYSTAL-AF represents the state of the art for cardiac monitoring in cryptogenic stroke patients and makes the AAN guidelines obsolete," Dr. Berstein said. "[The study] shows that even intermediate-term monitoring (less than 1 month) will miss the majority of AF in this population, and that most of the AF we find with long-term (greater than 1 year) monitoring is likely to be clinically significant."

With regard to the AAN guideline, he added: "There is no discussion of truly long-term monitoring in the guideline, which is unfortunate." That said, "anything that gets neurologists thinking about long-term cardiac monitoring is likely to be beneficial."

Anticoagulation for stroke prevention

The AAN guideline also provides general recommendations on the use of novel oral anticoagulant agents (NOACs) as alternatives to warfarin. Specifically, it notes that in comparison with warfarin, these NOACs are probably at least as effective (rivaroxaban) or more effective (dabigatran and apixaban). Additionally, while apixaban is also likely to be more effective than aspirin, it is associated with a similar risk for bleeding. NOACs have the following advantages over warfarin: an overall lower risk of intracranial hemorrhage and no need for routine anticoagulant monitoring.

From a practical perspective, the AAN guideline suggests that clinicians have the following options available: warfarin to reach an INR of 2.0-3.0, dabigatran 150 mg twice daily, rivaroxaban 15-20 mg/dL, apixaban 2.5-5 mg twice a day, and triflusal 600 mg plus acenocoumarol to reach an INR target of 1.25-2.0. If a patient is already taking warfarin and is well controlled, then they should remain on that therapy and not switch to a newer oral anticoagulant.

The guideline also notes that clopidogrel plus aspirin is probably less effective than warfarin, but the combination is probably better than aspirin alone. However, the risk of hemorrhage is higher.

Where used, triflusal plus acenocoumarol is "likely more effective" than acenocoumarol alone. Triflusal is an antiplatelet drug related to aspirin, used in Europe, Latin America, and Southeast Asia. Acenocoumarol is mostly used in European countries.

Dr. Culebras explained that the guideline was not intended to dictate which treatment to use. "The guideline leaves room on purpose for clinicians to use their judgment," he said. "The overall objective of the guideline is to reduce therapeutic uncertainty and not to issue commandments for treatment."

Although Dr. Bernstein was critical of the guidelines for not advocating the use of anticoagulants strongly enough, he said that the recommendations on anticoagulant choice are "reasonable in that they impute potential clinical profiles of patients who might particularly benefit from one NOAC over another, without making a claim that these recommendations are based on solid data. This reflects how doctors make decisions when we don’t have direct comparative studies, and I think that is helpful."

The guideline was developed with financial support from the American Academy of Neurology. None of the authors received reimbursement, honoraria, or stipends for their participation in the development of the guideline.

Dr. Culebras has received one-time funding for travel from J. Uriach & Co, and he serves on the editorial boards of MedLink, UpToDate.com, and the International Journal of Stroke. He has received royalties from Informa Healthcare and Cambridge University Press, and has held stock in Clinical Stroke Research. Other authors reported current or past ties to companies marketing oral anticoagulants and stroke treatments.

Dr. Bernstein was on the steering committee for the CRYSTAL-AF study and is a paid speaker, researcher, and consultant for Medtronic, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, and Lifewatch.

*Correction, 4/8/2014: The article previously misstated what the implantable device was detecting in the CRYSTAL-AF study.

A new evidence-based guideline on how to identify and treat patients with nonvalvular atrial fibrillation to prevent cardioembolic stroke from the American Academy of Neurology suggests when to conduct cardiac rhythm monitoring and offer anticoagulation, including newer agents in place of warfarin.

But the guideline might already be outdated in not considering the results of the recent CRYSTAL-AF study, in which long-term cardiac rhythm monitoring of patients with a previous cryptogenic stroke detected asymptomatic patients at a significantly higher rate than did standard monitoring methods.

The guideline also extends the routine use of anticoagulation for patients with nonvalvular atrial fibrillation (NVAF) who are generally undertreated or whose health was thought a possible barrier to their use, such as those aged 75 years or older, those with mild dementia, and those at moderate risk of falls.

"Cognizant of the global reach of the AAN [American Academy of Neurology], the guideline also examines the evidence base for a treatment alternative to warfarin or its analogues for patients in developing countries who may not have access to the new oral anticoagulants," said lead author Dr. Antonio Culebras in an interview.

"The World Health Organization has determined that atrial fibrillation has reached near-epidemic proportions," observed Dr. Culebras of the State University of New York, Syracuse. "Approximately 1 in 20 individuals with AF will have a stroke unless treated appropriately."

The risk for stroke among patients with NVAF is highest in those with a history of transient ischemic attack (TIA) or prior stroke, at an absolute value of around 10% per year. Patients with "lone NVAF," meaning they have no additional risk factors, have less than a 2% increased risk of stroke per year.

The AAN issued a practice parameter on this topic in 1998 (Neurology 1998;51:671-3). At the time, warfarin, adjusted to an international normalized ratio (INR) of 2.0, was, and largely remains, the recommended standard for patients at risk for cardioembolic stroke. Aspirin was the only recommended alterative for those unable to receive the vitamin K antagonist or who were deemed to be at low risk of stroke, although the evidence was scanty.

Since then, several new oral anticoagulant agents have become available, including the direct thrombin inhibitor dabigatran (Pradaxa), and two factor Xa inhibitors – rivaroxaban (Xarelto) and apixaban (Eliquis) – which have been shown to be at least as effective as, if not more effective than, warfarin. Cardiac rhythm monitoring via a variety of methods has also been introduced as a means to try to detect NVAF in asymptomatic patients.

The aim of the AAN guideline (Neurology 2014;82:716-24) was therefore to look at the latest evidence on the detection of AF using new technologies, as well as the use of treatments to reduce the risk of stroke without increasing the risk of hemorrhage versus the long-standing standard of therapy, warfarin. Data published from 1998 to March 2013 were considered in the preparation of the guideline.

Cardiac rhythm monitoring for NVAF

Seventeen studies were found that examined the use of cardiac monitoring technologies to detect new cases of NVAF. The most common methods used were 24-hour Holter monitoring and serial electrocardiograms, but some emerging evidence on newer technologies was included. The proportion of patients identified with NVAF ranged from 0% to 23%, with the average detection rate 10.7% in all of the studies included.

"The guideline addresses the question of long-term monitoring of patients with NVAF," Dr. Culebras said. "It recommends that clinicians ‘might’ [level C evidence] obtain outpatient cardiac rhythm studies in patients with cryptogenic stroke without known NVAF to identify patients with occult NVAF." He added that the guideline also recommends that monitoring might be needed for prolonged periods of 1 or more weeks rather than for shorter periods, such as 24 hours.

However, at the time the guideline was being prepared, recent data from the CRYSTAL-AF study were not available, and this means the guideline is already outdated, Dr. Richard A. Bernstein, professor of neurology at Northwestern University, Chicago, said in an interview. He was not a guideline author.

Dr. Bernstein was on the steering committee for the CRYSTAL-AF trial, which assessed the performance of Medtronic’s Reveal XT Insertable Cardiac Monitor and found that the implanted device could detect NVAF better than serial ECGs or Holter monitoring (8.6% vs. 1.4%; P = .0006); most (74%) cases of NVAF found were asymptomatic.*

"CRYSTAL-AF represents the state of the art for cardiac monitoring in cryptogenic stroke patients and makes the AAN guidelines obsolete," Dr. Berstein said. "[The study] shows that even intermediate-term monitoring (less than 1 month) will miss the majority of AF in this population, and that most of the AF we find with long-term (greater than 1 year) monitoring is likely to be clinically significant."

With regard to the AAN guideline, he added: "There is no discussion of truly long-term monitoring in the guideline, which is unfortunate." That said, "anything that gets neurologists thinking about long-term cardiac monitoring is likely to be beneficial."

Anticoagulation for stroke prevention

The AAN guideline also provides general recommendations on the use of novel oral anticoagulant agents (NOACs) as alternatives to warfarin. Specifically, it notes that in comparison with warfarin, these NOACs are probably at least as effective (rivaroxaban) or more effective (dabigatran and apixaban). Additionally, while apixaban is also likely to be more effective than aspirin, it is associated with a similar risk for bleeding. NOACs have the following advantages over warfarin: an overall lower risk of intracranial hemorrhage and no need for routine anticoagulant monitoring.

From a practical perspective, the AAN guideline suggests that clinicians have the following options available: warfarin to reach an INR of 2.0-3.0, dabigatran 150 mg twice daily, rivaroxaban 15-20 mg/dL, apixaban 2.5-5 mg twice a day, and triflusal 600 mg plus acenocoumarol to reach an INR target of 1.25-2.0. If a patient is already taking warfarin and is well controlled, then they should remain on that therapy and not switch to a newer oral anticoagulant.

The guideline also notes that clopidogrel plus aspirin is probably less effective than warfarin, but the combination is probably better than aspirin alone. However, the risk of hemorrhage is higher.

Where used, triflusal plus acenocoumarol is "likely more effective" than acenocoumarol alone. Triflusal is an antiplatelet drug related to aspirin, used in Europe, Latin America, and Southeast Asia. Acenocoumarol is mostly used in European countries.

Dr. Culebras explained that the guideline was not intended to dictate which treatment to use. "The guideline leaves room on purpose for clinicians to use their judgment," he said. "The overall objective of the guideline is to reduce therapeutic uncertainty and not to issue commandments for treatment."

Although Dr. Bernstein was critical of the guidelines for not advocating the use of anticoagulants strongly enough, he said that the recommendations on anticoagulant choice are "reasonable in that they impute potential clinical profiles of patients who might particularly benefit from one NOAC over another, without making a claim that these recommendations are based on solid data. This reflects how doctors make decisions when we don’t have direct comparative studies, and I think that is helpful."

The guideline was developed with financial support from the American Academy of Neurology. None of the authors received reimbursement, honoraria, or stipends for their participation in the development of the guideline.

Dr. Culebras has received one-time funding for travel from J. Uriach & Co, and he serves on the editorial boards of MedLink, UpToDate.com, and the International Journal of Stroke. He has received royalties from Informa Healthcare and Cambridge University Press, and has held stock in Clinical Stroke Research. Other authors reported current or past ties to companies marketing oral anticoagulants and stroke treatments.

Dr. Bernstein was on the steering committee for the CRYSTAL-AF study and is a paid speaker, researcher, and consultant for Medtronic, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, and Lifewatch.

*Correction, 4/8/2014: The article previously misstated what the implantable device was detecting in the CRYSTAL-AF study.

A new evidence-based guideline on how to identify and treat patients with nonvalvular atrial fibrillation to prevent cardioembolic stroke from the American Academy of Neurology suggests when to conduct cardiac rhythm monitoring and offer anticoagulation, including newer agents in place of warfarin.

But the guideline might already be outdated in not considering the results of the recent CRYSTAL-AF study, in which long-term cardiac rhythm monitoring of patients with a previous cryptogenic stroke detected asymptomatic patients at a significantly higher rate than did standard monitoring methods.

The guideline also extends the routine use of anticoagulation for patients with nonvalvular atrial fibrillation (NVAF) who are generally undertreated or whose health was thought a possible barrier to their use, such as those aged 75 years or older, those with mild dementia, and those at moderate risk of falls.

"Cognizant of the global reach of the AAN [American Academy of Neurology], the guideline also examines the evidence base for a treatment alternative to warfarin or its analogues for patients in developing countries who may not have access to the new oral anticoagulants," said lead author Dr. Antonio Culebras in an interview.

"The World Health Organization has determined that atrial fibrillation has reached near-epidemic proportions," observed Dr. Culebras of the State University of New York, Syracuse. "Approximately 1 in 20 individuals with AF will have a stroke unless treated appropriately."

The risk for stroke among patients with NVAF is highest in those with a history of transient ischemic attack (TIA) or prior stroke, at an absolute value of around 10% per year. Patients with "lone NVAF," meaning they have no additional risk factors, have less than a 2% increased risk of stroke per year.

The AAN issued a practice parameter on this topic in 1998 (Neurology 1998;51:671-3). At the time, warfarin, adjusted to an international normalized ratio (INR) of 2.0, was, and largely remains, the recommended standard for patients at risk for cardioembolic stroke. Aspirin was the only recommended alterative for those unable to receive the vitamin K antagonist or who were deemed to be at low risk of stroke, although the evidence was scanty.

Since then, several new oral anticoagulant agents have become available, including the direct thrombin inhibitor dabigatran (Pradaxa), and two factor Xa inhibitors – rivaroxaban (Xarelto) and apixaban (Eliquis) – which have been shown to be at least as effective as, if not more effective than, warfarin. Cardiac rhythm monitoring via a variety of methods has also been introduced as a means to try to detect NVAF in asymptomatic patients.

The aim of the AAN guideline (Neurology 2014;82:716-24) was therefore to look at the latest evidence on the detection of AF using new technologies, as well as the use of treatments to reduce the risk of stroke without increasing the risk of hemorrhage versus the long-standing standard of therapy, warfarin. Data published from 1998 to March 2013 were considered in the preparation of the guideline.

Cardiac rhythm monitoring for NVAF

Seventeen studies were found that examined the use of cardiac monitoring technologies to detect new cases of NVAF. The most common methods used were 24-hour Holter monitoring and serial electrocardiograms, but some emerging evidence on newer technologies was included. The proportion of patients identified with NVAF ranged from 0% to 23%, with the average detection rate 10.7% in all of the studies included.

"The guideline addresses the question of long-term monitoring of patients with NVAF," Dr. Culebras said. "It recommends that clinicians ‘might’ [level C evidence] obtain outpatient cardiac rhythm studies in patients with cryptogenic stroke without known NVAF to identify patients with occult NVAF." He added that the guideline also recommends that monitoring might be needed for prolonged periods of 1 or more weeks rather than for shorter periods, such as 24 hours.

However, at the time the guideline was being prepared, recent data from the CRYSTAL-AF study were not available, and this means the guideline is already outdated, Dr. Richard A. Bernstein, professor of neurology at Northwestern University, Chicago, said in an interview. He was not a guideline author.

Dr. Bernstein was on the steering committee for the CRYSTAL-AF trial, which assessed the performance of Medtronic’s Reveal XT Insertable Cardiac Monitor and found that the implanted device could detect NVAF better than serial ECGs or Holter monitoring (8.6% vs. 1.4%; P = .0006); most (74%) cases of NVAF found were asymptomatic.*

"CRYSTAL-AF represents the state of the art for cardiac monitoring in cryptogenic stroke patients and makes the AAN guidelines obsolete," Dr. Berstein said. "[The study] shows that even intermediate-term monitoring (less than 1 month) will miss the majority of AF in this population, and that most of the AF we find with long-term (greater than 1 year) monitoring is likely to be clinically significant."

With regard to the AAN guideline, he added: "There is no discussion of truly long-term monitoring in the guideline, which is unfortunate." That said, "anything that gets neurologists thinking about long-term cardiac monitoring is likely to be beneficial."

Anticoagulation for stroke prevention

The AAN guideline also provides general recommendations on the use of novel oral anticoagulant agents (NOACs) as alternatives to warfarin. Specifically, it notes that in comparison with warfarin, these NOACs are probably at least as effective (rivaroxaban) or more effective (dabigatran and apixaban). Additionally, while apixaban is also likely to be more effective than aspirin, it is associated with a similar risk for bleeding. NOACs have the following advantages over warfarin: an overall lower risk of intracranial hemorrhage and no need for routine anticoagulant monitoring.

From a practical perspective, the AAN guideline suggests that clinicians have the following options available: warfarin to reach an INR of 2.0-3.0, dabigatran 150 mg twice daily, rivaroxaban 15-20 mg/dL, apixaban 2.5-5 mg twice a day, and triflusal 600 mg plus acenocoumarol to reach an INR target of 1.25-2.0. If a patient is already taking warfarin and is well controlled, then they should remain on that therapy and not switch to a newer oral anticoagulant.

The guideline also notes that clopidogrel plus aspirin is probably less effective than warfarin, but the combination is probably better than aspirin alone. However, the risk of hemorrhage is higher.

Where used, triflusal plus acenocoumarol is "likely more effective" than acenocoumarol alone. Triflusal is an antiplatelet drug related to aspirin, used in Europe, Latin America, and Southeast Asia. Acenocoumarol is mostly used in European countries.

Dr. Culebras explained that the guideline was not intended to dictate which treatment to use. "The guideline leaves room on purpose for clinicians to use their judgment," he said. "The overall objective of the guideline is to reduce therapeutic uncertainty and not to issue commandments for treatment."

Although Dr. Bernstein was critical of the guidelines for not advocating the use of anticoagulants strongly enough, he said that the recommendations on anticoagulant choice are "reasonable in that they impute potential clinical profiles of patients who might particularly benefit from one NOAC over another, without making a claim that these recommendations are based on solid data. This reflects how doctors make decisions when we don’t have direct comparative studies, and I think that is helpful."

The guideline was developed with financial support from the American Academy of Neurology. None of the authors received reimbursement, honoraria, or stipends for their participation in the development of the guideline.

Dr. Culebras has received one-time funding for travel from J. Uriach & Co, and he serves on the editorial boards of MedLink, UpToDate.com, and the International Journal of Stroke. He has received royalties from Informa Healthcare and Cambridge University Press, and has held stock in Clinical Stroke Research. Other authors reported current or past ties to companies marketing oral anticoagulants and stroke treatments.

Dr. Bernstein was on the steering committee for the CRYSTAL-AF study and is a paid speaker, researcher, and consultant for Medtronic, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, and Lifewatch.

*Correction, 4/8/2014: The article previously misstated what the implantable device was detecting in the CRYSTAL-AF study.

I remember that day like it was yesterday, though it occurred more than a decade ago. I stood leaning over a black entertainment center in my family room, legs wobbly, heart weary – a surreal and solemn snapshot in time. From a speaker streamed a now-favorite Donnie McClurkin song, called "Stand," with its introspective lyrics: "You’ve prayed and you’ve cried ... . After you’ve done all you can, you just stand."

In the next room I could hear her softly gurgling on her secretions. I needed a moment, no, two or three moments, to collect my thoughts and pull myself together before I returned to face the nightmare I was living. My mother was actively dying in my guestroom. Why? I believed then and, today, many years later, believe just as strongly it was because she had not been getting her mammograms.

National Institutes of Health/Department of Health and Human Services

As a writer, sometimes I struggle with how personal to get in my blogs, but rest assured. I got her permission to share her story while she was still very lucid and competent. You see, she did not want others’ lives to end as hers was ending. She realized, in her final stages of life, that things would have likely been much different had she had her screening mammograms as recommended.

By the time of her diagnosis in her early 60s, the cancer had already spread. Would a mammogram in her late 50s have saved her life? I believe so, and I’m not alone. So I take issue with a recent article published in BMJ that downplays the significance of mammography (BMJ 2014;348:g366).

In 1980, Canadian researchers randomized 89,835 women, aged 40-59 to receive five annual mammograms or physical breast examinations. They followed these women over a 25-year period, and concluded that yearly mammography in women aged 40-59 did not decrease breast cancer mortality "beyond that of physical examination or usual care when adjuvant therapy for breast cancer is freely available."

Well, how many of us have taken care of women in their 50s, 40s, and even 30s with terminal breast cancer? How many of us would advise a mother, aunt, sister (or self) not to have routine mammography? Not many, I’m sure. There is the art of medicine and the science of medicine. Sometimes these two clash, but I believe the art of medicine is realizing that the science of medicine really doesn’t matter to dying patients and their family members. Sometimes, we have to act in the best interest of individual patients and not rely too heavily on the "data." Data changes, risk factors emerge, or research findings may prove to be skewed or wrong in hindsight. Explains Dr. Poornima Sharma, an oncologist/hematologist at the University of Maryland Baltimore-Washington Medical Center: "While the methodology, mammographic technique, and equipment used in the Canadian study is being assessed and compared to the mammography standards used in the United States, the standard in this country remains annual mammography starting at age 40."

 Still, many women consider themselves at low risk for breast cancer if they have no close relatives with the disease. As erroneous as this assumption may be, this subset of women may be particularly vulnerable to the implication that yearly mammography is not needed.

So do this: Discuss screening mammography with your own family and then use those feelings when a teachable moment presents itself at bedside.

Our patients rely on us to look into their eyes and give them our best advice. Even though I am a hospitalist, there are still those women I feel compelled to counsel about screening mammography, and this study will not lessen my fervor. 

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.

I remember that day like it was yesterday, though it occurred more than a decade ago. I stood leaning over a black entertainment center in my family room, legs wobbly, heart weary – a surreal and solemn snapshot in time. From a speaker streamed a now-favorite Donnie McClurkin song, called "Stand," with its introspective lyrics: "You’ve prayed and you’ve cried ... . After you’ve done all you can, you just stand."

In the next room I could hear her softly gurgling on her secretions. I needed a moment, no, two or three moments, to collect my thoughts and pull myself together before I returned to face the nightmare I was living. My mother was actively dying in my guestroom. Why? I believed then and, today, many years later, believe just as strongly it was because she had not been getting her mammograms.

National Institutes of Health/Department of Health and Human Services

As a writer, sometimes I struggle with how personal to get in my blogs, but rest assured. I got her permission to share her story while she was still very lucid and competent. You see, she did not want others’ lives to end as hers was ending. She realized, in her final stages of life, that things would have likely been much different had she had her screening mammograms as recommended.

By the time of her diagnosis in her early 60s, the cancer had already spread. Would a mammogram in her late 50s have saved her life? I believe so, and I’m not alone. So I take issue with a recent article published in BMJ that downplays the significance of mammography (BMJ 2014;348:g366).

In 1980, Canadian researchers randomized 89,835 women, aged 40-59 to receive five annual mammograms or physical breast examinations. They followed these women over a 25-year period, and concluded that yearly mammography in women aged 40-59 did not decrease breast cancer mortality "beyond that of physical examination or usual care when adjuvant therapy for breast cancer is freely available."

Well, how many of us have taken care of women in their 50s, 40s, and even 30s with terminal breast cancer? How many of us would advise a mother, aunt, sister (or self) not to have routine mammography? Not many, I’m sure. There is the art of medicine and the science of medicine. Sometimes these two clash, but I believe the art of medicine is realizing that the science of medicine really doesn’t matter to dying patients and their family members. Sometimes, we have to act in the best interest of individual patients and not rely too heavily on the "data." Data changes, risk factors emerge, or research findings may prove to be skewed or wrong in hindsight. Explains Dr. Poornima Sharma, an oncologist/hematologist at the University of Maryland Baltimore-Washington Medical Center: "While the methodology, mammographic technique, and equipment used in the Canadian study is being assessed and compared to the mammography standards used in the United States, the standard in this country remains annual mammography starting at age 40."

 Still, many women consider themselves at low risk for breast cancer if they have no close relatives with the disease. As erroneous as this assumption may be, this subset of women may be particularly vulnerable to the implication that yearly mammography is not needed.

So do this: Discuss screening mammography with your own family and then use those feelings when a teachable moment presents itself at bedside.

Our patients rely on us to look into their eyes and give them our best advice. Even though I am a hospitalist, there are still those women I feel compelled to counsel about screening mammography, and this study will not lessen my fervor. 

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.

I remember that day like it was yesterday, though it occurred more than a decade ago. I stood leaning over a black entertainment center in my family room, legs wobbly, heart weary – a surreal and solemn snapshot in time. From a speaker streamed a now-favorite Donnie McClurkin song, called "Stand," with its introspective lyrics: "You’ve prayed and you’ve cried ... . After you’ve done all you can, you just stand."

In the next room I could hear her softly gurgling on her secretions. I needed a moment, no, two or three moments, to collect my thoughts and pull myself together before I returned to face the nightmare I was living. My mother was actively dying in my guestroom. Why? I believed then and, today, many years later, believe just as strongly it was because she had not been getting her mammograms.

National Institutes of Health/Department of Health and Human Services

As a writer, sometimes I struggle with how personal to get in my blogs, but rest assured. I got her permission to share her story while she was still very lucid and competent. You see, she did not want others’ lives to end as hers was ending. She realized, in her final stages of life, that things would have likely been much different had she had her screening mammograms as recommended.

By the time of her diagnosis in her early 60s, the cancer had already spread. Would a mammogram in her late 50s have saved her life? I believe so, and I’m not alone. So I take issue with a recent article published in BMJ that downplays the significance of mammography (BMJ 2014;348:g366).

In 1980, Canadian researchers randomized 89,835 women, aged 40-59 to receive five annual mammograms or physical breast examinations. They followed these women over a 25-year period, and concluded that yearly mammography in women aged 40-59 did not decrease breast cancer mortality "beyond that of physical examination or usual care when adjuvant therapy for breast cancer is freely available."

Well, how many of us have taken care of women in their 50s, 40s, and even 30s with terminal breast cancer? How many of us would advise a mother, aunt, sister (or self) not to have routine mammography? Not many, I’m sure. There is the art of medicine and the science of medicine. Sometimes these two clash, but I believe the art of medicine is realizing that the science of medicine really doesn’t matter to dying patients and their family members. Sometimes, we have to act in the best interest of individual patients and not rely too heavily on the "data." Data changes, risk factors emerge, or research findings may prove to be skewed or wrong in hindsight. Explains Dr. Poornima Sharma, an oncologist/hematologist at the University of Maryland Baltimore-Washington Medical Center: "While the methodology, mammographic technique, and equipment used in the Canadian study is being assessed and compared to the mammography standards used in the United States, the standard in this country remains annual mammography starting at age 40."

 Still, many women consider themselves at low risk for breast cancer if they have no close relatives with the disease. As erroneous as this assumption may be, this subset of women may be particularly vulnerable to the implication that yearly mammography is not needed.

So do this: Discuss screening mammography with your own family and then use those feelings when a teachable moment presents itself at bedside.

Our patients rely on us to look into their eyes and give them our best advice. Even though I am a hospitalist, there are still those women I feel compelled to counsel about screening mammography, and this study will not lessen my fervor. 

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.

P falciparum parasites in the

gametocyte stage (blue) and

uninfected red blood cells

Credit: The Llinás lab

Results of 2 new studies suggest that a single regulatory protein acts as a master switch to trigger development of the sexual forms of malaria parasites.

It appears that the protein, AP2-G, is necessary for activating a set of genes that initiate the development of Plasmodium gametocytes, the only forms of the parasite that are infectious to mosquitoes.

This suggests that if researchers can target AP2-G, they can stop sexual parasites from forming.

And if the sexual forms of the parasite never develop in an infected person’s blood, none will enter the mosquito’s gut, and the mosquito will be unable to infect anyone else with malaria.

“Exciting opportunities now lie ahead for finding an effective way to break the chain of malaria transmission by preventing the malaria parasite from completing its full lifecycle,” said Manuel Llinás, PhD, a professor at Pennsylvania State University who was involved in both studies.

The 2 studies, which were published as letters to Nature, had remarkably similar results, despite the fact that the groups worked with 2 different malaria parasites—Plasmodium falciparum and Plasmodium berghei.

In one study, researchers analyzed the whole-genome sequences of 2 P falciparum strains that were unable to produce gametocytes. The only mutated, non-functional gene common to both strains was the AP2-G gene.

In the other study, researchers sequenced P berghei parasites that had lost their ability to make gametocytes. Again, the only common mutated gene in these parasites was AP2-G.

To confirm these observations, both groups of researchers disabled the AP2-G gene in parasites that could generate gametocytes.

As expected, disabling the gene prevented the parasites from producing gametocytes. But the parasites regained their ability to make gametocytes when the mutated gene was repaired.

These results, as well as results of additional experiments, suggest that sexual-stage malaria parasites are produced only when the AP2-G protein is in working order.

“Our research has demonstrated unequivocally that the AP2-G transcription factor protein is essential for flipping the switch that initiates the transformation of malaria parasites in the blood from the asexual stage to the critical sexual stage of their life cycle,” Dr Llinás said.

He and his colleagues believe their discovery is exciting for the future of malaria research. It could spur the development of a sexual-stage vaccine, which would help a person infected with malaria mount an immune response to prevent their parasites from being transmitted to a mosquito, effectively ending the life cycle for that person’s batch of malaria parasites.

P falciparum parasites in the

gametocyte stage (blue) and

uninfected red blood cells

Credit: The Llinás lab

Results of 2 new studies suggest that a single regulatory protein acts as a master switch to trigger development of the sexual forms of malaria parasites.

It appears that the protein, AP2-G, is necessary for activating a set of genes that initiate the development of Plasmodium gametocytes, the only forms of the parasite that are infectious to mosquitoes.

This suggests that if researchers can target AP2-G, they can stop sexual parasites from forming.

And if the sexual forms of the parasite never develop in an infected person’s blood, none will enter the mosquito’s gut, and the mosquito will be unable to infect anyone else with malaria.

“Exciting opportunities now lie ahead for finding an effective way to break the chain of malaria transmission by preventing the malaria parasite from completing its full lifecycle,” said Manuel Llinás, PhD, a professor at Pennsylvania State University who was involved in both studies.

The 2 studies, which were published as letters to Nature, had remarkably similar results, despite the fact that the groups worked with 2 different malaria parasites—Plasmodium falciparum and Plasmodium berghei.

In one study, researchers analyzed the whole-genome sequences of 2 P falciparum strains that were unable to produce gametocytes. The only mutated, non-functional gene common to both strains was the AP2-G gene.

In the other study, researchers sequenced P berghei parasites that had lost their ability to make gametocytes. Again, the only common mutated gene in these parasites was AP2-G.

To confirm these observations, both groups of researchers disabled the AP2-G gene in parasites that could generate gametocytes.

As expected, disabling the gene prevented the parasites from producing gametocytes. But the parasites regained their ability to make gametocytes when the mutated gene was repaired.

These results, as well as results of additional experiments, suggest that sexual-stage malaria parasites are produced only when the AP2-G protein is in working order.

“Our research has demonstrated unequivocally that the AP2-G transcription factor protein is essential for flipping the switch that initiates the transformation of malaria parasites in the blood from the asexual stage to the critical sexual stage of their life cycle,” Dr Llinás said.

He and his colleagues believe their discovery is exciting for the future of malaria research. It could spur the development of a sexual-stage vaccine, which would help a person infected with malaria mount an immune response to prevent their parasites from being transmitted to a mosquito, effectively ending the life cycle for that person’s batch of malaria parasites.

P falciparum parasites in the

gametocyte stage (blue) and

uninfected red blood cells

Credit: The Llinás lab

Results of 2 new studies suggest that a single regulatory protein acts as a master switch to trigger development of the sexual forms of malaria parasites.

It appears that the protein, AP2-G, is necessary for activating a set of genes that initiate the development of Plasmodium gametocytes, the only forms of the parasite that are infectious to mosquitoes.

This suggests that if researchers can target AP2-G, they can stop sexual parasites from forming.

And if the sexual forms of the parasite never develop in an infected person’s blood, none will enter the mosquito’s gut, and the mosquito will be unable to infect anyone else with malaria.

“Exciting opportunities now lie ahead for finding an effective way to break the chain of malaria transmission by preventing the malaria parasite from completing its full lifecycle,” said Manuel Llinás, PhD, a professor at Pennsylvania State University who was involved in both studies.

The 2 studies, which were published as letters to Nature, had remarkably similar results, despite the fact that the groups worked with 2 different malaria parasites—Plasmodium falciparum and Plasmodium berghei.

In one study, researchers analyzed the whole-genome sequences of 2 P falciparum strains that were unable to produce gametocytes. The only mutated, non-functional gene common to both strains was the AP2-G gene.

In the other study, researchers sequenced P berghei parasites that had lost their ability to make gametocytes. Again, the only common mutated gene in these parasites was AP2-G.

To confirm these observations, both groups of researchers disabled the AP2-G gene in parasites that could generate gametocytes.

As expected, disabling the gene prevented the parasites from producing gametocytes. But the parasites regained their ability to make gametocytes when the mutated gene was repaired.

These results, as well as results of additional experiments, suggest that sexual-stage malaria parasites are produced only when the AP2-G protein is in working order.

“Our research has demonstrated unequivocally that the AP2-G transcription factor protein is essential for flipping the switch that initiates the transformation of malaria parasites in the blood from the asexual stage to the critical sexual stage of their life cycle,” Dr Llinás said.

He and his colleagues believe their discovery is exciting for the future of malaria research. It could spur the development of a sexual-stage vaccine, which would help a person infected with malaria mount an immune response to prevent their parasites from being transmitted to a mosquito, effectively ending the life cycle for that person’s batch of malaria parasites.

Patient receiving chemotherapy

Credit: Rhoda Baer

The drug spironolactone could improve the efficacy of platinum-based chemotherapy by preventing tumor cell repair, according to research published in Chemistry & Biology.

The researchers knew that platinum-based chemotherapy drugs bind to cellular DNA to induce damage.

So they theorized that blocking DNA repair mechanisms would help potentiate chemotherapy by reducing cancer cells’ resistance to treatment.

The team focused their efforts on inhibiting nucleotide excision repair (NER), in which a damaged DNA fragment is replaced with an intact fragment.

Frédéric Coin, PhD, of the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France, and his colleagues screened more than 1200 drugs looking for one that would inhibit NER activity.

And they found that spironolactone—a drug already used to treat fluid retention, high blood pressure, and other conditions—affects NER activity.

Specifically, the team found that, when combined with platinum derivatives, spironolactone significantly increased cytotoxicity in ovarian and colon cancer cells.

As platinum-based chemotherapy is used to treat a range of cancers, similar results might occur in other malignancies as well.

The researchers also noted that, because spironolactone is already in use for other purposes, it doesn’t require a new application for marketing authorization. And its side effects are already known.

The team said this suggests that protocols testing spironolactone in combination with platinum-based chemotherapy could be organized rather quickly.

Patient receiving chemotherapy

Credit: Rhoda Baer

The drug spironolactone could improve the efficacy of platinum-based chemotherapy by preventing tumor cell repair, according to research published in Chemistry & Biology.

The researchers knew that platinum-based chemotherapy drugs bind to cellular DNA to induce damage.

So they theorized that blocking DNA repair mechanisms would help potentiate chemotherapy by reducing cancer cells’ resistance to treatment.

The team focused their efforts on inhibiting nucleotide excision repair (NER), in which a damaged DNA fragment is replaced with an intact fragment.

Frédéric Coin, PhD, of the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France, and his colleagues screened more than 1200 drugs looking for one that would inhibit NER activity.

And they found that spironolactone—a drug already used to treat fluid retention, high blood pressure, and other conditions—affects NER activity.

Specifically, the team found that, when combined with platinum derivatives, spironolactone significantly increased cytotoxicity in ovarian and colon cancer cells.

As platinum-based chemotherapy is used to treat a range of cancers, similar results might occur in other malignancies as well.

The researchers also noted that, because spironolactone is already in use for other purposes, it doesn’t require a new application for marketing authorization. And its side effects are already known.

The team said this suggests that protocols testing spironolactone in combination with platinum-based chemotherapy could be organized rather quickly.

Patient receiving chemotherapy

Credit: Rhoda Baer

The drug spironolactone could improve the efficacy of platinum-based chemotherapy by preventing tumor cell repair, according to research published in Chemistry & Biology.

The researchers knew that platinum-based chemotherapy drugs bind to cellular DNA to induce damage.

So they theorized that blocking DNA repair mechanisms would help potentiate chemotherapy by reducing cancer cells’ resistance to treatment.

The team focused their efforts on inhibiting nucleotide excision repair (NER), in which a damaged DNA fragment is replaced with an intact fragment.

Frédéric Coin, PhD, of the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France, and his colleagues screened more than 1200 drugs looking for one that would inhibit NER activity.

And they found that spironolactone—a drug already used to treat fluid retention, high blood pressure, and other conditions—affects NER activity.

Specifically, the team found that, when combined with platinum derivatives, spironolactone significantly increased cytotoxicity in ovarian and colon cancer cells.

As platinum-based chemotherapy is used to treat a range of cancers, similar results might occur in other malignancies as well.

The researchers also noted that, because spironolactone is already in use for other purposes, it doesn’t require a new application for marketing authorization. And its side effects are already known.

The team said this suggests that protocols testing spironolactone in combination with platinum-based chemotherapy could be organized rather quickly.