At least half of all cases of maternal morbidity and mortality could be prevented, or so studies suggest.^1,2

The main stumbling block?

Faulty communication.

That’s the word from the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, the American College of Nurse-Midwives, and the Association of Women’s Health, Obstetric and Neonatal Nurses.³

In a joint “blueprint” to transform communication and enhance the safety culture in intrapartum care, these organizations, led by Audrey Lyndon, PhD, RN, FAAN, from the University of California, San Francisco, School of Nursing, describe the extent of the problem, steps that various team members can take to improve safety, notable success stories, and communication strategies.³ In this article, the joint blueprint is summarized, with a focus on steps obstetricians can take to improve the intrapartum safety culture.

Scope of the problem
A study of more than 3,282 physicians, midwives, and registered nurses produced a troubling statistic: More than 90% of respondents said that they had “witnessed shortcuts, missing competencies, disrespect, or performance problems” during the preceding year of practice.⁴ Few of these clinicians reported that they had discussed their concerns with the parties involved.

A second study of 1,932 clinicians found that 34% of physicians, 40% of midwives, and 56% of registered nurses had witnessed patients being put at risk within the preceding 2 years by other team members’ inattentiveness or lack of responsiveness.⁵

These findings suggest that health care providers often witness weak links in intrapartum safety but do not always address or report them. Among the reasons team members may be hesitant to speak up when they perceive a potential problem:

Although Lyndon and colleagues acknowledge that it is impossible to eliminate adverse outcomes entirely or completely eradicate human error, they argue that significant improvements can be made by adopting a number of manageable strategies.

Recommended strategies
Lyndon and colleagues describe some of the challenges of effective communication in a health care setting:

Lyndon and colleagues go on to mention a number of strategies to improve communication, boost safety, and reduce medical errors.

1. Remember that the patient is part of the team
The patient and her family play a key role in identifying the potential for harm during labor and delivery, Lyndon and colleagues assert. They should be considered members of the intrapartum team, care should be patient-focused, and any communications from the patient should not only be heard but fully considered. In fact, explicit elicitation of her experience and concerns is recommended.

2. Consider that you might be part of the problem
It is human nature to attribute a communication problem to the other people involved, rather than take responsibility for it oneself. One potential solution to this mindset is team training, where all members are encouraged to communicate clearly and listen attentively. Organizations that have been successful at improving their culture of safety have implemented such training, as well as the use of checklists, training in fetal heart-rate monitoring, formation of a patient safety committee, external review of safety practices, and designation of a key clinician to lead the safety program and oversee team training.

3. Structure handoffs 
The team should standardize handoffs so that they occur smoothly and all channels of communication remain open and clear.

“Having structured formats for debriefing and handoffs are steps in the right direction, but solving the problem of communication breakdowns is more complicated than standardizing the flow and format of information transfer,” Lyndon and colleagues assert. “Indeed, solving communication breakdowns is a matter of individual, group, organizational, and professional responsibility for creating and sustaining an environment of mutual respect, curiosity, and accountability for behavior and performance.”³

4. Learn to communicate responsibly
“Differences of opinion about clinical assessments, goals of care, and the pathway to optimal outcomes are bound to occur with some regularity in the dynamic environment of labor and delivery,” note Lyndon and colleagues. “Every person has the responsibility to contribute to improving how we relate to and communicate with each other. Collectively, we must create environments in which every team member (woman, family member, physician, midwife, nurse, unit clerk, patient care assistant, or scrub tech) is comfortable expressing and discussing concerns about safety or performance, is encouraged to do so, and has the support of the team to articulate the rationale for and urgency of the concern without fear of put-downs, retribution, or receiving poor-quality care.”³

5. Be persistent and proactive
When team members have differing expectations and communication styles, useful approaches include structured communication tools such as situation, background, assessment, recommendation (SBAR); structured handoffs; board rounds; huddles; attentive listening; and explicit elicitation of the patient’s concerns and desires.³

If someone fails to pay attention to a concern you raise, be persistent about restating that concern until you elicit a response.

If someone exhibits disruptive behavior, point to or establish a code of conduct that clearly describes professional behavior.

If there is a difference of opinion on patient management, such as fetal monitoring and interpretation, conduct regular case reviews and standardize a plan for notification of complications.

6. If you’re a team leader, set clear goals
Then ask team members what will be needed to achieve the outcomes desired.

“Team leaders need to develop outstanding skills for listening and eliciting feedback and cross-monitoring (being aware of each other’s actions and performance) from other team members,” note Lyndon and colleagues.

7. Increase public awareness of safety concepts
When these concepts and best practices are made known to the public, women and families become “empowered” to speak up when they have concerns about care.

And when they do speak up, it pays to listen.

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

At least half of all cases of maternal morbidity and mortality could be prevented, or so studies suggest.^1,2

The main stumbling block?

Faulty communication.

That’s the word from the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, the American College of Nurse-Midwives, and the Association of Women’s Health, Obstetric and Neonatal Nurses.³

In a joint “blueprint” to transform communication and enhance the safety culture in intrapartum care, these organizations, led by Audrey Lyndon, PhD, RN, FAAN, from the University of California, San Francisco, School of Nursing, describe the extent of the problem, steps that various team members can take to improve safety, notable success stories, and communication strategies.³ In this article, the joint blueprint is summarized, with a focus on steps obstetricians can take to improve the intrapartum safety culture.

Scope of the problem
A study of more than 3,282 physicians, midwives, and registered nurses produced a troubling statistic: More than 90% of respondents said that they had “witnessed shortcuts, missing competencies, disrespect, or performance problems” during the preceding year of practice.⁴ Few of these clinicians reported that they had discussed their concerns with the parties involved.

A second study of 1,932 clinicians found that 34% of physicians, 40% of midwives, and 56% of registered nurses had witnessed patients being put at risk within the preceding 2 years by other team members’ inattentiveness or lack of responsiveness.⁵

These findings suggest that health care providers often witness weak links in intrapartum safety but do not always address or report them. Among the reasons team members may be hesitant to speak up when they perceive a potential problem:

Although Lyndon and colleagues acknowledge that it is impossible to eliminate adverse outcomes entirely or completely eradicate human error, they argue that significant improvements can be made by adopting a number of manageable strategies.

Recommended strategies
Lyndon and colleagues describe some of the challenges of effective communication in a health care setting:

Lyndon and colleagues go on to mention a number of strategies to improve communication, boost safety, and reduce medical errors.

1. Remember that the patient is part of the team
The patient and her family play a key role in identifying the potential for harm during labor and delivery, Lyndon and colleagues assert. They should be considered members of the intrapartum team, care should be patient-focused, and any communications from the patient should not only be heard but fully considered. In fact, explicit elicitation of her experience and concerns is recommended.

2. Consider that you might be part of the problem
It is human nature to attribute a communication problem to the other people involved, rather than take responsibility for it oneself. One potential solution to this mindset is team training, where all members are encouraged to communicate clearly and listen attentively. Organizations that have been successful at improving their culture of safety have implemented such training, as well as the use of checklists, training in fetal heart-rate monitoring, formation of a patient safety committee, external review of safety practices, and designation of a key clinician to lead the safety program and oversee team training.

3. Structure handoffs 
The team should standardize handoffs so that they occur smoothly and all channels of communication remain open and clear.

“Having structured formats for debriefing and handoffs are steps in the right direction, but solving the problem of communication breakdowns is more complicated than standardizing the flow and format of information transfer,” Lyndon and colleagues assert. “Indeed, solving communication breakdowns is a matter of individual, group, organizational, and professional responsibility for creating and sustaining an environment of mutual respect, curiosity, and accountability for behavior and performance.”³

4. Learn to communicate responsibly
“Differences of opinion about clinical assessments, goals of care, and the pathway to optimal outcomes are bound to occur with some regularity in the dynamic environment of labor and delivery,” note Lyndon and colleagues. “Every person has the responsibility to contribute to improving how we relate to and communicate with each other. Collectively, we must create environments in which every team member (woman, family member, physician, midwife, nurse, unit clerk, patient care assistant, or scrub tech) is comfortable expressing and discussing concerns about safety or performance, is encouraged to do so, and has the support of the team to articulate the rationale for and urgency of the concern without fear of put-downs, retribution, or receiving poor-quality care.”³

5. Be persistent and proactive
When team members have differing expectations and communication styles, useful approaches include structured communication tools such as situation, background, assessment, recommendation (SBAR); structured handoffs; board rounds; huddles; attentive listening; and explicit elicitation of the patient’s concerns and desires.³

If someone fails to pay attention to a concern you raise, be persistent about restating that concern until you elicit a response.

If someone exhibits disruptive behavior, point to or establish a code of conduct that clearly describes professional behavior.

If there is a difference of opinion on patient management, such as fetal monitoring and interpretation, conduct regular case reviews and standardize a plan for notification of complications.

6. If you’re a team leader, set clear goals
Then ask team members what will be needed to achieve the outcomes desired.

“Team leaders need to develop outstanding skills for listening and eliciting feedback and cross-monitoring (being aware of each other’s actions and performance) from other team members,” note Lyndon and colleagues.

7. Increase public awareness of safety concepts
When these concepts and best practices are made known to the public, women and families become “empowered” to speak up when they have concerns about care.

And when they do speak up, it pays to listen.

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

At least half of all cases of maternal morbidity and mortality could be prevented, or so studies suggest.^1,2

The main stumbling block?

Faulty communication.

That’s the word from the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, the American College of Nurse-Midwives, and the Association of Women’s Health, Obstetric and Neonatal Nurses.³

In a joint “blueprint” to transform communication and enhance the safety culture in intrapartum care, these organizations, led by Audrey Lyndon, PhD, RN, FAAN, from the University of California, San Francisco, School of Nursing, describe the extent of the problem, steps that various team members can take to improve safety, notable success stories, and communication strategies.³ In this article, the joint blueprint is summarized, with a focus on steps obstetricians can take to improve the intrapartum safety culture.

Scope of the problem
A study of more than 3,282 physicians, midwives, and registered nurses produced a troubling statistic: More than 90% of respondents said that they had “witnessed shortcuts, missing competencies, disrespect, or performance problems” during the preceding year of practice.⁴ Few of these clinicians reported that they had discussed their concerns with the parties involved.

A second study of 1,932 clinicians found that 34% of physicians, 40% of midwives, and 56% of registered nurses had witnessed patients being put at risk within the preceding 2 years by other team members’ inattentiveness or lack of responsiveness.⁵

These findings suggest that health care providers often witness weak links in intrapartum safety but do not always address or report them. Among the reasons team members may be hesitant to speak up when they perceive a potential problem:

Although Lyndon and colleagues acknowledge that it is impossible to eliminate adverse outcomes entirely or completely eradicate human error, they argue that significant improvements can be made by adopting a number of manageable strategies.

Recommended strategies
Lyndon and colleagues describe some of the challenges of effective communication in a health care setting:

Lyndon and colleagues go on to mention a number of strategies to improve communication, boost safety, and reduce medical errors.

1. Remember that the patient is part of the team
The patient and her family play a key role in identifying the potential for harm during labor and delivery, Lyndon and colleagues assert. They should be considered members of the intrapartum team, care should be patient-focused, and any communications from the patient should not only be heard but fully considered. In fact, explicit elicitation of her experience and concerns is recommended.

2. Consider that you might be part of the problem
It is human nature to attribute a communication problem to the other people involved, rather than take responsibility for it oneself. One potential solution to this mindset is team training, where all members are encouraged to communicate clearly and listen attentively. Organizations that have been successful at improving their culture of safety have implemented such training, as well as the use of checklists, training in fetal heart-rate monitoring, formation of a patient safety committee, external review of safety practices, and designation of a key clinician to lead the safety program and oversee team training.

3. Structure handoffs 
The team should standardize handoffs so that they occur smoothly and all channels of communication remain open and clear.

“Having structured formats for debriefing and handoffs are steps in the right direction, but solving the problem of communication breakdowns is more complicated than standardizing the flow and format of information transfer,” Lyndon and colleagues assert. “Indeed, solving communication breakdowns is a matter of individual, group, organizational, and professional responsibility for creating and sustaining an environment of mutual respect, curiosity, and accountability for behavior and performance.”³

4. Learn to communicate responsibly
“Differences of opinion about clinical assessments, goals of care, and the pathway to optimal outcomes are bound to occur with some regularity in the dynamic environment of labor and delivery,” note Lyndon and colleagues. “Every person has the responsibility to contribute to improving how we relate to and communicate with each other. Collectively, we must create environments in which every team member (woman, family member, physician, midwife, nurse, unit clerk, patient care assistant, or scrub tech) is comfortable expressing and discussing concerns about safety or performance, is encouraged to do so, and has the support of the team to articulate the rationale for and urgency of the concern without fear of put-downs, retribution, or receiving poor-quality care.”³

5. Be persistent and proactive
When team members have differing expectations and communication styles, useful approaches include structured communication tools such as situation, background, assessment, recommendation (SBAR); structured handoffs; board rounds; huddles; attentive listening; and explicit elicitation of the patient’s concerns and desires.³

If someone fails to pay attention to a concern you raise, be persistent about restating that concern until you elicit a response.

If someone exhibits disruptive behavior, point to or establish a code of conduct that clearly describes professional behavior.

If there is a difference of opinion on patient management, such as fetal monitoring and interpretation, conduct regular case reviews and standardize a plan for notification of complications.

6. If you’re a team leader, set clear goals
Then ask team members what will be needed to achieve the outcomes desired.

“Team leaders need to develop outstanding skills for listening and eliciting feedback and cross-monitoring (being aware of each other’s actions and performance) from other team members,” note Lyndon and colleagues.

7. Increase public awareness of safety concepts
When these concepts and best practices are made known to the public, women and families become “empowered” to speak up when they have concerns about care.

And when they do speak up, it pays to listen.

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

In a poster presented at the 2015 ACOG Annual Clinical Meeting in San Francisco, Neal Marc Lonky, MD, and colleagues from the Southern California Permanente Group assessed the clinical acumen of physicians in estimating uterine size prior to elective hysterectomy for benign indications. They found that the correlation between estimates and actual uterine weight was 0.79 (P<.001), with a very low conversion rate for the surgery.¹

Lonky and colleagues collected preoperative uterine estimates and actual specimen weights prospectively for 1,079 cases of benign hysterectomy. The surgeries were performed by 186 primary surgeons and assistant surgeons at 10 Kaiser Permanente Southern California medical centers. Surgeons based the route of hysterectomy on estimates of uterine size, which were calculated using bimanual examination, ultrasonography, or both. Linear regression was used to measure and compare the relationship between estimated uterine size and the pelvic specimen weight.

Uterine size estimates ranged from 4 cm to 40 cm, and specimen weights ranged from 2 g to 4,607 g. The mean (SD) estimate of uterine size was 11.7 (4.43) cm, and the mean actual specimen weight was 334.6 (401.42) g.

The mean age of women in the sample was 47.2 (8.35) years. Overall, 379 women (35.1%) were Hispanic, 325 (30.1%) were non-Hispanic white, 281 (26.0%) were non-Hispanic black, and 81 (7.5%) were Asian/Pacific Islander. The mean body mass index (BMI) was 30.0 (6.37) kg/m², with a range of 16.8 to 67.9 kg/m².

“This is real world research,” said Dr. Lonky. “It’s called comparative effectiveness research. Basically, all patients who are undergoing the procedure are entered in the registry, and the clinical acumen of the physician—either using or not using ultrasound—is assessed.”  

“We looked at whether or not we had a bias toward one patient age group, race/ethnicity, BMI, or estimated uterine size. But there were no clusters, so this was truly a random distribution,” said Dr. Lonky.

“These findings may be population-specific to my group of doctors,” he added. “They should be replicated in other settings. It may be that residents are not going to be as linear.”

In a poster presented at the 2015 ACOG Annual Clinical Meeting in San Francisco, Neal Marc Lonky, MD, and colleagues from the Southern California Permanente Group assessed the clinical acumen of physicians in estimating uterine size prior to elective hysterectomy for benign indications. They found that the correlation between estimates and actual uterine weight was 0.79 (P<.001), with a very low conversion rate for the surgery.¹

Lonky and colleagues collected preoperative uterine estimates and actual specimen weights prospectively for 1,079 cases of benign hysterectomy. The surgeries were performed by 186 primary surgeons and assistant surgeons at 10 Kaiser Permanente Southern California medical centers. Surgeons based the route of hysterectomy on estimates of uterine size, which were calculated using bimanual examination, ultrasonography, or both. Linear regression was used to measure and compare the relationship between estimated uterine size and the pelvic specimen weight.

Uterine size estimates ranged from 4 cm to 40 cm, and specimen weights ranged from 2 g to 4,607 g. The mean (SD) estimate of uterine size was 11.7 (4.43) cm, and the mean actual specimen weight was 334.6 (401.42) g.

The mean age of women in the sample was 47.2 (8.35) years. Overall, 379 women (35.1%) were Hispanic, 325 (30.1%) were non-Hispanic white, 281 (26.0%) were non-Hispanic black, and 81 (7.5%) were Asian/Pacific Islander. The mean body mass index (BMI) was 30.0 (6.37) kg/m², with a range of 16.8 to 67.9 kg/m².

“This is real world research,” said Dr. Lonky. “It’s called comparative effectiveness research. Basically, all patients who are undergoing the procedure are entered in the registry, and the clinical acumen of the physician—either using or not using ultrasound—is assessed.”  

“We looked at whether or not we had a bias toward one patient age group, race/ethnicity, BMI, or estimated uterine size. But there were no clusters, so this was truly a random distribution,” said Dr. Lonky.

“These findings may be population-specific to my group of doctors,” he added. “They should be replicated in other settings. It may be that residents are not going to be as linear.”

In a poster presented at the 2015 ACOG Annual Clinical Meeting in San Francisco, Neal Marc Lonky, MD, and colleagues from the Southern California Permanente Group assessed the clinical acumen of physicians in estimating uterine size prior to elective hysterectomy for benign indications. They found that the correlation between estimates and actual uterine weight was 0.79 (P<.001), with a very low conversion rate for the surgery.¹

Lonky and colleagues collected preoperative uterine estimates and actual specimen weights prospectively for 1,079 cases of benign hysterectomy. The surgeries were performed by 186 primary surgeons and assistant surgeons at 10 Kaiser Permanente Southern California medical centers. Surgeons based the route of hysterectomy on estimates of uterine size, which were calculated using bimanual examination, ultrasonography, or both. Linear regression was used to measure and compare the relationship between estimated uterine size and the pelvic specimen weight.

Uterine size estimates ranged from 4 cm to 40 cm, and specimen weights ranged from 2 g to 4,607 g. The mean (SD) estimate of uterine size was 11.7 (4.43) cm, and the mean actual specimen weight was 334.6 (401.42) g.

The mean age of women in the sample was 47.2 (8.35) years. Overall, 379 women (35.1%) were Hispanic, 325 (30.1%) were non-Hispanic white, 281 (26.0%) were non-Hispanic black, and 81 (7.5%) were Asian/Pacific Islander. The mean body mass index (BMI) was 30.0 (6.37) kg/m², with a range of 16.8 to 67.9 kg/m².

“This is real world research,” said Dr. Lonky. “It’s called comparative effectiveness research. Basically, all patients who are undergoing the procedure are entered in the registry, and the clinical acumen of the physician—either using or not using ultrasound—is assessed.”  

“We looked at whether or not we had a bias toward one patient age group, race/ethnicity, BMI, or estimated uterine size. But there were no clusters, so this was truly a random distribution,” said Dr. Lonky.

“These findings may be population-specific to my group of doctors,” he added. “They should be replicated in other settings. It may be that residents are not going to be as linear.”

Photographs from the first day of Hospital Medicine 2015, which took place March 29-April 1 at the Gaylord National Hotel and Conference Center in National Harbor, Md.

Photos by Manuel Noguera

[gallery ids="9553,9555,9556,9557,9558,9559,9560,9561,9562,9563,9564,9565,9566,9567,9568,9569,9570,9571,9572,9573,9574,9575,9576,9577,9578,9579,9580,9581,9582,9583,9584"]

Photographs from the first day of Hospital Medicine 2015, which took place March 29-April 1 at the Gaylord National Hotel and Conference Center in National Harbor, Md.

Photos by Manuel Noguera

[gallery ids="9553,9555,9556,9557,9558,9559,9560,9561,9562,9563,9564,9565,9566,9567,9568,9569,9570,9571,9572,9573,9574,9575,9576,9577,9578,9579,9580,9581,9582,9583,9584"]

Photographs from the first day of Hospital Medicine 2015, which took place March 29-April 1 at the Gaylord National Hotel and Conference Center in National Harbor, Md.

Photos by Manuel Noguera

[gallery ids="9553,9555,9556,9557,9558,9559,9560,9561,9562,9563,9564,9565,9566,9567,9568,9569,9570,9571,9572,9573,9574,9575,9576,9577,9578,9579,9580,9581,9582,9583,9584"]

Tissue extraction during laparoscopic or robot-assisted laparoscopic gynecologic surgery raises safety concerns for dissemination of tissue during the open, or uncontained, electromechanical morcellation process. Researchers from Brigham & Women’s Hospital in Boston, Massachusetts, investigated whether contained tissue extraction using power morcellators entirely within a bag is safe and practical for preventing tissue spillage. Goggins and colleagues presented their findings in a poster at the 2015 Annual Clinical Meeting of the American College of Obstetricians and Gynecologists in San Francisco, California.

A total of 76 women at 4 institutions underwent laparoscopic or robotic multiport surgery (42 hysterectomy; 34 myomectomy). The average (SD) age and body mass index of the women were 43.16 (8.53) years and 26.47 kg/m² (5.93), respectively. After surgical dissection, each specimen was placed into a containment bag that also included blue dye. The bag was insufflated intracorporeally and electromechanical morcellation and extraction of tissue were performed. The bag was evaluated visually for dye leakage or tears before and after the procedure.

Results
In one case, there was a tear in the bag before morcellation; no bag tears occurred during the morcellation process. Spillage of dye or tissue was noted in 7 cases, although containment bags were intact in each instance. One patient experienced intraoperative blood loss (3600 mL), and that procedure was converted to open radical hysterectomy. The most common pathologic finding was benign leiomyoma.

Conclusion
Goggins and colleagues concluded, “Contained tissue extraction using electromechanical morcellation and intracorporeally insufflated bags may provide a safe alternative to uncontained morcellation by decreasing the spread of tissue in the peritoneal cavity while allowing for the traditional benefits of laparoscopy.”

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

Tissue extraction during laparoscopic or robot-assisted laparoscopic gynecologic surgery raises safety concerns for dissemination of tissue during the open, or uncontained, electromechanical morcellation process. Researchers from Brigham & Women’s Hospital in Boston, Massachusetts, investigated whether contained tissue extraction using power morcellators entirely within a bag is safe and practical for preventing tissue spillage. Goggins and colleagues presented their findings in a poster at the 2015 Annual Clinical Meeting of the American College of Obstetricians and Gynecologists in San Francisco, California.

A total of 76 women at 4 institutions underwent laparoscopic or robotic multiport surgery (42 hysterectomy; 34 myomectomy). The average (SD) age and body mass index of the women were 43.16 (8.53) years and 26.47 kg/m² (5.93), respectively. After surgical dissection, each specimen was placed into a containment bag that also included blue dye. The bag was insufflated intracorporeally and electromechanical morcellation and extraction of tissue were performed. The bag was evaluated visually for dye leakage or tears before and after the procedure.

Results
In one case, there was a tear in the bag before morcellation; no bag tears occurred during the morcellation process. Spillage of dye or tissue was noted in 7 cases, although containment bags were intact in each instance. One patient experienced intraoperative blood loss (3600 mL), and that procedure was converted to open radical hysterectomy. The most common pathologic finding was benign leiomyoma.

Conclusion
Goggins and colleagues concluded, “Contained tissue extraction using electromechanical morcellation and intracorporeally insufflated bags may provide a safe alternative to uncontained morcellation by decreasing the spread of tissue in the peritoneal cavity while allowing for the traditional benefits of laparoscopy.”

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

Tissue extraction during laparoscopic or robot-assisted laparoscopic gynecologic surgery raises safety concerns for dissemination of tissue during the open, or uncontained, electromechanical morcellation process. Researchers from Brigham & Women’s Hospital in Boston, Massachusetts, investigated whether contained tissue extraction using power morcellators entirely within a bag is safe and practical for preventing tissue spillage. Goggins and colleagues presented their findings in a poster at the 2015 Annual Clinical Meeting of the American College of Obstetricians and Gynecologists in San Francisco, California.

A total of 76 women at 4 institutions underwent laparoscopic or robotic multiport surgery (42 hysterectomy; 34 myomectomy). The average (SD) age and body mass index of the women were 43.16 (8.53) years and 26.47 kg/m² (5.93), respectively. After surgical dissection, each specimen was placed into a containment bag that also included blue dye. The bag was insufflated intracorporeally and electromechanical morcellation and extraction of tissue were performed. The bag was evaluated visually for dye leakage or tears before and after the procedure.

Results
In one case, there was a tear in the bag before morcellation; no bag tears occurred during the morcellation process. Spillage of dye or tissue was noted in 7 cases, although containment bags were intact in each instance. One patient experienced intraoperative blood loss (3600 mL), and that procedure was converted to open radical hysterectomy. The most common pathologic finding was benign leiomyoma.

Conclusion
Goggins and colleagues concluded, “Contained tissue extraction using electromechanical morcellation and intracorporeally insufflated bags may provide a safe alternative to uncontained morcellation by decreasing the spread of tissue in the peritoneal cavity while allowing for the traditional benefits of laparoscopy.”

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

Thrombus

Photo by Andre E.X. Brown

SEATTLE—Patients who undergo surgery for lung cancer may have a higher risk of developing venous thromboembolism (VTE) than we thought, according to a

new study.

About 12% of the patients studied developed deep vein thrombosis (DVT), pulmonary embolism (PE), or both, although they had received VTE prophylaxis until hospital discharge.

Only about 21% of these patients showed symptoms of VTE, and the clots conferred a higher risk of mortality at 30 days.

“This study shows that a significant proportion of lung cancer surgery patients are at risk of VTE and indicates a need for future research into minimizing the occurrence of DVT and PE,” said investigator Yaron Shargall, MD, of McMaster University in Hamilton, Ontario, Canada.

“It is possible that extended use of blood thinners beyond hospital discharge may reduce the number of patients who experience these life-threatening events and may help to reduce the rates of death after lung surgery.”

Dr Shargall presented this viewpoint at the 95th Annual Meeting of the American Association for Thoracic Surgery.

For their study, he and his colleagues evaluated 157 patients who underwent thoracic surgery for primary lung cancer (89.9%) or metastatic cancer (6.3%).

All patients received unfractionated heparin or low-molecular-weight heparin and graduated compression stockings as VTE prophylaxis from the time of surgery until leaving the hospital.

Two weeks later, these patients were evaluated for signs and symptoms of VTE. The investigators evaluated clinical outcomes at 30 ± 5 days post-operatively using CT pulmonary angiography and bilateral Doppler venous ultrasonography.

Patients who had developed symptoms suggestive of VTE within the 30 days after surgery underwent urgent CT-PE examination and had a repeat scan 30 days after surgery if the first scan was negative. Patients with VTE were monitored and treated.

In all, there were 19 VTEs, a 12.1% incidence rate. These included 14 PEs (8.9%), 3 DVTs (1.9%), and 1 combined PE/DVT. One patient developed a massive left atrial thrombus originating from a surgical stump and died.

For all 157 patients, the 30-day mortality rate was 0.64%. For those with VTE, it was 5.2%.

“This demonstrates the clinical importance and relative fatality of VTE following lung cancer surgery,” Dr Shargall said.

All of the patients who were diagnosed with a VTE had undergone anatomic resections (lobectomy or segmentectomy), and most had primary lung cancer. The clots tended to form on the same side as the lung surgery. The majority of patients developed lung clots without forming DVTs beforehand.

The investigators examined factors that might distinguish patients who developed VTEs from those who did not and could not find differences in patient age, lung function, hospital length of stay, comorbidities, lung cancer stage, smoking status, or Caprini Score.

Among patients diagnosed with a VTE, only 4 (21.1%) showed symptoms. All the events were diagnosed after the patient left the hospital and only because these patients were screened for VTEs as part of the study.

Thrombus

Photo by Andre E.X. Brown

SEATTLE—Patients who undergo surgery for lung cancer may have a higher risk of developing venous thromboembolism (VTE) than we thought, according to a

new study.

About 12% of the patients studied developed deep vein thrombosis (DVT), pulmonary embolism (PE), or both, although they had received VTE prophylaxis until hospital discharge.

Only about 21% of these patients showed symptoms of VTE, and the clots conferred a higher risk of mortality at 30 days.

“This study shows that a significant proportion of lung cancer surgery patients are at risk of VTE and indicates a need for future research into minimizing the occurrence of DVT and PE,” said investigator Yaron Shargall, MD, of McMaster University in Hamilton, Ontario, Canada.

“It is possible that extended use of blood thinners beyond hospital discharge may reduce the number of patients who experience these life-threatening events and may help to reduce the rates of death after lung surgery.”

Dr Shargall presented this viewpoint at the 95th Annual Meeting of the American Association for Thoracic Surgery.

For their study, he and his colleagues evaluated 157 patients who underwent thoracic surgery for primary lung cancer (89.9%) or metastatic cancer (6.3%).

All patients received unfractionated heparin or low-molecular-weight heparin and graduated compression stockings as VTE prophylaxis from the time of surgery until leaving the hospital.

Two weeks later, these patients were evaluated for signs and symptoms of VTE. The investigators evaluated clinical outcomes at 30 ± 5 days post-operatively using CT pulmonary angiography and bilateral Doppler venous ultrasonography.

Patients who had developed symptoms suggestive of VTE within the 30 days after surgery underwent urgent CT-PE examination and had a repeat scan 30 days after surgery if the first scan was negative. Patients with VTE were monitored and treated.

In all, there were 19 VTEs, a 12.1% incidence rate. These included 14 PEs (8.9%), 3 DVTs (1.9%), and 1 combined PE/DVT. One patient developed a massive left atrial thrombus originating from a surgical stump and died.

For all 157 patients, the 30-day mortality rate was 0.64%. For those with VTE, it was 5.2%.

“This demonstrates the clinical importance and relative fatality of VTE following lung cancer surgery,” Dr Shargall said.

All of the patients who were diagnosed with a VTE had undergone anatomic resections (lobectomy or segmentectomy), and most had primary lung cancer. The clots tended to form on the same side as the lung surgery. The majority of patients developed lung clots without forming DVTs beforehand.

The investigators examined factors that might distinguish patients who developed VTEs from those who did not and could not find differences in patient age, lung function, hospital length of stay, comorbidities, lung cancer stage, smoking status, or Caprini Score.

Among patients diagnosed with a VTE, only 4 (21.1%) showed symptoms. All the events were diagnosed after the patient left the hospital and only because these patients were screened for VTEs as part of the study.

Thrombus

Photo by Andre E.X. Brown

SEATTLE—Patients who undergo surgery for lung cancer may have a higher risk of developing venous thromboembolism (VTE) than we thought, according to a

new study.

About 12% of the patients studied developed deep vein thrombosis (DVT), pulmonary embolism (PE), or both, although they had received VTE prophylaxis until hospital discharge.

Only about 21% of these patients showed symptoms of VTE, and the clots conferred a higher risk of mortality at 30 days.

“This study shows that a significant proportion of lung cancer surgery patients are at risk of VTE and indicates a need for future research into minimizing the occurrence of DVT and PE,” said investigator Yaron Shargall, MD, of McMaster University in Hamilton, Ontario, Canada.

“It is possible that extended use of blood thinners beyond hospital discharge may reduce the number of patients who experience these life-threatening events and may help to reduce the rates of death after lung surgery.”

Dr Shargall presented this viewpoint at the 95th Annual Meeting of the American Association for Thoracic Surgery.

For their study, he and his colleagues evaluated 157 patients who underwent thoracic surgery for primary lung cancer (89.9%) or metastatic cancer (6.3%).

All patients received unfractionated heparin or low-molecular-weight heparin and graduated compression stockings as VTE prophylaxis from the time of surgery until leaving the hospital.

Two weeks later, these patients were evaluated for signs and symptoms of VTE. The investigators evaluated clinical outcomes at 30 ± 5 days post-operatively using CT pulmonary angiography and bilateral Doppler venous ultrasonography.

Patients who had developed symptoms suggestive of VTE within the 30 days after surgery underwent urgent CT-PE examination and had a repeat scan 30 days after surgery if the first scan was negative. Patients with VTE were monitored and treated.

In all, there were 19 VTEs, a 12.1% incidence rate. These included 14 PEs (8.9%), 3 DVTs (1.9%), and 1 combined PE/DVT. One patient developed a massive left atrial thrombus originating from a surgical stump and died.

For all 157 patients, the 30-day mortality rate was 0.64%. For those with VTE, it was 5.2%.

“This demonstrates the clinical importance and relative fatality of VTE following lung cancer surgery,” Dr Shargall said.

All of the patients who were diagnosed with a VTE had undergone anatomic resections (lobectomy or segmentectomy), and most had primary lung cancer. The clots tended to form on the same side as the lung surgery. The majority of patients developed lung clots without forming DVTs beforehand.

The investigators examined factors that might distinguish patients who developed VTEs from those who did not and could not find differences in patient age, lung function, hospital length of stay, comorbidities, lung cancer stage, smoking status, or Caprini Score.

Among patients diagnosed with a VTE, only 4 (21.1%) showed symptoms. All the events were diagnosed after the patient left the hospital and only because these patients were screened for VTEs as part of the study.

Binata Joddar, PhD

Photo courtesy of University

of Texas at El Paso

Researchers say they have developed a protocol to prepare human induced pluripotent stem (hiPS) cells using chemically fixed feeder cells.

This method saves time and money by avoiding the need for colony formation of live feeder cells, which is required by current conventional methods.

The new protocol challenges the theory that live feeder cells are required to provide nutrients to growing stem cells.

“We’ve proved an important phenomenon,” said Binata Joddar, PhD, of the University of Texas at El Paso. “And it suggests that these feeder cells, which are difficult to grow, may not be important at all for stem cell growth.”

Dr Joddar and her colleagues described the phenomenon in Journal of Materials Chemistry B.

Using 2.5% glutaraldehyde (GA) or formaldehyde (FA) for 10 minutes, the researchers prepared a niche matrix from autologus human dermal fibroblast (HDF) feeder cells.

They then introduced hiPS cells to the niche matrix, which adhered to and were maintained as colonies on the fixed feeder cells.

The colony doubling times of the cells grown this way were similar to those of hiPS cells grown on mitomycin-C-treated HDF or SNL feeders. (SNL cells are derived from mouse fibroblast STO cells transformed with a neomycin resistance gene.)

But the colony doubling time for the hiPS cells was shorter with the fixed feeder than for cells cultured on laminin-5.

The researchers also discovered that the average number of colonies per passage was signficiantly higher for hiPS cells cultured on fixed feeder cells compared to those cultured without feeders.

They noted hiPS cells cultured on gelatin did not grow beyond the first passage.

The team concluded that the two types of chemically fixed HDF feeder cells (HDF-glutaraldehyde and HDF-formaldehyde) can be used as substitutes for mitomycin-C-treated HDF feeders to culture hiPS cells.

This new method would not extend the doubling time, would save preparation time, and would avoid labor-intensive protocols to prepare.

In addition, after chemical fixation, the feeder cells are non-viable and cannot release active growth factors or chemokines into the cell culture. Therefore, fixed feeder cells can be refrigerated for long-term storage prior to use.

“Because feeder cells don’t need to stay alive in the process, we can store them at room temperature and spend less time cultivating them,” Dr Joddar said.

“This makes me think that we [could] use a nanomanufacturing approach to grow stem cells. We could mimic feeder cells’ nanotopology with 3-D printing techniques and skip using feeder cells altogether in the future.”

Binata Joddar, PhD

Photo courtesy of University

of Texas at El Paso

Researchers say they have developed a protocol to prepare human induced pluripotent stem (hiPS) cells using chemically fixed feeder cells.

This method saves time and money by avoiding the need for colony formation of live feeder cells, which is required by current conventional methods.

The new protocol challenges the theory that live feeder cells are required to provide nutrients to growing stem cells.

“We’ve proved an important phenomenon,” said Binata Joddar, PhD, of the University of Texas at El Paso. “And it suggests that these feeder cells, which are difficult to grow, may not be important at all for stem cell growth.”

Dr Joddar and her colleagues described the phenomenon in Journal of Materials Chemistry B.

Using 2.5% glutaraldehyde (GA) or formaldehyde (FA) for 10 minutes, the researchers prepared a niche matrix from autologus human dermal fibroblast (HDF) feeder cells.

They then introduced hiPS cells to the niche matrix, which adhered to and were maintained as colonies on the fixed feeder cells.

The colony doubling times of the cells grown this way were similar to those of hiPS cells grown on mitomycin-C-treated HDF or SNL feeders. (SNL cells are derived from mouse fibroblast STO cells transformed with a neomycin resistance gene.)

But the colony doubling time for the hiPS cells was shorter with the fixed feeder than for cells cultured on laminin-5.

The researchers also discovered that the average number of colonies per passage was signficiantly higher for hiPS cells cultured on fixed feeder cells compared to those cultured without feeders.

They noted hiPS cells cultured on gelatin did not grow beyond the first passage.

The team concluded that the two types of chemically fixed HDF feeder cells (HDF-glutaraldehyde and HDF-formaldehyde) can be used as substitutes for mitomycin-C-treated HDF feeders to culture hiPS cells.

This new method would not extend the doubling time, would save preparation time, and would avoid labor-intensive protocols to prepare.

In addition, after chemical fixation, the feeder cells are non-viable and cannot release active growth factors or chemokines into the cell culture. Therefore, fixed feeder cells can be refrigerated for long-term storage prior to use.

“Because feeder cells don’t need to stay alive in the process, we can store them at room temperature and spend less time cultivating them,” Dr Joddar said.

“This makes me think that we [could] use a nanomanufacturing approach to grow stem cells. We could mimic feeder cells’ nanotopology with 3-D printing techniques and skip using feeder cells altogether in the future.”

Binata Joddar, PhD

Photo courtesy of University

of Texas at El Paso

Researchers say they have developed a protocol to prepare human induced pluripotent stem (hiPS) cells using chemically fixed feeder cells.

This method saves time and money by avoiding the need for colony formation of live feeder cells, which is required by current conventional methods.

The new protocol challenges the theory that live feeder cells are required to provide nutrients to growing stem cells.

“We’ve proved an important phenomenon,” said Binata Joddar, PhD, of the University of Texas at El Paso. “And it suggests that these feeder cells, which are difficult to grow, may not be important at all for stem cell growth.”

Dr Joddar and her colleagues described the phenomenon in Journal of Materials Chemistry B.

Using 2.5% glutaraldehyde (GA) or formaldehyde (FA) for 10 minutes, the researchers prepared a niche matrix from autologus human dermal fibroblast (HDF) feeder cells.

They then introduced hiPS cells to the niche matrix, which adhered to and were maintained as colonies on the fixed feeder cells.

The colony doubling times of the cells grown this way were similar to those of hiPS cells grown on mitomycin-C-treated HDF or SNL feeders. (SNL cells are derived from mouse fibroblast STO cells transformed with a neomycin resistance gene.)

But the colony doubling time for the hiPS cells was shorter with the fixed feeder than for cells cultured on laminin-5.

The researchers also discovered that the average number of colonies per passage was signficiantly higher for hiPS cells cultured on fixed feeder cells compared to those cultured without feeders.

They noted hiPS cells cultured on gelatin did not grow beyond the first passage.

The team concluded that the two types of chemically fixed HDF feeder cells (HDF-glutaraldehyde and HDF-formaldehyde) can be used as substitutes for mitomycin-C-treated HDF feeders to culture hiPS cells.

This new method would not extend the doubling time, would save preparation time, and would avoid labor-intensive protocols to prepare.

In addition, after chemical fixation, the feeder cells are non-viable and cannot release active growth factors or chemokines into the cell culture. Therefore, fixed feeder cells can be refrigerated for long-term storage prior to use.

“Because feeder cells don’t need to stay alive in the process, we can store them at room temperature and spend less time cultivating them,” Dr Joddar said.

“This makes me think that we [could] use a nanomanufacturing approach to grow stem cells. We could mimic feeder cells’ nanotopology with 3-D printing techniques and skip using feeder cells altogether in the future.”

Study Overview

Objective. To determine the effectiveness of a nurse-led, telephone-delivered behavioral intervention for diabetes (DM) and hypertension (HTN) versus an attention control within primary care community practices.

Study design. A 9-site, 2-arm randomized controlled trial.

Setting and participants. Study participants were recruited from 9 community practices within the Duke Primary Care Research Consortium. The practices were chosen because they traditionally operate outside of the academic context. Subjects were required to have both type 2 DM and HTN, as indicated by their medications and confirmed by administrative data as well as patient self-reporting. Participants had to have been seen at participating practices for at least 1 year and have poorly controlled DM (indicated by most recent A1c ≥ 7.5%), but they were not required to have poorly controlled HTN. Exclusion criteria included fewer than 1 primary care clinic visit during the previous year, serious comorbid illness, type 1 diabetes, inability to receive a telephone intervention in English, residence in a nursing home, and participation in another hypertension or diabetes study [1]. Participants were randomly assigned using a computer-generated randomization sequence [1] to either the intervention or control groups at a 1:1 ratio, stratified by clinic and baseline blood pressure (BP) control.

Intervention. A single nurse with extensive experience in case management delivered both the behavioral intervention and attention control by telephone. In both arms, calls were conducted once every 2 months over a 24-month period.

The calls in the intervention arm consisted of tailored behavior-modifying techniques according to patient barriers. This content was divided into a series of modules relevant to behaviors associated with improving control of BP or blood sugar, including physical activity, weight reduction, sodium intake, smoking cessation, medication adherence, and others. These modules were scheduled according to patient needs (based on certain parameters such as high body mass index or use of insulin) and preferences [1].

The calls in the attention control were not tailored but rather consisted of didactic health-related information unrelated to HTN or DM (eg, flu shots, skin cancer prevention). This content was also highly scripted and designed to limit the potential for interaction between the nurse and patient.

Main outcome measures. A1c and systolic blood pressure (SBP) were primary outcomes. Key secondary outcomes were diastolic blood pressure (DBP), overall BP control, weight, physical activity, self-efficacy, and medication adherence. Study staff obtained measurements at baseline and 6, 12, and 24 months [1].

Results. The researchers assessed 2601 patients for eligibility and excluded 2224. Most patients were excluded for not meeting inclusion criteria (n = 1156), in particular because of improved HbA1c control (n = 983), and 1064 declined to participate. They randomized 377 patients—193 to the intervention arm and 184 to the attention control arm. Participants had an average age of 58.7, 49.1% had an education level of high school or less, 50.1% were non-white, and 54.9% were unemployed/retired. Patient characteristics in the intervention and control arms were similar at baseline. Seventy-eight percent of patients completed the 12-month follow-up and 70% (263) reached the 24-month endpoint. Patients in the intervention arm completed 78% of scheduled calls while patients in the control group completed 81%.

After adjusting for stratification variables, the estimated mean A1c and SBP were similar between arms at 24 months (intervention 0.1% higher than control, 95% CI −0.3 % to 0.5 %, P = 0.50 for A1c; intervention 0.9 mm Hg lower than control, 95% CI −5.4 to 3.5, P = 0.69 for SBP). There were also no significant differences between arms in mean A1c or SBP at 6 or 12 months. However, A1c levels did improve within each arm at the end of the study, with the intervention group improving by approx-imately 0.5% and the control group improving by approximately 0.6%. In terms of secondary outcomes, there were no significant differences between arms in DBP, weight, physical activity, or BP control rates throughout the 2-year study period.

Conclusion. Overall, the intervention and control groups did not differ significantly in terms of A1c, SBP, or any of the secondary outcomes at any point during the 2-year study.

Commentary

The prevalence of type 2 diabetes and its comorbidities (such as hypertension and obesity) have increased due to a variety of factors including an aging population and an increasingly sedentary lifestyle. Several nurse management programs for DM and HTN have been shown to be efficacious in reducing blood sugar levels [2–4] and promoting BP control [5,6]. However, these interventions were conducted in tightly controlled academic settings, and it is unclear how well these programs may translate into community settings. The aim of this study was to test the effectiveness of a nurse-led behavioral telephone intervention for the comanagement of DM and HTN within non–academically affiliated community practices. Results indicated no significant differences between the intervention and control groups for A1c levels or SBP at any point during the 2-year study, but A1c levels did improve for both arms.

Despite this being a negative study, it is a unique and important contribution to the literature. It is the only trial as of yet that has tested the effectiveness of a nurse management intervention targeting both DM and HTN in a real-world, community setting. This novel approach is supported by data that suggests BP control is actually more cost-effective than intensive glycemic control in treating patients with type 2 diabetes [7]. There were several strengths to the study design, including the use of intention-to-treat analysis, stratified randomization, a diverse patient population, and blinding of the study staff who took BP and A1c measurements. Furthermore, a single nurse conducted all telephone calls, ensuring that differences in counseling skill levels would not affect the results of the study. The few weaknesses of the study included the fact that the nurse who delivered the intervention (as well as the patients) could not be blinded to treatment allocation, and the income of study participants was not reported.

The reasons for the negative outcomes of this study are unclear. The authors claim that similar interventions within academic settings have been shown to be effective and speculate that time and financial pressures of community practices may be reasons that the intervention was not successful. However, the “successful” interventions that they cite were quite different from and more intensive than this intervention. For instance, many of these studies used at least 1 call per month [3,4,8], and one even conducted several calls each week [3]. Furthermore, a DM study conducted by Blackberry et al in a community setting with less than 1 call per month (8 calls over 18 months) similarly failed to produce significant results [9], and therefore more frequent calls may be necessary in DM and HTN interventions. In a systematic review, Eakin et al demonstrated that 12 or more calls in a 6- to 12-month period were associated with better outcomes in physical activity and diet interventions [10], and this may also translate to closely related DM and HTN interventions.

In addition to the infrequent calls, this intervention also lacked communication and integration with patients’ primary care teams. Several studies have demonstrated that integration with primary care teams can improve outcomes in DM and HTN interventions [11,12], and nearly all of the successful studies cited by the authors also included at least some form of communication with patients’ primary care providers (PCPs) [2–4,5,8]. In many of these studies the nurse also had prescribing rights to alter medications [2,3,5]. The nurse in this study met monthly with an expert team of clinicians to discuss patient issues but did not communicate directly with any of the patients’ PCPs [1]. The authors acknowledge that this lack of integration may have contributed to their negative results and point to the fact that it is harder to integrate interventions within community practices that often lack internal integration. However, Walsh, Harris, and Roberts demonstrated that integration between primary and secondary care teams was both feasible and effective for a diabetes initiative within community practices [13].

An additional important feature not present in this intervention was self-monitoring of BP levels. Home self-monitoring of BP has been demonstrated to significantly improve BP levels [14], and 2 of the successful studies in academic settings cited by the authors also included a BP self-monitoring component [5,6]. In one of these studies [6], Bosworth et al conducted a 2 × 2 randomized trial to improve HTN control in which the arms consisted of (a) usual care, (b) bimonthly nurse administered telephone intervention only (this arm was highly similar to the intervention arm in this study), (c) BP monitoring 3 times a week only, and (d) a combination of the telephone intervention with the BP monitoring. Interestingly, the only arm that was successful relative to usual care was the combination of the telephone intervention and BP self-monitoring; the arm consisting only of bi-monthly telephone calls (very similar to this intervention) failed despite the study taking place in an academic setting (it was also less effective than BP monitoring only). Thus, the addition of self-monitoring to a nurse case management telephone intervention can achieve better results.

Applications for Clinical Practice

A telephone-based intervention delivered by a trained nurse for co-management of DM and HTN was not more effective than an attention control delivered by the same nurse in a community setting. This may have been due to several factors, including low intensity marked by less than 1 call per month, a lack of integration with other members of the primary care team, and lack of a BP self-monitoring component. Future studies are needed to determine the optimal type and duration of nurse case management interventions targeting glucose and BP control for diabetic patients in community settings.

—Sandeep Sikerwar, BA, and Melanie Jay, MD, MS

Study Overview

Objective. To determine the effectiveness of a nurse-led, telephone-delivered behavioral intervention for diabetes (DM) and hypertension (HTN) versus an attention control within primary care community practices.

Study design. A 9-site, 2-arm randomized controlled trial.

Setting and participants. Study participants were recruited from 9 community practices within the Duke Primary Care Research Consortium. The practices were chosen because they traditionally operate outside of the academic context. Subjects were required to have both type 2 DM and HTN, as indicated by their medications and confirmed by administrative data as well as patient self-reporting. Participants had to have been seen at participating practices for at least 1 year and have poorly controlled DM (indicated by most recent A1c ≥ 7.5%), but they were not required to have poorly controlled HTN. Exclusion criteria included fewer than 1 primary care clinic visit during the previous year, serious comorbid illness, type 1 diabetes, inability to receive a telephone intervention in English, residence in a nursing home, and participation in another hypertension or diabetes study [1]. Participants were randomly assigned using a computer-generated randomization sequence [1] to either the intervention or control groups at a 1:1 ratio, stratified by clinic and baseline blood pressure (BP) control.

Intervention. A single nurse with extensive experience in case management delivered both the behavioral intervention and attention control by telephone. In both arms, calls were conducted once every 2 months over a 24-month period.

The calls in the intervention arm consisted of tailored behavior-modifying techniques according to patient barriers. This content was divided into a series of modules relevant to behaviors associated with improving control of BP or blood sugar, including physical activity, weight reduction, sodium intake, smoking cessation, medication adherence, and others. These modules were scheduled according to patient needs (based on certain parameters such as high body mass index or use of insulin) and preferences [1].

The calls in the attention control were not tailored but rather consisted of didactic health-related information unrelated to HTN or DM (eg, flu shots, skin cancer prevention). This content was also highly scripted and designed to limit the potential for interaction between the nurse and patient.

Main outcome measures. A1c and systolic blood pressure (SBP) were primary outcomes. Key secondary outcomes were diastolic blood pressure (DBP), overall BP control, weight, physical activity, self-efficacy, and medication adherence. Study staff obtained measurements at baseline and 6, 12, and 24 months [1].

Results. The researchers assessed 2601 patients for eligibility and excluded 2224. Most patients were excluded for not meeting inclusion criteria (n = 1156), in particular because of improved HbA1c control (n = 983), and 1064 declined to participate. They randomized 377 patients—193 to the intervention arm and 184 to the attention control arm. Participants had an average age of 58.7, 49.1% had an education level of high school or less, 50.1% were non-white, and 54.9% were unemployed/retired. Patient characteristics in the intervention and control arms were similar at baseline. Seventy-eight percent of patients completed the 12-month follow-up and 70% (263) reached the 24-month endpoint. Patients in the intervention arm completed 78% of scheduled calls while patients in the control group completed 81%.

After adjusting for stratification variables, the estimated mean A1c and SBP were similar between arms at 24 months (intervention 0.1% higher than control, 95% CI −0.3 % to 0.5 %, P = 0.50 for A1c; intervention 0.9 mm Hg lower than control, 95% CI −5.4 to 3.5, P = 0.69 for SBP). There were also no significant differences between arms in mean A1c or SBP at 6 or 12 months. However, A1c levels did improve within each arm at the end of the study, with the intervention group improving by approx-imately 0.5% and the control group improving by approximately 0.6%. In terms of secondary outcomes, there were no significant differences between arms in DBP, weight, physical activity, or BP control rates throughout the 2-year study period.

Conclusion. Overall, the intervention and control groups did not differ significantly in terms of A1c, SBP, or any of the secondary outcomes at any point during the 2-year study.

Commentary

The prevalence of type 2 diabetes and its comorbidities (such as hypertension and obesity) have increased due to a variety of factors including an aging population and an increasingly sedentary lifestyle. Several nurse management programs for DM and HTN have been shown to be efficacious in reducing blood sugar levels [2–4] and promoting BP control [5,6]. However, these interventions were conducted in tightly controlled academic settings, and it is unclear how well these programs may translate into community settings. The aim of this study was to test the effectiveness of a nurse-led behavioral telephone intervention for the comanagement of DM and HTN within non–academically affiliated community practices. Results indicated no significant differences between the intervention and control groups for A1c levels or SBP at any point during the 2-year study, but A1c levels did improve for both arms.

Despite this being a negative study, it is a unique and important contribution to the literature. It is the only trial as of yet that has tested the effectiveness of a nurse management intervention targeting both DM and HTN in a real-world, community setting. This novel approach is supported by data that suggests BP control is actually more cost-effective than intensive glycemic control in treating patients with type 2 diabetes [7]. There were several strengths to the study design, including the use of intention-to-treat analysis, stratified randomization, a diverse patient population, and blinding of the study staff who took BP and A1c measurements. Furthermore, a single nurse conducted all telephone calls, ensuring that differences in counseling skill levels would not affect the results of the study. The few weaknesses of the study included the fact that the nurse who delivered the intervention (as well as the patients) could not be blinded to treatment allocation, and the income of study participants was not reported.

The reasons for the negative outcomes of this study are unclear. The authors claim that similar interventions within academic settings have been shown to be effective and speculate that time and financial pressures of community practices may be reasons that the intervention was not successful. However, the “successful” interventions that they cite were quite different from and more intensive than this intervention. For instance, many of these studies used at least 1 call per month [3,4,8], and one even conducted several calls each week [3]. Furthermore, a DM study conducted by Blackberry et al in a community setting with less than 1 call per month (8 calls over 18 months) similarly failed to produce significant results [9], and therefore more frequent calls may be necessary in DM and HTN interventions. In a systematic review, Eakin et al demonstrated that 12 or more calls in a 6- to 12-month period were associated with better outcomes in physical activity and diet interventions [10], and this may also translate to closely related DM and HTN interventions.

In addition to the infrequent calls, this intervention also lacked communication and integration with patients’ primary care teams. Several studies have demonstrated that integration with primary care teams can improve outcomes in DM and HTN interventions [11,12], and nearly all of the successful studies cited by the authors also included at least some form of communication with patients’ primary care providers (PCPs) [2–4,5,8]. In many of these studies the nurse also had prescribing rights to alter medications [2,3,5]. The nurse in this study met monthly with an expert team of clinicians to discuss patient issues but did not communicate directly with any of the patients’ PCPs [1]. The authors acknowledge that this lack of integration may have contributed to their negative results and point to the fact that it is harder to integrate interventions within community practices that often lack internal integration. However, Walsh, Harris, and Roberts demonstrated that integration between primary and secondary care teams was both feasible and effective for a diabetes initiative within community practices [13].

An additional important feature not present in this intervention was self-monitoring of BP levels. Home self-monitoring of BP has been demonstrated to significantly improve BP levels [14], and 2 of the successful studies in academic settings cited by the authors also included a BP self-monitoring component [5,6]. In one of these studies [6], Bosworth et al conducted a 2 × 2 randomized trial to improve HTN control in which the arms consisted of (a) usual care, (b) bimonthly nurse administered telephone intervention only (this arm was highly similar to the intervention arm in this study), (c) BP monitoring 3 times a week only, and (d) a combination of the telephone intervention with the BP monitoring. Interestingly, the only arm that was successful relative to usual care was the combination of the telephone intervention and BP self-monitoring; the arm consisting only of bi-monthly telephone calls (very similar to this intervention) failed despite the study taking place in an academic setting (it was also less effective than BP monitoring only). Thus, the addition of self-monitoring to a nurse case management telephone intervention can achieve better results.

Applications for Clinical Practice

A telephone-based intervention delivered by a trained nurse for co-management of DM and HTN was not more effective than an attention control delivered by the same nurse in a community setting. This may have been due to several factors, including low intensity marked by less than 1 call per month, a lack of integration with other members of the primary care team, and lack of a BP self-monitoring component. Future studies are needed to determine the optimal type and duration of nurse case management interventions targeting glucose and BP control for diabetic patients in community settings.

—Sandeep Sikerwar, BA, and Melanie Jay, MD, MS

Study Overview

Objective. To determine the effectiveness of a nurse-led, telephone-delivered behavioral intervention for diabetes (DM) and hypertension (HTN) versus an attention control within primary care community practices.

Study design. A 9-site, 2-arm randomized controlled trial.

Setting and participants. Study participants were recruited from 9 community practices within the Duke Primary Care Research Consortium. The practices were chosen because they traditionally operate outside of the academic context. Subjects were required to have both type 2 DM and HTN, as indicated by their medications and confirmed by administrative data as well as patient self-reporting. Participants had to have been seen at participating practices for at least 1 year and have poorly controlled DM (indicated by most recent A1c ≥ 7.5%), but they were not required to have poorly controlled HTN. Exclusion criteria included fewer than 1 primary care clinic visit during the previous year, serious comorbid illness, type 1 diabetes, inability to receive a telephone intervention in English, residence in a nursing home, and participation in another hypertension or diabetes study [1]. Participants were randomly assigned using a computer-generated randomization sequence [1] to either the intervention or control groups at a 1:1 ratio, stratified by clinic and baseline blood pressure (BP) control.

Intervention. A single nurse with extensive experience in case management delivered both the behavioral intervention and attention control by telephone. In both arms, calls were conducted once every 2 months over a 24-month period.

The calls in the intervention arm consisted of tailored behavior-modifying techniques according to patient barriers. This content was divided into a series of modules relevant to behaviors associated with improving control of BP or blood sugar, including physical activity, weight reduction, sodium intake, smoking cessation, medication adherence, and others. These modules were scheduled according to patient needs (based on certain parameters such as high body mass index or use of insulin) and preferences [1].

The calls in the attention control were not tailored but rather consisted of didactic health-related information unrelated to HTN or DM (eg, flu shots, skin cancer prevention). This content was also highly scripted and designed to limit the potential for interaction between the nurse and patient.

Main outcome measures. A1c and systolic blood pressure (SBP) were primary outcomes. Key secondary outcomes were diastolic blood pressure (DBP), overall BP control, weight, physical activity, self-efficacy, and medication adherence. Study staff obtained measurements at baseline and 6, 12, and 24 months [1].

Results. The researchers assessed 2601 patients for eligibility and excluded 2224. Most patients were excluded for not meeting inclusion criteria (n = 1156), in particular because of improved HbA1c control (n = 983), and 1064 declined to participate. They randomized 377 patients—193 to the intervention arm and 184 to the attention control arm. Participants had an average age of 58.7, 49.1% had an education level of high school or less, 50.1% were non-white, and 54.9% were unemployed/retired. Patient characteristics in the intervention and control arms were similar at baseline. Seventy-eight percent of patients completed the 12-month follow-up and 70% (263) reached the 24-month endpoint. Patients in the intervention arm completed 78% of scheduled calls while patients in the control group completed 81%.

After adjusting for stratification variables, the estimated mean A1c and SBP were similar between arms at 24 months (intervention 0.1% higher than control, 95% CI −0.3 % to 0.5 %, P = 0.50 for A1c; intervention 0.9 mm Hg lower than control, 95% CI −5.4 to 3.5, P = 0.69 for SBP). There were also no significant differences between arms in mean A1c or SBP at 6 or 12 months. However, A1c levels did improve within each arm at the end of the study, with the intervention group improving by approx-imately 0.5% and the control group improving by approximately 0.6%. In terms of secondary outcomes, there were no significant differences between arms in DBP, weight, physical activity, or BP control rates throughout the 2-year study period.

Conclusion. Overall, the intervention and control groups did not differ significantly in terms of A1c, SBP, or any of the secondary outcomes at any point during the 2-year study.

Commentary

The prevalence of type 2 diabetes and its comorbidities (such as hypertension and obesity) have increased due to a variety of factors including an aging population and an increasingly sedentary lifestyle. Several nurse management programs for DM and HTN have been shown to be efficacious in reducing blood sugar levels [2–4] and promoting BP control [5,6]. However, these interventions were conducted in tightly controlled academic settings, and it is unclear how well these programs may translate into community settings. The aim of this study was to test the effectiveness of a nurse-led behavioral telephone intervention for the comanagement of DM and HTN within non–academically affiliated community practices. Results indicated no significant differences between the intervention and control groups for A1c levels or SBP at any point during the 2-year study, but A1c levels did improve for both arms.

Despite this being a negative study, it is a unique and important contribution to the literature. It is the only trial as of yet that has tested the effectiveness of a nurse management intervention targeting both DM and HTN in a real-world, community setting. This novel approach is supported by data that suggests BP control is actually more cost-effective than intensive glycemic control in treating patients with type 2 diabetes [7]. There were several strengths to the study design, including the use of intention-to-treat analysis, stratified randomization, a diverse patient population, and blinding of the study staff who took BP and A1c measurements. Furthermore, a single nurse conducted all telephone calls, ensuring that differences in counseling skill levels would not affect the results of the study. The few weaknesses of the study included the fact that the nurse who delivered the intervention (as well as the patients) could not be blinded to treatment allocation, and the income of study participants was not reported.

The reasons for the negative outcomes of this study are unclear. The authors claim that similar interventions within academic settings have been shown to be effective and speculate that time and financial pressures of community practices may be reasons that the intervention was not successful. However, the “successful” interventions that they cite were quite different from and more intensive than this intervention. For instance, many of these studies used at least 1 call per month [3,4,8], and one even conducted several calls each week [3]. Furthermore, a DM study conducted by Blackberry et al in a community setting with less than 1 call per month (8 calls over 18 months) similarly failed to produce significant results [9], and therefore more frequent calls may be necessary in DM and HTN interventions. In a systematic review, Eakin et al demonstrated that 12 or more calls in a 6- to 12-month period were associated with better outcomes in physical activity and diet interventions [10], and this may also translate to closely related DM and HTN interventions.

In addition to the infrequent calls, this intervention also lacked communication and integration with patients’ primary care teams. Several studies have demonstrated that integration with primary care teams can improve outcomes in DM and HTN interventions [11,12], and nearly all of the successful studies cited by the authors also included at least some form of communication with patients’ primary care providers (PCPs) [2–4,5,8]. In many of these studies the nurse also had prescribing rights to alter medications [2,3,5]. The nurse in this study met monthly with an expert team of clinicians to discuss patient issues but did not communicate directly with any of the patients’ PCPs [1]. The authors acknowledge that this lack of integration may have contributed to their negative results and point to the fact that it is harder to integrate interventions within community practices that often lack internal integration. However, Walsh, Harris, and Roberts demonstrated that integration between primary and secondary care teams was both feasible and effective for a diabetes initiative within community practices [13].

An additional important feature not present in this intervention was self-monitoring of BP levels. Home self-monitoring of BP has been demonstrated to significantly improve BP levels [14], and 2 of the successful studies in academic settings cited by the authors also included a BP self-monitoring component [5,6]. In one of these studies [6], Bosworth et al conducted a 2 × 2 randomized trial to improve HTN control in which the arms consisted of (a) usual care, (b) bimonthly nurse administered telephone intervention only (this arm was highly similar to the intervention arm in this study), (c) BP monitoring 3 times a week only, and (d) a combination of the telephone intervention with the BP monitoring. Interestingly, the only arm that was successful relative to usual care was the combination of the telephone intervention and BP self-monitoring; the arm consisting only of bi-monthly telephone calls (very similar to this intervention) failed despite the study taking place in an academic setting (it was also less effective than BP monitoring only). Thus, the addition of self-monitoring to a nurse case management telephone intervention can achieve better results.

Applications for Clinical Practice

A telephone-based intervention delivered by a trained nurse for co-management of DM and HTN was not more effective than an attention control delivered by the same nurse in a community setting. This may have been due to several factors, including low intensity marked by less than 1 call per month, a lack of integration with other members of the primary care team, and lack of a BP self-monitoring component. Future studies are needed to determine the optimal type and duration of nurse case management interventions targeting glucose and BP control for diabetic patients in community settings.

—Sandeep Sikerwar, BA, and Melanie Jay, MD, MS

Study Overview

Objective. To compare percutaneous coronary intervention (PCI) using second-generation drug-eluting stents (everolimus-eluting stents) with coronary artery bypass grafting (CABG) among patients with multivessel coronary disease.

Design. Observational registry study with propensity-score matching.

Setting and participants. The study relies on patients identified from the Cardiac Surgery Reporting System (CSRS) and Percutaneous Coronary Intervention Reporting System (PCIRS) registries of the New York State Department of Health. These 2 registries were linked to the New York State Vital Statistics Death registry and to the Statewide Planning and Research Cooperative System registry (SPARCS) to obtain further information like dates of admission, surgery, discharge, and death. Subjects were eligible for inclusion if they had multivessel disease (defined as severe stenosis [≥ 70%] in at least 2 diseased major epicardial coronary arteries) and if they had undergone either PCI with implantation of an everolimus-eluting stent or CABG. Subjects were excluded if they had revascularization within 1 year before index procedure; previous cardiac surgery; severe left main coronary artery disease (degree of stenosis ≥ 50%); PCI with a stent other than an everolimus-eluting stent; myocardial infarction without 24 hours before the index procedure; and unstable hemodynamics or cardiogenic shock.

Main outcome measures. The primary outcome of the study was all-cause mortality. Various secondary outcomes included rates of myocardial infarction, stroke, and repeat vascularization.

Main results. Among 116,915 patients assessed for eligibility, 82,096 were excluded. Among 34,819 who met inclusion criteria, 18,446 were included in the propensity score–matched analysis. With a 1:1 matching algorithm, 9223 were in the PCI with everolimus-eluting stent group and 9223 were in the CABG group. Short-term outcomes (in hospital or ≤ 30 days after the index procedure) favored PCI with everolimus-eluting stents over CABG, with a significantly lower risk of death (0.6% vs. 1.1%; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.35 to 0.69; P < 0.002) as well as stroke (0.2% vs 1.2%; HR, 0.18; 95% CI, 0.11 to 0.29; P < 0.001). The 2 groups had similar rates of myocardial infarction in the short-term (0.5% and 0.4%; HR, 1.37; 95% CI, 0.89 to 2.12; P = 0.16). After a mean follow-up of 2.9 years, there was a similar annual death rate between groups: 3.1% for PCI and 2.9% for CABG (HR, 1.04; 95% CI, 0.93 to 1.17; P = 0.50). PCI with everolimus-eluting stents was associated with a higher risk of a first myocardial infarction than was CABG (1.9% vs 1.1% per year; HR, 1.51; 95% CI, 1.29 to 1.77; P < 0.001). PCI with everolimus-eluting stents was associated with a lower risk of a first stroke than CABG (0.7% vs. 1.0% per year; HR, 0.62; 95% CI, 0.50 to 0.76; P < 0.001). Finally, PCI with everolimus-eluting stents was associated with a higher risk of a first repeat-revascularization procedure than CABG (7.2% vs. 3.1% per year; HR, 2.35; 95% CI, 2.14 to 2.58; P < 0.001).

Conclusion. In the setting of newer stent technology with second-generation everolimus-eluting stents, the risk of death associated with PCI was similar to that associated with CABG for multivessel coronary artery disease. In the long-term, PCI was associated with a higher risk of myocardial infarction and repeat revascularization, whereas CABG was associated with an increased risk of stroke. In the short-term, PCI had lower risks of both death and stroke.

Commentary

Coronary artery disease is a major public health problem. For patients for whom revascularization is deemed to be appropriate, a choice must be made between PCI and CABG. In previous studies that compared PCI and CABG, CABG was shown to have less need for repeat revascularizations as well as mortality benefits [1–3]. However, these prior studies compared CABG with older generations of stents. In the past decade, stent technologies have improved, as the bare-metal stent era gave way to the first generation of of drug-eluting stents (with sirolimus or paclitaxel), to be followed by second-generation drug-eluting stents (with everolimus or zotarolimus) [4].

In this article, Bangalore and colleagues addressed the issue of whether the use of second-generation drug-eluting stents close the outcome gap that favors CABG over PCI in patients with multivessel coronary artery disease. In patients who were considered to have had complete revascularization performed during PCI (ie, revascularization of all major vessels with clinically significant stenosis), they noted mitigation of the outcome differences between the PCI group and the CABG group. They conclude that the decision-making process by patients and their providers regarding revascularization be placed in the context of individual values and preferences.

One major limitation is that the study is an observational study from registry data. Despite the use of sophisticated statistical techniques including propensity score matching to adjust for confounders that are implicit in any nonrandomized comparison of treatment strategies, observational studies suffer from the definitely proof of causality. These limitations are especially important when the two groups being compared have modest differences in outcome.

Applications for Clinical Practice

This observational study, together with a recent randomized clinical trial in which CABG was compared with PCI with the use of everolimus-eluting stents from the BEST trial [5], provided new insights of the 2 revascularization strategies. Clinicians should engage and empower patients with a shared decision-making approach. The early hazard of CABG in stroke and death may be unacceptable to some patients, whereas others might want to avoid the later hazards of PCI in repeat procedure or having a myocardial infarction. Until a definitive study is available, patients should be informed of the best current knowledge of the pros and cons of the two revascularization strategies.

 —Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To compare percutaneous coronary intervention (PCI) using second-generation drug-eluting stents (everolimus-eluting stents) with coronary artery bypass grafting (CABG) among patients with multivessel coronary disease.

Design. Observational registry study with propensity-score matching.

Setting and participants. The study relies on patients identified from the Cardiac Surgery Reporting System (CSRS) and Percutaneous Coronary Intervention Reporting System (PCIRS) registries of the New York State Department of Health. These 2 registries were linked to the New York State Vital Statistics Death registry and to the Statewide Planning and Research Cooperative System registry (SPARCS) to obtain further information like dates of admission, surgery, discharge, and death. Subjects were eligible for inclusion if they had multivessel disease (defined as severe stenosis [≥ 70%] in at least 2 diseased major epicardial coronary arteries) and if they had undergone either PCI with implantation of an everolimus-eluting stent or CABG. Subjects were excluded if they had revascularization within 1 year before index procedure; previous cardiac surgery; severe left main coronary artery disease (degree of stenosis ≥ 50%); PCI with a stent other than an everolimus-eluting stent; myocardial infarction without 24 hours before the index procedure; and unstable hemodynamics or cardiogenic shock.

Main outcome measures. The primary outcome of the study was all-cause mortality. Various secondary outcomes included rates of myocardial infarction, stroke, and repeat vascularization.

Main results. Among 116,915 patients assessed for eligibility, 82,096 were excluded. Among 34,819 who met inclusion criteria, 18,446 were included in the propensity score–matched analysis. With a 1:1 matching algorithm, 9223 were in the PCI with everolimus-eluting stent group and 9223 were in the CABG group. Short-term outcomes (in hospital or ≤ 30 days after the index procedure) favored PCI with everolimus-eluting stents over CABG, with a significantly lower risk of death (0.6% vs. 1.1%; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.35 to 0.69; P < 0.002) as well as stroke (0.2% vs 1.2%; HR, 0.18; 95% CI, 0.11 to 0.29; P < 0.001). The 2 groups had similar rates of myocardial infarction in the short-term (0.5% and 0.4%; HR, 1.37; 95% CI, 0.89 to 2.12; P = 0.16). After a mean follow-up of 2.9 years, there was a similar annual death rate between groups: 3.1% for PCI and 2.9% for CABG (HR, 1.04; 95% CI, 0.93 to 1.17; P = 0.50). PCI with everolimus-eluting stents was associated with a higher risk of a first myocardial infarction than was CABG (1.9% vs 1.1% per year; HR, 1.51; 95% CI, 1.29 to 1.77; P < 0.001). PCI with everolimus-eluting stents was associated with a lower risk of a first stroke than CABG (0.7% vs. 1.0% per year; HR, 0.62; 95% CI, 0.50 to 0.76; P < 0.001). Finally, PCI with everolimus-eluting stents was associated with a higher risk of a first repeat-revascularization procedure than CABG (7.2% vs. 3.1% per year; HR, 2.35; 95% CI, 2.14 to 2.58; P < 0.001).

Conclusion. In the setting of newer stent technology with second-generation everolimus-eluting stents, the risk of death associated with PCI was similar to that associated with CABG for multivessel coronary artery disease. In the long-term, PCI was associated with a higher risk of myocardial infarction and repeat revascularization, whereas CABG was associated with an increased risk of stroke. In the short-term, PCI had lower risks of both death and stroke.

Commentary

Coronary artery disease is a major public health problem. For patients for whom revascularization is deemed to be appropriate, a choice must be made between PCI and CABG. In previous studies that compared PCI and CABG, CABG was shown to have less need for repeat revascularizations as well as mortality benefits [1–3]. However, these prior studies compared CABG with older generations of stents. In the past decade, stent technologies have improved, as the bare-metal stent era gave way to the first generation of of drug-eluting stents (with sirolimus or paclitaxel), to be followed by second-generation drug-eluting stents (with everolimus or zotarolimus) [4].

In this article, Bangalore and colleagues addressed the issue of whether the use of second-generation drug-eluting stents close the outcome gap that favors CABG over PCI in patients with multivessel coronary artery disease. In patients who were considered to have had complete revascularization performed during PCI (ie, revascularization of all major vessels with clinically significant stenosis), they noted mitigation of the outcome differences between the PCI group and the CABG group. They conclude that the decision-making process by patients and their providers regarding revascularization be placed in the context of individual values and preferences.

One major limitation is that the study is an observational study from registry data. Despite the use of sophisticated statistical techniques including propensity score matching to adjust for confounders that are implicit in any nonrandomized comparison of treatment strategies, observational studies suffer from the definitely proof of causality. These limitations are especially important when the two groups being compared have modest differences in outcome.

Applications for Clinical Practice

This observational study, together with a recent randomized clinical trial in which CABG was compared with PCI with the use of everolimus-eluting stents from the BEST trial [5], provided new insights of the 2 revascularization strategies. Clinicians should engage and empower patients with a shared decision-making approach. The early hazard of CABG in stroke and death may be unacceptable to some patients, whereas others might want to avoid the later hazards of PCI in repeat procedure or having a myocardial infarction. Until a definitive study is available, patients should be informed of the best current knowledge of the pros and cons of the two revascularization strategies.

 —Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To compare percutaneous coronary intervention (PCI) using second-generation drug-eluting stents (everolimus-eluting stents) with coronary artery bypass grafting (CABG) among patients with multivessel coronary disease.

Design. Observational registry study with propensity-score matching.

Setting and participants. The study relies on patients identified from the Cardiac Surgery Reporting System (CSRS) and Percutaneous Coronary Intervention Reporting System (PCIRS) registries of the New York State Department of Health. These 2 registries were linked to the New York State Vital Statistics Death registry and to the Statewide Planning and Research Cooperative System registry (SPARCS) to obtain further information like dates of admission, surgery, discharge, and death. Subjects were eligible for inclusion if they had multivessel disease (defined as severe stenosis [≥ 70%] in at least 2 diseased major epicardial coronary arteries) and if they had undergone either PCI with implantation of an everolimus-eluting stent or CABG. Subjects were excluded if they had revascularization within 1 year before index procedure; previous cardiac surgery; severe left main coronary artery disease (degree of stenosis ≥ 50%); PCI with a stent other than an everolimus-eluting stent; myocardial infarction without 24 hours before the index procedure; and unstable hemodynamics or cardiogenic shock.

Main outcome measures. The primary outcome of the study was all-cause mortality. Various secondary outcomes included rates of myocardial infarction, stroke, and repeat vascularization.

Main results. Among 116,915 patients assessed for eligibility, 82,096 were excluded. Among 34,819 who met inclusion criteria, 18,446 were included in the propensity score–matched analysis. With a 1:1 matching algorithm, 9223 were in the PCI with everolimus-eluting stent group and 9223 were in the CABG group. Short-term outcomes (in hospital or ≤ 30 days after the index procedure) favored PCI with everolimus-eluting stents over CABG, with a significantly lower risk of death (0.6% vs. 1.1%; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.35 to 0.69; P < 0.002) as well as stroke (0.2% vs 1.2%; HR, 0.18; 95% CI, 0.11 to 0.29; P < 0.001). The 2 groups had similar rates of myocardial infarction in the short-term (0.5% and 0.4%; HR, 1.37; 95% CI, 0.89 to 2.12; P = 0.16). After a mean follow-up of 2.9 years, there was a similar annual death rate between groups: 3.1% for PCI and 2.9% for CABG (HR, 1.04; 95% CI, 0.93 to 1.17; P = 0.50). PCI with everolimus-eluting stents was associated with a higher risk of a first myocardial infarction than was CABG (1.9% vs 1.1% per year; HR, 1.51; 95% CI, 1.29 to 1.77; P < 0.001). PCI with everolimus-eluting stents was associated with a lower risk of a first stroke than CABG (0.7% vs. 1.0% per year; HR, 0.62; 95% CI, 0.50 to 0.76; P < 0.001). Finally, PCI with everolimus-eluting stents was associated with a higher risk of a first repeat-revascularization procedure than CABG (7.2% vs. 3.1% per year; HR, 2.35; 95% CI, 2.14 to 2.58; P < 0.001).

Conclusion. In the setting of newer stent technology with second-generation everolimus-eluting stents, the risk of death associated with PCI was similar to that associated with CABG for multivessel coronary artery disease. In the long-term, PCI was associated with a higher risk of myocardial infarction and repeat revascularization, whereas CABG was associated with an increased risk of stroke. In the short-term, PCI had lower risks of both death and stroke.

Commentary

Coronary artery disease is a major public health problem. For patients for whom revascularization is deemed to be appropriate, a choice must be made between PCI and CABG. In previous studies that compared PCI and CABG, CABG was shown to have less need for repeat revascularizations as well as mortality benefits [1–3]. However, these prior studies compared CABG with older generations of stents. In the past decade, stent technologies have improved, as the bare-metal stent era gave way to the first generation of of drug-eluting stents (with sirolimus or paclitaxel), to be followed by second-generation drug-eluting stents (with everolimus or zotarolimus) [4].

In this article, Bangalore and colleagues addressed the issue of whether the use of second-generation drug-eluting stents close the outcome gap that favors CABG over PCI in patients with multivessel coronary artery disease. In patients who were considered to have had complete revascularization performed during PCI (ie, revascularization of all major vessels with clinically significant stenosis), they noted mitigation of the outcome differences between the PCI group and the CABG group. They conclude that the decision-making process by patients and their providers regarding revascularization be placed in the context of individual values and preferences.

One major limitation is that the study is an observational study from registry data. Despite the use of sophisticated statistical techniques including propensity score matching to adjust for confounders that are implicit in any nonrandomized comparison of treatment strategies, observational studies suffer from the definitely proof of causality. These limitations are especially important when the two groups being compared have modest differences in outcome.

Applications for Clinical Practice

This observational study, together with a recent randomized clinical trial in which CABG was compared with PCI with the use of everolimus-eluting stents from the BEST trial [5], provided new insights of the 2 revascularization strategies. Clinicians should engage and empower patients with a shared decision-making approach. The early hazard of CABG in stroke and death may be unacceptable to some patients, whereas others might want to avoid the later hazards of PCI in repeat procedure or having a myocardial infarction. Until a definitive study is available, patients should be informed of the best current knowledge of the pros and cons of the two revascularization strategies.

 —Ka Ming Gordon Ngai, MD, MPH

From the Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA.

Abstract

• Objective: To review the diagnosis and management of venous thromboembolism (VTE).
• Methods: Review of the literature.
• Results: VTE and its associated complications account for significant morbidity and mortality. Various imaging modalities can be employed to support a diagnosis of a VTE and are used based on clinical suspicion arising from the presence of signs and symptoms. Clinical decision rules have been developed  that can help determine which patients warrant further testing. Anticoagulation, the mainstay of VTE treatment, increases bleeding risk, necessitating tailored treatment strategies that must incorporate etiology, risk, benefit, cost, and patient preference.
• Conclusion: Further study is needed to understand individual patient risks and to identify treatments that will lead to improved patient outcomes.

Venous thromboembolism (VTE) and its associated complications account for significant morbidity and mortality. Each year between 100 and 180 persons per 100,000 in Western countries develop VTE. The majority of VTEs are classified as either pulmonary embolism (PE), which accounts for one third of the events, or deep vein thrombosis (DVT), which is responsible for the remaining two thirds. Between 20% and 30% of those patients diagnosed with thrombotic events will die within the first month after diagnosis [1].PE is a common consequence of DVT; 40% of patients who are diagnosed with DVT will be subsequently found to have PE upon further imaging. This high rate of association is also seen in those who present with PE, 70% of whom will also be found to have concomitant DVT [2,3].

Anatomic risk factors include Paget-Schroetter syndrome (compression of upper extremity veins due to abnormalities at the thoracic outlet), May-Thurner syndrome (significant compression of the left common iliac vein by the right common iliac artery), and abnormalities of the inferior vena cava [14–16].Medications that are associated with increased risk of VTE include but are not limited to estrogen (both in oral contraceptives as well as hormone replacement therapy) [17,18],the selective estrogen receptor modulator tamoxifen [19],testosterone [20],and glucocorticoids [21].It is important to note that many patients with VTE have more than one acquired risk factor for thrombosis [22],and also that acquired risk factors are more likely to lead to VTE in the setting of underlying inherited thrombophilic conditions [23].

Pathogenesis

Abnormalities in both coagulation factors and the vascular bed are at the core of the pathogenesis of VTE. The multifaceted etiology of thrombosis was first described in 1856 by Virchow, who defined a triad of defects in the vessel wall, platelets, and coagulation proteins [24].Usually the vessel wall is lined with endothelial cells that provide a nonthrombotic surface and limit platelet aggregation through release of prostacyclins and nitric oxide. When the endothelial lining is compromised, the homeostatic surveillance system is disturbed and platelet activation and the coagulation system are initiated. Tissue factor exposure in the damaged area of the vessel leads to activation of the coagulation cascade. Collagen that is present in the area of the wound is also exposed and can activate platelets, which provide the phospholipid surface upon which the coagulation cascade occurs. Platelets initially tether to the exposed collagen through binding of glycoprotein Ib-V-IX in association with von Willebrand factor [25].The thrombus is initiated as more platelets are recruited to exposed collagen of the injured endothelium through aggregation in response to the binding of GPIIIb/IIa with fibrinogen. This process is self-perpetuating as these activated platelets release additional proteins such as adenosine diphosphate (ADP), serotonin, and thromboxane A2, all of which fuel the recruitment and activation of additional platelets [26].

Diagnosis

The key to decreasing the morbidity and mortality associated with VTE is timely diagnosis and early initiation of therapy. Various imaging modalities can be employed to support a diagnosis of a VTE and are used based on clinical suspicion arising from the presence of signs and symptoms. DVT is usually associated with pain in calf or thigh, unilateral swelling, tenderness, and redness. PE can present as chest pain, shortness of breath, syncope, hemoptysis, and/or cardiac palpitations.

Decision Rules

Clinical decision rules based on signs, symptoms, and risk factors have been developed to estimate the pretest probability of PE or DVT and to help determine which patients warrant further testing. These clinical decision rules include the Wells criteria (separate rules for DVT and PE) [27,28],as well as the Geneva score [29],which is focused on identifying patients with a likelihood of having a PE. In general, these clinical rules are applied at presentation to predict the risk of VTE, and patients who score high are evaluated by imaging modalities, while those with lower scores should be considered for further stratification based on D-dimer testing. The goal of clinical assessment and use of a decision rule is to identify patients at low risk of VTE to reduce the number of imaging studies performed. Most of the decision rules focus on the use of noninvasive evaluations that are easily implemented, including clinical history and presentation, abnormalities in oxygen saturation, chest radiography findings, and electro-cardiography.

D-Dimer Testing

D-dimer testing is at the core of all predictive models for VTE. D-dimer is a fibrin degradation product that is detectable in the blood during active fibrinolysis and occurs after clot formation. The concentration of D-dimer increases in patients with active clot. D-dimer testing is usually performed as a quantitative ELISA or automated turbidometric assay and is highly sensitive (> 95%) in excluding a diagnosis of VTE if results are in the normal range [30].The presence of a normal D-dimer and a low probability based on clinical assessment criteria can be integrated to determine which patients have a low (generally < 99%) likelihood of having VTE [31].It should be noted that other factors can lead to an increased D-dimer, including malignancy, trauma, critical illness, disseminated intravascular coagulation, pregnancy, infection, and postoperative status, which can produce false-positive results and cloud the utility of the test in excluding those at low risk of VTE from undergoing imaging [32–34].Additionally, D-dimer values naturally increase with age and recent work has shown utility of an age-adjusted D-dimer threshold, though this method is not yet widespread in clinical practice [35,36].

Imaging

After application of a clinical prediction rule, the mainstay of diagnosis of VTE is imaging. For DVT the use of ultrasonography is considered the gold standard, with both high sensitivity (89–100%) and specificity (86–100%), especially when the DVT is located proximally [37–39].We generally recommend compression ultrasound starting with the proximal veins but expanding to include the whole leg if the proximal studies are negative [40–42].Other diagnostic options include computed tomography (CT) venography, which is not first line as it is highly invasive and exposes the patient to iodine-based contrast dyes, and magnetic resonance venography (MRV), which offers superb visualization for diagnosis of pelvic vein thrombosis but is limited because of availability and cost issues.

Helical CT pulmonary angiography (CTPA) is the diagnostic test of choice in PE, with high sensitivity (96%) and specificity (95%), and has replaced conventional ventilation perfusion (VQ) scanning or other methods such as magnetic resonance pulmonary angiography in most settings [43,44].CTPA should be avoided in patients who have severe chronic kidney disease or a contrast allergy, and is often avoided in patients who are pregnant due to potential risk of radiation exposure, and in such situations VQ scanning may be employed.

Algorithmic Approach to Workup

Of note, there are multiple clinical situations in which the application of a clinical prediction rule followed by D-dimer testing and/or imaging cannot be “standardized” with such algorithms. These include situations where D-dimer may be falsely positive (as above), situations in which alternative imaging strategies should be used to avoid contrast exposure in workup of PE (as above), and workup of suspected upper extremity DVT. Upper extremity ultrasound comprises about 10% of all DVT and frequently occurs in the setting of risk factors such as central venous catheters or pacemakers; specific upper-extremity risk-assessment rules have been developed [47,48].

Acute Treatment Options

The first step in treatment is identification of patients who are at high risk of 

In standard cases of DVT and PE without hemodynamic compromise, the current standard of care is to initiate parenteral anticoagulation. The immediate goal of therapy is to treat rapidly with anticoagulants to prevent the thrombus from propagating further and to prevent DVT from embolization to the lungs or other vascular beds. The initial treatment of VTE has been extensively discussed and guidelines have been established with recommendations for initiation of anticoagulation; the American College of Chest Physicians (ACCP) released the 9th edition of their guidelines in 2012 based on consensus agreements derived from primary data [51].

Heparin-based drugs are the mainstay of initial treatment. These drugs act by potentiating antithrombin and therefore inactivating thrombin and other coagulation factors such as Xa. Unfractionated heparin (UFH) can be administered as an initial bolus followed by a continuous infusion with dosing being based on weight and titrated to activated partial thromboplastin time (aPTT) or the anti-factor Xa level. Alternatively, patients may be treated with a low molecular weight heparin (LMWH) administered subcutaneously in fixed weight-adjusted doses, which obviates the need for monitoring in most cases [52].LMWHs work in a similar manner to UFH but have more anti-Xa activity in comparison to anti-thrombin activity. LMWH appears to be more effective than UFH for initial treatment of VTE and has been associated with lower risk of major hemorrhage [53].The options for treatment of VTE have expanded in recent years with the approval of fondparinux, a pentasaccharide specifically targeted to inhibit factor Xa. Fondaparinux has been shown to have similar efficacy to LMWH in patients with DVT [54],and while it has not been evaluated directly against LMWH for initial treatment of PE it has been shown to be at least as effective and safe as UFH [55].

Both LMWH and fondaparinux are cleared renally and therefore have increased bleeding risk in patients with renal impairment. In patients with creatinine clearance of less than 30 mL/min, dose reduction or lengthening of dosing interval may be appropriate. Anti-factor Xa activity can be used as a functional assay to monitor and titrate the level of anticoagulation in patients treated with UFH, LMWH, and fondaparinux. Monitoring is useful in the setting of impaired renal function (as above) in addition to extremes of body weight and pregnancy. When used for monitoring of UFH, the anti-factor Xa activity can be measured at any time during administration with a therapeutic goal range of 0.3–0.7 international units (IU)/mL. When used for LMWH, a “peak” anti-factor Xa should be measured approximately 4 hours after dosing, with therapeutic goals depending on preparation and schedule of treatment but generally between 0.6 to 1.0 IU/mL for twice daily and around 1.0 -2.0 IU/mL for once-daily [56].For patients on dialysis, we generally use intravenous UFH for acute treatment of VTE, though recent work has shown that enoxaparin (doses of 0.4 to 1 mg/kg/day) was as safe as UFH with respect to bleeding and was associated with shorter hospital length of stay [57].For long-term treatment of VTE, warfarin is generally preferred based on clinical experience with this agent, though small studies have suggested that parenteral agents may be useful alternatives to warfarin [58].

In many patients who are clinically stable without significant medical comorbidities, outpatient administration of these medications without hospitalization is considered safe. Patients with DVT are often safe to manage as outpatients unless significant clot burden is present and thrombolysis is being considered. For PE, the pulmonary embolism severity index (PESI) and simplified index (sPESI) may be useful to risk-stratify patients and identify those at low risk of complications who may be suitable for outpatient treatment [59,60].Studies have shown that hemodynamically stable patients who did not require supplemental oxygenation or have contraindications to LMWH therapy were safely managed as outpatients with low risk of recurrent VTE and bleeding [61,62].One exception may be patients with intermediate risk PE, who are hemodynamically stable but have evidence of right ventricular dysfunction and may be better served by an initial in-hospital observation period, especially if thrombolysis is being considered.

Most patients who present with VTE are transitioned to warfarin for long-term therapy. Warfarin can be started on the same day as parenteral anticoagulation. Both drugs are overlapped for at least 5 days, with a target INR of 2.0–3.0. Patients may achieve the target INR level quickly because factor VII has a short half-life and the level drops quickly; however, the overlap of 5 days is essential even when the INR is in the target range because a full anticoagulant affect is not achieved until prothrombin levels decline, and this is a slow process due to the long half-life of prothrombin. Warfarin also causes rapid decrease in levels of natural anticoagulants such as protein C and protein S, which further exacerbates the net hypercoagulable state in the short-term. Warfarin without a bridging parenteral agent carries a risk of warfarin-induced skin necrosis [63]and is not effective as an initial anticoagulant treatment in acute VTE as there is a relatively high risk of symptomatic clot extension or recurrent VTE compared to warfarin with use of a bridging agent [64].In specific cases such as cancer-associated VTE (see discussion below), LMWH is preferred to warfarin for long-term active therapy.

Long-Term Active Therapy After Acute Treatment

Duration of Anticoagulation

Recommended duration of anticoagulation depends on a myriad of factors including severity of VTE, risk of recurrence, bleeding risk, and lifestyle modification issues, as well as on the safety and availability of alternative therapies such as low-intensity warfarin, aspirin, or the new oral anticoagulants. The decision tree for length of treatment starts with whether the VTE was a provoked or a spontaneous event. Provoked events occur when the event is associated with an identifiable risk factor, such as immobilization from prolonged medical illness or surgical intervention, pregnancy or oral contraceptive use, and prolonged air travel.

Consensus guidelines suggest that 3 months of anti-coagulation are generally sufficient treatment for a provoked VTE [51,65,66]. Data from multiple studies and a meta-analysis suggests that less than 3 months of anticoagulation (4 to 6 weeks in most trials) is associated with an approximately 1.5-fold higher risk of recurrent VTE than 3 months [67,68].However, data from this meta-analysis also suggests that anticoagulation for longer than 3 months (6 to 12 months in most trials) is not associated with higher rates of recurrent VTE. We generally anticoagulate for 3 months in patients with provoked VTE.

Determining the duration of anticoagulation is more complex in patients with idiopathic/unprovoked VTE. Kearon and colleagues found that in patients with first idiopathic VTE, patients who were anticoagulated for 24 months versus 3 months had lower risk of recurrent VTE (1.3% per patient-year with 24 months versus 27.4% per patient-year with 3 months) [69].Similar studies and meta-analyses have demonstrated decreased recurrence rates in patients anticoagulated for a prolonged period of time. However, one study of prolonged anticoagulation revealed that at 3 years there was no difference in recurrence rate in patients with PE who were anticoagulated for 6 months versus 1 year [70].The likelihood of recurrent DVT in patients with first episode of idiopathic proximal DVT treated with either 3 months or 12 months of warfarin was similar after treatment was discontinued [71].Prolonged periods of anticoagulation do not directly influence risk of recurrence but instead may only delay occurrence of a second event [72].For that reason, the decision is essentially whether to anticoagulate for 3 months or to continue therapy indefinitely [73]. Current guidelines recommend continuing anticoagulation for 3 months in those at high risk of bleeding, and continuing for an extended duration in those at low or moderate bleeding risk [51]. Patients' values and perferences should be entertained and decisions made on a patient-by-patient basis.

For patients at high risk of recurrent VTE, we generally recommend indefinite anticoagulation unless the patient has a significantly elevated bleeding risk or strongly prefers to discontinue anticoagulation and compliance concerns are evident. High-risk patients are those who have suffered from multiple episodes of recurrent VTE, those who have clotted while being anticoagulated, and those with acquired risk factors, such as antiphospholipid antibodies and malignancy. Other high-risk groups are those with high-risk thrombophilias such as deficiency of protein S, protein C, or antithrombin, homozygous factor V Leiden or prothrombin gene mutations, and compound heterozygous factor V Leiden/prothrombin gene mutation in the setting of an unprovoked event. Further discussion of models for risk assessment of recurrence is provided below.

Assessment of Bleeding Risk

The bleeding risk associated with the use of anticoagulation must be weighed against the risk of clotting events when determining duration of anticoagulation, especially in those patients for whom indefinite anticoagulation is a consideration. Risk of bleeding while on anticoagulation is approximately 1–3% per 100 patient-years [74],but concomitant medical conditions such as renal failure, diabetes-related cerebrovascular disease, malignancy, advanced age, and use of antiplatelet agents all increase the risk of bleeding. Bleeding risk is highest when patients first initiate anticoagulation and is approximately 10 times the risk in the first month of therapy than after the first year of therapy [75].

Risk assessment models such as the RIETE score may be helpful when indefinite anticoagulation is a possibility [76].The RIETE score encompasses 6 risk factors (age > 75 years, recent bleeding, cancer, creatinine level > 1.2 mg/dL, anemia, or PE at baseline) to categorize patients into low risk (0 points, 0.3% risk of bleeding), intermediate risk (1–4 points, 2.6% risk of bleeding) and high risk (> 4 points, 6.2% risk of bleeding) within 3 months of anticoagulant therapy. The ACCP has developed a more extensive list of 17 potential risk factors for bleeding to categorize patients into low risk (no risk factors, 0.8%/year risk of bleeding), intermediate risk (1 risk factor, 1.6%/year risk of bleeding) and high risk (2 or more risk factors, >6.5%/year risk of bleeding) categories [77].The RIETE score is simpler to use but was not developed for assessing risk of bleeding during indefinite therapy, while the ACCP risk categorization predicts a yearly risk and is therefore applicable for long-term risk assessment but is more cumbersome to use. In practice, we generally use a clinical gestalt of a patient’s clinical risk factors (particularly age, renal or hepatic dysfunction, and frequent falls) to assess if they may be at high risk of bleeding and if the risk of indefinite anticoagulation may thus outweigh the potential benefit.

We also note that several scoring systems (HAS-BLED, HEMORR2HAGES, and ATRIA scores) have been developed to predict those at high risk of bleeding on anticoagulation for atrial fibrillation [78–80].These scores generally include similar clinical risk factors to those in the RIETE and ACCP scoring systems. Several studies have compared the HAS-BLED, HEMORR2HAGES, and ATRIA scores and a systematic review and meta-analysis concluded that the HAS-BLED score is recommended, due to increased sensitivity and ease of application [81].However, as these scores have not been validated for anticoagulation in the setting of VTE, we do not use them in this capacity.

Risk Stratification for Recurrent VTE

When predicting risk of recurrent VTE, clinical risk factors including obesity, male gender, and underlying thrombophilia (including the “high risk” inherited thrombophilias identified above) must taken into consideration. Location of the thrombus must also be considered; it has also been demonstrated that patients with DVT involving the iliofemoral veins are at higher risk of recurrence than those without iliac involvement [82].Other factors that may be useful in risk stratification include D-dimer level and ultrasound to search for residual venous thrombosis.

D-dimer Levels

D-dimer levels are one of the more promising methods for assessing the risk of recurrent VTE after cessation of anticoagulation, especially in the case of idiopathic VTE where indefinite anticoagulation should be considered but may pose either risk of bleeding or significant inconvenience to patients. A normal D-dimer measured 1 month after cessation of anticoagulation offers a high negative predictive value for risk of recurrence [83].A number of studies have demonstrated that patients with elevated D-dimer 1 month after anticoagulation cessation are at increased risk for a recurrent event [84–86].Two predictive models that have been developed incorporate D-dimer testing into decision making [87,88].The DASH predictive model relies on the D-dimer result in addition to age, male sex, and use of hormone therapy as a method of risk stratification for recurrent VTE in patients with a first unprovoked event. Using this scoring system, patients with a score of 0 or 1 had a recurrence rate of 3.1%, those with a score of 2 a recurrence rate of 6.4%, and those with a score of 3 or greater a recurrence rate of 12.3%. The authors postulate that by using this assessment scheme they can avoid lifelong anticoagulation in 51% of patients. The Vienna prediction model uses male sex, location of VTE (proximal DVT and PE are at higher risk), and D-dimer level to predict risk of recurrent VTE. This model has recently been updated to include a “dynamic” component to predict risk of recurrence of VTE from multiple random time points [89].

Overall, D-dimer may be useful for risk stratification. We often employ the method of stopping anticoagulation in patients with unprovoked VTE after 3 months (if the patient has no identifiable clinical risk factors that place them at high risk of recurrence) and testing D-dimer 1 month after cessation of anticoagulation. An elevated D-dimer is a solid reason to restart anticoagulation (potentially on an indefinite basis), while a negative D-dimer provides support for withholding further anticoagulation in the absence of other significant risk factors for recurrence. However, lack of agreement regarding assay cut-points as well as multiple reasons other than VTE for D-dimer elevation may limit widespread use of this method. We generally use a cutpoint of 250 ug/L as “negative,” though at least one study showed that cut-points of 250 ug/L versus 500 ug/L did not change the utility of this method [90].In our practice, risk prediction models are most useful to provide patients with additional information and a visual presentation to support our recommendation. This is particularly true of the Vienna prediction rule, which is available in a printable nomogram which can be distributed to patients and completed together during the clinic visit.

Imaging Analysis

Imaging analysis may also assist with risk stratification. Clinical assessment modules have been developed that incorporate repeat imaging studies for assessment of recannulization of affected veins. In patients with residual vein thrombosis (RVT) at the time anticoagulation was stopped, the hazard ratio for recurrence was 2.4 compared to those without RVT [91].There are a number of ways RVT could impact recurrence, including inpaired venous flow leading to stasis and activation of the coagulation cascade. Subsequent studies used serial ultrasound to determine when to stop anticoagulation. In one study, patients were anticoagulated for 3 months and for those that had RVT, anticoagulation was continued for up to 9 months for provoked and 21 months for unprovoked VTE. In comparison to fixed dosing of 6 months of anti-coagulation, those who had their length of anticoagulation tailored to ultrasonography findings had a lower rate of recurrent VTE [92].Limitations to using RVT in clinical decision-making include lack of a standard definition of RVT and variability in both timing of ultrasound (operator variability) and interpretation of results [93].

Other Options

Another option in patients who are being considered for indefinite anticoagulation is to decrease the intensity of anticoagulation. Since this would theoretically lower the risk of bleeding, the perceived benefit of long-term, low-intensity anticoagulation would be reduction in both bleeding and clotting risk. The PREVENT trial randomized patients who had received full-dose anticoagulation for a median of 6.5 months to either low-intensity warfarin (INR goal of 1.5-2.0 instead of 2.0-3.0) or placebo. In the anticoagulation group, there was a 64% risk reduction in recurrent VTE (hazard ratio 0.36, 95% CI 0.19 to 0.67) but an increased risk of bleeding (hazard ratio 1.92, 95% CI 1.26 to 2.93) [94].The ELATE study randomized patients with unprovoked VTE who had completed 3 or more months of full-intensity warfarin therapy (target INR 2.0–3.0) to continue therapy with either low-intensity warfarin (target INR 1.5–2.0) or full-intensity warfarin (target INR 2.0-3.0). Compared to the low-intensity group, the conventional-intensity group had lower rates of recurrent VTE and no increased rates of major bleeding [95].This study, however, has been criticized because of its overall low bleeding rate in both treatment groups.

Aspirin is an option in patients in whom long-term anticoagulation is untenable. The ASPIRE trial demonstrated that in patients with unprovoked VTE who had completed a course of initial anticoagulation, aspirin 100 mg daily reduced the risk of major vascular events compared to placebo with no increase in bleeding [96].However, aspirin was not associated with a significant reduction in risk of VTE alone (only the composite vascular event endpoint). The WARFASA trial, however, demonstrated that aspirin 100 mg daily was associated with a significant reduction in recurrent VTE compared to placebo after 6 to 18 months of anticoagulation without an increase in major bleeding [97].The absolute risk of recurrence was 11% in the placebo group and 5.9% in the aspirin group. More recently, the INSPIRE collaboration analyzed data from both trials and found that aspirin after initial anticoagulation reduced the risk of recurrent VTE by approximately 42% with a low rate of major bleeding [98].The absolute risk reduction was even larger in men and older patients. For this reason, we recommend aspirin to those patients in whom indefinite anticoagulation may be warranted from the standpoint of reducing risk of recurrent VTE but in whom the risk of bleeding precludes its use.

Hypercoagulable States In Specific Populations

Inherited Thrombophilias

Patients with a hereditary thrombophilia are at increased risk for incident VTE [99].These inherited mutations result in either a loss of normal anticoagulant function or gain of a prothrombotic state. Hereditary disorders associated with VTE include deficiency of antithrombin, protein C, or protein S, or the presence of factor V Leiden and/or prothrombin G20210A mutations. Although deficiency of protein C, protein S, or antithrombin is uncommon and affects only 0.5% of the population, these states have been associated with a 10-fold increased risk of thrombosis in comparison to the general population. Factor V Leiden and prothrombin gene mutation are less likely to be associated with incident thrombosis (2 to 5-fold increased risk of VTE) and are more prevalent in the Caucasian population [100].Though these hereditary thrombophilias increase risk of VTE, prophylactic anti-coagulation prior to a first VTE is not generally indicated.

Data regarding the impact of the inherited thrombophilias on risk of recurrent VTE is less well defined. While some data suggest that inherited thrombophilias are associated with increased risk of recurrent VTE, the degree of impact may be clinically modest especially in those with heterozygous factor V Leiden or prothrombin gene mutations [101].Ideally, a clinical trial would be designed to assess whether hereditary thrombophilia testing is beneficial for patients with VTE in decision-making regarding length of anticoagulation, type of anticoagulation, and risk of recurrence. If a patient with a low-risk inherited thrombophilia has a DVT in the setting of an additional provoking risk factor (surgery, pregnancy, etc), a 3-month course of anticoagulation followed by D-dimer assessment as above is reasonable. If a patient with an inherited thrombophilia experiences an idiopathic VTE, or if a patient with a “high-risk” thrombophilia as described above experiences any type of VTE, we generally recommend indefinite anticoagulation in the absence of high bleeding risk, though again this is a very patient-dependent choice.

Acquired Thrombophilias

Antiphospholipid Syndrome

Antibodies directed against proteins that bind phospho-lipids are associated with an acquired hypercoagulable state. The autoantibodies are categorized as antiphospho-lipid antibodies (APLAs), which include anticardiolipin antibodies (IgG and IgM), beta-2 glycoprotein 1 antibodies (anti-B2 GP), and lupus anticoagulant. These antibodies can form autonomously, as seen in primary disorders, or in association with autoimmune disease as a secondary disorder.

Criteria have been developed to distinguish antiphospholipid-associated clotting disorders from other forms of thrombophilia. The updated Sapporo criteria depend on both laboratory and clinical diagnostic criteria [102].The laboratory diagnosis of APLAs requires the presence of lupus anticoagulants, anticardiolipin antibodies, or anti-B2 GP on at least 2 assays at least 12 weeks apart with elevation above the 99th percentile of the testing laboratory’s normal distribution [103].Testing for lupus anticoagulant is based on 3 stages, the first of which is inhibition of phospholipid-dependent coagulation tests with prolonged clotting time (eg, aPTT or dilute Russell’s viper venom time). The diagnosis is confirmed by a secondary test in which excess hexagonal phase phospholipids are added to incubate with the patient’s plasma to absorb the APLA [104].The presence of anticardiolipin antibodies and anti beta-2 GP antibodies is determined using ELISA based immunoassays. Unlike most other thrombophilias, antiphospholipid syndrome is associated with both arterial and venous thromboembolic events and may be an indication for lifelong anticoagulation after a first thrombotic event. We generally recommend indefinite anticoagulation in the absence of significant bleeding risk.

Cancer-Associated Hypercoagulable State

Patients with cancer have a propensity for thromboembolic events. The underlying mechanisms responsible for cancer-associated clotting events are multifactorial and an area of intense research. Tumor cells can initiate activation of the clotting cascade through release of tissue factor and other pro-coagulant molecules [105].Type and stage of cancer impact risk of VTE, and the tumor itself can compress vasculature leading to venous stasis. Furthermore, chemotherapy, hormone therapy, antiangiogenic drugs, erythropoietin agents, and indwelling central venous catheters all are associated with increased risk of thrombotic events. Approximately 25% of all cancer patients will experience a thrombotic event during the course of their disease [106]. In fact, the presence of a spontaneous clot may be a harbinger of underlying malignancy [107].Approximately 10% of patients who present with an idiopathic VTE are diagnosed with cancer in the next 1 to 2 years.

The utility of extensive cancer screening in patients with spontaneous clotting events is often debated. The small studies that have addressed cancer associated clots have not demonstrated any mortality benefit with extensive screening. A prospective cohort study addressed the utility of limited versus extensive screening [108].In this study, all patients underwent a series of basic screening tests such as history taking, physical examination, chest radiograph, and basic laboratory parameters. Approximately half of the patients underwent additional testing (CT of chest and abdomen and mammography for women). Screening did not result in increased survival or fewer cancer-related deaths. 3.5 % of patients in the extensive screening group were diagnosed with malignancy in comparison to 2.4% in the limited screening group. During follow-up, cancer was diagnosed in 3.7% and 5.0% in the extensive and limited screening groups, respectively. The authors concluded that the low yield of extensive screening and lack of survival benefit did not warrant routinely ordering cancer screening tests above and beyond age-appropriate screening in patients with idiopathic VTE. However, it is known that identification of occult malignancy at an earlier stage of disease is beneficial, and cancer diagnosed within one year of an episode of VTE is generally more advanced and associated with a poorer prognosis [109].It is our practice to take a through history from patients with unprovoked clots particularly focusing on symptoms suggestive of an underlying cancer. We recommend that patients be up to date with all age-appropriate cancer screening.

Heparin-based products (rather than warfarin) are recommended for long-term treatment of cancer-associated DVT. Several trials, most prominently the CLOT trial, have demonstrated that LMWH is associated with reduced risk of recurrent VTE compared with warfarin in cancer patients [110].Fondaparinux may be a reasonable alternative if a patient is unable to tolerate a LMWH. In terms of treatment duration, patients with cancer-associated VTE should be anticoagulated indefinitely as long as they continue to have evidence of active malignancy and/or remain on antineoplastic treatment [111].

Heparin has potential anticancer effects beyond its anticoagulation properties. It is believed that heparin use in patients with cancer can influence cancer progression by acting as an antimetastatic agent. The molecular mechanisms underlying this significant observation are not completely understood, although the first documented benefit of these drugs dates back to the 1970s [112].Overall, LMWH have been associated with improved overall survival in cancer patients and this effect appears to be distinct from its ability to prevent life-threatening VTE episodes [113].

Estrogen-Related Thromboembolic Disease

Pregnancy is a well-established acquired hypercoagulable state, and thromboembolic disease accounts for significant morbidity and mortality in pregnancy and the postpartum period. Approximately 1 in 1000 women will suffer from a thrombotic event during pregnancy or shortly after delivery [8]. The etiology of the tendency to clot during pregnancy is multifactorial and mainly reflects venous stasis due to vasculature compression by the uterus, changes in coagulation factors as the pregnancy progresses, and endothelial damage during delivery, especially Cesarean section. Both factor VIII and von Willebrand factor levels increase, especially in the final months of pregnancy. Simultaneously, levels of the natural anticoagulant protein S diminish, leading to an acquired resistance to activated protein C which results in increased thrombin generation and therefore a hypercoagulable state [114].The risk of thrombosis in pregnancy is clearly heightened in women with inherited thrombophilias, especially in the postpartum period [115].

Similarly to pregnancy, hormone-based contraceptive agents and estrogen replacement therapies are also associated with increased thrombotic risk. Over the years, drug manufacturers have tried to mitigate the clotting risk associated with these drugs by reducing the amount of estrogen and altering the type of progesterone used, yet a risk still remains, resulting in a VTE incidence 2 to 7 times higher in this population [116].The risk is highest in the first 4 months of use and is unaffected by duration of use; risk extends for 3 months after cessation of estrogen-containing therapy. Patients who develop VTE while taking an oral contraceptive are generally instructed to stop the contraceptive and consider an alternative form of birth control. Although routine screening for thrombophilia is not offered to women before prescribing oral contraceptives, a thorough personal and family history regarding venous and arterial thrombotic events as well as recurrent pregnancy loss in women should be taken to evaluate thromboembolic risk factors. We generally avoid use of oral contraceptives in patients with a known hereditary thrombophilia, and consider screening prior to initiation of therapy in those with a strong family history of VTE.

Superficial VTE

Although the main disorders that comprise VTE are DVT and PE, another common presentation is superficial venous thromboembolism (SVT). The risk factors for developing an SVT are similar to those for DVT. In addition, varicose veins also increase the incidence of developing SVT [117].SVT is not associated with excessive mortality, and the main concern with it is progression to DVT. About 25% of patients diagnosed with SVT may have DVT or PE at the time of diagnosis and about 3% without DVT or PE at time of diagnosis developed one of these complications over the following 3 months; clot propagation is another common complication [118].Ultrasound may be of utility in diagnosing occult DVT in patients who initially diagnosed with SVT [119].

For patients who have only SVT at baseline without concomitant DVT or PE, it is difficult to determine which patients are at risk for developing DVT. Some risk stratification models include clot location. Since SVT clots usually develop in the saphenous vein, the clot would need to either progress from the sapheno-femoral junction to the common femoral vein; thus, any clots located near the sapheno-femoral junction are at risk of progressing into the deep vasculature [120].Clots within 3 cm of the junction may be more likely to progress to DVT [121].Chengelis and colleagues feel that proximal saphenous vein thrombosis should likely be treated with anticoagulation [122].Others have taken a more general approach, stating that all clots above the knee or in the thigh area should be treated aggressively [123].

There are solid data for the use of anticoagulation in SVT. In the STEFLUX (Superficial ThromboEmbolism and Fluxum) study, participants received the LMWH parnaparin at one of 3 doses: 8500 IU once daily for 10 days followed by placebo for 20 days, 8500 IU once daily for 10 days and then 6400 IU once daily for 20 days, or 4250 IU once daily for 30 days. Those who received the intermediate dosing had lower rates of DVT, PE, and relapse/SVT recurrence in the first 33 days [124].In the CALISTO trial, fondaparinux 2.5mg per day for 45 days effectively reduced the risk of symptomatic DVT, PE, or SVT recurrence or extension and was not associated with any increased major bleeding compared to placebo [125].A Cochrane review included 30 studies involving over 6500 participants with SVT of the lower extremities. The treatments used in these studies included fondaparinux, LMWH, UFH, non-steriodal anti-inflammatory agents, topical treatment, and surgery. According to the findings, use of fondaparinux at prophylactic dosing for 6 weeks is considered a valid therapeutic option for SVT [126].It is our practice to consider the use of anticoagulants (generally LMWH or fondaparinux) as part of the treatment regimen for SVT.

Target-Specific Oral Anticoagulants And Treatment of VTE

The direct thrombin inhibitor dabigatran directly binds to thrombin in a concentration-dependent manner [127].Peak plasma concentration is achieved within 0.5 to 2.0 hours after ingestion, and its half-life is 12 to 17 hours. Use of dabigatran in both primary and secondary prevention of VTE has been extensively studied, especially in orthopedic surgery where there have been 4 main trials (RE-MOBILIZE, RE-MODEL, RE-NOVATE, and RE-NOVATE I and II). While RE-MOBILIZE showed that dabigatran 220 mg or 150 mg once daily was inferior to enoxaparin 30 mg twice daily in preventing VTE after total knee arthroplasty, RE-MODEL and RE-NOVATE I and II demonstrated that dabigatran 150 mg or 220 mg once daily was noninferior to enoxaparin 40 mg once daily for prevention of VTE in patients undergoing total knee replacement and hip replacement [128–131].The side effect profile was also promising, with no significant differences in the frequency of major bleeding between dabigatran and enoxaparin. Pooled data and meta-analyses from these trials have demonstrated that for prevention of VTE associated with hip or knee surgery, dabigatran 220 mg or 150 mg once daily is as effective as 40 mg of enoxaparin given daily or 30 mg given twice a day, with a similar bleeding profile [132,133].

More recently, dabigatran been used in the acute treatment and secondary prevention of VTE. In the RE-COVER trial, dabigatran 150 mg twice daily was compared to warfarin (INR 2–3) in the treatment of acute VTE for 6 months, after an initial treatment period of up to 9 days with LMWH or UFH. Dabigatran was noninferior to warfarin with respect to 6-month incidence of recurrent symptomatic objectively confirmed VTE and related deaths, and was not associated with increased bleeding [134].In the RE-MEDY and RE-SONATE trials of extended anticoagulation, dabigatran was as effective as warfarin for prevention of recurrent VTE when continued after 3 months of initial anticoagulation and associated with less bleeding, and was more effective than placebo in preventing recurrent VTE but associated with a higher risk of bleeding [135].Unexpectedly, the risk of acute coronary syndrome was slightly higher in the dabigatran group than the warfarin group, as seen in other studies.

Rivaroxaban, a TSOAC that targets factor Xa, has also shown efficacy in preventing VTE after knee or hip surgery. The RE-CORD 1-4 studies all focused on the use of rivaroxaban in comparison to enoxaparin and found that rivaroxaban 10 mg once daily was superior to enoxaparin 40 mg once daily in prevention of VTE in total knee and total hip arthroplasty [136–138].Meta-analysis of multiple rivaroxaban VTE prophylaxis trials also demonstrated that rivaroxaban significantly lowered the risk of VTE in these surgical patients in comparison to the use of enoxaparin [139].Prophylactic use of rivaroxaban was also studied in acutely ill hospitalized patients in the MAGELLAN trial. Rivaroxaban 10 mg daily for 35 days was compared to enoxaparin 40 mg daily for 10 days followed by placebo and was found to be noninferior to enoxaparin in reduction of VTE risk at day 10 and superior to placebo at day 35 [140].However, the rate of bleeding, although low in both arms, was higher in the rivaroxaban arm.

Rivaroxaban has been studied in randomized clinical trials for acute treatment of DVT and PE and for extended prophylaxis for recurrent VTE (EINSTEIN-DVT, EINSTEIN-PE and EINSTEIN-Extension, respectively).  The treatment strategy for use of rivaroxaban differed from that of dabigatran (in the RE-COVER trial), as rivaroxaban was used upfront as initial anticoagulation rather than after an initial period of parenteral therapy with LMWH or UFH. In both the DVT and PE trials, rivaroxaban was noninferior to standard treatment with enoxaparin followed by warfarin therapy, with no significant difference in major bleeding at 6 months of treatment [141,142].The extension trial also demonstrated that use of rivaroxaban in comparison to placebo for an additional 6 or 12 months after standard therapy was associated with significantly fewer recurrent VTE [141]. These studies led to FDA approval for rivaroxaban for primary prevention of VTE in patients undergoing elective total hip or knee repair surgery, for treatment of acute DVT or PE, and for extended prophylaxis in patients following initial treatment.

The anti-factor Xa TSOAC apixaban has been studied in similar fashion as rivaroxaban. In the AMPLIFY study, apixaban was given at a dose of 10 mg twice daily for 7 days followed by 5 mg twice daily for 6 months (as monotherapy, without initial parenteral agent) and compared to enoxaparin followed by warfarin for treatment of acute VTE. Apixaban was as effective as warfarin in terms of recurrent symptomatic VTE or VTE-related death, and was associated with significantly fewer bleeding events [143].Extended-duration apixaban given at treatment dose (5 mg twice daily) or at prophylactic dose (2.5 mg twice daily) for 12 months after completion of treatment-dose apixaban for VTE demonstrated superiority to placebo for extended prophylaxis in AMPLIFY-EXT, and there was no increase in major bleeding compared to placebo [144].Apixaban was recently approved by the FDA for both treatment and secondary prophylaxis of VTE.

More recently, a third anti-factor Xa TSOAC edoxaban demonstrated noninferiority to warfarin in prevention of recurrent symptomatic VTE when administered to patients with DVT or PE at 60 mg once daily for 3 to 12 months [145].Edoxaban also led to significantly less bleeding than warfarin. Edoxaban was recently approved by the FDA for treatment of VTE.

These TSOACs show promise in treatment and prevention of VTE but should be used in patients who meet appropriate criteria for renal function, age, and bleeding risk, as there are currently no available antidotes to reverse their effects. If significant bleeding occurs and cannot be controlled by usual maneuvers such as mechanical compression or surgical intervention, there is little data to guide the use of pharmacologic interventions. Plasma dabigatran levels can be reduced through the use of hemodialysis [146].Antibodies capable of neutralizing dabigatran have been developed, and one specific antibody, idarucizumab, was well-tolerated and showed immediate and complete reversal of dabigatran in subjects of different age and renal function [147,148].Andexanet, a modified recombinant derivative of factor Xa with no catalytic activty, acts as a “decoy receptor” with higher affinity to factor Xa inhibitors than natural factor Xa.  Phase II studies in healthy volunteers demonstrated that andexanet immediately reversed the anticoagulation activity of apixaban, rivaroxaban, enoxaparin, and most recently edoxaban without thrombotic consequences [149].Two randomized, double-blind, placebo-controlled phase III studies (ANNEXA-A, looking at the reversal of apixaban, and ANNEXA-R, looking at reversal of rivaroxaban) are underway, and preliminary results show that a single intravenous bolus of andexanet demonstrated almost complete reversal [150].Finally, aripazine (PER977), a synthetic small molecule that binds to heparins as well as all TSOACs, was shown in a phase II trial to decrease blood clotting time to within 10% above baseline value in 10 minutes or less with an effect lasting for 24 hours [151].

Some have advocated for use of prothrombin complex concentrate (PCC) or recombinant factor VIIa for reversal of TSOAC-associated bleeding. Rivaroxaban was demonstrated to be partially reversible by PCC, whereas this approach was not as successful for dabigatran in healthy volunteers [152].In vitro evidence, however, showed that PCC did not significantly change aPTT [153].At present, the use of nonspecific hemostatic agents (including recombinant factor VIIa, 4-factor prothrombin complex concentrate, and activated prothrombin complex concentrates) is suggested for reversal of TSOACs in patients who present with life-threatening bleeding [154,155].

Conclusion

Patients with VTE present with a wide range of findings and factors that impact management. Decision making in VTE management is a fluid process that should be re-evaluated as new data emerge and individual circumstances change. There is more focus on VTE prevention and treatment today than there was even a decade ago. Diagnostic algorithms, identification of new risk factors, refinement in understanding of the pathogenesis of thrombosis, and identification of new anticoagulants with more favorable risk-benefit profiles will all ultimately contribute to improved patient care.

Corresponding author: Jean M. Connors, MD, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02215.

From the Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA.

Abstract

• Objective: To review the diagnosis and management of venous thromboembolism (VTE).
• Methods: Review of the literature.
• Results: VTE and its associated complications account for significant morbidity and mortality. Various imaging modalities can be employed to support a diagnosis of a VTE and are used based on clinical suspicion arising from the presence of signs and symptoms. Clinical decision rules have been developed  that can help determine which patients warrant further testing. Anticoagulation, the mainstay of VTE treatment, increases bleeding risk, necessitating tailored treatment strategies that must incorporate etiology, risk, benefit, cost, and patient preference.
• Conclusion: Further study is needed to understand individual patient risks and to identify treatments that will lead to improved patient outcomes.

Venous thromboembolism (VTE) and its associated complications account for significant morbidity and mortality. Each year between 100 and 180 persons per 100,000 in Western countries develop VTE. The majority of VTEs are classified as either pulmonary embolism (PE), which accounts for one third of the events, or deep vein thrombosis (DVT), which is responsible for the remaining two thirds. Between 20% and 30% of those patients diagnosed with thrombotic events will die within the first month after diagnosis [1].PE is a common consequence of DVT; 40% of patients who are diagnosed with DVT will be subsequently found to have PE upon further imaging. This high rate of association is also seen in those who present with PE, 70% of whom will also be found to have concomitant DVT [2,3].

Anatomic risk factors include Paget-Schroetter syndrome (compression of upper extremity veins due to abnormalities at the thoracic outlet), May-Thurner syndrome (significant compression of the left common iliac vein by the right common iliac artery), and abnormalities of the inferior vena cava [14–16].Medications that are associated with increased risk of VTE include but are not limited to estrogen (both in oral contraceptives as well as hormone replacement therapy) [17,18],the selective estrogen receptor modulator tamoxifen [19],testosterone [20],and glucocorticoids [21].It is important to note that many patients with VTE have more than one acquired risk factor for thrombosis [22],and also that acquired risk factors are more likely to lead to VTE in the setting of underlying inherited thrombophilic conditions [23].

Pathogenesis

Abnormalities in both coagulation factors and the vascular bed are at the core of the pathogenesis of VTE. The multifaceted etiology of thrombosis was first described in 1856 by Virchow, who defined a triad of defects in the vessel wall, platelets, and coagulation proteins [24].Usually the vessel wall is lined with endothelial cells that provide a nonthrombotic surface and limit platelet aggregation through release of prostacyclins and nitric oxide. When the endothelial lining is compromised, the homeostatic surveillance system is disturbed and platelet activation and the coagulation system are initiated. Tissue factor exposure in the damaged area of the vessel leads to activation of the coagulation cascade. Collagen that is present in the area of the wound is also exposed and can activate platelets, which provide the phospholipid surface upon which the coagulation cascade occurs. Platelets initially tether to the exposed collagen through binding of glycoprotein Ib-V-IX in association with von Willebrand factor [25].The thrombus is initiated as more platelets are recruited to exposed collagen of the injured endothelium through aggregation in response to the binding of GPIIIb/IIa with fibrinogen. This process is self-perpetuating as these activated platelets release additional proteins such as adenosine diphosphate (ADP), serotonin, and thromboxane A2, all of which fuel the recruitment and activation of additional platelets [26].

Diagnosis

The key to decreasing the morbidity and mortality associated with VTE is timely diagnosis and early initiation of therapy. Various imaging modalities can be employed to support a diagnosis of a VTE and are used based on clinical suspicion arising from the presence of signs and symptoms. DVT is usually associated with pain in calf or thigh, unilateral swelling, tenderness, and redness. PE can present as chest pain, shortness of breath, syncope, hemoptysis, and/or cardiac palpitations.

Decision Rules

Clinical decision rules based on signs, symptoms, and risk factors have been developed to estimate the pretest probability of PE or DVT and to help determine which patients warrant further testing. These clinical decision rules include the Wells criteria (separate rules for DVT and PE) [27,28],as well as the Geneva score [29],which is focused on identifying patients with a likelihood of having a PE. In general, these clinical rules are applied at presentation to predict the risk of VTE, and patients who score high are evaluated by imaging modalities, while those with lower scores should be considered for further stratification based on D-dimer testing. The goal of clinical assessment and use of a decision rule is to identify patients at low risk of VTE to reduce the number of imaging studies performed. Most of the decision rules focus on the use of noninvasive evaluations that are easily implemented, including clinical history and presentation, abnormalities in oxygen saturation, chest radiography findings, and electro-cardiography.

D-Dimer Testing

D-dimer testing is at the core of all predictive models for VTE. D-dimer is a fibrin degradation product that is detectable in the blood during active fibrinolysis and occurs after clot formation. The concentration of D-dimer increases in patients with active clot. D-dimer testing is usually performed as a quantitative ELISA or automated turbidometric assay and is highly sensitive (> 95%) in excluding a diagnosis of VTE if results are in the normal range [30].The presence of a normal D-dimer and a low probability based on clinical assessment criteria can be integrated to determine which patients have a low (generally < 99%) likelihood of having VTE [31].It should be noted that other factors can lead to an increased D-dimer, including malignancy, trauma, critical illness, disseminated intravascular coagulation, pregnancy, infection, and postoperative status, which can produce false-positive results and cloud the utility of the test in excluding those at low risk of VTE from undergoing imaging [32–34].Additionally, D-dimer values naturally increase with age and recent work has shown utility of an age-adjusted D-dimer threshold, though this method is not yet widespread in clinical practice [35,36].

Imaging

After application of a clinical prediction rule, the mainstay of diagnosis of VTE is imaging. For DVT the use of ultrasonography is considered the gold standard, with both high sensitivity (89–100%) and specificity (86–100%), especially when the DVT is located proximally [37–39].We generally recommend compression ultrasound starting with the proximal veins but expanding to include the whole leg if the proximal studies are negative [40–42].Other diagnostic options include computed tomography (CT) venography, which is not first line as it is highly invasive and exposes the patient to iodine-based contrast dyes, and magnetic resonance venography (MRV), which offers superb visualization for diagnosis of pelvic vein thrombosis but is limited because of availability and cost issues.

Helical CT pulmonary angiography (CTPA) is the diagnostic test of choice in PE, with high sensitivity (96%) and specificity (95%), and has replaced conventional ventilation perfusion (VQ) scanning or other methods such as magnetic resonance pulmonary angiography in most settings [43,44].CTPA should be avoided in patients who have severe chronic kidney disease or a contrast allergy, and is often avoided in patients who are pregnant due to potential risk of radiation exposure, and in such situations VQ scanning may be employed.

Algorithmic Approach to Workup

Of note, there are multiple clinical situations in which the application of a clinical prediction rule followed by D-dimer testing and/or imaging cannot be “standardized” with such algorithms. These include situations where D-dimer may be falsely positive (as above), situations in which alternative imaging strategies should be used to avoid contrast exposure in workup of PE (as above), and workup of suspected upper extremity DVT. Upper extremity ultrasound comprises about 10% of all DVT and frequently occurs in the setting of risk factors such as central venous catheters or pacemakers; specific upper-extremity risk-assessment rules have been developed [47,48].

Acute Treatment Options

The first step in treatment is identification of patients who are at high risk of 

In standard cases of DVT and PE without hemodynamic compromise, the current standard of care is to initiate parenteral anticoagulation. The immediate goal of therapy is to treat rapidly with anticoagulants to prevent the thrombus from propagating further and to prevent DVT from embolization to the lungs or other vascular beds. The initial treatment of VTE has been extensively discussed and guidelines have been established with recommendations for initiation of anticoagulation; the American College of Chest Physicians (ACCP) released the 9th edition of their guidelines in 2012 based on consensus agreements derived from primary data [51].

Heparin-based drugs are the mainstay of initial treatment. These drugs act by potentiating antithrombin and therefore inactivating thrombin and other coagulation factors such as Xa. Unfractionated heparin (UFH) can be administered as an initial bolus followed by a continuous infusion with dosing being based on weight and titrated to activated partial thromboplastin time (aPTT) or the anti-factor Xa level. Alternatively, patients may be treated with a low molecular weight heparin (LMWH) administered subcutaneously in fixed weight-adjusted doses, which obviates the need for monitoring in most cases [52].LMWHs work in a similar manner to UFH but have more anti-Xa activity in comparison to anti-thrombin activity. LMWH appears to be more effective than UFH for initial treatment of VTE and has been associated with lower risk of major hemorrhage [53].The options for treatment of VTE have expanded in recent years with the approval of fondparinux, a pentasaccharide specifically targeted to inhibit factor Xa. Fondaparinux has been shown to have similar efficacy to LMWH in patients with DVT [54],and while it has not been evaluated directly against LMWH for initial treatment of PE it has been shown to be at least as effective and safe as UFH [55].

Both LMWH and fondaparinux are cleared renally and therefore have increased bleeding risk in patients with renal impairment. In patients with creatinine clearance of less than 30 mL/min, dose reduction or lengthening of dosing interval may be appropriate. Anti-factor Xa activity can be used as a functional assay to monitor and titrate the level of anticoagulation in patients treated with UFH, LMWH, and fondaparinux. Monitoring is useful in the setting of impaired renal function (as above) in addition to extremes of body weight and pregnancy. When used for monitoring of UFH, the anti-factor Xa activity can be measured at any time during administration with a therapeutic goal range of 0.3–0.7 international units (IU)/mL. When used for LMWH, a “peak” anti-factor Xa should be measured approximately 4 hours after dosing, with therapeutic goals depending on preparation and schedule of treatment but generally between 0.6 to 1.0 IU/mL for twice daily and around 1.0 -2.0 IU/mL for once-daily [56].For patients on dialysis, we generally use intravenous UFH for acute treatment of VTE, though recent work has shown that enoxaparin (doses of 0.4 to 1 mg/kg/day) was as safe as UFH with respect to bleeding and was associated with shorter hospital length of stay [57].For long-term treatment of VTE, warfarin is generally preferred based on clinical experience with this agent, though small studies have suggested that parenteral agents may be useful alternatives to warfarin [58].

In many patients who are clinically stable without significant medical comorbidities, outpatient administration of these medications without hospitalization is considered safe. Patients with DVT are often safe to manage as outpatients unless significant clot burden is present and thrombolysis is being considered. For PE, the pulmonary embolism severity index (PESI) and simplified index (sPESI) may be useful to risk-stratify patients and identify those at low risk of complications who may be suitable for outpatient treatment [59,60].Studies have shown that hemodynamically stable patients who did not require supplemental oxygenation or have contraindications to LMWH therapy were safely managed as outpatients with low risk of recurrent VTE and bleeding [61,62].One exception may be patients with intermediate risk PE, who are hemodynamically stable but have evidence of right ventricular dysfunction and may be better served by an initial in-hospital observation period, especially if thrombolysis is being considered.

Most patients who present with VTE are transitioned to warfarin for long-term therapy. Warfarin can be started on the same day as parenteral anticoagulation. Both drugs are overlapped for at least 5 days, with a target INR of 2.0–3.0. Patients may achieve the target INR level quickly because factor VII has a short half-life and the level drops quickly; however, the overlap of 5 days is essential even when the INR is in the target range because a full anticoagulant affect is not achieved until prothrombin levels decline, and this is a slow process due to the long half-life of prothrombin. Warfarin also causes rapid decrease in levels of natural anticoagulants such as protein C and protein S, which further exacerbates the net hypercoagulable state in the short-term. Warfarin without a bridging parenteral agent carries a risk of warfarin-induced skin necrosis [63]and is not effective as an initial anticoagulant treatment in acute VTE as there is a relatively high risk of symptomatic clot extension or recurrent VTE compared to warfarin with use of a bridging agent [64].In specific cases such as cancer-associated VTE (see discussion below), LMWH is preferred to warfarin for long-term active therapy.

Long-Term Active Therapy After Acute Treatment

Duration of Anticoagulation

Recommended duration of anticoagulation depends on a myriad of factors including severity of VTE, risk of recurrence, bleeding risk, and lifestyle modification issues, as well as on the safety and availability of alternative therapies such as low-intensity warfarin, aspirin, or the new oral anticoagulants. The decision tree for length of treatment starts with whether the VTE was a provoked or a spontaneous event. Provoked events occur when the event is associated with an identifiable risk factor, such as immobilization from prolonged medical illness or surgical intervention, pregnancy or oral contraceptive use, and prolonged air travel.

Consensus guidelines suggest that 3 months of anti-coagulation are generally sufficient treatment for a provoked VTE [51,65,66]. Data from multiple studies and a meta-analysis suggests that less than 3 months of anticoagulation (4 to 6 weeks in most trials) is associated with an approximately 1.5-fold higher risk of recurrent VTE than 3 months [67,68].However, data from this meta-analysis also suggests that anticoagulation for longer than 3 months (6 to 12 months in most trials) is not associated with higher rates of recurrent VTE. We generally anticoagulate for 3 months in patients with provoked VTE.

Determining the duration of anticoagulation is more complex in patients with idiopathic/unprovoked VTE. Kearon and colleagues found that in patients with first idiopathic VTE, patients who were anticoagulated for 24 months versus 3 months had lower risk of recurrent VTE (1.3% per patient-year with 24 months versus 27.4% per patient-year with 3 months) [69].Similar studies and meta-analyses have demonstrated decreased recurrence rates in patients anticoagulated for a prolonged period of time. However, one study of prolonged anticoagulation revealed that at 3 years there was no difference in recurrence rate in patients with PE who were anticoagulated for 6 months versus 1 year [70].The likelihood of recurrent DVT in patients with first episode of idiopathic proximal DVT treated with either 3 months or 12 months of warfarin was similar after treatment was discontinued [71].Prolonged periods of anticoagulation do not directly influence risk of recurrence but instead may only delay occurrence of a second event [72].For that reason, the decision is essentially whether to anticoagulate for 3 months or to continue therapy indefinitely [73]. Current guidelines recommend continuing anticoagulation for 3 months in those at high risk of bleeding, and continuing for an extended duration in those at low or moderate bleeding risk [51]. Patients' values and perferences should be entertained and decisions made on a patient-by-patient basis.

For patients at high risk of recurrent VTE, we generally recommend indefinite anticoagulation unless the patient has a significantly elevated bleeding risk or strongly prefers to discontinue anticoagulation and compliance concerns are evident. High-risk patients are those who have suffered from multiple episodes of recurrent VTE, those who have clotted while being anticoagulated, and those with acquired risk factors, such as antiphospholipid antibodies and malignancy. Other high-risk groups are those with high-risk thrombophilias such as deficiency of protein S, protein C, or antithrombin, homozygous factor V Leiden or prothrombin gene mutations, and compound heterozygous factor V Leiden/prothrombin gene mutation in the setting of an unprovoked event. Further discussion of models for risk assessment of recurrence is provided below.

Assessment of Bleeding Risk

The bleeding risk associated with the use of anticoagulation must be weighed against the risk of clotting events when determining duration of anticoagulation, especially in those patients for whom indefinite anticoagulation is a consideration. Risk of bleeding while on anticoagulation is approximately 1–3% per 100 patient-years [74],but concomitant medical conditions such as renal failure, diabetes-related cerebrovascular disease, malignancy, advanced age, and use of antiplatelet agents all increase the risk of bleeding. Bleeding risk is highest when patients first initiate anticoagulation and is approximately 10 times the risk in the first month of therapy than after the first year of therapy [75].

Risk assessment models such as the RIETE score may be helpful when indefinite anticoagulation is a possibility [76].The RIETE score encompasses 6 risk factors (age > 75 years, recent bleeding, cancer, creatinine level > 1.2 mg/dL, anemia, or PE at baseline) to categorize patients into low risk (0 points, 0.3% risk of bleeding), intermediate risk (1–4 points, 2.6% risk of bleeding) and high risk (> 4 points, 6.2% risk of bleeding) within 3 months of anticoagulant therapy. The ACCP has developed a more extensive list of 17 potential risk factors for bleeding to categorize patients into low risk (no risk factors, 0.8%/year risk of bleeding), intermediate risk (1 risk factor, 1.6%/year risk of bleeding) and high risk (2 or more risk factors, >6.5%/year risk of bleeding) categories [77].The RIETE score is simpler to use but was not developed for assessing risk of bleeding during indefinite therapy, while the ACCP risk categorization predicts a yearly risk and is therefore applicable for long-term risk assessment but is more cumbersome to use. In practice, we generally use a clinical gestalt of a patient’s clinical risk factors (particularly age, renal or hepatic dysfunction, and frequent falls) to assess if they may be at high risk of bleeding and if the risk of indefinite anticoagulation may thus outweigh the potential benefit.

We also note that several scoring systems (HAS-BLED, HEMORR2HAGES, and ATRIA scores) have been developed to predict those at high risk of bleeding on anticoagulation for atrial fibrillation [78–80].These scores generally include similar clinical risk factors to those in the RIETE and ACCP scoring systems. Several studies have compared the HAS-BLED, HEMORR2HAGES, and ATRIA scores and a systematic review and meta-analysis concluded that the HAS-BLED score is recommended, due to increased sensitivity and ease of application [81].However, as these scores have not been validated for anticoagulation in the setting of VTE, we do not use them in this capacity.

Risk Stratification for Recurrent VTE

When predicting risk of recurrent VTE, clinical risk factors including obesity, male gender, and underlying thrombophilia (including the “high risk” inherited thrombophilias identified above) must taken into consideration. Location of the thrombus must also be considered; it has also been demonstrated that patients with DVT involving the iliofemoral veins are at higher risk of recurrence than those without iliac involvement [82].Other factors that may be useful in risk stratification include D-dimer level and ultrasound to search for residual venous thrombosis.

D-dimer Levels

D-dimer levels are one of the more promising methods for assessing the risk of recurrent VTE after cessation of anticoagulation, especially in the case of idiopathic VTE where indefinite anticoagulation should be considered but may pose either risk of bleeding or significant inconvenience to patients. A normal D-dimer measured 1 month after cessation of anticoagulation offers a high negative predictive value for risk of recurrence [83].A number of studies have demonstrated that patients with elevated D-dimer 1 month after anticoagulation cessation are at increased risk for a recurrent event [84–86].Two predictive models that have been developed incorporate D-dimer testing into decision making [87,88].The DASH predictive model relies on the D-dimer result in addition to age, male sex, and use of hormone therapy as a method of risk stratification for recurrent VTE in patients with a first unprovoked event. Using this scoring system, patients with a score of 0 or 1 had a recurrence rate of 3.1%, those with a score of 2 a recurrence rate of 6.4%, and those with a score of 3 or greater a recurrence rate of 12.3%. The authors postulate that by using this assessment scheme they can avoid lifelong anticoagulation in 51% of patients. The Vienna prediction model uses male sex, location of VTE (proximal DVT and PE are at higher risk), and D-dimer level to predict risk of recurrent VTE. This model has recently been updated to include a “dynamic” component to predict risk of recurrence of VTE from multiple random time points [89].

Overall, D-dimer may be useful for risk stratification. We often employ the method of stopping anticoagulation in patients with unprovoked VTE after 3 months (if the patient has no identifiable clinical risk factors that place them at high risk of recurrence) and testing D-dimer 1 month after cessation of anticoagulation. An elevated D-dimer is a solid reason to restart anticoagulation (potentially on an indefinite basis), while a negative D-dimer provides support for withholding further anticoagulation in the absence of other significant risk factors for recurrence. However, lack of agreement regarding assay cut-points as well as multiple reasons other than VTE for D-dimer elevation may limit widespread use of this method. We generally use a cutpoint of 250 ug/L as “negative,” though at least one study showed that cut-points of 250 ug/L versus 500 ug/L did not change the utility of this method [90].In our practice, risk prediction models are most useful to provide patients with additional information and a visual presentation to support our recommendation. This is particularly true of the Vienna prediction rule, which is available in a printable nomogram which can be distributed to patients and completed together during the clinic visit.

Imaging Analysis

Imaging analysis may also assist with risk stratification. Clinical assessment modules have been developed that incorporate repeat imaging studies for assessment of recannulization of affected veins. In patients with residual vein thrombosis (RVT) at the time anticoagulation was stopped, the hazard ratio for recurrence was 2.4 compared to those without RVT [91].There are a number of ways RVT could impact recurrence, including inpaired venous flow leading to stasis and activation of the coagulation cascade. Subsequent studies used serial ultrasound to determine when to stop anticoagulation. In one study, patients were anticoagulated for 3 months and for those that had RVT, anticoagulation was continued for up to 9 months for provoked and 21 months for unprovoked VTE. In comparison to fixed dosing of 6 months of anti-coagulation, those who had their length of anticoagulation tailored to ultrasonography findings had a lower rate of recurrent VTE [92].Limitations to using RVT in clinical decision-making include lack of a standard definition of RVT and variability in both timing of ultrasound (operator variability) and interpretation of results [93].

Other Options

Another option in patients who are being considered for indefinite anticoagulation is to decrease the intensity of anticoagulation. Since this would theoretically lower the risk of bleeding, the perceived benefit of long-term, low-intensity anticoagulation would be reduction in both bleeding and clotting risk. The PREVENT trial randomized patients who had received full-dose anticoagulation for a median of 6.5 months to either low-intensity warfarin (INR goal of 1.5-2.0 instead of 2.0-3.0) or placebo. In the anticoagulation group, there was a 64% risk reduction in recurrent VTE (hazard ratio 0.36, 95% CI 0.19 to 0.67) but an increased risk of bleeding (hazard ratio 1.92, 95% CI 1.26 to 2.93) [94].The ELATE study randomized patients with unprovoked VTE who had completed 3 or more months of full-intensity warfarin therapy (target INR 2.0–3.0) to continue therapy with either low-intensity warfarin (target INR 1.5–2.0) or full-intensity warfarin (target INR 2.0-3.0). Compared to the low-intensity group, the conventional-intensity group had lower rates of recurrent VTE and no increased rates of major bleeding [95].This study, however, has been criticized because of its overall low bleeding rate in both treatment groups.

Aspirin is an option in patients in whom long-term anticoagulation is untenable. The ASPIRE trial demonstrated that in patients with unprovoked VTE who had completed a course of initial anticoagulation, aspirin 100 mg daily reduced the risk of major vascular events compared to placebo with no increase in bleeding [96].However, aspirin was not associated with a significant reduction in risk of VTE alone (only the composite vascular event endpoint). The WARFASA trial, however, demonstrated that aspirin 100 mg daily was associated with a significant reduction in recurrent VTE compared to placebo after 6 to 18 months of anticoagulation without an increase in major bleeding [97].The absolute risk of recurrence was 11% in the placebo group and 5.9% in the aspirin group. More recently, the INSPIRE collaboration analyzed data from both trials and found that aspirin after initial anticoagulation reduced the risk of recurrent VTE by approximately 42% with a low rate of major bleeding [98].The absolute risk reduction was even larger in men and older patients. For this reason, we recommend aspirin to those patients in whom indefinite anticoagulation may be warranted from the standpoint of reducing risk of recurrent VTE but in whom the risk of bleeding precludes its use.

Hypercoagulable States In Specific Populations

Inherited Thrombophilias

Patients with a hereditary thrombophilia are at increased risk for incident VTE [99].These inherited mutations result in either a loss of normal anticoagulant function or gain of a prothrombotic state. Hereditary disorders associated with VTE include deficiency of antithrombin, protein C, or protein S, or the presence of factor V Leiden and/or prothrombin G20210A mutations. Although deficiency of protein C, protein S, or antithrombin is uncommon and affects only 0.5% of the population, these states have been associated with a 10-fold increased risk of thrombosis in comparison to the general population. Factor V Leiden and prothrombin gene mutation are less likely to be associated with incident thrombosis (2 to 5-fold increased risk of VTE) and are more prevalent in the Caucasian population [100].Though these hereditary thrombophilias increase risk of VTE, prophylactic anti-coagulation prior to a first VTE is not generally indicated.

Data regarding the impact of the inherited thrombophilias on risk of recurrent VTE is less well defined. While some data suggest that inherited thrombophilias are associated with increased risk of recurrent VTE, the degree of impact may be clinically modest especially in those with heterozygous factor V Leiden or prothrombin gene mutations [101].Ideally, a clinical trial would be designed to assess whether hereditary thrombophilia testing is beneficial for patients with VTE in decision-making regarding length of anticoagulation, type of anticoagulation, and risk of recurrence. If a patient with a low-risk inherited thrombophilia has a DVT in the setting of an additional provoking risk factor (surgery, pregnancy, etc), a 3-month course of anticoagulation followed by D-dimer assessment as above is reasonable. If a patient with an inherited thrombophilia experiences an idiopathic VTE, or if a patient with a “high-risk” thrombophilia as described above experiences any type of VTE, we generally recommend indefinite anticoagulation in the absence of high bleeding risk, though again this is a very patient-dependent choice.

Acquired Thrombophilias

Antiphospholipid Syndrome

Antibodies directed against proteins that bind phospho-lipids are associated with an acquired hypercoagulable state. The autoantibodies are categorized as antiphospho-lipid antibodies (APLAs), which include anticardiolipin antibodies (IgG and IgM), beta-2 glycoprotein 1 antibodies (anti-B2 GP), and lupus anticoagulant. These antibodies can form autonomously, as seen in primary disorders, or in association with autoimmune disease as a secondary disorder.

Criteria have been developed to distinguish antiphospholipid-associated clotting disorders from other forms of thrombophilia. The updated Sapporo criteria depend on both laboratory and clinical diagnostic criteria [102].The laboratory diagnosis of APLAs requires the presence of lupus anticoagulants, anticardiolipin antibodies, or anti-B2 GP on at least 2 assays at least 12 weeks apart with elevation above the 99th percentile of the testing laboratory’s normal distribution [103].Testing for lupus anticoagulant is based on 3 stages, the first of which is inhibition of phospholipid-dependent coagulation tests with prolonged clotting time (eg, aPTT or dilute Russell’s viper venom time). The diagnosis is confirmed by a secondary test in which excess hexagonal phase phospholipids are added to incubate with the patient’s plasma to absorb the APLA [104].The presence of anticardiolipin antibodies and anti beta-2 GP antibodies is determined using ELISA based immunoassays. Unlike most other thrombophilias, antiphospholipid syndrome is associated with both arterial and venous thromboembolic events and may be an indication for lifelong anticoagulation after a first thrombotic event. We generally recommend indefinite anticoagulation in the absence of significant bleeding risk.

Cancer-Associated Hypercoagulable State

Patients with cancer have a propensity for thromboembolic events. The underlying mechanisms responsible for cancer-associated clotting events are multifactorial and an area of intense research. Tumor cells can initiate activation of the clotting cascade through release of tissue factor and other pro-coagulant molecules [105].Type and stage of cancer impact risk of VTE, and the tumor itself can compress vasculature leading to venous stasis. Furthermore, chemotherapy, hormone therapy, antiangiogenic drugs, erythropoietin agents, and indwelling central venous catheters all are associated with increased risk of thrombotic events. Approximately 25% of all cancer patients will experience a thrombotic event during the course of their disease [106]. In fact, the presence of a spontaneous clot may be a harbinger of underlying malignancy [107].Approximately 10% of patients who present with an idiopathic VTE are diagnosed with cancer in the next 1 to 2 years.

The utility of extensive cancer screening in patients with spontaneous clotting events is often debated. The small studies that have addressed cancer associated clots have not demonstrated any mortality benefit with extensive screening. A prospective cohort study addressed the utility of limited versus extensive screening [108].In this study, all patients underwent a series of basic screening tests such as history taking, physical examination, chest radiograph, and basic laboratory parameters. Approximately half of the patients underwent additional testing (CT of chest and abdomen and mammography for women). Screening did not result in increased survival or fewer cancer-related deaths. 3.5 % of patients in the extensive screening group were diagnosed with malignancy in comparison to 2.4% in the limited screening group. During follow-up, cancer was diagnosed in 3.7% and 5.0% in the extensive and limited screening groups, respectively. The authors concluded that the low yield of extensive screening and lack of survival benefit did not warrant routinely ordering cancer screening tests above and beyond age-appropriate screening in patients with idiopathic VTE. However, it is known that identification of occult malignancy at an earlier stage of disease is beneficial, and cancer diagnosed within one year of an episode of VTE is generally more advanced and associated with a poorer prognosis [109].It is our practice to take a through history from patients with unprovoked clots particularly focusing on symptoms suggestive of an underlying cancer. We recommend that patients be up to date with all age-appropriate cancer screening.

Heparin-based products (rather than warfarin) are recommended for long-term treatment of cancer-associated DVT. Several trials, most prominently the CLOT trial, have demonstrated that LMWH is associated with reduced risk of recurrent VTE compared with warfarin in cancer patients [110].Fondaparinux may be a reasonable alternative if a patient is unable to tolerate a LMWH. In terms of treatment duration, patients with cancer-associated VTE should be anticoagulated indefinitely as long as they continue to have evidence of active malignancy and/or remain on antineoplastic treatment [111].

Heparin has potential anticancer effects beyond its anticoagulation properties. It is believed that heparin use in patients with cancer can influence cancer progression by acting as an antimetastatic agent. The molecular mechanisms underlying this significant observation are not completely understood, although the first documented benefit of these drugs dates back to the 1970s [112].Overall, LMWH have been associated with improved overall survival in cancer patients and this effect appears to be distinct from its ability to prevent life-threatening VTE episodes [113].

Estrogen-Related Thromboembolic Disease

Pregnancy is a well-established acquired hypercoagulable state, and thromboembolic disease accounts for significant morbidity and mortality in pregnancy and the postpartum period. Approximately 1 in 1000 women will suffer from a thrombotic event during pregnancy or shortly after delivery [8]. The etiology of the tendency to clot during pregnancy is multifactorial and mainly reflects venous stasis due to vasculature compression by the uterus, changes in coagulation factors as the pregnancy progresses, and endothelial damage during delivery, especially Cesarean section. Both factor VIII and von Willebrand factor levels increase, especially in the final months of pregnancy. Simultaneously, levels of the natural anticoagulant protein S diminish, leading to an acquired resistance to activated protein C which results in increased thrombin generation and therefore a hypercoagulable state [114].The risk of thrombosis in pregnancy is clearly heightened in women with inherited thrombophilias, especially in the postpartum period [115].

Similarly to pregnancy, hormone-based contraceptive agents and estrogen replacement therapies are also associated with increased thrombotic risk. Over the years, drug manufacturers have tried to mitigate the clotting risk associated with these drugs by reducing the amount of estrogen and altering the type of progesterone used, yet a risk still remains, resulting in a VTE incidence 2 to 7 times higher in this population [116].The risk is highest in the first 4 months of use and is unaffected by duration of use; risk extends for 3 months after cessation of estrogen-containing therapy. Patients who develop VTE while taking an oral contraceptive are generally instructed to stop the contraceptive and consider an alternative form of birth control. Although routine screening for thrombophilia is not offered to women before prescribing oral contraceptives, a thorough personal and family history regarding venous and arterial thrombotic events as well as recurrent pregnancy loss in women should be taken to evaluate thromboembolic risk factors. We generally avoid use of oral contraceptives in patients with a known hereditary thrombophilia, and consider screening prior to initiation of therapy in those with a strong family history of VTE.

Superficial VTE

Although the main disorders that comprise VTE are DVT and PE, another common presentation is superficial venous thromboembolism (SVT). The risk factors for developing an SVT are similar to those for DVT. In addition, varicose veins also increase the incidence of developing SVT [117].SVT is not associated with excessive mortality, and the main concern with it is progression to DVT. About 25% of patients diagnosed with SVT may have DVT or PE at the time of diagnosis and about 3% without DVT or PE at time of diagnosis developed one of these complications over the following 3 months; clot propagation is another common complication [118].Ultrasound may be of utility in diagnosing occult DVT in patients who initially diagnosed with SVT [119].

For patients who have only SVT at baseline without concomitant DVT or PE, it is difficult to determine which patients are at risk for developing DVT. Some risk stratification models include clot location. Since SVT clots usually develop in the saphenous vein, the clot would need to either progress from the sapheno-femoral junction to the common femoral vein; thus, any clots located near the sapheno-femoral junction are at risk of progressing into the deep vasculature [120].Clots within 3 cm of the junction may be more likely to progress to DVT [121].Chengelis and colleagues feel that proximal saphenous vein thrombosis should likely be treated with anticoagulation [122].Others have taken a more general approach, stating that all clots above the knee or in the thigh area should be treated aggressively [123].

There are solid data for the use of anticoagulation in SVT. In the STEFLUX (Superficial ThromboEmbolism and Fluxum) study, participants received the LMWH parnaparin at one of 3 doses: 8500 IU once daily for 10 days followed by placebo for 20 days, 8500 IU once daily for 10 days and then 6400 IU once daily for 20 days, or 4250 IU once daily for 30 days. Those who received the intermediate dosing had lower rates of DVT, PE, and relapse/SVT recurrence in the first 33 days [124].In the CALISTO trial, fondaparinux 2.5mg per day for 45 days effectively reduced the risk of symptomatic DVT, PE, or SVT recurrence or extension and was not associated with any increased major bleeding compared to placebo [125].A Cochrane review included 30 studies involving over 6500 participants with SVT of the lower extremities. The treatments used in these studies included fondaparinux, LMWH, UFH, non-steriodal anti-inflammatory agents, topical treatment, and surgery. According to the findings, use of fondaparinux at prophylactic dosing for 6 weeks is considered a valid therapeutic option for SVT [126].It is our practice to consider the use of anticoagulants (generally LMWH or fondaparinux) as part of the treatment regimen for SVT.

Target-Specific Oral Anticoagulants And Treatment of VTE

The direct thrombin inhibitor dabigatran directly binds to thrombin in a concentration-dependent manner [127].Peak plasma concentration is achieved within 0.5 to 2.0 hours after ingestion, and its half-life is 12 to 17 hours. Use of dabigatran in both primary and secondary prevention of VTE has been extensively studied, especially in orthopedic surgery where there have been 4 main trials (RE-MOBILIZE, RE-MODEL, RE-NOVATE, and RE-NOVATE I and II). While RE-MOBILIZE showed that dabigatran 220 mg or 150 mg once daily was inferior to enoxaparin 30 mg twice daily in preventing VTE after total knee arthroplasty, RE-MODEL and RE-NOVATE I and II demonstrated that dabigatran 150 mg or 220 mg once daily was noninferior to enoxaparin 40 mg once daily for prevention of VTE in patients undergoing total knee replacement and hip replacement [128–131].The side effect profile was also promising, with no significant differences in the frequency of major bleeding between dabigatran and enoxaparin. Pooled data and meta-analyses from these trials have demonstrated that for prevention of VTE associated with hip or knee surgery, dabigatran 220 mg or 150 mg once daily is as effective as 40 mg of enoxaparin given daily or 30 mg given twice a day, with a similar bleeding profile [132,133].

More recently, dabigatran been used in the acute treatment and secondary prevention of VTE. In the RE-COVER trial, dabigatran 150 mg twice daily was compared to warfarin (INR 2–3) in the treatment of acute VTE for 6 months, after an initial treatment period of up to 9 days with LMWH or UFH. Dabigatran was noninferior to warfarin with respect to 6-month incidence of recurrent symptomatic objectively confirmed VTE and related deaths, and was not associated with increased bleeding [134].In the RE-MEDY and RE-SONATE trials of extended anticoagulation, dabigatran was as effective as warfarin for prevention of recurrent VTE when continued after 3 months of initial anticoagulation and associated with less bleeding, and was more effective than placebo in preventing recurrent VTE but associated with a higher risk of bleeding [135].Unexpectedly, the risk of acute coronary syndrome was slightly higher in the dabigatran group than the warfarin group, as seen in other studies.

Rivaroxaban, a TSOAC that targets factor Xa, has also shown efficacy in preventing VTE after knee or hip surgery. The RE-CORD 1-4 studies all focused on the use of rivaroxaban in comparison to enoxaparin and found that rivaroxaban 10 mg once daily was superior to enoxaparin 40 mg once daily in prevention of VTE in total knee and total hip arthroplasty [136–138].Meta-analysis of multiple rivaroxaban VTE prophylaxis trials also demonstrated that rivaroxaban significantly lowered the risk of VTE in these surgical patients in comparison to the use of enoxaparin [139].Prophylactic use of rivaroxaban was also studied in acutely ill hospitalized patients in the MAGELLAN trial. Rivaroxaban 10 mg daily for 35 days was compared to enoxaparin 40 mg daily for 10 days followed by placebo and was found to be noninferior to enoxaparin in reduction of VTE risk at day 10 and superior to placebo at day 35 [140].However, the rate of bleeding, although low in both arms, was higher in the rivaroxaban arm.

Rivaroxaban has been studied in randomized clinical trials for acute treatment of DVT and PE and for extended prophylaxis for recurrent VTE (EINSTEIN-DVT, EINSTEIN-PE and EINSTEIN-Extension, respectively).  The treatment strategy for use of rivaroxaban differed from that of dabigatran (in the RE-COVER trial), as rivaroxaban was used upfront as initial anticoagulation rather than after an initial period of parenteral therapy with LMWH or UFH. In both the DVT and PE trials, rivaroxaban was noninferior to standard treatment with enoxaparin followed by warfarin therapy, with no significant difference in major bleeding at 6 months of treatment [141,142].The extension trial also demonstrated that use of rivaroxaban in comparison to placebo for an additional 6 or 12 months after standard therapy was associated with significantly fewer recurrent VTE [141]. These studies led to FDA approval for rivaroxaban for primary prevention of VTE in patients undergoing elective total hip or knee repair surgery, for treatment of acute DVT or PE, and for extended prophylaxis in patients following initial treatment.

The anti-factor Xa TSOAC apixaban has been studied in similar fashion as rivaroxaban. In the AMPLIFY study, apixaban was given at a dose of 10 mg twice daily for 7 days followed by 5 mg twice daily for 6 months (as monotherapy, without initial parenteral agent) and compared to enoxaparin followed by warfarin for treatment of acute VTE. Apixaban was as effective as warfarin in terms of recurrent symptomatic VTE or VTE-related death, and was associated with significantly fewer bleeding events [143].Extended-duration apixaban given at treatment dose (5 mg twice daily) or at prophylactic dose (2.5 mg twice daily) for 12 months after completion of treatment-dose apixaban for VTE demonstrated superiority to placebo for extended prophylaxis in AMPLIFY-EXT, and there was no increase in major bleeding compared to placebo [144].Apixaban was recently approved by the FDA for both treatment and secondary prophylaxis of VTE.

More recently, a third anti-factor Xa TSOAC edoxaban demonstrated noninferiority to warfarin in prevention of recurrent symptomatic VTE when administered to patients with DVT or PE at 60 mg once daily for 3 to 12 months [145].Edoxaban also led to significantly less bleeding than warfarin. Edoxaban was recently approved by the FDA for treatment of VTE.

These TSOACs show promise in treatment and prevention of VTE but should be used in patients who meet appropriate criteria for renal function, age, and bleeding risk, as there are currently no available antidotes to reverse their effects. If significant bleeding occurs and cannot be controlled by usual maneuvers such as mechanical compression or surgical intervention, there is little data to guide the use of pharmacologic interventions. Plasma dabigatran levels can be reduced through the use of hemodialysis [146].Antibodies capable of neutralizing dabigatran have been developed, and one specific antibody, idarucizumab, was well-tolerated and showed immediate and complete reversal of dabigatran in subjects of different age and renal function [147,148].Andexanet, a modified recombinant derivative of factor Xa with no catalytic activty, acts as a “decoy receptor” with higher affinity to factor Xa inhibitors than natural factor Xa.  Phase II studies in healthy volunteers demonstrated that andexanet immediately reversed the anticoagulation activity of apixaban, rivaroxaban, enoxaparin, and most recently edoxaban without thrombotic consequences [149].Two randomized, double-blind, placebo-controlled phase III studies (ANNEXA-A, looking at the reversal of apixaban, and ANNEXA-R, looking at reversal of rivaroxaban) are underway, and preliminary results show that a single intravenous bolus of andexanet demonstrated almost complete reversal [150].Finally, aripazine (PER977), a synthetic small molecule that binds to heparins as well as all TSOACs, was shown in a phase II trial to decrease blood clotting time to within 10% above baseline value in 10 minutes or less with an effect lasting for 24 hours [151].

Some have advocated for use of prothrombin complex concentrate (PCC) or recombinant factor VIIa for reversal of TSOAC-associated bleeding. Rivaroxaban was demonstrated to be partially reversible by PCC, whereas this approach was not as successful for dabigatran in healthy volunteers [152].In vitro evidence, however, showed that PCC did not significantly change aPTT [153].At present, the use of nonspecific hemostatic agents (including recombinant factor VIIa, 4-factor prothrombin complex concentrate, and activated prothrombin complex concentrates) is suggested for reversal of TSOACs in patients who present with life-threatening bleeding [154,155].

Conclusion

Patients with VTE present with a wide range of findings and factors that impact management. Decision making in VTE management is a fluid process that should be re-evaluated as new data emerge and individual circumstances change. There is more focus on VTE prevention and treatment today than there was even a decade ago. Diagnostic algorithms, identification of new risk factors, refinement in understanding of the pathogenesis of thrombosis, and identification of new anticoagulants with more favorable risk-benefit profiles will all ultimately contribute to improved patient care.

Corresponding author: Jean M. Connors, MD, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02215.

From the Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA.

Abstract

• Objective: To review the diagnosis and management of venous thromboembolism (VTE).
• Methods: Review of the literature.
• Results: VTE and its associated complications account for significant morbidity and mortality. Various imaging modalities can be employed to support a diagnosis of a VTE and are used based on clinical suspicion arising from the presence of signs and symptoms. Clinical decision rules have been developed  that can help determine which patients warrant further testing. Anticoagulation, the mainstay of VTE treatment, increases bleeding risk, necessitating tailored treatment strategies that must incorporate etiology, risk, benefit, cost, and patient preference.
• Conclusion: Further study is needed to understand individual patient risks and to identify treatments that will lead to improved patient outcomes.

Venous thromboembolism (VTE) and its associated complications account for significant morbidity and mortality. Each year between 100 and 180 persons per 100,000 in Western countries develop VTE. The majority of VTEs are classified as either pulmonary embolism (PE), which accounts for one third of the events, or deep vein thrombosis (DVT), which is responsible for the remaining two thirds. Between 20% and 30% of those patients diagnosed with thrombotic events will die within the first month after diagnosis [1].PE is a common consequence of DVT; 40% of patients who are diagnosed with DVT will be subsequently found to have PE upon further imaging. This high rate of association is also seen in those who present with PE, 70% of whom will also be found to have concomitant DVT [2,3].

Anatomic risk factors include Paget-Schroetter syndrome (compression of upper extremity veins due to abnormalities at the thoracic outlet), May-Thurner syndrome (significant compression of the left common iliac vein by the right common iliac artery), and abnormalities of the inferior vena cava [14–16].Medications that are associated with increased risk of VTE include but are not limited to estrogen (both in oral contraceptives as well as hormone replacement therapy) [17,18],the selective estrogen receptor modulator tamoxifen [19],testosterone [20],and glucocorticoids [21].It is important to note that many patients with VTE have more than one acquired risk factor for thrombosis [22],and also that acquired risk factors are more likely to lead to VTE in the setting of underlying inherited thrombophilic conditions [23].

Pathogenesis

Abnormalities in both coagulation factors and the vascular bed are at the core of the pathogenesis of VTE. The multifaceted etiology of thrombosis was first described in 1856 by Virchow, who defined a triad of defects in the vessel wall, platelets, and coagulation proteins [24].Usually the vessel wall is lined with endothelial cells that provide a nonthrombotic surface and limit platelet aggregation through release of prostacyclins and nitric oxide. When the endothelial lining is compromised, the homeostatic surveillance system is disturbed and platelet activation and the coagulation system are initiated. Tissue factor exposure in the damaged area of the vessel leads to activation of the coagulation cascade. Collagen that is present in the area of the wound is also exposed and can activate platelets, which provide the phospholipid surface upon which the coagulation cascade occurs. Platelets initially tether to the exposed collagen through binding of glycoprotein Ib-V-IX in association with von Willebrand factor [25].The thrombus is initiated as more platelets are recruited to exposed collagen of the injured endothelium through aggregation in response to the binding of GPIIIb/IIa with fibrinogen. This process is self-perpetuating as these activated platelets release additional proteins such as adenosine diphosphate (ADP), serotonin, and thromboxane A2, all of which fuel the recruitment and activation of additional platelets [26].

Diagnosis

The key to decreasing the morbidity and mortality associated with VTE is timely diagnosis and early initiation of therapy. Various imaging modalities can be employed to support a diagnosis of a VTE and are used based on clinical suspicion arising from the presence of signs and symptoms. DVT is usually associated with pain in calf or thigh, unilateral swelling, tenderness, and redness. PE can present as chest pain, shortness of breath, syncope, hemoptysis, and/or cardiac palpitations.

Decision Rules

Clinical decision rules based on signs, symptoms, and risk factors have been developed to estimate the pretest probability of PE or DVT and to help determine which patients warrant further testing. These clinical decision rules include the Wells criteria (separate rules for DVT and PE) [27,28],as well as the Geneva score [29],which is focused on identifying patients with a likelihood of having a PE. In general, these clinical rules are applied at presentation to predict the risk of VTE, and patients who score high are evaluated by imaging modalities, while those with lower scores should be considered for further stratification based on D-dimer testing. The goal of clinical assessment and use of a decision rule is to identify patients at low risk of VTE to reduce the number of imaging studies performed. Most of the decision rules focus on the use of noninvasive evaluations that are easily implemented, including clinical history and presentation, abnormalities in oxygen saturation, chest radiography findings, and electro-cardiography.

D-Dimer Testing

D-dimer testing is at the core of all predictive models for VTE. D-dimer is a fibrin degradation product that is detectable in the blood during active fibrinolysis and occurs after clot formation. The concentration of D-dimer increases in patients with active clot. D-dimer testing is usually performed as a quantitative ELISA or automated turbidometric assay and is highly sensitive (> 95%) in excluding a diagnosis of VTE if results are in the normal range [30].The presence of a normal D-dimer and a low probability based on clinical assessment criteria can be integrated to determine which patients have a low (generally < 99%) likelihood of having VTE [31].It should be noted that other factors can lead to an increased D-dimer, including malignancy, trauma, critical illness, disseminated intravascular coagulation, pregnancy, infection, and postoperative status, which can produce false-positive results and cloud the utility of the test in excluding those at low risk of VTE from undergoing imaging [32–34].Additionally, D-dimer values naturally increase with age and recent work has shown utility of an age-adjusted D-dimer threshold, though this method is not yet widespread in clinical practice [35,36].

Imaging

After application of a clinical prediction rule, the mainstay of diagnosis of VTE is imaging. For DVT the use of ultrasonography is considered the gold standard, with both high sensitivity (89–100%) and specificity (86–100%), especially when the DVT is located proximally [37–39].We generally recommend compression ultrasound starting with the proximal veins but expanding to include the whole leg if the proximal studies are negative [40–42].Other diagnostic options include computed tomography (CT) venography, which is not first line as it is highly invasive and exposes the patient to iodine-based contrast dyes, and magnetic resonance venography (MRV), which offers superb visualization for diagnosis of pelvic vein thrombosis but is limited because of availability and cost issues.

Helical CT pulmonary angiography (CTPA) is the diagnostic test of choice in PE, with high sensitivity (96%) and specificity (95%), and has replaced conventional ventilation perfusion (VQ) scanning or other methods such as magnetic resonance pulmonary angiography in most settings [43,44].CTPA should be avoided in patients who have severe chronic kidney disease or a contrast allergy, and is often avoided in patients who are pregnant due to potential risk of radiation exposure, and in such situations VQ scanning may be employed.

Algorithmic Approach to Workup

Of note, there are multiple clinical situations in which the application of a clinical prediction rule followed by D-dimer testing and/or imaging cannot be “standardized” with such algorithms. These include situations where D-dimer may be falsely positive (as above), situations in which alternative imaging strategies should be used to avoid contrast exposure in workup of PE (as above), and workup of suspected upper extremity DVT. Upper extremity ultrasound comprises about 10% of all DVT and frequently occurs in the setting of risk factors such as central venous catheters or pacemakers; specific upper-extremity risk-assessment rules have been developed [47,48].

Acute Treatment Options

The first step in treatment is identification of patients who are at high risk of 

In standard cases of DVT and PE without hemodynamic compromise, the current standard of care is to initiate parenteral anticoagulation. The immediate goal of therapy is to treat rapidly with anticoagulants to prevent the thrombus from propagating further and to prevent DVT from embolization to the lungs or other vascular beds. The initial treatment of VTE has been extensively discussed and guidelines have been established with recommendations for initiation of anticoagulation; the American College of Chest Physicians (ACCP) released the 9th edition of their guidelines in 2012 based on consensus agreements derived from primary data [51].

Heparin-based drugs are the mainstay of initial treatment. These drugs act by potentiating antithrombin and therefore inactivating thrombin and other coagulation factors such as Xa. Unfractionated heparin (UFH) can be administered as an initial bolus followed by a continuous infusion with dosing being based on weight and titrated to activated partial thromboplastin time (aPTT) or the anti-factor Xa level. Alternatively, patients may be treated with a low molecular weight heparin (LMWH) administered subcutaneously in fixed weight-adjusted doses, which obviates the need for monitoring in most cases [52].LMWHs work in a similar manner to UFH but have more anti-Xa activity in comparison to anti-thrombin activity. LMWH appears to be more effective than UFH for initial treatment of VTE and has been associated with lower risk of major hemorrhage [53].The options for treatment of VTE have expanded in recent years with the approval of fondparinux, a pentasaccharide specifically targeted to inhibit factor Xa. Fondaparinux has been shown to have similar efficacy to LMWH in patients with DVT [54],and while it has not been evaluated directly against LMWH for initial treatment of PE it has been shown to be at least as effective and safe as UFH [55].

Both LMWH and fondaparinux are cleared renally and therefore have increased bleeding risk in patients with renal impairment. In patients with creatinine clearance of less than 30 mL/min, dose reduction or lengthening of dosing interval may be appropriate. Anti-factor Xa activity can be used as a functional assay to monitor and titrate the level of anticoagulation in patients treated with UFH, LMWH, and fondaparinux. Monitoring is useful in the setting of impaired renal function (as above) in addition to extremes of body weight and pregnancy. When used for monitoring of UFH, the anti-factor Xa activity can be measured at any time during administration with a therapeutic goal range of 0.3–0.7 international units (IU)/mL. When used for LMWH, a “peak” anti-factor Xa should be measured approximately 4 hours after dosing, with therapeutic goals depending on preparation and schedule of treatment but generally between 0.6 to 1.0 IU/mL for twice daily and around 1.0 -2.0 IU/mL for once-daily [56].For patients on dialysis, we generally use intravenous UFH for acute treatment of VTE, though recent work has shown that enoxaparin (doses of 0.4 to 1 mg/kg/day) was as safe as UFH with respect to bleeding and was associated with shorter hospital length of stay [57].For long-term treatment of VTE, warfarin is generally preferred based on clinical experience with this agent, though small studies have suggested that parenteral agents may be useful alternatives to warfarin [58].

In many patients who are clinically stable without significant medical comorbidities, outpatient administration of these medications without hospitalization is considered safe. Patients with DVT are often safe to manage as outpatients unless significant clot burden is present and thrombolysis is being considered. For PE, the pulmonary embolism severity index (PESI) and simplified index (sPESI) may be useful to risk-stratify patients and identify those at low risk of complications who may be suitable for outpatient treatment [59,60].Studies have shown that hemodynamically stable patients who did not require supplemental oxygenation or have contraindications to LMWH therapy were safely managed as outpatients with low risk of recurrent VTE and bleeding [61,62].One exception may be patients with intermediate risk PE, who are hemodynamically stable but have evidence of right ventricular dysfunction and may be better served by an initial in-hospital observation period, especially if thrombolysis is being considered.

Most patients who present with VTE are transitioned to warfarin for long-term therapy. Warfarin can be started on the same day as parenteral anticoagulation. Both drugs are overlapped for at least 5 days, with a target INR of 2.0–3.0. Patients may achieve the target INR level quickly because factor VII has a short half-life and the level drops quickly; however, the overlap of 5 days is essential even when the INR is in the target range because a full anticoagulant affect is not achieved until prothrombin levels decline, and this is a slow process due to the long half-life of prothrombin. Warfarin also causes rapid decrease in levels of natural anticoagulants such as protein C and protein S, which further exacerbates the net hypercoagulable state in the short-term. Warfarin without a bridging parenteral agent carries a risk of warfarin-induced skin necrosis [63]and is not effective as an initial anticoagulant treatment in acute VTE as there is a relatively high risk of symptomatic clot extension or recurrent VTE compared to warfarin with use of a bridging agent [64].In specific cases such as cancer-associated VTE (see discussion below), LMWH is preferred to warfarin for long-term active therapy.

Long-Term Active Therapy After Acute Treatment

Duration of Anticoagulation

Recommended duration of anticoagulation depends on a myriad of factors including severity of VTE, risk of recurrence, bleeding risk, and lifestyle modification issues, as well as on the safety and availability of alternative therapies such as low-intensity warfarin, aspirin, or the new oral anticoagulants. The decision tree for length of treatment starts with whether the VTE was a provoked or a spontaneous event. Provoked events occur when the event is associated with an identifiable risk factor, such as immobilization from prolonged medical illness or surgical intervention, pregnancy or oral contraceptive use, and prolonged air travel.

Consensus guidelines suggest that 3 months of anti-coagulation are generally sufficient treatment for a provoked VTE [51,65,66]. Data from multiple studies and a meta-analysis suggests that less than 3 months of anticoagulation (4 to 6 weeks in most trials) is associated with an approximately 1.5-fold higher risk of recurrent VTE than 3 months [67,68].However, data from this meta-analysis also suggests that anticoagulation for longer than 3 months (6 to 12 months in most trials) is not associated with higher rates of recurrent VTE. We generally anticoagulate for 3 months in patients with provoked VTE.

Determining the duration of anticoagulation is more complex in patients with idiopathic/unprovoked VTE. Kearon and colleagues found that in patients with first idiopathic VTE, patients who were anticoagulated for 24 months versus 3 months had lower risk of recurrent VTE (1.3% per patient-year with 24 months versus 27.4% per patient-year with 3 months) [69].Similar studies and meta-analyses have demonstrated decreased recurrence rates in patients anticoagulated for a prolonged period of time. However, one study of prolonged anticoagulation revealed that at 3 years there was no difference in recurrence rate in patients with PE who were anticoagulated for 6 months versus 1 year [70].The likelihood of recurrent DVT in patients with first episode of idiopathic proximal DVT treated with either 3 months or 12 months of warfarin was similar after treatment was discontinued [71].Prolonged periods of anticoagulation do not directly influence risk of recurrence but instead may only delay occurrence of a second event [72].For that reason, the decision is essentially whether to anticoagulate for 3 months or to continue therapy indefinitely [73]. Current guidelines recommend continuing anticoagulation for 3 months in those at high risk of bleeding, and continuing for an extended duration in those at low or moderate bleeding risk [51]. Patients' values and perferences should be entertained and decisions made on a patient-by-patient basis.

For patients at high risk of recurrent VTE, we generally recommend indefinite anticoagulation unless the patient has a significantly elevated bleeding risk or strongly prefers to discontinue anticoagulation and compliance concerns are evident. High-risk patients are those who have suffered from multiple episodes of recurrent VTE, those who have clotted while being anticoagulated, and those with acquired risk factors, such as antiphospholipid antibodies and malignancy. Other high-risk groups are those with high-risk thrombophilias such as deficiency of protein S, protein C, or antithrombin, homozygous factor V Leiden or prothrombin gene mutations, and compound heterozygous factor V Leiden/prothrombin gene mutation in the setting of an unprovoked event. Further discussion of models for risk assessment of recurrence is provided below.

Assessment of Bleeding Risk

The bleeding risk associated with the use of anticoagulation must be weighed against the risk of clotting events when determining duration of anticoagulation, especially in those patients for whom indefinite anticoagulation is a consideration. Risk of bleeding while on anticoagulation is approximately 1–3% per 100 patient-years [74],but concomitant medical conditions such as renal failure, diabetes-related cerebrovascular disease, malignancy, advanced age, and use of antiplatelet agents all increase the risk of bleeding. Bleeding risk is highest when patients first initiate anticoagulation and is approximately 10 times the risk in the first month of therapy than after the first year of therapy [75].

Risk assessment models such as the RIETE score may be helpful when indefinite anticoagulation is a possibility [76].The RIETE score encompasses 6 risk factors (age > 75 years, recent bleeding, cancer, creatinine level > 1.2 mg/dL, anemia, or PE at baseline) to categorize patients into low risk (0 points, 0.3% risk of bleeding), intermediate risk (1–4 points, 2.6% risk of bleeding) and high risk (> 4 points, 6.2% risk of bleeding) within 3 months of anticoagulant therapy. The ACCP has developed a more extensive list of 17 potential risk factors for bleeding to categorize patients into low risk (no risk factors, 0.8%/year risk of bleeding), intermediate risk (1 risk factor, 1.6%/year risk of bleeding) and high risk (2 or more risk factors, >6.5%/year risk of bleeding) categories [77].The RIETE score is simpler to use but was not developed for assessing risk of bleeding during indefinite therapy, while the ACCP risk categorization predicts a yearly risk and is therefore applicable for long-term risk assessment but is more cumbersome to use. In practice, we generally use a clinical gestalt of a patient’s clinical risk factors (particularly age, renal or hepatic dysfunction, and frequent falls) to assess if they may be at high risk of bleeding and if the risk of indefinite anticoagulation may thus outweigh the potential benefit.

We also note that several scoring systems (HAS-BLED, HEMORR2HAGES, and ATRIA scores) have been developed to predict those at high risk of bleeding on anticoagulation for atrial fibrillation [78–80].These scores generally include similar clinical risk factors to those in the RIETE and ACCP scoring systems. Several studies have compared the HAS-BLED, HEMORR2HAGES, and ATRIA scores and a systematic review and meta-analysis concluded that the HAS-BLED score is recommended, due to increased sensitivity and ease of application [81].However, as these scores have not been validated for anticoagulation in the setting of VTE, we do not use them in this capacity.

Risk Stratification for Recurrent VTE

When predicting risk of recurrent VTE, clinical risk factors including obesity, male gender, and underlying thrombophilia (including the “high risk” inherited thrombophilias identified above) must taken into consideration. Location of the thrombus must also be considered; it has also been demonstrated that patients with DVT involving the iliofemoral veins are at higher risk of recurrence than those without iliac involvement [82].Other factors that may be useful in risk stratification include D-dimer level and ultrasound to search for residual venous thrombosis.

D-dimer Levels

D-dimer levels are one of the more promising methods for assessing the risk of recurrent VTE after cessation of anticoagulation, especially in the case of idiopathic VTE where indefinite anticoagulation should be considered but may pose either risk of bleeding or significant inconvenience to patients. A normal D-dimer measured 1 month after cessation of anticoagulation offers a high negative predictive value for risk of recurrence [83].A number of studies have demonstrated that patients with elevated D-dimer 1 month after anticoagulation cessation are at increased risk for a recurrent event [84–86].Two predictive models that have been developed incorporate D-dimer testing into decision making [87,88].The DASH predictive model relies on the D-dimer result in addition to age, male sex, and use of hormone therapy as a method of risk stratification for recurrent VTE in patients with a first unprovoked event. Using this scoring system, patients with a score of 0 or 1 had a recurrence rate of 3.1%, those with a score of 2 a recurrence rate of 6.4%, and those with a score of 3 or greater a recurrence rate of 12.3%. The authors postulate that by using this assessment scheme they can avoid lifelong anticoagulation in 51% of patients. The Vienna prediction model uses male sex, location of VTE (proximal DVT and PE are at higher risk), and D-dimer level to predict risk of recurrent VTE. This model has recently been updated to include a “dynamic” component to predict risk of recurrence of VTE from multiple random time points [89].

Overall, D-dimer may be useful for risk stratification. We often employ the method of stopping anticoagulation in patients with unprovoked VTE after 3 months (if the patient has no identifiable clinical risk factors that place them at high risk of recurrence) and testing D-dimer 1 month after cessation of anticoagulation. An elevated D-dimer is a solid reason to restart anticoagulation (potentially on an indefinite basis), while a negative D-dimer provides support for withholding further anticoagulation in the absence of other significant risk factors for recurrence. However, lack of agreement regarding assay cut-points as well as multiple reasons other than VTE for D-dimer elevation may limit widespread use of this method. We generally use a cutpoint of 250 ug/L as “negative,” though at least one study showed that cut-points of 250 ug/L versus 500 ug/L did not change the utility of this method [90].In our practice, risk prediction models are most useful to provide patients with additional information and a visual presentation to support our recommendation. This is particularly true of the Vienna prediction rule, which is available in a printable nomogram which can be distributed to patients and completed together during the clinic visit.

Imaging Analysis

Imaging analysis may also assist with risk stratification. Clinical assessment modules have been developed that incorporate repeat imaging studies for assessment of recannulization of affected veins. In patients with residual vein thrombosis (RVT) at the time anticoagulation was stopped, the hazard ratio for recurrence was 2.4 compared to those without RVT [91].There are a number of ways RVT could impact recurrence, including inpaired venous flow leading to stasis and activation of the coagulation cascade. Subsequent studies used serial ultrasound to determine when to stop anticoagulation. In one study, patients were anticoagulated for 3 months and for those that had RVT, anticoagulation was continued for up to 9 months for provoked and 21 months for unprovoked VTE. In comparison to fixed dosing of 6 months of anti-coagulation, those who had their length of anticoagulation tailored to ultrasonography findings had a lower rate of recurrent VTE [92].Limitations to using RVT in clinical decision-making include lack of a standard definition of RVT and variability in both timing of ultrasound (operator variability) and interpretation of results [93].

Other Options

Another option in patients who are being considered for indefinite anticoagulation is to decrease the intensity of anticoagulation. Since this would theoretically lower the risk of bleeding, the perceived benefit of long-term, low-intensity anticoagulation would be reduction in both bleeding and clotting risk. The PREVENT trial randomized patients who had received full-dose anticoagulation for a median of 6.5 months to either low-intensity warfarin (INR goal of 1.5-2.0 instead of 2.0-3.0) or placebo. In the anticoagulation group, there was a 64% risk reduction in recurrent VTE (hazard ratio 0.36, 95% CI 0.19 to 0.67) but an increased risk of bleeding (hazard ratio 1.92, 95% CI 1.26 to 2.93) [94].The ELATE study randomized patients with unprovoked VTE who had completed 3 or more months of full-intensity warfarin therapy (target INR 2.0–3.0) to continue therapy with either low-intensity warfarin (target INR 1.5–2.0) or full-intensity warfarin (target INR 2.0-3.0). Compared to the low-intensity group, the conventional-intensity group had lower rates of recurrent VTE and no increased rates of major bleeding [95].This study, however, has been criticized because of its overall low bleeding rate in both treatment groups.

Aspirin is an option in patients in whom long-term anticoagulation is untenable. The ASPIRE trial demonstrated that in patients with unprovoked VTE who had completed a course of initial anticoagulation, aspirin 100 mg daily reduced the risk of major vascular events compared to placebo with no increase in bleeding [96].However, aspirin was not associated with a significant reduction in risk of VTE alone (only the composite vascular event endpoint). The WARFASA trial, however, demonstrated that aspirin 100 mg daily was associated with a significant reduction in recurrent VTE compared to placebo after 6 to 18 months of anticoagulation without an increase in major bleeding [97].The absolute risk of recurrence was 11% in the placebo group and 5.9% in the aspirin group. More recently, the INSPIRE collaboration analyzed data from both trials and found that aspirin after initial anticoagulation reduced the risk of recurrent VTE by approximately 42% with a low rate of major bleeding [98].The absolute risk reduction was even larger in men and older patients. For this reason, we recommend aspirin to those patients in whom indefinite anticoagulation may be warranted from the standpoint of reducing risk of recurrent VTE but in whom the risk of bleeding precludes its use.

Hypercoagulable States In Specific Populations

Inherited Thrombophilias

Patients with a hereditary thrombophilia are at increased risk for incident VTE [99].These inherited mutations result in either a loss of normal anticoagulant function or gain of a prothrombotic state. Hereditary disorders associated with VTE include deficiency of antithrombin, protein C, or protein S, or the presence of factor V Leiden and/or prothrombin G20210A mutations. Although deficiency of protein C, protein S, or antithrombin is uncommon and affects only 0.5% of the population, these states have been associated with a 10-fold increased risk of thrombosis in comparison to the general population. Factor V Leiden and prothrombin gene mutation are less likely to be associated with incident thrombosis (2 to 5-fold increased risk of VTE) and are more prevalent in the Caucasian population [100].Though these hereditary thrombophilias increase risk of VTE, prophylactic anti-coagulation prior to a first VTE is not generally indicated.

Data regarding the impact of the inherited thrombophilias on risk of recurrent VTE is less well defined. While some data suggest that inherited thrombophilias are associated with increased risk of recurrent VTE, the degree of impact may be clinically modest especially in those with heterozygous factor V Leiden or prothrombin gene mutations [101].Ideally, a clinical trial would be designed to assess whether hereditary thrombophilia testing is beneficial for patients with VTE in decision-making regarding length of anticoagulation, type of anticoagulation, and risk of recurrence. If a patient with a low-risk inherited thrombophilia has a DVT in the setting of an additional provoking risk factor (surgery, pregnancy, etc), a 3-month course of anticoagulation followed by D-dimer assessment as above is reasonable. If a patient with an inherited thrombophilia experiences an idiopathic VTE, or if a patient with a “high-risk” thrombophilia as described above experiences any type of VTE, we generally recommend indefinite anticoagulation in the absence of high bleeding risk, though again this is a very patient-dependent choice.

Acquired Thrombophilias

Antiphospholipid Syndrome

Antibodies directed against proteins that bind phospho-lipids are associated with an acquired hypercoagulable state. The autoantibodies are categorized as antiphospho-lipid antibodies (APLAs), which include anticardiolipin antibodies (IgG and IgM), beta-2 glycoprotein 1 antibodies (anti-B2 GP), and lupus anticoagulant. These antibodies can form autonomously, as seen in primary disorders, or in association with autoimmune disease as a secondary disorder.

Criteria have been developed to distinguish antiphospholipid-associated clotting disorders from other forms of thrombophilia. The updated Sapporo criteria depend on both laboratory and clinical diagnostic criteria [102].The laboratory diagnosis of APLAs requires the presence of lupus anticoagulants, anticardiolipin antibodies, or anti-B2 GP on at least 2 assays at least 12 weeks apart with elevation above the 99th percentile of the testing laboratory’s normal distribution [103].Testing for lupus anticoagulant is based on 3 stages, the first of which is inhibition of phospholipid-dependent coagulation tests with prolonged clotting time (eg, aPTT or dilute Russell’s viper venom time). The diagnosis is confirmed by a secondary test in which excess hexagonal phase phospholipids are added to incubate with the patient’s plasma to absorb the APLA [104].The presence of anticardiolipin antibodies and anti beta-2 GP antibodies is determined using ELISA based immunoassays. Unlike most other thrombophilias, antiphospholipid syndrome is associated with both arterial and venous thromboembolic events and may be an indication for lifelong anticoagulation after a first thrombotic event. We generally recommend indefinite anticoagulation in the absence of significant bleeding risk.

Cancer-Associated Hypercoagulable State

Patients with cancer have a propensity for thromboembolic events. The underlying mechanisms responsible for cancer-associated clotting events are multifactorial and an area of intense research. Tumor cells can initiate activation of the clotting cascade through release of tissue factor and other pro-coagulant molecules [105].Type and stage of cancer impact risk of VTE, and the tumor itself can compress vasculature leading to venous stasis. Furthermore, chemotherapy, hormone therapy, antiangiogenic drugs, erythropoietin agents, and indwelling central venous catheters all are associated with increased risk of thrombotic events. Approximately 25% of all cancer patients will experience a thrombotic event during the course of their disease [106]. In fact, the presence of a spontaneous clot may be a harbinger of underlying malignancy [107].Approximately 10% of patients who present with an idiopathic VTE are diagnosed with cancer in the next 1 to 2 years.

The utility of extensive cancer screening in patients with spontaneous clotting events is often debated. The small studies that have addressed cancer associated clots have not demonstrated any mortality benefit with extensive screening. A prospective cohort study addressed the utility of limited versus extensive screening [108].In this study, all patients underwent a series of basic screening tests such as history taking, physical examination, chest radiograph, and basic laboratory parameters. Approximately half of the patients underwent additional testing (CT of chest and abdomen and mammography for women). Screening did not result in increased survival or fewer cancer-related deaths. 3.5 % of patients in the extensive screening group were diagnosed with malignancy in comparison to 2.4% in the limited screening group. During follow-up, cancer was diagnosed in 3.7% and 5.0% in the extensive and limited screening groups, respectively. The authors concluded that the low yield of extensive screening and lack of survival benefit did not warrant routinely ordering cancer screening tests above and beyond age-appropriate screening in patients with idiopathic VTE. However, it is known that identification of occult malignancy at an earlier stage of disease is beneficial, and cancer diagnosed within one year of an episode of VTE is generally more advanced and associated with a poorer prognosis [109].It is our practice to take a through history from patients with unprovoked clots particularly focusing on symptoms suggestive of an underlying cancer. We recommend that patients be up to date with all age-appropriate cancer screening.

Heparin-based products (rather than warfarin) are recommended for long-term treatment of cancer-associated DVT. Several trials, most prominently the CLOT trial, have demonstrated that LMWH is associated with reduced risk of recurrent VTE compared with warfarin in cancer patients [110].Fondaparinux may be a reasonable alternative if a patient is unable to tolerate a LMWH. In terms of treatment duration, patients with cancer-associated VTE should be anticoagulated indefinitely as long as they continue to have evidence of active malignancy and/or remain on antineoplastic treatment [111].

Heparin has potential anticancer effects beyond its anticoagulation properties. It is believed that heparin use in patients with cancer can influence cancer progression by acting as an antimetastatic agent. The molecular mechanisms underlying this significant observation are not completely understood, although the first documented benefit of these drugs dates back to the 1970s [112].Overall, LMWH have been associated with improved overall survival in cancer patients and this effect appears to be distinct from its ability to prevent life-threatening VTE episodes [113].

Estrogen-Related Thromboembolic Disease

Pregnancy is a well-established acquired hypercoagulable state, and thromboembolic disease accounts for significant morbidity and mortality in pregnancy and the postpartum period. Approximately 1 in 1000 women will suffer from a thrombotic event during pregnancy or shortly after delivery [8]. The etiology of the tendency to clot during pregnancy is multifactorial and mainly reflects venous stasis due to vasculature compression by the uterus, changes in coagulation factors as the pregnancy progresses, and endothelial damage during delivery, especially Cesarean section. Both factor VIII and von Willebrand factor levels increase, especially in the final months of pregnancy. Simultaneously, levels of the natural anticoagulant protein S diminish, leading to an acquired resistance to activated protein C which results in increased thrombin generation and therefore a hypercoagulable state [114].The risk of thrombosis in pregnancy is clearly heightened in women with inherited thrombophilias, especially in the postpartum period [115].

Similarly to pregnancy, hormone-based contraceptive agents and estrogen replacement therapies are also associated with increased thrombotic risk. Over the years, drug manufacturers have tried to mitigate the clotting risk associated with these drugs by reducing the amount of estrogen and altering the type of progesterone used, yet a risk still remains, resulting in a VTE incidence 2 to 7 times higher in this population [116].The risk is highest in the first 4 months of use and is unaffected by duration of use; risk extends for 3 months after cessation of estrogen-containing therapy. Patients who develop VTE while taking an oral contraceptive are generally instructed to stop the contraceptive and consider an alternative form of birth control. Although routine screening for thrombophilia is not offered to women before prescribing oral contraceptives, a thorough personal and family history regarding venous and arterial thrombotic events as well as recurrent pregnancy loss in women should be taken to evaluate thromboembolic risk factors. We generally avoid use of oral contraceptives in patients with a known hereditary thrombophilia, and consider screening prior to initiation of therapy in those with a strong family history of VTE.

Superficial VTE

Although the main disorders that comprise VTE are DVT and PE, another common presentation is superficial venous thromboembolism (SVT). The risk factors for developing an SVT are similar to those for DVT. In addition, varicose veins also increase the incidence of developing SVT [117].SVT is not associated with excessive mortality, and the main concern with it is progression to DVT. About 25% of patients diagnosed with SVT may have DVT or PE at the time of diagnosis and about 3% without DVT or PE at time of diagnosis developed one of these complications over the following 3 months; clot propagation is another common complication [118].Ultrasound may be of utility in diagnosing occult DVT in patients who initially diagnosed with SVT [119].

For patients who have only SVT at baseline without concomitant DVT or PE, it is difficult to determine which patients are at risk for developing DVT. Some risk stratification models include clot location. Since SVT clots usually develop in the saphenous vein, the clot would need to either progress from the sapheno-femoral junction to the common femoral vein; thus, any clots located near the sapheno-femoral junction are at risk of progressing into the deep vasculature [120].Clots within 3 cm of the junction may be more likely to progress to DVT [121].Chengelis and colleagues feel that proximal saphenous vein thrombosis should likely be treated with anticoagulation [122].Others have taken a more general approach, stating that all clots above the knee or in the thigh area should be treated aggressively [123].

There are solid data for the use of anticoagulation in SVT. In the STEFLUX (Superficial ThromboEmbolism and Fluxum) study, participants received the LMWH parnaparin at one of 3 doses: 8500 IU once daily for 10 days followed by placebo for 20 days, 8500 IU once daily for 10 days and then 6400 IU once daily for 20 days, or 4250 IU once daily for 30 days. Those who received the intermediate dosing had lower rates of DVT, PE, and relapse/SVT recurrence in the first 33 days [124].In the CALISTO trial, fondaparinux 2.5mg per day for 45 days effectively reduced the risk of symptomatic DVT, PE, or SVT recurrence or extension and was not associated with any increased major bleeding compared to placebo [125].A Cochrane review included 30 studies involving over 6500 participants with SVT of the lower extremities. The treatments used in these studies included fondaparinux, LMWH, UFH, non-steriodal anti-inflammatory agents, topical treatment, and surgery. According to the findings, use of fondaparinux at prophylactic dosing for 6 weeks is considered a valid therapeutic option for SVT [126].It is our practice to consider the use of anticoagulants (generally LMWH or fondaparinux) as part of the treatment regimen for SVT.

Target-Specific Oral Anticoagulants And Treatment of VTE

The direct thrombin inhibitor dabigatran directly binds to thrombin in a concentration-dependent manner [127].Peak plasma concentration is achieved within 0.5 to 2.0 hours after ingestion, and its half-life is 12 to 17 hours. Use of dabigatran in both primary and secondary prevention of VTE has been extensively studied, especially in orthopedic surgery where there have been 4 main trials (RE-MOBILIZE, RE-MODEL, RE-NOVATE, and RE-NOVATE I and II). While RE-MOBILIZE showed that dabigatran 220 mg or 150 mg once daily was inferior to enoxaparin 30 mg twice daily in preventing VTE after total knee arthroplasty, RE-MODEL and RE-NOVATE I and II demonstrated that dabigatran 150 mg or 220 mg once daily was noninferior to enoxaparin 40 mg once daily for prevention of VTE in patients undergoing total knee replacement and hip replacement [128–131].The side effect profile was also promising, with no significant differences in the frequency of major bleeding between dabigatran and enoxaparin. Pooled data and meta-analyses from these trials have demonstrated that for prevention of VTE associated with hip or knee surgery, dabigatran 220 mg or 150 mg once daily is as effective as 40 mg of enoxaparin given daily or 30 mg given twice a day, with a similar bleeding profile [132,133].

More recently, dabigatran been used in the acute treatment and secondary prevention of VTE. In the RE-COVER trial, dabigatran 150 mg twice daily was compared to warfarin (INR 2–3) in the treatment of acute VTE for 6 months, after an initial treatment period of up to 9 days with LMWH or UFH. Dabigatran was noninferior to warfarin with respect to 6-month incidence of recurrent symptomatic objectively confirmed VTE and related deaths, and was not associated with increased bleeding [134].In the RE-MEDY and RE-SONATE trials of extended anticoagulation, dabigatran was as effective as warfarin for prevention of recurrent VTE when continued after 3 months of initial anticoagulation and associated with less bleeding, and was more effective than placebo in preventing recurrent VTE but associated with a higher risk of bleeding [135].Unexpectedly, the risk of acute coronary syndrome was slightly higher in the dabigatran group than the warfarin group, as seen in other studies.

Rivaroxaban, a TSOAC that targets factor Xa, has also shown efficacy in preventing VTE after knee or hip surgery. The RE-CORD 1-4 studies all focused on the use of rivaroxaban in comparison to enoxaparin and found that rivaroxaban 10 mg once daily was superior to enoxaparin 40 mg once daily in prevention of VTE in total knee and total hip arthroplasty [136–138].Meta-analysis of multiple rivaroxaban VTE prophylaxis trials also demonstrated that rivaroxaban significantly lowered the risk of VTE in these surgical patients in comparison to the use of enoxaparin [139].Prophylactic use of rivaroxaban was also studied in acutely ill hospitalized patients in the MAGELLAN trial. Rivaroxaban 10 mg daily for 35 days was compared to enoxaparin 40 mg daily for 10 days followed by placebo and was found to be noninferior to enoxaparin in reduction of VTE risk at day 10 and superior to placebo at day 35 [140].However, the rate of bleeding, although low in both arms, was higher in the rivaroxaban arm.

Rivaroxaban has been studied in randomized clinical trials for acute treatment of DVT and PE and for extended prophylaxis for recurrent VTE (EINSTEIN-DVT, EINSTEIN-PE and EINSTEIN-Extension, respectively).  The treatment strategy for use of rivaroxaban differed from that of dabigatran (in the RE-COVER trial), as rivaroxaban was used upfront as initial anticoagulation rather than after an initial period of parenteral therapy with LMWH or UFH. In both the DVT and PE trials, rivaroxaban was noninferior to standard treatment with enoxaparin followed by warfarin therapy, with no significant difference in major bleeding at 6 months of treatment [141,142].The extension trial also demonstrated that use of rivaroxaban in comparison to placebo for an additional 6 or 12 months after standard therapy was associated with significantly fewer recurrent VTE [141]. These studies led to FDA approval for rivaroxaban for primary prevention of VTE in patients undergoing elective total hip or knee repair surgery, for treatment of acute DVT or PE, and for extended prophylaxis in patients following initial treatment.

The anti-factor Xa TSOAC apixaban has been studied in similar fashion as rivaroxaban. In the AMPLIFY study, apixaban was given at a dose of 10 mg twice daily for 7 days followed by 5 mg twice daily for 6 months (as monotherapy, without initial parenteral agent) and compared to enoxaparin followed by warfarin for treatment of acute VTE. Apixaban was as effective as warfarin in terms of recurrent symptomatic VTE or VTE-related death, and was associated with significantly fewer bleeding events [143].Extended-duration apixaban given at treatment dose (5 mg twice daily) or at prophylactic dose (2.5 mg twice daily) for 12 months after completion of treatment-dose apixaban for VTE demonstrated superiority to placebo for extended prophylaxis in AMPLIFY-EXT, and there was no increase in major bleeding compared to placebo [144].Apixaban was recently approved by the FDA for both treatment and secondary prophylaxis of VTE.

More recently, a third anti-factor Xa TSOAC edoxaban demonstrated noninferiority to warfarin in prevention of recurrent symptomatic VTE when administered to patients with DVT or PE at 60 mg once daily for 3 to 12 months [145].Edoxaban also led to significantly less bleeding than warfarin. Edoxaban was recently approved by the FDA for treatment of VTE.

These TSOACs show promise in treatment and prevention of VTE but should be used in patients who meet appropriate criteria for renal function, age, and bleeding risk, as there are currently no available antidotes to reverse their effects. If significant bleeding occurs and cannot be controlled by usual maneuvers such as mechanical compression or surgical intervention, there is little data to guide the use of pharmacologic interventions. Plasma dabigatran levels can be reduced through the use of hemodialysis [146].Antibodies capable of neutralizing dabigatran have been developed, and one specific antibody, idarucizumab, was well-tolerated and showed immediate and complete reversal of dabigatran in subjects of different age and renal function [147,148].Andexanet, a modified recombinant derivative of factor Xa with no catalytic activty, acts as a “decoy receptor” with higher affinity to factor Xa inhibitors than natural factor Xa.  Phase II studies in healthy volunteers demonstrated that andexanet immediately reversed the anticoagulation activity of apixaban, rivaroxaban, enoxaparin, and most recently edoxaban without thrombotic consequences [149].Two randomized, double-blind, placebo-controlled phase III studies (ANNEXA-A, looking at the reversal of apixaban, and ANNEXA-R, looking at reversal of rivaroxaban) are underway, and preliminary results show that a single intravenous bolus of andexanet demonstrated almost complete reversal [150].Finally, aripazine (PER977), a synthetic small molecule that binds to heparins as well as all TSOACs, was shown in a phase II trial to decrease blood clotting time to within 10% above baseline value in 10 minutes or less with an effect lasting for 24 hours [151].

Some have advocated for use of prothrombin complex concentrate (PCC) or recombinant factor VIIa for reversal of TSOAC-associated bleeding. Rivaroxaban was demonstrated to be partially reversible by PCC, whereas this approach was not as successful for dabigatran in healthy volunteers [152].In vitro evidence, however, showed that PCC did not significantly change aPTT [153].At present, the use of nonspecific hemostatic agents (including recombinant factor VIIa, 4-factor prothrombin complex concentrate, and activated prothrombin complex concentrates) is suggested for reversal of TSOACs in patients who present with life-threatening bleeding [154,155].

Conclusion

Patients with VTE present with a wide range of findings and factors that impact management. Decision making in VTE management is a fluid process that should be re-evaluated as new data emerge and individual circumstances change. There is more focus on VTE prevention and treatment today than there was even a decade ago. Diagnostic algorithms, identification of new risk factors, refinement in understanding of the pathogenesis of thrombosis, and identification of new anticoagulants with more favorable risk-benefit profiles will all ultimately contribute to improved patient care.

Corresponding author: Jean M. Connors, MD, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02215.