Management of thyroid disease during pregnancy presents unique challenges due to physiologic changes that occur. These include
• Serum levels of thyroxine-binding globulin (TBG) increase along with estrogen; in turn, total thyroxine (T4) and triiodothyronine (T3) levels increase.
• Human chorionic gonadotropin (hCG) stimulates the thyroid stimulating hormone (TSH) receptors.¹

Since hCG and TSH share similar glycoprotein subunits, a transient suppression of TSH—especially around weeks 10 to 12, when hCG concentrations peak—is considered a physiologic finding. Interpretation of thyroid function testing should be made in relation to the hCG-mediated decrease in serum TSH levels.²

The following four cases will help guide your clinical management of thyroid disease in both preconception and pregnancy. Inadequately controlled thyroid dysfunction can lead to poor pregnancy outcomes for both mother and child, which will be further discussed.

Continue for Case 1: Stable Hypothyroidism >>

CASE 1: STABLE ­HYPOTHYROIDISM
A 29-year-old woman with stable primary hypothyroidism calls your office to report that she is pregnant. She has taken levothyroxine (100 mg) for the past three years, and her TSH level was 1.21 mIU/L at last measurement. She denies any symptoms of hyperthyroidism or hypothyroidism. What is your next step in her management?

Recommendation
The American Thyroid Association recommends monitoring serum TSH every four weeks during the first half of pregnancy and at least once per trimester thereafter, with frequency depending on symptoms and TSH levels.³ Most women will require higher doses of levothyroxine supplementation to maintain therapeutic TSH levels.

Prior to 18 weeks’ gestation, the fetus is dependent on maternal thyroid hormone. When pregnancy is confirmed, there is support in the literature for having the patient take two additional doses of levothyroxine per week until TSH can be tested.⁴ However, many endocrinology practices opt to check TSH and total T4 as soon as pregnancy is confirmed.

Since free T4 results may be unreliable during pregnancy (due to the effect of TBG), free thyroxine index (FTI) or total T4 should be monitored instead. FTI mathematically corrects free T4 for TBG levels, making it a useful marker. If total T4 is measured, it is important to remember that results will be approximately 1.5x the nonpregnancy value; thus, the reference range must be multiplied by 1.5 to calculate appropriate high and low parameters for pregnant patients.

Ideally, all women of childbearing age should be encouraged to plan pregnancy, to ensure TSH is at target prior to conception. Maintaining a euthyroid state throughout pregnancy (starting at conception) is important to decrease risk for such adverse outcomes as spontaneous abortion, placental abruption, and gestational hypertension.² Low birth weight and respiratory distress are potential complications for newborns whose mothers have inadequately controlled hypothyroidism.

Patients should be counseled against simultaneous dosing of prenatal vitamins and levothyroxine. Prenatal vitamins contain iron, which reduces absorption of levothyroxine; therefore, it is recommended that the levothyroxine be taken four hours or more apart from prenatal vitamins.

The Endocrine Society recommends a TSH no higher than 2.5 mIU/L for hypothyroidism diagnosed prior to pregnancy.^2,3 After delivery, levothyroxine doses should be reduced to prepregnancy levels, with close monitoring of TSH.²

Next page: Case 2 >>

CASE 2: HISTORY OF SPONTANEOUS ABORTION
A 36-year-old G3P0 woman visits your office for a work-up after her third spontaneous abortion at 16 weeks. The patient denies history of thyroid disease but notes her maternal grandmother has Hashimoto disease. She denies symptoms of hyperthyroidism or hypothyroidism. 

Recommendation
Both hyperthyroidism and hypothyroidism are associated with an increase in spontaneous abortion, premature labor, and low birth weight. Negro et al observed an increased risk for fetal loss, small-for-gestational-age fetus, premature delivery, and premature mortality in women who were TPO-antibody-positive, even if they were euthyroid. Improved fetal outcomes occurred when TPO-antibody-positive mothers received supplemental levothyroxine.⁵

However, the American Thyroid Association and the Endocrine Society state there is currently insufficient evidence to recommend universal screening of thyroid antibodies during pregnancy.^2,3 Obtaining thyroid function studies and TPO-antibody tests could be considered as part of a work-up for women who experience multiple spontaneous abortions or have a personal or family history of autoimmune diseases.

Continue for Case 3: Cardiovascular Symptoms >>

Next page: Case 4 >>

Rationale for targeted screening of asymptomatic women: Large-scale research has not demonstrated significantly better outcomes in those with subclinical hypothyroidism who receive treatment.⁷ Small studies² have demonstrated improved fetal outcomes when subclinical hypothyroidism is treated, but for large bodies  (eg, the US Preventive Services Task Force) to recommend screening, a clear improvement in health outcomes must be established via controlled studies. Future research should evaluate the effect of treating subclinical hypothyroidism during pregnancy.

REFERENCES
1. Ballabio, M, Poshychinda M, Ekins RP. Pregnancy-induced changes in thyroid function: role of human chorionic gonadotropin as putative regulator of maternal thyroid. J Clin Endocrinol Metab. 1991;73(4):824.
2. The Endocrine Society. Management of thyroid disease in pregnancy and postpartum. J Clin Endocrinol Metab. 2012;97:2543–2565.
3. Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21(10):1081-1125.
4. Alexander EK, Marqusee E, Lawrence J, et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med. 2004;351:241-249.
5. Negro R, Formoso G, Mangieri T, et al. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. Clin Endocrinol Metab. 2006;91(7):2587-2591.
6. Cooper DH. Antithyroid drugs. N Engl J Med. 2005;352:905-917.
7. American College of Obstetricians and Gynecologists. Routine thyroid screening not recommended for pregnant women. J Obstet Gynecol. 2007;110:959-960.

Management of thyroid disease during pregnancy presents unique challenges due to physiologic changes that occur. These include
• Serum levels of thyroxine-binding globulin (TBG) increase along with estrogen; in turn, total thyroxine (T4) and triiodothyronine (T3) levels increase.
• Human chorionic gonadotropin (hCG) stimulates the thyroid stimulating hormone (TSH) receptors.¹

Since hCG and TSH share similar glycoprotein subunits, a transient suppression of TSH—especially around weeks 10 to 12, when hCG concentrations peak—is considered a physiologic finding. Interpretation of thyroid function testing should be made in relation to the hCG-mediated decrease in serum TSH levels.²

The following four cases will help guide your clinical management of thyroid disease in both preconception and pregnancy. Inadequately controlled thyroid dysfunction can lead to poor pregnancy outcomes for both mother and child, which will be further discussed.

Continue for Case 1: Stable Hypothyroidism >>

CASE 1: STABLE ­HYPOTHYROIDISM
A 29-year-old woman with stable primary hypothyroidism calls your office to report that she is pregnant. She has taken levothyroxine (100 mg) for the past three years, and her TSH level was 1.21 mIU/L at last measurement. She denies any symptoms of hyperthyroidism or hypothyroidism. What is your next step in her management?

Recommendation
The American Thyroid Association recommends monitoring serum TSH every four weeks during the first half of pregnancy and at least once per trimester thereafter, with frequency depending on symptoms and TSH levels.³ Most women will require higher doses of levothyroxine supplementation to maintain therapeutic TSH levels.

Prior to 18 weeks’ gestation, the fetus is dependent on maternal thyroid hormone. When pregnancy is confirmed, there is support in the literature for having the patient take two additional doses of levothyroxine per week until TSH can be tested.⁴ However, many endocrinology practices opt to check TSH and total T4 as soon as pregnancy is confirmed.

Since free T4 results may be unreliable during pregnancy (due to the effect of TBG), free thyroxine index (FTI) or total T4 should be monitored instead. FTI mathematically corrects free T4 for TBG levels, making it a useful marker. If total T4 is measured, it is important to remember that results will be approximately 1.5x the nonpregnancy value; thus, the reference range must be multiplied by 1.5 to calculate appropriate high and low parameters for pregnant patients.

Ideally, all women of childbearing age should be encouraged to plan pregnancy, to ensure TSH is at target prior to conception. Maintaining a euthyroid state throughout pregnancy (starting at conception) is important to decrease risk for such adverse outcomes as spontaneous abortion, placental abruption, and gestational hypertension.² Low birth weight and respiratory distress are potential complications for newborns whose mothers have inadequately controlled hypothyroidism.

Patients should be counseled against simultaneous dosing of prenatal vitamins and levothyroxine. Prenatal vitamins contain iron, which reduces absorption of levothyroxine; therefore, it is recommended that the levothyroxine be taken four hours or more apart from prenatal vitamins.

The Endocrine Society recommends a TSH no higher than 2.5 mIU/L for hypothyroidism diagnosed prior to pregnancy.^2,3 After delivery, levothyroxine doses should be reduced to prepregnancy levels, with close monitoring of TSH.²

Next page: Case 2 >>

CASE 2: HISTORY OF SPONTANEOUS ABORTION
A 36-year-old G3P0 woman visits your office for a work-up after her third spontaneous abortion at 16 weeks. The patient denies history of thyroid disease but notes her maternal grandmother has Hashimoto disease. She denies symptoms of hyperthyroidism or hypothyroidism. 

Recommendation
Both hyperthyroidism and hypothyroidism are associated with an increase in spontaneous abortion, premature labor, and low birth weight. Negro et al observed an increased risk for fetal loss, small-for-gestational-age fetus, premature delivery, and premature mortality in women who were TPO-antibody-positive, even if they were euthyroid. Improved fetal outcomes occurred when TPO-antibody-positive mothers received supplemental levothyroxine.⁵

However, the American Thyroid Association and the Endocrine Society state there is currently insufficient evidence to recommend universal screening of thyroid antibodies during pregnancy.^2,3 Obtaining thyroid function studies and TPO-antibody tests could be considered as part of a work-up for women who experience multiple spontaneous abortions or have a personal or family history of autoimmune diseases.

Continue for Case 3: Cardiovascular Symptoms >>

Next page: Case 4 >>

Rationale for targeted screening of asymptomatic women: Large-scale research has not demonstrated significantly better outcomes in those with subclinical hypothyroidism who receive treatment.⁷ Small studies² have demonstrated improved fetal outcomes when subclinical hypothyroidism is treated, but for large bodies  (eg, the US Preventive Services Task Force) to recommend screening, a clear improvement in health outcomes must be established via controlled studies. Future research should evaluate the effect of treating subclinical hypothyroidism during pregnancy.

REFERENCES
1. Ballabio, M, Poshychinda M, Ekins RP. Pregnancy-induced changes in thyroid function: role of human chorionic gonadotropin as putative regulator of maternal thyroid. J Clin Endocrinol Metab. 1991;73(4):824.
2. The Endocrine Society. Management of thyroid disease in pregnancy and postpartum. J Clin Endocrinol Metab. 2012;97:2543–2565.
3. Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21(10):1081-1125.
4. Alexander EK, Marqusee E, Lawrence J, et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med. 2004;351:241-249.
5. Negro R, Formoso G, Mangieri T, et al. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. Clin Endocrinol Metab. 2006;91(7):2587-2591.
6. Cooper DH. Antithyroid drugs. N Engl J Med. 2005;352:905-917.
7. American College of Obstetricians and Gynecologists. Routine thyroid screening not recommended for pregnant women. J Obstet Gynecol. 2007;110:959-960.

Management of thyroid disease during pregnancy presents unique challenges due to physiologic changes that occur. These include
• Serum levels of thyroxine-binding globulin (TBG) increase along with estrogen; in turn, total thyroxine (T4) and triiodothyronine (T3) levels increase.
• Human chorionic gonadotropin (hCG) stimulates the thyroid stimulating hormone (TSH) receptors.¹

Since hCG and TSH share similar glycoprotein subunits, a transient suppression of TSH—especially around weeks 10 to 12, when hCG concentrations peak—is considered a physiologic finding. Interpretation of thyroid function testing should be made in relation to the hCG-mediated decrease in serum TSH levels.²

The following four cases will help guide your clinical management of thyroid disease in both preconception and pregnancy. Inadequately controlled thyroid dysfunction can lead to poor pregnancy outcomes for both mother and child, which will be further discussed.

Continue for Case 1: Stable Hypothyroidism >>

CASE 1: STABLE ­HYPOTHYROIDISM
A 29-year-old woman with stable primary hypothyroidism calls your office to report that she is pregnant. She has taken levothyroxine (100 mg) for the past three years, and her TSH level was 1.21 mIU/L at last measurement. She denies any symptoms of hyperthyroidism or hypothyroidism. What is your next step in her management?

Recommendation
The American Thyroid Association recommends monitoring serum TSH every four weeks during the first half of pregnancy and at least once per trimester thereafter, with frequency depending on symptoms and TSH levels.³ Most women will require higher doses of levothyroxine supplementation to maintain therapeutic TSH levels.

Prior to 18 weeks’ gestation, the fetus is dependent on maternal thyroid hormone. When pregnancy is confirmed, there is support in the literature for having the patient take two additional doses of levothyroxine per week until TSH can be tested.⁴ However, many endocrinology practices opt to check TSH and total T4 as soon as pregnancy is confirmed.

Since free T4 results may be unreliable during pregnancy (due to the effect of TBG), free thyroxine index (FTI) or total T4 should be monitored instead. FTI mathematically corrects free T4 for TBG levels, making it a useful marker. If total T4 is measured, it is important to remember that results will be approximately 1.5x the nonpregnancy value; thus, the reference range must be multiplied by 1.5 to calculate appropriate high and low parameters for pregnant patients.

Ideally, all women of childbearing age should be encouraged to plan pregnancy, to ensure TSH is at target prior to conception. Maintaining a euthyroid state throughout pregnancy (starting at conception) is important to decrease risk for such adverse outcomes as spontaneous abortion, placental abruption, and gestational hypertension.² Low birth weight and respiratory distress are potential complications for newborns whose mothers have inadequately controlled hypothyroidism.

Patients should be counseled against simultaneous dosing of prenatal vitamins and levothyroxine. Prenatal vitamins contain iron, which reduces absorption of levothyroxine; therefore, it is recommended that the levothyroxine be taken four hours or more apart from prenatal vitamins.

The Endocrine Society recommends a TSH no higher than 2.5 mIU/L for hypothyroidism diagnosed prior to pregnancy.^2,3 After delivery, levothyroxine doses should be reduced to prepregnancy levels, with close monitoring of TSH.²

Next page: Case 2 >>

CASE 2: HISTORY OF SPONTANEOUS ABORTION
A 36-year-old G3P0 woman visits your office for a work-up after her third spontaneous abortion at 16 weeks. The patient denies history of thyroid disease but notes her maternal grandmother has Hashimoto disease. She denies symptoms of hyperthyroidism or hypothyroidism. 

Recommendation
Both hyperthyroidism and hypothyroidism are associated with an increase in spontaneous abortion, premature labor, and low birth weight. Negro et al observed an increased risk for fetal loss, small-for-gestational-age fetus, premature delivery, and premature mortality in women who were TPO-antibody-positive, even if they were euthyroid. Improved fetal outcomes occurred when TPO-antibody-positive mothers received supplemental levothyroxine.⁵

However, the American Thyroid Association and the Endocrine Society state there is currently insufficient evidence to recommend universal screening of thyroid antibodies during pregnancy.^2,3 Obtaining thyroid function studies and TPO-antibody tests could be considered as part of a work-up for women who experience multiple spontaneous abortions or have a personal or family history of autoimmune diseases.

Continue for Case 3: Cardiovascular Symptoms >>

Next page: Case 4 >>

Rationale for targeted screening of asymptomatic women: Large-scale research has not demonstrated significantly better outcomes in those with subclinical hypothyroidism who receive treatment.⁷ Small studies² have demonstrated improved fetal outcomes when subclinical hypothyroidism is treated, but for large bodies  (eg, the US Preventive Services Task Force) to recommend screening, a clear improvement in health outcomes must be established via controlled studies. Future research should evaluate the effect of treating subclinical hypothyroidism during pregnancy.

REFERENCES
1. Ballabio, M, Poshychinda M, Ekins RP. Pregnancy-induced changes in thyroid function: role of human chorionic gonadotropin as putative regulator of maternal thyroid. J Clin Endocrinol Metab. 1991;73(4):824.
2. The Endocrine Society. Management of thyroid disease in pregnancy and postpartum. J Clin Endocrinol Metab. 2012;97:2543–2565.
3. Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21(10):1081-1125.
4. Alexander EK, Marqusee E, Lawrence J, et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med. 2004;351:241-249.
5. Negro R, Formoso G, Mangieri T, et al. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. Clin Endocrinol Metab. 2006;91(7):2587-2591.
6. Cooper DH. Antithyroid drugs. N Engl J Med. 2005;352:905-917.
7. American College of Obstetricians and Gynecologists. Routine thyroid screening not recommended for pregnant women. J Obstet Gynecol. 2007;110:959-960.

In January 2009, an Alabama woman with multiple sclerosis visited Dr T., the defendant ob-gyn, for severe pelvic pain. Dr T. made a diagnosis of a fibroid uterus and ovarian cysts. The patient underwent a transvaginal hysterectomy, but her pain persisted after the surgery.

After being discharged, she discovered a long strip of packing protruding from her vagina, which Dr T. instructed her to extract herself. After doing so, however, the patient continued to have pain, bleeding, and a foul–smelling vaginal discharge. Dr T. diagnosed urinary tract infection and bacterial vaginosis. Antibiotics and pain medication were prescribed, but the patient’s pelvic pain persisted.

In April 2009, Dr T. ordered CT to rule out an abscess or a foreign body. A gauze surgical sponge, left at the conclusion of the patient’s hysterectomy, was detected. Surgery was performed to remove the sponge.

The plaintiff alleged negligence in the sponge’s retention, maintaining that not only was a second surgery required, but that her multiple sclerosis was exacerbated as a result of the entire situation.

The defendant claimed that tests had been performed to investigate the possibility of a foreign body, and that as soon as the surgical sponge was detected, it was removed.

What was the outcome? >>

OUTCOME
According to a published report, a defense verdict was returned.

COMMENT
The defense verdict here is surprising. In most cases in which surgical instruments are left in patients, plaintiffs prevail by using a legal doctrine known as res ipsa loquitur—a Latin legal term of art meaning “the thing speaks for itself.” This is generally requested as a jury charge, wherein the plaintiff asks the judge to explain to the jury that they may find negligence from a certain unusual fact that cannot have occurred without negligence (eg, a sponge left in a patient after surgery).

The history of res ipsa loquitur dates back to 1863 in the case of Byrne v Boadle, in which a barrel of flour rolled from a second-story window and struck a pedestrian below, causing serious injury. The defendants’ claim was that the plaintiff (who had no recollection of the event) was unable to show evidence of negligence. The court created the doctrine, holding that the fact of the accident itself provided ample evidence of negligence, excusing the plaintiff from the burden of proving that negligent acts (eg, inadequate harnessing of the barrels) led to the accident.

Why is this important? The concept of res ipsa loquitur is commonly invoked in medical malpractice actions. It generally requires three elements: the plaintiff suffers an unusual injury, the plaintiff was under the exclusive control of the medical defendants, and the plaintiff did not contribute to the injury.

In a leading malpractice case, Ybarra v Spangard (1944), a plaintiff awoke after undergoing an appendectomy with difficulty moving his arm as a result of reflex sympathetic dystrophy. The plaintiff alleged negligence stemming from the intraoperative positioning of his body, but he could not show the specifics of positioning during surgery. The court held that the patient’s body was under the exclusive control of the team of medical professionals, and that negligence could be inferred because loss of an arm’s function following an appendectomy is unusual and cannot occur without some negligent action involved.

When successfully used in malpractice cases, res ipsa loquitur relieves the plaintiff of the need to prove by a preponderance of the evidence the actions that led to the breach of the standard of care. In order to prevail, she must show the injury, the defendants’ exclusive control, and no contribution on her part. Practically, this permits the case to withstand defense motions for summary judgment and to be brought before a jury with scant to no evidence on the purported negligent act itself—merely the unusual injury and the defendants’ exclusive control.

Traditional application of the doctrine was limited to cases in which negligence was obvious to a layperson: for example, instruments left in patients or amputation of the wrong leg—the thing that “speaks for itself.” Newer evolution of the doctrine is problematic when extended to cases in which expert testimony should be required to demonstrate the standard of care and the defendant’s breach of it. When courts are willing to extend the doctrine, the plaintiff is awarded the presumption of negligence, which the defendant(s) must now come forward to rebut. For example, in a 2010 case in Illinois, a jury returned a $3.6 million verdict following the death of a 2-year-old who had had a seizure. The child’s seizure was reportedly controlled, but he was allegedly hypoventilated while undergoing CT and unfortunately died. The plaintiff was permitted to invoke the doctrine of res ipsa loquitur and was allowed the presumption that medical negligence was responsible for the outcome.

Unlike the surgical sponge left in a patient, matters of central nervous system status, monitoring during CT, airway and ventilation status, hypoxemia, and postictal states are not within the experience of the typical juror. The negligent “thing” is not a sponge that “speaks for itself,” but a course of actions that requires expert testimony precisely because it does not “speak for itself.” In cases in which an injury is ­beyond the average juror’s realm of experience, courts should require the plaintiff to prove her case. The doctrine should not “evolve” to excuse a plaintiff from the burden of producing evidence and persuading a jury. This forms the foundation of our civil law system. —DML

In January 2009, an Alabama woman with multiple sclerosis visited Dr T., the defendant ob-gyn, for severe pelvic pain. Dr T. made a diagnosis of a fibroid uterus and ovarian cysts. The patient underwent a transvaginal hysterectomy, but her pain persisted after the surgery.

After being discharged, she discovered a long strip of packing protruding from her vagina, which Dr T. instructed her to extract herself. After doing so, however, the patient continued to have pain, bleeding, and a foul–smelling vaginal discharge. Dr T. diagnosed urinary tract infection and bacterial vaginosis. Antibiotics and pain medication were prescribed, but the patient’s pelvic pain persisted.

In April 2009, Dr T. ordered CT to rule out an abscess or a foreign body. A gauze surgical sponge, left at the conclusion of the patient’s hysterectomy, was detected. Surgery was performed to remove the sponge.

The plaintiff alleged negligence in the sponge’s retention, maintaining that not only was a second surgery required, but that her multiple sclerosis was exacerbated as a result of the entire situation.

The defendant claimed that tests had been performed to investigate the possibility of a foreign body, and that as soon as the surgical sponge was detected, it was removed.

What was the outcome? >>

OUTCOME
According to a published report, a defense verdict was returned.

COMMENT
The defense verdict here is surprising. In most cases in which surgical instruments are left in patients, plaintiffs prevail by using a legal doctrine known as res ipsa loquitur—a Latin legal term of art meaning “the thing speaks for itself.” This is generally requested as a jury charge, wherein the plaintiff asks the judge to explain to the jury that they may find negligence from a certain unusual fact that cannot have occurred without negligence (eg, a sponge left in a patient after surgery).

The history of res ipsa loquitur dates back to 1863 in the case of Byrne v Boadle, in which a barrel of flour rolled from a second-story window and struck a pedestrian below, causing serious injury. The defendants’ claim was that the plaintiff (who had no recollection of the event) was unable to show evidence of negligence. The court created the doctrine, holding that the fact of the accident itself provided ample evidence of negligence, excusing the plaintiff from the burden of proving that negligent acts (eg, inadequate harnessing of the barrels) led to the accident.

Why is this important? The concept of res ipsa loquitur is commonly invoked in medical malpractice actions. It generally requires three elements: the plaintiff suffers an unusual injury, the plaintiff was under the exclusive control of the medical defendants, and the plaintiff did not contribute to the injury.

In a leading malpractice case, Ybarra v Spangard (1944), a plaintiff awoke after undergoing an appendectomy with difficulty moving his arm as a result of reflex sympathetic dystrophy. The plaintiff alleged negligence stemming from the intraoperative positioning of his body, but he could not show the specifics of positioning during surgery. The court held that the patient’s body was under the exclusive control of the team of medical professionals, and that negligence could be inferred because loss of an arm’s function following an appendectomy is unusual and cannot occur without some negligent action involved.

When successfully used in malpractice cases, res ipsa loquitur relieves the plaintiff of the need to prove by a preponderance of the evidence the actions that led to the breach of the standard of care. In order to prevail, she must show the injury, the defendants’ exclusive control, and no contribution on her part. Practically, this permits the case to withstand defense motions for summary judgment and to be brought before a jury with scant to no evidence on the purported negligent act itself—merely the unusual injury and the defendants’ exclusive control.

Traditional application of the doctrine was limited to cases in which negligence was obvious to a layperson: for example, instruments left in patients or amputation of the wrong leg—the thing that “speaks for itself.” Newer evolution of the doctrine is problematic when extended to cases in which expert testimony should be required to demonstrate the standard of care and the defendant’s breach of it. When courts are willing to extend the doctrine, the plaintiff is awarded the presumption of negligence, which the defendant(s) must now come forward to rebut. For example, in a 2010 case in Illinois, a jury returned a $3.6 million verdict following the death of a 2-year-old who had had a seizure. The child’s seizure was reportedly controlled, but he was allegedly hypoventilated while undergoing CT and unfortunately died. The plaintiff was permitted to invoke the doctrine of res ipsa loquitur and was allowed the presumption that medical negligence was responsible for the outcome.

Unlike the surgical sponge left in a patient, matters of central nervous system status, monitoring during CT, airway and ventilation status, hypoxemia, and postictal states are not within the experience of the typical juror. The negligent “thing” is not a sponge that “speaks for itself,” but a course of actions that requires expert testimony precisely because it does not “speak for itself.” In cases in which an injury is ­beyond the average juror’s realm of experience, courts should require the plaintiff to prove her case. The doctrine should not “evolve” to excuse a plaintiff from the burden of producing evidence and persuading a jury. This forms the foundation of our civil law system. —DML

In January 2009, an Alabama woman with multiple sclerosis visited Dr T., the defendant ob-gyn, for severe pelvic pain. Dr T. made a diagnosis of a fibroid uterus and ovarian cysts. The patient underwent a transvaginal hysterectomy, but her pain persisted after the surgery.

After being discharged, she discovered a long strip of packing protruding from her vagina, which Dr T. instructed her to extract herself. After doing so, however, the patient continued to have pain, bleeding, and a foul–smelling vaginal discharge. Dr T. diagnosed urinary tract infection and bacterial vaginosis. Antibiotics and pain medication were prescribed, but the patient’s pelvic pain persisted.

In April 2009, Dr T. ordered CT to rule out an abscess or a foreign body. A gauze surgical sponge, left at the conclusion of the patient’s hysterectomy, was detected. Surgery was performed to remove the sponge.

The plaintiff alleged negligence in the sponge’s retention, maintaining that not only was a second surgery required, but that her multiple sclerosis was exacerbated as a result of the entire situation.

The defendant claimed that tests had been performed to investigate the possibility of a foreign body, and that as soon as the surgical sponge was detected, it was removed.

What was the outcome? >>

OUTCOME
According to a published report, a defense verdict was returned.

COMMENT
The defense verdict here is surprising. In most cases in which surgical instruments are left in patients, plaintiffs prevail by using a legal doctrine known as res ipsa loquitur—a Latin legal term of art meaning “the thing speaks for itself.” This is generally requested as a jury charge, wherein the plaintiff asks the judge to explain to the jury that they may find negligence from a certain unusual fact that cannot have occurred without negligence (eg, a sponge left in a patient after surgery).

The history of res ipsa loquitur dates back to 1863 in the case of Byrne v Boadle, in which a barrel of flour rolled from a second-story window and struck a pedestrian below, causing serious injury. The defendants’ claim was that the plaintiff (who had no recollection of the event) was unable to show evidence of negligence. The court created the doctrine, holding that the fact of the accident itself provided ample evidence of negligence, excusing the plaintiff from the burden of proving that negligent acts (eg, inadequate harnessing of the barrels) led to the accident.

Why is this important? The concept of res ipsa loquitur is commonly invoked in medical malpractice actions. It generally requires three elements: the plaintiff suffers an unusual injury, the plaintiff was under the exclusive control of the medical defendants, and the plaintiff did not contribute to the injury.

In a leading malpractice case, Ybarra v Spangard (1944), a plaintiff awoke after undergoing an appendectomy with difficulty moving his arm as a result of reflex sympathetic dystrophy. The plaintiff alleged negligence stemming from the intraoperative positioning of his body, but he could not show the specifics of positioning during surgery. The court held that the patient’s body was under the exclusive control of the team of medical professionals, and that negligence could be inferred because loss of an arm’s function following an appendectomy is unusual and cannot occur without some negligent action involved.

When successfully used in malpractice cases, res ipsa loquitur relieves the plaintiff of the need to prove by a preponderance of the evidence the actions that led to the breach of the standard of care. In order to prevail, she must show the injury, the defendants’ exclusive control, and no contribution on her part. Practically, this permits the case to withstand defense motions for summary judgment and to be brought before a jury with scant to no evidence on the purported negligent act itself—merely the unusual injury and the defendants’ exclusive control.

Traditional application of the doctrine was limited to cases in which negligence was obvious to a layperson: for example, instruments left in patients or amputation of the wrong leg—the thing that “speaks for itself.” Newer evolution of the doctrine is problematic when extended to cases in which expert testimony should be required to demonstrate the standard of care and the defendant’s breach of it. When courts are willing to extend the doctrine, the plaintiff is awarded the presumption of negligence, which the defendant(s) must now come forward to rebut. For example, in a 2010 case in Illinois, a jury returned a $3.6 million verdict following the death of a 2-year-old who had had a seizure. The child’s seizure was reportedly controlled, but he was allegedly hypoventilated while undergoing CT and unfortunately died. The plaintiff was permitted to invoke the doctrine of res ipsa loquitur and was allowed the presumption that medical negligence was responsible for the outcome.

Unlike the surgical sponge left in a patient, matters of central nervous system status, monitoring during CT, airway and ventilation status, hypoxemia, and postictal states are not within the experience of the typical juror. The negligent “thing” is not a sponge that “speaks for itself,” but a course of actions that requires expert testimony precisely because it does not “speak for itself.” In cases in which an injury is ­beyond the average juror’s realm of experience, courts should require the plaintiff to prove her case. The doctrine should not “evolve” to excuse a plaintiff from the burden of producing evidence and persuading a jury. This forms the foundation of our civil law system. —DML

Researchers in the lab

Photo by Rhoda Baer

New research suggests that heritable mutations in the gene ETV6 can predispose people to acute lymphoblastic leukemia (ALL).

Somatic mutations in ETV6 have previously been implicated in the development of ALL and other hematologic malignancies.

The new study, published in Nature Genetics, has shown that germline mutations in ETV6 are associated with thrombocytopenia, red blood cell (RBC) macrocytosis, and predisposition to ALL.

The research began with a family (family 1) that had autosomal dominant thrombocytopenia  (67,000-132,000 platelets/μL), high RBC mean corpuscular volume (MCV,  92.5-101.5 fl), and 2 cases of B-cell-precursor ALL.

“All of them had big red blood cells, low platelet counts, and propensity to bleed,” said study author Christopher Porter, MD, of the University of Colorado Denver.

This familial link to abnormal blood dynamics and predisposition to ALL implied a common genetic denominator. To find it, the researchers performed whole-exome sequencing and found a heterozygous single-nucleotide change in ETV6, c.641C>T, encoding a p.Pro214Leu substitution in the central domain.

The researchers then screened 23 other families with similar phenotypes as the first and identified 2 families with ETV6 mutations.

One family (family 2) had members with platelet counts ranging from 44,000 to 115,000 platelets/μL, RBC MCVs ranging from 88 to 97 fl, and a member with ALL. All affected family members had a c.641C>T mutation identical to the one identified in family 1.

Another family (family 3) had members with platelet counts ranging from 99,000 to 101,000 platelets/μL and RBC MCVs ranging from 93 to 98 fl but no malignancies. Members of this family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping.

The researchers said these mutations partially disrupt ETV6 transcriptional repression in vitro and cause aberrant cytoplasmic localization of both mutant and endogenous ETV6, suggesting a dominant-negative effect. The mutations also impair megakaryocyte development and proplatelet formation in culture.

Dr Porter and his colleagues noted that another team of researchers recently discovered germline missense mutations in ETV6 in 3 unrelated families. Dr Porter’s group hopes future work will show the prevalence of germline mutations in ETV6.

“It’s not common in a general population, but we think it might be much more common in people who develop ALL,” Dr Porter said. “[Our] paper highlights this gene in the development of leukemia. By studying this mutation, we should be able to gather a better understanding of how leukemia develops.”

Researchers in the lab

Photo by Rhoda Baer

New research suggests that heritable mutations in the gene ETV6 can predispose people to acute lymphoblastic leukemia (ALL).

Somatic mutations in ETV6 have previously been implicated in the development of ALL and other hematologic malignancies.

The new study, published in Nature Genetics, has shown that germline mutations in ETV6 are associated with thrombocytopenia, red blood cell (RBC) macrocytosis, and predisposition to ALL.

The research began with a family (family 1) that had autosomal dominant thrombocytopenia  (67,000-132,000 platelets/μL), high RBC mean corpuscular volume (MCV,  92.5-101.5 fl), and 2 cases of B-cell-precursor ALL.

“All of them had big red blood cells, low platelet counts, and propensity to bleed,” said study author Christopher Porter, MD, of the University of Colorado Denver.

This familial link to abnormal blood dynamics and predisposition to ALL implied a common genetic denominator. To find it, the researchers performed whole-exome sequencing and found a heterozygous single-nucleotide change in ETV6, c.641C>T, encoding a p.Pro214Leu substitution in the central domain.

The researchers then screened 23 other families with similar phenotypes as the first and identified 2 families with ETV6 mutations.

One family (family 2) had members with platelet counts ranging from 44,000 to 115,000 platelets/μL, RBC MCVs ranging from 88 to 97 fl, and a member with ALL. All affected family members had a c.641C>T mutation identical to the one identified in family 1.

Another family (family 3) had members with platelet counts ranging from 99,000 to 101,000 platelets/μL and RBC MCVs ranging from 93 to 98 fl but no malignancies. Members of this family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping.

The researchers said these mutations partially disrupt ETV6 transcriptional repression in vitro and cause aberrant cytoplasmic localization of both mutant and endogenous ETV6, suggesting a dominant-negative effect. The mutations also impair megakaryocyte development and proplatelet formation in culture.

Dr Porter and his colleagues noted that another team of researchers recently discovered germline missense mutations in ETV6 in 3 unrelated families. Dr Porter’s group hopes future work will show the prevalence of germline mutations in ETV6.

“It’s not common in a general population, but we think it might be much more common in people who develop ALL,” Dr Porter said. “[Our] paper highlights this gene in the development of leukemia. By studying this mutation, we should be able to gather a better understanding of how leukemia develops.”

Researchers in the lab

Photo by Rhoda Baer

New research suggests that heritable mutations in the gene ETV6 can predispose people to acute lymphoblastic leukemia (ALL).

Somatic mutations in ETV6 have previously been implicated in the development of ALL and other hematologic malignancies.

The new study, published in Nature Genetics, has shown that germline mutations in ETV6 are associated with thrombocytopenia, red blood cell (RBC) macrocytosis, and predisposition to ALL.

The research began with a family (family 1) that had autosomal dominant thrombocytopenia  (67,000-132,000 platelets/μL), high RBC mean corpuscular volume (MCV,  92.5-101.5 fl), and 2 cases of B-cell-precursor ALL.

“All of them had big red blood cells, low platelet counts, and propensity to bleed,” said study author Christopher Porter, MD, of the University of Colorado Denver.

This familial link to abnormal blood dynamics and predisposition to ALL implied a common genetic denominator. To find it, the researchers performed whole-exome sequencing and found a heterozygous single-nucleotide change in ETV6, c.641C>T, encoding a p.Pro214Leu substitution in the central domain.

The researchers then screened 23 other families with similar phenotypes as the first and identified 2 families with ETV6 mutations.

One family (family 2) had members with platelet counts ranging from 44,000 to 115,000 platelets/μL, RBC MCVs ranging from 88 to 97 fl, and a member with ALL. All affected family members had a c.641C>T mutation identical to the one identified in family 1.

Another family (family 3) had members with platelet counts ranging from 99,000 to 101,000 platelets/μL and RBC MCVs ranging from 93 to 98 fl but no malignancies. Members of this family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping.

The researchers said these mutations partially disrupt ETV6 transcriptional repression in vitro and cause aberrant cytoplasmic localization of both mutant and endogenous ETV6, suggesting a dominant-negative effect. The mutations also impair megakaryocyte development and proplatelet formation in culture.

Dr Porter and his colleagues noted that another team of researchers recently discovered germline missense mutations in ETV6 in 3 unrelated families. Dr Porter’s group hopes future work will show the prevalence of germline mutations in ETV6.

“It’s not common in a general population, but we think it might be much more common in people who develop ALL,” Dr Porter said. “[Our] paper highlights this gene in the development of leukemia. By studying this mutation, we should be able to gather a better understanding of how leukemia develops.”

Colony of iPSCs

Image by James Thomson

A new study has improved researchers’ understanding of a genetic defect associated with myelodysplastic syndromes (MDS), and the team hopes this will ultimately help us correct the defect in patients.

The researchers used induced pluripotent stem cells (iPSCs) to study del(7q), a chromosomal abnormality found in patients with MDS.

This provided the team with new insight into how the deletion contributes to MDS development.

Steven D. Nimer, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described this work in Nature Biotechnology.

To determine how del(7q) contributes to MDS development, the researchers isolated hematopoietic cells from a patient with del(7q) and reprogrammed them into iPSCs. These iPSCs recapitulated MDS-associated phenotypes, including impaired hematopoietic differentiation.

The researchers also showed that, by engineering heterozygous chromosome 7q loss, they could recapitulate in normal iPSCs the characteristics they observed in the del(7q) iPSCs.

So the team was not surprised to find that disease phenotypes were rescued when del(7q) iPSC lines acquired a duplicate copy of chromosome 7q material.

The researchers also found that hemizygosity of chromosome 7q reduced the expression of many genes in the chromosome7q-deleted region. But gene expression was restored upon chromosome 7q dosage correction.

“[W]e were able to pinpoint a region on chromosome 7 that is critical and were able to identify candidate genes residing there that may cause this disease,” said study author Eirini Papapetrou, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York.

Focusing on hits residing in this region, 7q32.3–7q36.1, the researchers found 10 genes that were enriched (by >1.5-fold) recurrently.

Further investigation confirmed that 4 of these genes—HIPK2, ATP6V0E2, LUC7L2, and EZH2—could partially rescue the emergence of CD45⁺ hematopoietic progenitors when overexpressed in del(7q) iPSCs.

The researchers conducted additional experiments focusing on EZH2 alone and found that haploinsufficiency of EZH2 decreases cells’ hematopoietic potential.

But it seems the hematopoietic defects caused by chromosome 7q hemizygosity are mediated through the haploinsufficiency of EZH2 in combination with 1 or more additional genes, which might include LUC7L2, HIPK2, ATP6V0E2, and/or other genes.

Colony of iPSCs

Image by James Thomson

A new study has improved researchers’ understanding of a genetic defect associated with myelodysplastic syndromes (MDS), and the team hopes this will ultimately help us correct the defect in patients.

The researchers used induced pluripotent stem cells (iPSCs) to study del(7q), a chromosomal abnormality found in patients with MDS.

This provided the team with new insight into how the deletion contributes to MDS development.

Steven D. Nimer, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described this work in Nature Biotechnology.

To determine how del(7q) contributes to MDS development, the researchers isolated hematopoietic cells from a patient with del(7q) and reprogrammed them into iPSCs. These iPSCs recapitulated MDS-associated phenotypes, including impaired hematopoietic differentiation.

The researchers also showed that, by engineering heterozygous chromosome 7q loss, they could recapitulate in normal iPSCs the characteristics they observed in the del(7q) iPSCs.

So the team was not surprised to find that disease phenotypes were rescued when del(7q) iPSC lines acquired a duplicate copy of chromosome 7q material.

The researchers also found that hemizygosity of chromosome 7q reduced the expression of many genes in the chromosome7q-deleted region. But gene expression was restored upon chromosome 7q dosage correction.

“[W]e were able to pinpoint a region on chromosome 7 that is critical and were able to identify candidate genes residing there that may cause this disease,” said study author Eirini Papapetrou, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York.

Focusing on hits residing in this region, 7q32.3–7q36.1, the researchers found 10 genes that were enriched (by >1.5-fold) recurrently.

Further investigation confirmed that 4 of these genes—HIPK2, ATP6V0E2, LUC7L2, and EZH2—could partially rescue the emergence of CD45⁺ hematopoietic progenitors when overexpressed in del(7q) iPSCs.

The researchers conducted additional experiments focusing on EZH2 alone and found that haploinsufficiency of EZH2 decreases cells’ hematopoietic potential.

But it seems the hematopoietic defects caused by chromosome 7q hemizygosity are mediated through the haploinsufficiency of EZH2 in combination with 1 or more additional genes, which might include LUC7L2, HIPK2, ATP6V0E2, and/or other genes.

Colony of iPSCs

Image by James Thomson

A new study has improved researchers’ understanding of a genetic defect associated with myelodysplastic syndromes (MDS), and the team hopes this will ultimately help us correct the defect in patients.

The researchers used induced pluripotent stem cells (iPSCs) to study del(7q), a chromosomal abnormality found in patients with MDS.

This provided the team with new insight into how the deletion contributes to MDS development.

Steven D. Nimer, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described this work in Nature Biotechnology.

To determine how del(7q) contributes to MDS development, the researchers isolated hematopoietic cells from a patient with del(7q) and reprogrammed them into iPSCs. These iPSCs recapitulated MDS-associated phenotypes, including impaired hematopoietic differentiation.

The researchers also showed that, by engineering heterozygous chromosome 7q loss, they could recapitulate in normal iPSCs the characteristics they observed in the del(7q) iPSCs.

So the team was not surprised to find that disease phenotypes were rescued when del(7q) iPSC lines acquired a duplicate copy of chromosome 7q material.

The researchers also found that hemizygosity of chromosome 7q reduced the expression of many genes in the chromosome7q-deleted region. But gene expression was restored upon chromosome 7q dosage correction.

“[W]e were able to pinpoint a region on chromosome 7 that is critical and were able to identify candidate genes residing there that may cause this disease,” said study author Eirini Papapetrou, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York.

Focusing on hits residing in this region, 7q32.3–7q36.1, the researchers found 10 genes that were enriched (by >1.5-fold) recurrently.

Further investigation confirmed that 4 of these genes—HIPK2, ATP6V0E2, LUC7L2, and EZH2—could partially rescue the emergence of CD45⁺ hematopoietic progenitors when overexpressed in del(7q) iPSCs.

The researchers conducted additional experiments focusing on EZH2 alone and found that haploinsufficiency of EZH2 decreases cells’ hematopoietic potential.

But it seems the hematopoietic defects caused by chromosome 7q hemizygosity are mediated through the haploinsufficiency of EZH2 in combination with 1 or more additional genes, which might include LUC7L2, HIPK2, ATP6V0E2, and/or other genes.

Doctor consults with a family

Photo by Rhoda Baer

Patients want more information about medical imaging tests that use radiation, according to research published in Radiology.

Most of the 30 subjects involved in this study said their healthcare providers did not initiate a discussion about the risks and benefits of imaging tests.

So a majority of participants obtained information from the Internet. Researchers said these findings highlight a need for better communication between patients and providers.

“This may not be what we in the medical field want to hear, but I think it’s important that we hear it,” said study author Jennifer Hay, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“Patients want this information, and they prefer to receive it from doctors they know and trust.”

Dr Hay and her colleagues analyzed over 9 hours of transcribed conversations with 30 people who had undergone medical imaging exams or consented for their children to undergo such exams.

The goal was to determine the subjects’ understanding of the benefits and risks associated with various medical imaging procedures and their expectations regarding communication of those benefits and risks.

The study group was divided into 6 focus groups, including 5 groups of cancer patients (or parents of young cancer patients) and 1 group of participants in a lung cancer screening program.

Quantifying subjects’ knowledge

The researchers found that participants perceived clear benefits from imaging tests like X-rays, computed tomography (CT) scans, and nuclear medicine examinations.

And most subjects were highly aware of the risks associated with ionizing radiation exposure, including the potential risk of future cancer. But their knowledge regarding which imaging tests use ionizing radiation varied.

In general, participants were more likely to understand that X-rays, CTs, and positron emission tomography (PET) scans deliver ionizing radiation and less likely to know about mammography, bone scanning, or stress tests. Many subjects did not know if magnetic resonance imaging (MRI) involved ionizing radiation.

Some participants did not know how tests differed, and some believed there was a “best” imaging test. Occasionally, subjects confused ionizing radiation from diagnostic medical imaging with radiation therapy.

Desire for information

Participants considered the availability of basic benefit-risk information to be a fundamental component of care. And they expressed a desire for a wide range of information about medical imaging tests.

Most subjects wanted basic education about which imaging tests use ionizing radiation and how doses compare among them. Nearly all subjects wanted to understand how tests differ, what governs selection of one over another, and why multiple tests are sometimes ordered.

A majority of participants met their needs for more information through self-directed Internet searches.

Concern about risks

Most subjects agreed that learning about possible future risks was important, but having this information would probably not alter their decision to proceed with a recommended test.

The desire for information about risks was strongest among cancer patients who had made the transition from treatment to survivorship.

These patients wanted to know how risk accumulates from multiple exams over time, whether additional ionizing radiation exposure could be avoided by substituting MRI for CT, and if longer intervals between follow-up examinations could be negotiated.

“Interest in having more information and participating in decision-making about medical imaging clearly increased as patients transitioned from active cancer treatment to survivorship,” said study author Raymond H. Thornton, MD, of Memorial Sloan Kettering Cancer Center.

“Cancer survivors typically focus on healthful living and risk-factor reduction, so they were particularly eager to participate in discussions about potential long-term risks of radiation.”

The different levels of desire for information among the study subjects lend support to a tiered approach for patient-centered communication, according to Dr Hay.

“A tiered approach would provide all patients with information and offer additional options to those who want to dig deeper and find out more,” she said.

Presenting information

Subjects expressed interest in 2 different modes of information exchange. Many participants said the ideal situation would be a face-to-face discussion with their personal physician, a medical physicist, or radiologist.

Others expressed an interest in written resources, especially hospital-endorsed Internet sites and printed materials.

Doctor consults with a family

Photo by Rhoda Baer

Patients want more information about medical imaging tests that use radiation, according to research published in Radiology.

Most of the 30 subjects involved in this study said their healthcare providers did not initiate a discussion about the risks and benefits of imaging tests.

So a majority of participants obtained information from the Internet. Researchers said these findings highlight a need for better communication between patients and providers.

“This may not be what we in the medical field want to hear, but I think it’s important that we hear it,” said study author Jennifer Hay, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“Patients want this information, and they prefer to receive it from doctors they know and trust.”

Dr Hay and her colleagues analyzed over 9 hours of transcribed conversations with 30 people who had undergone medical imaging exams or consented for their children to undergo such exams.

The goal was to determine the subjects’ understanding of the benefits and risks associated with various medical imaging procedures and their expectations regarding communication of those benefits and risks.

The study group was divided into 6 focus groups, including 5 groups of cancer patients (or parents of young cancer patients) and 1 group of participants in a lung cancer screening program.

Quantifying subjects’ knowledge

The researchers found that participants perceived clear benefits from imaging tests like X-rays, computed tomography (CT) scans, and nuclear medicine examinations.

And most subjects were highly aware of the risks associated with ionizing radiation exposure, including the potential risk of future cancer. But their knowledge regarding which imaging tests use ionizing radiation varied.

In general, participants were more likely to understand that X-rays, CTs, and positron emission tomography (PET) scans deliver ionizing radiation and less likely to know about mammography, bone scanning, or stress tests. Many subjects did not know if magnetic resonance imaging (MRI) involved ionizing radiation.

Some participants did not know how tests differed, and some believed there was a “best” imaging test. Occasionally, subjects confused ionizing radiation from diagnostic medical imaging with radiation therapy.

Desire for information

Participants considered the availability of basic benefit-risk information to be a fundamental component of care. And they expressed a desire for a wide range of information about medical imaging tests.

Most subjects wanted basic education about which imaging tests use ionizing radiation and how doses compare among them. Nearly all subjects wanted to understand how tests differ, what governs selection of one over another, and why multiple tests are sometimes ordered.

A majority of participants met their needs for more information through self-directed Internet searches.

Concern about risks

Most subjects agreed that learning about possible future risks was important, but having this information would probably not alter their decision to proceed with a recommended test.

The desire for information about risks was strongest among cancer patients who had made the transition from treatment to survivorship.

These patients wanted to know how risk accumulates from multiple exams over time, whether additional ionizing radiation exposure could be avoided by substituting MRI for CT, and if longer intervals between follow-up examinations could be negotiated.

“Interest in having more information and participating in decision-making about medical imaging clearly increased as patients transitioned from active cancer treatment to survivorship,” said study author Raymond H. Thornton, MD, of Memorial Sloan Kettering Cancer Center.

“Cancer survivors typically focus on healthful living and risk-factor reduction, so they were particularly eager to participate in discussions about potential long-term risks of radiation.”

The different levels of desire for information among the study subjects lend support to a tiered approach for patient-centered communication, according to Dr Hay.

“A tiered approach would provide all patients with information and offer additional options to those who want to dig deeper and find out more,” she said.

Presenting information

Subjects expressed interest in 2 different modes of information exchange. Many participants said the ideal situation would be a face-to-face discussion with their personal physician, a medical physicist, or radiologist.

Others expressed an interest in written resources, especially hospital-endorsed Internet sites and printed materials.

Doctor consults with a family

Photo by Rhoda Baer

Patients want more information about medical imaging tests that use radiation, according to research published in Radiology.

Most of the 30 subjects involved in this study said their healthcare providers did not initiate a discussion about the risks and benefits of imaging tests.

So a majority of participants obtained information from the Internet. Researchers said these findings highlight a need for better communication between patients and providers.

“This may not be what we in the medical field want to hear, but I think it’s important that we hear it,” said study author Jennifer Hay, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“Patients want this information, and they prefer to receive it from doctors they know and trust.”

Dr Hay and her colleagues analyzed over 9 hours of transcribed conversations with 30 people who had undergone medical imaging exams or consented for their children to undergo such exams.

The goal was to determine the subjects’ understanding of the benefits and risks associated with various medical imaging procedures and their expectations regarding communication of those benefits and risks.

The study group was divided into 6 focus groups, including 5 groups of cancer patients (or parents of young cancer patients) and 1 group of participants in a lung cancer screening program.

Quantifying subjects’ knowledge

The researchers found that participants perceived clear benefits from imaging tests like X-rays, computed tomography (CT) scans, and nuclear medicine examinations.

And most subjects were highly aware of the risks associated with ionizing radiation exposure, including the potential risk of future cancer. But their knowledge regarding which imaging tests use ionizing radiation varied.

In general, participants were more likely to understand that X-rays, CTs, and positron emission tomography (PET) scans deliver ionizing radiation and less likely to know about mammography, bone scanning, or stress tests. Many subjects did not know if magnetic resonance imaging (MRI) involved ionizing radiation.

Some participants did not know how tests differed, and some believed there was a “best” imaging test. Occasionally, subjects confused ionizing radiation from diagnostic medical imaging with radiation therapy.

Desire for information

Participants considered the availability of basic benefit-risk information to be a fundamental component of care. And they expressed a desire for a wide range of information about medical imaging tests.

Most subjects wanted basic education about which imaging tests use ionizing radiation and how doses compare among them. Nearly all subjects wanted to understand how tests differ, what governs selection of one over another, and why multiple tests are sometimes ordered.

A majority of participants met their needs for more information through self-directed Internet searches.

Concern about risks

Most subjects agreed that learning about possible future risks was important, but having this information would probably not alter their decision to proceed with a recommended test.

The desire for information about risks was strongest among cancer patients who had made the transition from treatment to survivorship.

These patients wanted to know how risk accumulates from multiple exams over time, whether additional ionizing radiation exposure could be avoided by substituting MRI for CT, and if longer intervals between follow-up examinations could be negotiated.

“Interest in having more information and participating in decision-making about medical imaging clearly increased as patients transitioned from active cancer treatment to survivorship,” said study author Raymond H. Thornton, MD, of Memorial Sloan Kettering Cancer Center.

“Cancer survivors typically focus on healthful living and risk-factor reduction, so they were particularly eager to participate in discussions about potential long-term risks of radiation.”

The different levels of desire for information among the study subjects lend support to a tiered approach for patient-centered communication, according to Dr Hay.

“A tiered approach would provide all patients with information and offer additional options to those who want to dig deeper and find out more,” she said.

Presenting information

Subjects expressed interest in 2 different modes of information exchange. Many participants said the ideal situation would be a face-to-face discussion with their personal physician, a medical physicist, or radiologist.

Others expressed an interest in written resources, especially hospital-endorsed Internet sites and printed materials.

Prescription drugs

Photo courtesy of CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued final guidance documents for rivaroxaban (Xarelto) and pomalidomide (Imnovid).

The agency is recommending rivaroxaban (in combination) as an option for preventing atherothrombotic events in patients with acute coronary syndrome (ACS).

But NICE said it cannot recommend pomalidomide (in combination) for the treatment of relapsed/refractory multiple myeloma (MM).

Rivaroxaban

Rivaroxaban is licensed in the European Union to prevent atherothrombotic events in adults who have an ACS severe enough to result in the release of cardiac biomarkers into the blood. The drug is given with aspirin and clopidogrel or aspirin alone.

Based on results of the ATLAS-ACS 2-TIMI 51 trial, an appraisal committee advising NICE concluded that rivaroxaban given at 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing further cardiovascular deaths and myocardial infarction in patients with ACS and raised cardiac biomarkers.

The committee also found rivaroxaban to be a cost-effective use of National Health Service (NHS) resources. They noted, however, that the drug can increase the risk of bleeding.

“Because rivaroxaban is associated with a higher risk of causing bleeding than clopidogrel in combination with aspirin or aspirin alone, the guidance recommends that, before starting treatment, doctors should carry out a careful assessment of a person’s bleeding risk,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The decision to start treatment should be made after an informed discussion between the doctor and patient about the benefits and risks of rivaroxaban. Also, because there is limited experience of treatment with rivaroxaban up to 24 months, the guidance recommends careful consideration should be given to whether treatment is continued beyond 12 months.”

Pomalidomide

NICE’s final guidance on pomalidomide said the agency cannot recommend the drug as a treatment option for MM.

Pomalidomide is approved in the European Union for use in combination with dexamethasone to treat adults with relapsed and refractory MM who have had at least 2 prior treatments, including lenalidomide and bortezomib, and whose disease has progressed on the last therapy.

“Unfortunately, we cannot recommend pomalidomide, as the analyses from Celgene, the company that markets the drug, showed that it does not offer enough benefit to justify its high price,” said Sir Andrew Dillon, NICE chief executive.

NICE said the appraisal committee could not judge with any confidence how effective pomalidomide is compared to current treatment options based on the available evidence provided before and after consultation.

Bearing in mind the magnitude of the differences in the overall survival estimates between pomalidomide and high-dose dexamethasone in the phase 3 MM-003 trial and all data presented to the committee for comparators, the committee was persuaded that pomalidomide extends life for at least 3 months on average when compared with standard NHS care.

However, considering the incremental cost-effectiveness ratios, the committee concluded that, even with the end-of-life criteria met, the weighting that would have to be placed on the quality-adjusted life-years gained would be too high to consider pomalidomide a cost-effective use of NHS resources.

The committee also said the uncertainty in the relative effectiveness of pomalidomide compared with established NHS practice would affect any weighting that could be placed on quality-adjusted life-years gained.

Prescription drugs

Photo courtesy of CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued final guidance documents for rivaroxaban (Xarelto) and pomalidomide (Imnovid).

The agency is recommending rivaroxaban (in combination) as an option for preventing atherothrombotic events in patients with acute coronary syndrome (ACS).

But NICE said it cannot recommend pomalidomide (in combination) for the treatment of relapsed/refractory multiple myeloma (MM).

Rivaroxaban

Rivaroxaban is licensed in the European Union to prevent atherothrombotic events in adults who have an ACS severe enough to result in the release of cardiac biomarkers into the blood. The drug is given with aspirin and clopidogrel or aspirin alone.

Based on results of the ATLAS-ACS 2-TIMI 51 trial, an appraisal committee advising NICE concluded that rivaroxaban given at 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing further cardiovascular deaths and myocardial infarction in patients with ACS and raised cardiac biomarkers.

The committee also found rivaroxaban to be a cost-effective use of National Health Service (NHS) resources. They noted, however, that the drug can increase the risk of bleeding.

“Because rivaroxaban is associated with a higher risk of causing bleeding than clopidogrel in combination with aspirin or aspirin alone, the guidance recommends that, before starting treatment, doctors should carry out a careful assessment of a person’s bleeding risk,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The decision to start treatment should be made after an informed discussion between the doctor and patient about the benefits and risks of rivaroxaban. Also, because there is limited experience of treatment with rivaroxaban up to 24 months, the guidance recommends careful consideration should be given to whether treatment is continued beyond 12 months.”

Pomalidomide

NICE’s final guidance on pomalidomide said the agency cannot recommend the drug as a treatment option for MM.

Pomalidomide is approved in the European Union for use in combination with dexamethasone to treat adults with relapsed and refractory MM who have had at least 2 prior treatments, including lenalidomide and bortezomib, and whose disease has progressed on the last therapy.

“Unfortunately, we cannot recommend pomalidomide, as the analyses from Celgene, the company that markets the drug, showed that it does not offer enough benefit to justify its high price,” said Sir Andrew Dillon, NICE chief executive.

NICE said the appraisal committee could not judge with any confidence how effective pomalidomide is compared to current treatment options based on the available evidence provided before and after consultation.

Bearing in mind the magnitude of the differences in the overall survival estimates between pomalidomide and high-dose dexamethasone in the phase 3 MM-003 trial and all data presented to the committee for comparators, the committee was persuaded that pomalidomide extends life for at least 3 months on average when compared with standard NHS care.

However, considering the incremental cost-effectiveness ratios, the committee concluded that, even with the end-of-life criteria met, the weighting that would have to be placed on the quality-adjusted life-years gained would be too high to consider pomalidomide a cost-effective use of NHS resources.

The committee also said the uncertainty in the relative effectiveness of pomalidomide compared with established NHS practice would affect any weighting that could be placed on quality-adjusted life-years gained.

Prescription drugs

Photo courtesy of CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued final guidance documents for rivaroxaban (Xarelto) and pomalidomide (Imnovid).

The agency is recommending rivaroxaban (in combination) as an option for preventing atherothrombotic events in patients with acute coronary syndrome (ACS).

But NICE said it cannot recommend pomalidomide (in combination) for the treatment of relapsed/refractory multiple myeloma (MM).

Rivaroxaban

Rivaroxaban is licensed in the European Union to prevent atherothrombotic events in adults who have an ACS severe enough to result in the release of cardiac biomarkers into the blood. The drug is given with aspirin and clopidogrel or aspirin alone.

Based on results of the ATLAS-ACS 2-TIMI 51 trial, an appraisal committee advising NICE concluded that rivaroxaban given at 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing further cardiovascular deaths and myocardial infarction in patients with ACS and raised cardiac biomarkers.

The committee also found rivaroxaban to be a cost-effective use of National Health Service (NHS) resources. They noted, however, that the drug can increase the risk of bleeding.

“Because rivaroxaban is associated with a higher risk of causing bleeding than clopidogrel in combination with aspirin or aspirin alone, the guidance recommends that, before starting treatment, doctors should carry out a careful assessment of a person’s bleeding risk,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The decision to start treatment should be made after an informed discussion between the doctor and patient about the benefits and risks of rivaroxaban. Also, because there is limited experience of treatment with rivaroxaban up to 24 months, the guidance recommends careful consideration should be given to whether treatment is continued beyond 12 months.”

Pomalidomide

NICE’s final guidance on pomalidomide said the agency cannot recommend the drug as a treatment option for MM.

Pomalidomide is approved in the European Union for use in combination with dexamethasone to treat adults with relapsed and refractory MM who have had at least 2 prior treatments, including lenalidomide and bortezomib, and whose disease has progressed on the last therapy.

“Unfortunately, we cannot recommend pomalidomide, as the analyses from Celgene, the company that markets the drug, showed that it does not offer enough benefit to justify its high price,” said Sir Andrew Dillon, NICE chief executive.

NICE said the appraisal committee could not judge with any confidence how effective pomalidomide is compared to current treatment options based on the available evidence provided before and after consultation.

Bearing in mind the magnitude of the differences in the overall survival estimates between pomalidomide and high-dose dexamethasone in the phase 3 MM-003 trial and all data presented to the committee for comparators, the committee was persuaded that pomalidomide extends life for at least 3 months on average when compared with standard NHS care.

However, considering the incremental cost-effectiveness ratios, the committee concluded that, even with the end-of-life criteria met, the weighting that would have to be placed on the quality-adjusted life-years gained would be too high to consider pomalidomide a cost-effective use of NHS resources.

The committee also said the uncertainty in the relative effectiveness of pomalidomide compared with established NHS practice would affect any weighting that could be placed on quality-adjusted life-years gained.

Anticoagulation may be an effective option for patients with superficial venous thrombosis and are at high risk of venous thromboembolism (VTE), according to an evidence-based review by Dr. Joseph Raffetto and Dr. Robert Eberhardt.

In particular, they reviewed the results of three clinical trials with a total of nearly 1400 patients: STENOX, STEFLUX, and CALISTO.

Based on their assessment, Dr. Raffetto and Dr. Eberhardt, summarized that surgery and anticoagulants were both acceptable treatments for SVT patients at high risk of VTE, who had severe symptoms, who presented with close proximity to the saphenofemoral junction, or who had recurrence. Anticoagulants seemed to have fewer complications and a lower VTE rate than did surgery. However, treating all SVT patients with anticoagulants is not recommended because of cost concerns.

While anticoagulants do appear to be an effective treatment for SVT, “it is not known if SVT is causative of or an epiphenomenon for VTE. The optimal treatment of SVT is unknown with respect to selection of patient and vein, preferred therapy, and timing and duration of therapy,” the authors cautioned.

Find the full report in the Journal of Vascular Surgery: Venous and Lymphatic Disorders (doi: 10.1016/j.jvsv.2014.11.005).

Anticoagulation may be an effective option for patients with superficial venous thrombosis and are at high risk of venous thromboembolism (VTE), according to an evidence-based review by Dr. Joseph Raffetto and Dr. Robert Eberhardt.

In particular, they reviewed the results of three clinical trials with a total of nearly 1400 patients: STENOX, STEFLUX, and CALISTO.

Based on their assessment, Dr. Raffetto and Dr. Eberhardt, summarized that surgery and anticoagulants were both acceptable treatments for SVT patients at high risk of VTE, who had severe symptoms, who presented with close proximity to the saphenofemoral junction, or who had recurrence. Anticoagulants seemed to have fewer complications and a lower VTE rate than did surgery. However, treating all SVT patients with anticoagulants is not recommended because of cost concerns.

While anticoagulants do appear to be an effective treatment for SVT, “it is not known if SVT is causative of or an epiphenomenon for VTE. The optimal treatment of SVT is unknown with respect to selection of patient and vein, preferred therapy, and timing and duration of therapy,” the authors cautioned.

Find the full report in the Journal of Vascular Surgery: Venous and Lymphatic Disorders (doi: 10.1016/j.jvsv.2014.11.005).

Anticoagulation may be an effective option for patients with superficial venous thrombosis and are at high risk of venous thromboembolism (VTE), according to an evidence-based review by Dr. Joseph Raffetto and Dr. Robert Eberhardt.

In particular, they reviewed the results of three clinical trials with a total of nearly 1400 patients: STENOX, STEFLUX, and CALISTO.

Based on their assessment, Dr. Raffetto and Dr. Eberhardt, summarized that surgery and anticoagulants were both acceptable treatments for SVT patients at high risk of VTE, who had severe symptoms, who presented with close proximity to the saphenofemoral junction, or who had recurrence. Anticoagulants seemed to have fewer complications and a lower VTE rate than did surgery. However, treating all SVT patients with anticoagulants is not recommended because of cost concerns.

While anticoagulants do appear to be an effective treatment for SVT, “it is not known if SVT is causative of or an epiphenomenon for VTE. The optimal treatment of SVT is unknown with respect to selection of patient and vein, preferred therapy, and timing and duration of therapy,” the authors cautioned.

Find the full report in the Journal of Vascular Surgery: Venous and Lymphatic Disorders (doi: 10.1016/j.jvsv.2014.11.005).

KAUAI, HAWAII – Using photodynamic therapy in place of blue-light therapy to reverse sun damage such as actinic keratosis is less expensive and associated with fewer adverse events such as pain, according to Dr. Christopher Zachary.

Dr. Zachary, chair of dermatology at the University of California, Irvine, shared his perspectives in a video on the advantages of photodynamic therapy over other field treatments, particularly in an era of changing health care reimbursements.

He spoke at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation. SDEF and this news organization are owned by the same parent company.

[email protected]


On Twitter @whitneymcknight

KAUAI, HAWAII – Using photodynamic therapy in place of blue-light therapy to reverse sun damage such as actinic keratosis is less expensive and associated with fewer adverse events such as pain, according to Dr. Christopher Zachary.

Dr. Zachary, chair of dermatology at the University of California, Irvine, shared his perspectives in a video on the advantages of photodynamic therapy over other field treatments, particularly in an era of changing health care reimbursements.

He spoke at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation. SDEF and this news organization are owned by the same parent company.

[email protected]


On Twitter @whitneymcknight

KAUAI, HAWAII – Using photodynamic therapy in place of blue-light therapy to reverse sun damage such as actinic keratosis is less expensive and associated with fewer adverse events such as pain, according to Dr. Christopher Zachary.

Dr. Zachary, chair of dermatology at the University of California, Irvine, shared his perspectives in a video on the advantages of photodynamic therapy over other field treatments, particularly in an era of changing health care reimbursements.

He spoke at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation. SDEF and this news organization are owned by the same parent company.

[email protected]


On Twitter @whitneymcknight

PRACTICE CHANGER
Consider adding simvastatin (40 mg/d) to standard wound care and compression for patients with venous stasis ulcers.¹

STRENGTH OF RECOMMENDATION
B: Based on a high-quality randomized controlled trial (RCT).¹

ILLUSTRATIVE CASE
A 74-year-old woman with chronic lower extremity edema seeks treatment for a nonhealing venous stasis ulcer. For the past nine months, she’s been wearing compression stockings and receiving intermittent home-based wound care, but nothing seems to help. She asks if there’s anything else she can try.

Venous stasis ulcers affect 1% of US adults and lead to substantial morbidity and more than $2 billion in annual health care expenditures.^1,2 Edema management—generally limb elevation and compression therapy—has been the mainstay of therapy. Treatment can be lengthy, and ulcer recurrence is common.^2,3

Statins have been found to aid wound healing through their diverse physiologic (pleiotropic) effects. Evidence indicates they can be beneficial in treatment of diabetic foot ulcers,⁴ pressure ulcers,⁵ and ulcerations associated with systemic sclerosis and Raynaud phenomenon.⁶ Evangelista et al¹ investigated whether adding a statin to standard wound care and compression could improve venous stasis ulcer healing.

Continue for study summary >>

STUDY SUMMARY
Ulcers more likely to close when statin added
This randomized, double-blind, placebo-controlled trial was performed at a large medical center in the Philippines. It was designed to assess the efficacy and safety of simvastatin (40 mg/d) for venous ulcer healing when combined with standard treatment (compression therapy, limb elevation, and standard wound care).¹

Study subjects were 66 patients, ages 41 to 71, who’d had one or more venous ulcers for at least three months. They were randomly assigned to receive either simvastatin (40 mg/d; n = 32) or an identical-appearing placebo (n = 34). Patients were excluded if they were pregnant, had an ulcer that was infected or > 10 cm in diameter, or were taking any medication that could interact with a statin. Patients were stratified according to ulcer diameter (≤ 5 cm and > 5 cm). There was no statistically significant difference between the two groups in the duration of venous ulceration (3.80 y in the placebo group vs 3.93 y in the simvastatin group) or incidence of diabetes (5% vs 3%, respectively).

The primary outcome was the proportion of patients whose ulcers completely healed at 10 weeks. Secondary outcomes were measures of the total surface area healed, healing time, and Dermatology Life Quality Index (DLQI) scores. Baseline ulcer diameter and surface area and DLQI scores were obtained prior to therapy initiation. The same dermatologist, who was blinded to the patients’ group assignments, evaluated all patients every two weeks until wound closure or for a maximum of 10 weeks.

Overall, 90% of the patients who received simvastatin had complete ulcer closure at 10 weeks, compared with 34% of patients in the control group (relative risk [RR], 0.16; number needed to treat [NNT], 2).

Among patients with ulcers ≤ 5 cm, 100% of the ulcers healed in the simvastatin group, compared to 50% in the control group (RR, 0.10; NNT, 2). Perhaps more importantly, in patients with ulcers > 5 cm, 67% in the simvastatin group had closure with a mean healing time of nine weeks, whereas none of the ulcers of this size closed in the control group (RR, 0.33; NNT, 1.5), and the mean healed area was significantly larger in patients who received simvastatin (28.9 cm² vs 19.6 cm²).

In addition, in the simvastatin group, healing times were significantly reduced (7.53 ± 1.34 wk vs 8.55 ± 1.13 wk) and quality of life (as evaluated by DLQI scoring) significantly improved compared to the control group.

Study dropouts were minimal (8%; two in the placebo group and three in the intervention group). Using intention-to-treat analysis and worst-case scenarios for those who dropped out did not affect the primary outcome. There were no withdrawals due to adverse reactions.

WHAT’S NEW
Statins offer significant benefits for treating venous stasis ulcers
This is the first human study to investigate the use of a statin in venous stasis ulcer healing. This intervention demonstrated significant improvements in healing rate and time, a very small NNT for benefit, and improved patient quality of life compared to placebo.

Next page: Caveats >>

CAVEATS
Carefully selected patients
Many wounds will heal with compression therapy alone, as occurred in this study, in which 50% of ulcers ≤ 5 cm treated with standard therapy healed, albeit at a somewhat slower rate. Adding another medication to the regimen when target patients generally have multiple comorbidities should always prompt caution.

The study by Evangelista et al¹ was performed in a select population, and the exclusion criteria included the use of some commonly prescribed medications, such as ACE inhibitors. No data were collected on patient BMI, which is a risk factor for delayed healing.

The prevalence of obesity is lower in the Philippines than in the US. It is uncertain what role this difference would have in the statin’s effectiveness.

Further studies, especially those conducted with a less selective population, would better clarify the generalizability of this intervention.

Nontheless, we found the results of this study impressive. The methods reported are rigorous and consistent with standard RCT methodologies.

This is the only study of a statin in human venous stasis disease, but studies in animals—and studies of statins for other types of ulcers in humans—have consistently suggested benefit. It seems hard to argue against adding this low-cost, low-risk intervention.

CHALLENGES TO IMPLEMENTATION
There are no known barriers to implementation of this practice.

REFERENCES
1. Evangelista MT, Casintahan MF, Villafuerte LL. Simvastatin as a novel therapeutic agent for venous ulcers: a randomized, double-blind, placebo-controlled trial. Br J Dermatol. 2014; 170:1151-1157.

2. Collins L, Seraj S. Diagnosis and treatment of venous ulcers. Am Fam Physician. 2010;81: 989-996.

3. The Australian Wound Management Association Inc, New Zealand Wound Care Society Inc. Australian and New Zealand clinical practice guideline for prevention and management of venous leg ulcers (2011). www.nhmrc.gov.au/_files_nhmrc/publications/attachments/ext003_venous_leg_ulcers_aust_nz_0.pdf. Accessed March 21, 2015.

4. Johansen OE, Birkeland KI, Jørgensen AP, et al. Diabetic foot ulcer burden may be modified by high-dose atorvastatin: a 6-month randomized controlled pilot trial. J Diabetes. 2009; 1:182-187.

5. Farsaei S, Khalili H, Farboud ES, et al. Efficacy of topical atorvastatin for the treatment of pressure ulcers: a randomized clinical trial. Pharmacotherapy. 2014;34:19-27.

6. Abou-Raya A, Abou-Raya S, Helmii M. Statins: potentially useful in therapy of systemic sclerosis-related Raynaud’s phenomenon and digital ulcers. J Rheumatol. 2008;35:1801-1808.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(3):182-184.

PRACTICE CHANGER
Consider adding simvastatin (40 mg/d) to standard wound care and compression for patients with venous stasis ulcers.¹

STRENGTH OF RECOMMENDATION
B: Based on a high-quality randomized controlled trial (RCT).¹

ILLUSTRATIVE CASE
A 74-year-old woman with chronic lower extremity edema seeks treatment for a nonhealing venous stasis ulcer. For the past nine months, she’s been wearing compression stockings and receiving intermittent home-based wound care, but nothing seems to help. She asks if there’s anything else she can try.

Venous stasis ulcers affect 1% of US adults and lead to substantial morbidity and more than $2 billion in annual health care expenditures.^1,2 Edema management—generally limb elevation and compression therapy—has been the mainstay of therapy. Treatment can be lengthy, and ulcer recurrence is common.^2,3

Statins have been found to aid wound healing through their diverse physiologic (pleiotropic) effects. Evidence indicates they can be beneficial in treatment of diabetic foot ulcers,⁴ pressure ulcers,⁵ and ulcerations associated with systemic sclerosis and Raynaud phenomenon.⁶ Evangelista et al¹ investigated whether adding a statin to standard wound care and compression could improve venous stasis ulcer healing.

Continue for study summary >>

STUDY SUMMARY
Ulcers more likely to close when statin added
This randomized, double-blind, placebo-controlled trial was performed at a large medical center in the Philippines. It was designed to assess the efficacy and safety of simvastatin (40 mg/d) for venous ulcer healing when combined with standard treatment (compression therapy, limb elevation, and standard wound care).¹

Study subjects were 66 patients, ages 41 to 71, who’d had one or more venous ulcers for at least three months. They were randomly assigned to receive either simvastatin (40 mg/d; n = 32) or an identical-appearing placebo (n = 34). Patients were excluded if they were pregnant, had an ulcer that was infected or > 10 cm in diameter, or were taking any medication that could interact with a statin. Patients were stratified according to ulcer diameter (≤ 5 cm and > 5 cm). There was no statistically significant difference between the two groups in the duration of venous ulceration (3.80 y in the placebo group vs 3.93 y in the simvastatin group) or incidence of diabetes (5% vs 3%, respectively).

The primary outcome was the proportion of patients whose ulcers completely healed at 10 weeks. Secondary outcomes were measures of the total surface area healed, healing time, and Dermatology Life Quality Index (DLQI) scores. Baseline ulcer diameter and surface area and DLQI scores were obtained prior to therapy initiation. The same dermatologist, who was blinded to the patients’ group assignments, evaluated all patients every two weeks until wound closure or for a maximum of 10 weeks.

Overall, 90% of the patients who received simvastatin had complete ulcer closure at 10 weeks, compared with 34% of patients in the control group (relative risk [RR], 0.16; number needed to treat [NNT], 2).

Among patients with ulcers ≤ 5 cm, 100% of the ulcers healed in the simvastatin group, compared to 50% in the control group (RR, 0.10; NNT, 2). Perhaps more importantly, in patients with ulcers > 5 cm, 67% in the simvastatin group had closure with a mean healing time of nine weeks, whereas none of the ulcers of this size closed in the control group (RR, 0.33; NNT, 1.5), and the mean healed area was significantly larger in patients who received simvastatin (28.9 cm² vs 19.6 cm²).

In addition, in the simvastatin group, healing times were significantly reduced (7.53 ± 1.34 wk vs 8.55 ± 1.13 wk) and quality of life (as evaluated by DLQI scoring) significantly improved compared to the control group.

Study dropouts were minimal (8%; two in the placebo group and three in the intervention group). Using intention-to-treat analysis and worst-case scenarios for those who dropped out did not affect the primary outcome. There were no withdrawals due to adverse reactions.

WHAT’S NEW
Statins offer significant benefits for treating venous stasis ulcers
This is the first human study to investigate the use of a statin in venous stasis ulcer healing. This intervention demonstrated significant improvements in healing rate and time, a very small NNT for benefit, and improved patient quality of life compared to placebo.

Next page: Caveats >>

CAVEATS
Carefully selected patients
Many wounds will heal with compression therapy alone, as occurred in this study, in which 50% of ulcers ≤ 5 cm treated with standard therapy healed, albeit at a somewhat slower rate. Adding another medication to the regimen when target patients generally have multiple comorbidities should always prompt caution.

The study by Evangelista et al¹ was performed in a select population, and the exclusion criteria included the use of some commonly prescribed medications, such as ACE inhibitors. No data were collected on patient BMI, which is a risk factor for delayed healing.

The prevalence of obesity is lower in the Philippines than in the US. It is uncertain what role this difference would have in the statin’s effectiveness.

Further studies, especially those conducted with a less selective population, would better clarify the generalizability of this intervention.

Nontheless, we found the results of this study impressive. The methods reported are rigorous and consistent with standard RCT methodologies.

This is the only study of a statin in human venous stasis disease, but studies in animals—and studies of statins for other types of ulcers in humans—have consistently suggested benefit. It seems hard to argue against adding this low-cost, low-risk intervention.

CHALLENGES TO IMPLEMENTATION
There are no known barriers to implementation of this practice.

REFERENCES
1. Evangelista MT, Casintahan MF, Villafuerte LL. Simvastatin as a novel therapeutic agent for venous ulcers: a randomized, double-blind, placebo-controlled trial. Br J Dermatol. 2014; 170:1151-1157.

2. Collins L, Seraj S. Diagnosis and treatment of venous ulcers. Am Fam Physician. 2010;81: 989-996.

3. The Australian Wound Management Association Inc, New Zealand Wound Care Society Inc. Australian and New Zealand clinical practice guideline for prevention and management of venous leg ulcers (2011). www.nhmrc.gov.au/_files_nhmrc/publications/attachments/ext003_venous_leg_ulcers_aust_nz_0.pdf. Accessed March 21, 2015.

4. Johansen OE, Birkeland KI, Jørgensen AP, et al. Diabetic foot ulcer burden may be modified by high-dose atorvastatin: a 6-month randomized controlled pilot trial. J Diabetes. 2009; 1:182-187.

5. Farsaei S, Khalili H, Farboud ES, et al. Efficacy of topical atorvastatin for the treatment of pressure ulcers: a randomized clinical trial. Pharmacotherapy. 2014;34:19-27.

6. Abou-Raya A, Abou-Raya S, Helmii M. Statins: potentially useful in therapy of systemic sclerosis-related Raynaud’s phenomenon and digital ulcers. J Rheumatol. 2008;35:1801-1808.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(3):182-184.

PRACTICE CHANGER
Consider adding simvastatin (40 mg/d) to standard wound care and compression for patients with venous stasis ulcers.¹

STRENGTH OF RECOMMENDATION
B: Based on a high-quality randomized controlled trial (RCT).¹

ILLUSTRATIVE CASE
A 74-year-old woman with chronic lower extremity edema seeks treatment for a nonhealing venous stasis ulcer. For the past nine months, she’s been wearing compression stockings and receiving intermittent home-based wound care, but nothing seems to help. She asks if there’s anything else she can try.

Venous stasis ulcers affect 1% of US adults and lead to substantial morbidity and more than $2 billion in annual health care expenditures.^1,2 Edema management—generally limb elevation and compression therapy—has been the mainstay of therapy. Treatment can be lengthy, and ulcer recurrence is common.^2,3

Statins have been found to aid wound healing through their diverse physiologic (pleiotropic) effects. Evidence indicates they can be beneficial in treatment of diabetic foot ulcers,⁴ pressure ulcers,⁵ and ulcerations associated with systemic sclerosis and Raynaud phenomenon.⁶ Evangelista et al¹ investigated whether adding a statin to standard wound care and compression could improve venous stasis ulcer healing.

Continue for study summary >>

STUDY SUMMARY
Ulcers more likely to close when statin added
This randomized, double-blind, placebo-controlled trial was performed at a large medical center in the Philippines. It was designed to assess the efficacy and safety of simvastatin (40 mg/d) for venous ulcer healing when combined with standard treatment (compression therapy, limb elevation, and standard wound care).¹

Study subjects were 66 patients, ages 41 to 71, who’d had one or more venous ulcers for at least three months. They were randomly assigned to receive either simvastatin (40 mg/d; n = 32) or an identical-appearing placebo (n = 34). Patients were excluded if they were pregnant, had an ulcer that was infected or > 10 cm in diameter, or were taking any medication that could interact with a statin. Patients were stratified according to ulcer diameter (≤ 5 cm and > 5 cm). There was no statistically significant difference between the two groups in the duration of venous ulceration (3.80 y in the placebo group vs 3.93 y in the simvastatin group) or incidence of diabetes (5% vs 3%, respectively).

The primary outcome was the proportion of patients whose ulcers completely healed at 10 weeks. Secondary outcomes were measures of the total surface area healed, healing time, and Dermatology Life Quality Index (DLQI) scores. Baseline ulcer diameter and surface area and DLQI scores were obtained prior to therapy initiation. The same dermatologist, who was blinded to the patients’ group assignments, evaluated all patients every two weeks until wound closure or for a maximum of 10 weeks.

Overall, 90% of the patients who received simvastatin had complete ulcer closure at 10 weeks, compared with 34% of patients in the control group (relative risk [RR], 0.16; number needed to treat [NNT], 2).

Among patients with ulcers ≤ 5 cm, 100% of the ulcers healed in the simvastatin group, compared to 50% in the control group (RR, 0.10; NNT, 2). Perhaps more importantly, in patients with ulcers > 5 cm, 67% in the simvastatin group had closure with a mean healing time of nine weeks, whereas none of the ulcers of this size closed in the control group (RR, 0.33; NNT, 1.5), and the mean healed area was significantly larger in patients who received simvastatin (28.9 cm² vs 19.6 cm²).

In addition, in the simvastatin group, healing times were significantly reduced (7.53 ± 1.34 wk vs 8.55 ± 1.13 wk) and quality of life (as evaluated by DLQI scoring) significantly improved compared to the control group.

Study dropouts were minimal (8%; two in the placebo group and three in the intervention group). Using intention-to-treat analysis and worst-case scenarios for those who dropped out did not affect the primary outcome. There were no withdrawals due to adverse reactions.

WHAT’S NEW
Statins offer significant benefits for treating venous stasis ulcers
This is the first human study to investigate the use of a statin in venous stasis ulcer healing. This intervention demonstrated significant improvements in healing rate and time, a very small NNT for benefit, and improved patient quality of life compared to placebo.

Next page: Caveats >>

CAVEATS
Carefully selected patients
Many wounds will heal with compression therapy alone, as occurred in this study, in which 50% of ulcers ≤ 5 cm treated with standard therapy healed, albeit at a somewhat slower rate. Adding another medication to the regimen when target patients generally have multiple comorbidities should always prompt caution.

The study by Evangelista et al¹ was performed in a select population, and the exclusion criteria included the use of some commonly prescribed medications, such as ACE inhibitors. No data were collected on patient BMI, which is a risk factor for delayed healing.

The prevalence of obesity is lower in the Philippines than in the US. It is uncertain what role this difference would have in the statin’s effectiveness.

Further studies, especially those conducted with a less selective population, would better clarify the generalizability of this intervention.

Nontheless, we found the results of this study impressive. The methods reported are rigorous and consistent with standard RCT methodologies.

This is the only study of a statin in human venous stasis disease, but studies in animals—and studies of statins for other types of ulcers in humans—have consistently suggested benefit. It seems hard to argue against adding this low-cost, low-risk intervention.

CHALLENGES TO IMPLEMENTATION
There are no known barriers to implementation of this practice.

REFERENCES
1. Evangelista MT, Casintahan MF, Villafuerte LL. Simvastatin as a novel therapeutic agent for venous ulcers: a randomized, double-blind, placebo-controlled trial. Br J Dermatol. 2014; 170:1151-1157.

2. Collins L, Seraj S. Diagnosis and treatment of venous ulcers. Am Fam Physician. 2010;81: 989-996.

3. The Australian Wound Management Association Inc, New Zealand Wound Care Society Inc. Australian and New Zealand clinical practice guideline for prevention and management of venous leg ulcers (2011). www.nhmrc.gov.au/_files_nhmrc/publications/attachments/ext003_venous_leg_ulcers_aust_nz_0.pdf. Accessed March 21, 2015.

4. Johansen OE, Birkeland KI, Jørgensen AP, et al. Diabetic foot ulcer burden may be modified by high-dose atorvastatin: a 6-month randomized controlled pilot trial. J Diabetes. 2009; 1:182-187.

5. Farsaei S, Khalili H, Farboud ES, et al. Efficacy of topical atorvastatin for the treatment of pressure ulcers: a randomized clinical trial. Pharmacotherapy. 2014;34:19-27.

6. Abou-Raya A, Abou-Raya S, Helmii M. Statins: potentially useful in therapy of systemic sclerosis-related Raynaud’s phenomenon and digital ulcers. J Rheumatol. 2008;35:1801-1808.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(3):182-184.

Cerebral blood flow recovery could be a biomarker of outcomes in athletes following concussion, according to an imaging study published online ahead of print March 2 in JAMA Neurology. “To our knowledge, this study provides the first prospective evidence of reduced cerebral blood flow and subsequent recovery following concussion in a homogeneous sample of collegiate football athletes and also demonstrates the potential of quantified cerebral blood flow as an objective biomarker for concussion,” said lead author Timothy B. Meier, PhD, and his research colleagues. According to the investigators, the resolution of cerebral blood flow abnormalities closely mirrors that of previous reports from the animal literature and shows real-world validity for predicting outcome following concussion.

Dr. Meier, of the Mind Research Network/Lovelace Biomedical and Environmental Research Institute in Albuquerque, and colleagues enrolled 44 collegiate football athletes in a mixed longitudinal and cross-sectional study at a private research institute specializing in neuroimaging. The study was conducted from March 2012 to December 2013.

Of the 44 football players, 17 were concussed and had serial imaging performed approximately one day, one week, and one month postconcussion. The study also included 27 healthy football players who served as a control group. All athletes reported no premorbid mood disorders, anxiety disorders, substance abuse, or alcohol abuse.

Arterial spin labeling MRI was used to collect voxelwise relative cerebral blood flow data at each visit. Neuropsychiatric evaluations and a brief cognitive screen also were performed at all three time points (ie, one day, one week, and one month). Clinicians trained in sports medicine provided an independent measure of real-world concussion outcome (ie, number of days withheld from competition).

Cognitive (ie, simple reaction time) and neuropsychiatric symptoms at one day postconcussion resolved at either one week postinjury or one month postinjury. Imaging data suggested cross-sectional (ie, healthy vs concussed athletes) and longitudinal (ie, one day and one week vs one month postinjury) evidence of cerebral blood flow recovery in the right insular and superior temporal cortex. The researchers also found that cerebral blood flow in the dorsal midinsular cortex was decreased at one month postinjury in slower-to-recover athletes and was inversely related to the magnitude of initial psychiatric symptoms, as rated on the Hamilton Depression Scale and the Hamilton Anxiety Scale.

“The current results suggest that regional cerebral blood flow may provide an objective biomarker for tracking both normal and potentially pathologic recovery from concussion,” the researchers concluded.

Future studies identifying the time course of metabolic dysfunction following concussion and its relationship to cerebral blood flow are crucial to characterize the physiologic effect of concussion, according to the investigators. “Specifically, the cerebral metabolic rate of glucose, the cerebral metabolic rate of oxygen, and cerebral blood flow are tightly coupled in health, but become dysregulated following mild traumatic brain injury.”

—Glenn S. Williams

Cerebral blood flow recovery could be a biomarker of outcomes in athletes following concussion, according to an imaging study published online ahead of print March 2 in JAMA Neurology. “To our knowledge, this study provides the first prospective evidence of reduced cerebral blood flow and subsequent recovery following concussion in a homogeneous sample of collegiate football athletes and also demonstrates the potential of quantified cerebral blood flow as an objective biomarker for concussion,” said lead author Timothy B. Meier, PhD, and his research colleagues. According to the investigators, the resolution of cerebral blood flow abnormalities closely mirrors that of previous reports from the animal literature and shows real-world validity for predicting outcome following concussion.

Dr. Meier, of the Mind Research Network/Lovelace Biomedical and Environmental Research Institute in Albuquerque, and colleagues enrolled 44 collegiate football athletes in a mixed longitudinal and cross-sectional study at a private research institute specializing in neuroimaging. The study was conducted from March 2012 to December 2013.

Of the 44 football players, 17 were concussed and had serial imaging performed approximately one day, one week, and one month postconcussion. The study also included 27 healthy football players who served as a control group. All athletes reported no premorbid mood disorders, anxiety disorders, substance abuse, or alcohol abuse.

Arterial spin labeling MRI was used to collect voxelwise relative cerebral blood flow data at each visit. Neuropsychiatric evaluations and a brief cognitive screen also were performed at all three time points (ie, one day, one week, and one month). Clinicians trained in sports medicine provided an independent measure of real-world concussion outcome (ie, number of days withheld from competition).

Cognitive (ie, simple reaction time) and neuropsychiatric symptoms at one day postconcussion resolved at either one week postinjury or one month postinjury. Imaging data suggested cross-sectional (ie, healthy vs concussed athletes) and longitudinal (ie, one day and one week vs one month postinjury) evidence of cerebral blood flow recovery in the right insular and superior temporal cortex. The researchers also found that cerebral blood flow in the dorsal midinsular cortex was decreased at one month postinjury in slower-to-recover athletes and was inversely related to the magnitude of initial psychiatric symptoms, as rated on the Hamilton Depression Scale and the Hamilton Anxiety Scale.

“The current results suggest that regional cerebral blood flow may provide an objective biomarker for tracking both normal and potentially pathologic recovery from concussion,” the researchers concluded.

Future studies identifying the time course of metabolic dysfunction following concussion and its relationship to cerebral blood flow are crucial to characterize the physiologic effect of concussion, according to the investigators. “Specifically, the cerebral metabolic rate of glucose, the cerebral metabolic rate of oxygen, and cerebral blood flow are tightly coupled in health, but become dysregulated following mild traumatic brain injury.”

—Glenn S. Williams

Cerebral blood flow recovery could be a biomarker of outcomes in athletes following concussion, according to an imaging study published online ahead of print March 2 in JAMA Neurology. “To our knowledge, this study provides the first prospective evidence of reduced cerebral blood flow and subsequent recovery following concussion in a homogeneous sample of collegiate football athletes and also demonstrates the potential of quantified cerebral blood flow as an objective biomarker for concussion,” said lead author Timothy B. Meier, PhD, and his research colleagues. According to the investigators, the resolution of cerebral blood flow abnormalities closely mirrors that of previous reports from the animal literature and shows real-world validity for predicting outcome following concussion.

Dr. Meier, of the Mind Research Network/Lovelace Biomedical and Environmental Research Institute in Albuquerque, and colleagues enrolled 44 collegiate football athletes in a mixed longitudinal and cross-sectional study at a private research institute specializing in neuroimaging. The study was conducted from March 2012 to December 2013.

Of the 44 football players, 17 were concussed and had serial imaging performed approximately one day, one week, and one month postconcussion. The study also included 27 healthy football players who served as a control group. All athletes reported no premorbid mood disorders, anxiety disorders, substance abuse, or alcohol abuse.

Arterial spin labeling MRI was used to collect voxelwise relative cerebral blood flow data at each visit. Neuropsychiatric evaluations and a brief cognitive screen also were performed at all three time points (ie, one day, one week, and one month). Clinicians trained in sports medicine provided an independent measure of real-world concussion outcome (ie, number of days withheld from competition).

Cognitive (ie, simple reaction time) and neuropsychiatric symptoms at one day postconcussion resolved at either one week postinjury or one month postinjury. Imaging data suggested cross-sectional (ie, healthy vs concussed athletes) and longitudinal (ie, one day and one week vs one month postinjury) evidence of cerebral blood flow recovery in the right insular and superior temporal cortex. The researchers also found that cerebral blood flow in the dorsal midinsular cortex was decreased at one month postinjury in slower-to-recover athletes and was inversely related to the magnitude of initial psychiatric symptoms, as rated on the Hamilton Depression Scale and the Hamilton Anxiety Scale.

“The current results suggest that regional cerebral blood flow may provide an objective biomarker for tracking both normal and potentially pathologic recovery from concussion,” the researchers concluded.

Future studies identifying the time course of metabolic dysfunction following concussion and its relationship to cerebral blood flow are crucial to characterize the physiologic effect of concussion, according to the investigators. “Specifically, the cerebral metabolic rate of glucose, the cerebral metabolic rate of oxygen, and cerebral blood flow are tightly coupled in health, but become dysregulated following mild traumatic brain injury.”

—Glenn S. Williams