Clinical Review

Ten years have passed since the Women’s Health Initiative (WHI) investigators published initial findings from the estrogen-progestin arm, shaking up the field of menopause management and leading to a sharp decline in the number of prescriptions being written for hormone therapy (HT). Over the course of the ensuing decade, numerous studies have filled in gaps in our understanding of the menopausal transition and the decades that follow—studies that have been detailed in OBG Management in this Update in Menopause and other articles. In this installment of the Update, I review:

• two studies that address the lower risk of venous thromboembolism (VTE) when transdermal HT is prescribed rather than oral estrogen
• the characteristics of a new oral medication to treat vulvar and vaginal atrophy
• a study highlighting the distinct effects on the breast of unopposed estrogen and combination estrogen-progestin HT
• two reports on ovarian conservation at the time of hysterectomy for benign indications
• a study from Sweden on the health impact of early menopause
• a closer look at the mood effects—or lack of them—of progestin therapy.

In addition, JoAnn E. Manson, MD, DrPH, NCMP, weighs in on what we have learned from the WHI and the Kronos Early Estrogen Prevention Study (KEEPS).

ACCUMULATING EVIDENCE POINTS TO A LOWER RISK OF VTE WITH TRANSDERMAL VERSUS ORAL HT

American College of Obstetricians and Gynecologists. Committee Opinion #556: Postmenopausal estrogen therapy: Route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121(4):887–890.

Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost. 2013;11(1):124–131.

Sweetland S, Beral V, Balkwill A, et al; The Million Women Study Collaborators. Venous thromboembolism risk in relation to use of different types of ­postmenopausal hormone therapy in a large prospective study [published online ahead of print September 10, 2012]. J Thromb Haemost. doi:10.1111/j.1538-7836.2012.04919.x.

The estrogen-progestin arm of the WHI clarified the most statistically prominent risk associated with combination HT: a higher incidence of VTE in women ­allocated to oral conjugated equine estrogen and medroxyprogesterone acetate (MPA).¹

Although no randomized trials have been large enough to compare the safety of oral versus transdermal HT with respect to VTE in a statistically meaningful manner, the issue has been investigated in observational (case-control and cohort) studies. In past Updates in Menopause, I have detailed studies from France,^2,3 the United Kingdom,⁴ and the United States,⁵ each of which has suggested that, in contrast with oral HT, transdermal HT does not increase the risk of VTE.

One British study also indicated that while oral estrogen therapy slightly increased the risk of stroke (as demonstrated by the WHI), transdermal estradiol at a dose of 0.05 mg or less did not.⁶ In 2012, two additional observational reports—one from the United Kingdom and one from Holland—provided additional data confirming the safety of transdermal HT with respect to thrombosis.

Sweetland and colleagues drew from a large population
Using data from the massive British Million Women’s Study (MWS), investigators compared the risk of VTE between oral and transdermal HT. Of 1,058,259 postmenopausal women followed in the MWS cohort, 36% were current HT users. Of current users, 23% were using oral and 14% were using transdermal HT.

The risk of VTE—including deep venous thrombosis and pulmonary embolism—was significantly elevated with the use of oral HT, with a relative risk (RR) of 1.42, compared with nonuse of HT (95% confidence interval [CI], 1.21–1.66).

The risk of VTE was not elevated among users of transdermal therapy (RR, 0.82; 95% CI, 0.54–1.06).

Roach and colleagues studied VTE among 1,000 HT users
In a large case-control study from the Netherlands, investigators identified 1,082 cases of VTE among women older than age 50. Women who used oral estrogen-progestin HT had four times the risk of VTE, compared with nonusers. Although oral unopposed estrogen therapy was also associated with an elevated risk of VTE, this risk was lower than with combination HT and appeared to be dose-dependent.

In contrast, the risk of VTE associated with transdermal estrogen therapy was almost identical to the risk observed in nonusers.

With the addition of these two new studies, there are now six observational studies that agree that transdermal estrogen is safer than oral estrogen with respect to the risk of VTE.^2–5

ACOG weighs in
In April 2013, ACOG published a Committee Opinion on the route of administration of HT and the risk of VTE, stating: “When prescribing estrogen therapy, the gynecologist should take into consideration the possible thrombosis-sparing properties of transdermal forms of estrogen therapy.”

What this EVIDENCE means for practice
Although the data comparing the risk of VTE between oral and transdermal estrogen is observational, my perspective is that it would be inappropriate to wait for randomized trials before informing our patients that transdermal estrogen appears to be safer than the oral route. Given the costs, logistical challenges (including likely low adherence to study medications) and time involved, we are unlikely to see randomized trials of HT large enough to more definitively compare the risks and benefits between oral and transdermal HT.
In my practice, although I continue to prescribe both oral and transdermal HT, a high percentage of my prescriptions are for transdermal formulations. For women who have an elevated baseline risk of VTE (especially overweight and obese women), I emphasize the safety benefits of transdermal HT in my counseling.

FDA APPROVES A NEW ORAL DRUG FOR VULVAR AND VAGINAL ATROPHY

Portman DJ, Bachmann GA, Simon JA; the Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy [published online ahead of print January 28, 2013]. Menopause. doi:10.1097/gme.0b013e318279ba64.

Simon JA, Lin VH, Radovich C, Bachmann GA. The Ospemifene Study Group. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause. 2013;20(4):418–427.

In February 2013, the US Food and Drug Administration (FDA) approved ospemifene (Osphena), an orally administered, tissue-selective estrogen agonist/antagonist, for the treatment of dyspareunia caused by vulvar and vaginal atrophy (VVA) in menopausal women. As with its pharmacologic relatives tamoxifen and raloxifene, ospemifene acts as an estrogen agonist in some tissues and an estrogen antagonist in others. In clinical trials, ospemifene has been found to reduce pain with sexual intercourse and increase vaginal mucosal maturation and vaginal pH to a greater extent than placebo.

Contraindications listed in package labeling for ospemifene include estrogen-dependent neoplasia, VTE (or a history of VTE), stroke, and myocardial infarction (or a history of it).

Although ospemifene acts as an estrogen agonist on the endometrium, no cases of endometrial cancer were noted in clinical ­trials, the longest of which was 12 months.

Adverse reactions most frequently reported in clinical trials were hot flushes (7.5% with ospemifene vs 2.6% with placebo), vaginal discharge (3.8% vs 0.3%), and muscle spasms  (3.2% vs 0.9%).

VVA has reached epidemic proportions
Although most women expect to continue their sexual lives during postmenopause, fewer of them are using hormone therapy. The result is an epidemic of symptomatic VVA. Against this backdrop, new treatment options represent good news for women.

Ospemifene may have special appeal for symptomatic women who prefer not to use vaginal cream, tablets, or the vaginal ring. However, in contrast with vaginal estrogen therapy, ospemifene increases hot flushes. In addition, like tamoxifen and raloxifene, it may increase the risk of VTE.

What this EVIDENCE means for practice
Package labeling recommends that clinicians consider adding a progestin to prevent endometrial neoplasia in women with an intact uterus using ospemifene, and that endometrial monitoring also be considered in long-term users. As with all menopausal women, any vaginal bleeding in a woman using ospemifene should be evaluated.
The use of vaginal or systemic estrogen is contraindicated in women with a history of breast cancer. As the ospemifene package label indicates, the drug has not been studied adequately in women with breast cancer; therefore, the FDA advises against the use of ospemifene in women with known or suspected breast cancer or a history of the malignancy.

UNOPPOSED ESTROGEN AND COMBINATION HORMONE THERAPY HAVE DISTINCTLY DIFFERENT EFFECTS ON THE BREAST

Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.

As I reported in this Update last year, a key finding of the WHI estrogen-only arm was a persistently reduced risk of invasive breast cancer among women without a uterus who used unopposed oral conjugated equine estrogen (CEE) for a median of 5.9 years.⁷ Since then, WHI investigators have reported additional details about breast cancer incidence and mortality after a median follow-up of 11.8 years.

They found CEE to be associated with a lower incidence of invasive breast cancer than placebo (annual incidence, 0.27% vs 0.35%; HR, 0.77; P = .02). The level of protection against breast cancer associated with CEE did not vary by duration of use during the intervention or postintervention phases. The incidence of breast cancer was even lower (HR, 0.68) when the analysis was restricted to patients most adherent to the study medication.

Among women given a diagnosis of breast cancer, both overall and breast cancer–related mortality were significantly lower in the CEE arm (HR, 0.62 and 0.37, respectively).

Detection bias is unlikely
Although many observational studies have reported a modestly elevated risk of breast cancer in women who use estrogen therapy, their findings could reflect detection bias. That is, women who use any HT tend to have more contact with clinicians and, as a result, may undergo more screening mammograms than nonusers. In the WHI randomized  trial, however, screening frequencies were similar among CEE and placebo users during and following the intervention phase.

What this EVIDENCE means for practice
These findings should reassure women who use estrogen to manage menopausal symptoms or prevent osteoporosis after hysterectomy that this therapy does not increase the risk of breast cancer.
The findings also underscore the importance of distinguishing between estrogen-only and estrogen-progestin therapy as we help our patients make sound decisions about HT.

NEW DATA SUPPORT THE PRACTICE OF OVARIAN CONSERVATION DURING BENIGN HYSTERECTOMY

Parker WH, Feskanich D, Broder MS, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study. Obstet Gynecol. 2013;121(4):709–716.

Perera HK, Ananth CV, Richards CA, et al. Variation in ovarian conservation in women undergoing hysterectomy for benign indications. Obstet Gynecol. 2013;121(4):717–726.

In recent years, studies have documented the health risks of routine bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign indications. The body of evidence of the potential risks of BSO continues to expand, with publication, in April 2013, of two large analyses.

In the first analysis, investigators from the Nurses’ Health Study (NHS), a large prospective cohort, extended follow-up to 28 years. Among more than 30,000 participating nurses who underwent hysterectomy for benign indications, 16.8% of those who underwent BSO died during follow-up, compared with 13.3% of those with ovarian conservation (hazard ratio [HR], 1.13; 95% CI, 1.06–1.21).

BSO was associated with a lower risk of fatal ovarian cancer and, if performed before age 47.5 years, a lower risk of breast cancer as well. However, at all ages, BSO was associated with higher other cause-specific deaths (coronary artery disease, stroke, lung cancer, colorectal malignancy) as well as all-cause mortality. Similar increases in overall and breast cancer deaths were associated with BSO regardless of family history (sibling or mother) of breast or ovarian cancer.

Among women younger than age 50 who had never used estrogen therapy at the time of BSO, the surgery was associated with significantly increased all-cause mortality (HR, 1.41; 95% CI, 1.04–1.92). However, BSO before age 50 was not associated with significantly higher all-cause mortality in current or previous users of estrogen (HR, 1.05; 95% CI, 0.94–1.17).

Ovarian conservation is more common in younger women
In the second large analysis published this year, Perera and colleagues used records that include approximately 15% of all US hospital discharges to explore recent practices with respect to ovarian conservation at the time of hysterectomy for benign indications. They found that, among more than 750,000 women who underwent hysterectomy between 2000 and 2010, the ovaries were conserved in 53.6% of cases.

Ovarian conservation was more common in younger women, as it was practiced in 74.3% of cases involving women younger than age 40 and in 31% of cases involving women aged 60 to 64 years.

Ovarian conservation was also more common in recent hysterectomies than in surgeries performed more remotely in time.

It is heartening to observe that US gynecologists are practicing ovarian conservation more often at the time of hysterectomy for benign indications. The new analysis from the NHS supports this practice unless the patient has a mutation (BRCA, Lynch) that substantially increases her risk of ovarian cancer.

What this EVIDENCE means for practice
Unless contraindications apply, ObGyns should encourage women who undergo BSO before age 50 to use HT, at least until they reach the normal age of spontaneous menopause.
Clinicians who are considering performing elective BSO at the time of hysterectomy despite this guidance should recognize that in the aftermath of the WHI, and in the absence of contraindications,it may not be wise to perform BSO in women younger than age 50, since many women currently are reluctant to use estrogen therapy.

SWEDISH COHORT CONFIRMS THE ILL EFFECTS OF EARLY MENOPAUSE

Svejme O, Ahlborg HG, Nilsson JA, Karlsson MK. Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. BJOG. 2012;119(7):810–816.

Although early menopause has been linked to osteoporosis and fragility fractures, most studies documenting this association have been cross-sectional and retrospective, raising concerns about recall bias (inaccurate recall of when menopause occurred).

In 1977, investigators began a study of women living in Malmö, Sweden, who were born in 1929. This ethnically homogeneous (white, Northern European) cohort of 390 women (age 48 at enrollment) underwent bone mineral density (BMD) assessment and were stratified into two groups:

• early menopause – those who entered menopause before age 47
• late menopause – those who became menopausal at or after age 47.

At age 77, 198 of the 298 surviving participants underwent BMD reassessment. Fracture history and mortality were documented at the study’s end in 2011.

BMD measurement at age 77 revealed osteoporosis in 56% of women with early menopause, compared with 30% of those with late menopause (P = .01). The incidence of fragility fractures per 1,000 person-years was 19.4 in the early menopause group, compared with 11.6 for late menopause (P = .01). The death rate during the 34-year follow-up was 52.4% for the early menopause group, compared with 35.2% for late menopause (P = .01). Twenty-two percent of women with early menopause had used HT, compared with 10% of those with late menopause (P  = .05).

Because it tracked health and mortality over multiple decades, this prospective, population-based study is particularly credible.

The use of HT was uncommon among women in this cohort.

What this EVIDENCE means for practice
Given our current understanding of the efficacy of HT in lowering the risk of osteoporotic fractures in menopausal women and reducing coronary artery disease and overall mortality among women in their 50s (or within 10 years of the onset of menopause), it is important to advise women who undergo early menopause to use HT unless they have specific contraindications.^8,9

PROGESTIN THERAPY MAY NOT IMPAIR MOOD, AFTER ALL

Rogines-Velo MP, Heberle AE, Joffe H. Effect of medroxyprogesterone on depressive symptoms in depressed and nondepressed perimenopausal and postmenopausal women after discontinuation of transdermal estradiol therapy. Menopause. 2012;19(4):471–475.

Although many ObGyns have noted anecdotally that progestin therapy precipitates negative mood reactions in some menopausal women, data addressing this issue have been scarce and inconsistent.

Rogines-Velo and colleagues analyzed the results of two short-term trials involving perimenopausal and postmenopausal women. One trial enrolled 52 nondepressed women, and the other enrolled 72 women with clinical depression. Participants were randomly allocated to transdermal estradiol or placebo for 2 or 3 months.

In both trials, women in the estradiol group who had a uterus received medroxyprogesterone acetate (MPA; 10 mg daily) for an additional 2 weeks to prevent endometrial hyperplasia. Depressive symptoms were assessed using the Beck Depression Inventory at study entry, after estradiol therapy, and again at the conclusion of MPA treatment.

Among women who received estradiol, 24 of 26 nondepressed women and 14 of 21 depressed women completed the course of MPA. Estradiol therapy was associated with mood improvement in both trials, with greater improvement among depressed women (P = .02). Subsequent use of MPA did not affect mood significantly in either depressed or nondepressed women, even after adjustment for educational status and presence of vasomotor symptoms.

What this EVIDENCE means for practice
Although considerable anecdotal experience suggests that progestational treatment can cause mood deterioration in some women, this effect had not been studied in depressed populations.^10,11 The two short-term trials on which this report is based confirm that estrogen has a positive effect on mood. Their findings suggest that progestin need not be withheld from depressed women on the assumption that it will worsen mood.

Ten years have passed since the Women’s Health Initiative (WHI) investigators published initial findings from the estrogen-progestin arm, shaking up the field of menopause management and leading to a sharp decline in the number of prescriptions being written for hormone therapy (HT). Over the course of the ensuing decade, numerous studies have filled in gaps in our understanding of the menopausal transition and the decades that follow—studies that have been detailed in OBG Management in this Update in Menopause and other articles. In this installment of the Update, I review:

• two studies that address the lower risk of venous thromboembolism (VTE) when transdermal HT is prescribed rather than oral estrogen
• the characteristics of a new oral medication to treat vulvar and vaginal atrophy
• a study highlighting the distinct effects on the breast of unopposed estrogen and combination estrogen-progestin HT
• two reports on ovarian conservation at the time of hysterectomy for benign indications
• a study from Sweden on the health impact of early menopause
• a closer look at the mood effects—or lack of them—of progestin therapy.

In addition, JoAnn E. Manson, MD, DrPH, NCMP, weighs in on what we have learned from the WHI and the Kronos Early Estrogen Prevention Study (KEEPS).

ACCUMULATING EVIDENCE POINTS TO A LOWER RISK OF VTE WITH TRANSDERMAL VERSUS ORAL HT

American College of Obstetricians and Gynecologists. Committee Opinion #556: Postmenopausal estrogen therapy: Route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121(4):887–890.

Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost. 2013;11(1):124–131.

Sweetland S, Beral V, Balkwill A, et al; The Million Women Study Collaborators. Venous thromboembolism risk in relation to use of different types of ­postmenopausal hormone therapy in a large prospective study [published online ahead of print September 10, 2012]. J Thromb Haemost. doi:10.1111/j.1538-7836.2012.04919.x.

The estrogen-progestin arm of the WHI clarified the most statistically prominent risk associated with combination HT: a higher incidence of VTE in women ­allocated to oral conjugated equine estrogen and medroxyprogesterone acetate (MPA).¹

Although no randomized trials have been large enough to compare the safety of oral versus transdermal HT with respect to VTE in a statistically meaningful manner, the issue has been investigated in observational (case-control and cohort) studies. In past Updates in Menopause, I have detailed studies from France,^2,3 the United Kingdom,⁴ and the United States,⁵ each of which has suggested that, in contrast with oral HT, transdermal HT does not increase the risk of VTE.

One British study also indicated that while oral estrogen therapy slightly increased the risk of stroke (as demonstrated by the WHI), transdermal estradiol at a dose of 0.05 mg or less did not.⁶ In 2012, two additional observational reports—one from the United Kingdom and one from Holland—provided additional data confirming the safety of transdermal HT with respect to thrombosis.

Sweetland and colleagues drew from a large population
Using data from the massive British Million Women’s Study (MWS), investigators compared the risk of VTE between oral and transdermal HT. Of 1,058,259 postmenopausal women followed in the MWS cohort, 36% were current HT users. Of current users, 23% were using oral and 14% were using transdermal HT.

The risk of VTE—including deep venous thrombosis and pulmonary embolism—was significantly elevated with the use of oral HT, with a relative risk (RR) of 1.42, compared with nonuse of HT (95% confidence interval [CI], 1.21–1.66).

The risk of VTE was not elevated among users of transdermal therapy (RR, 0.82; 95% CI, 0.54–1.06).

Roach and colleagues studied VTE among 1,000 HT users
In a large case-control study from the Netherlands, investigators identified 1,082 cases of VTE among women older than age 50. Women who used oral estrogen-progestin HT had four times the risk of VTE, compared with nonusers. Although oral unopposed estrogen therapy was also associated with an elevated risk of VTE, this risk was lower than with combination HT and appeared to be dose-dependent.

In contrast, the risk of VTE associated with transdermal estrogen therapy was almost identical to the risk observed in nonusers.

With the addition of these two new studies, there are now six observational studies that agree that transdermal estrogen is safer than oral estrogen with respect to the risk of VTE.^2–5

ACOG weighs in
In April 2013, ACOG published a Committee Opinion on the route of administration of HT and the risk of VTE, stating: “When prescribing estrogen therapy, the gynecologist should take into consideration the possible thrombosis-sparing properties of transdermal forms of estrogen therapy.”

What this EVIDENCE means for practice
Although the data comparing the risk of VTE between oral and transdermal estrogen is observational, my perspective is that it would be inappropriate to wait for randomized trials before informing our patients that transdermal estrogen appears to be safer than the oral route. Given the costs, logistical challenges (including likely low adherence to study medications) and time involved, we are unlikely to see randomized trials of HT large enough to more definitively compare the risks and benefits between oral and transdermal HT.
In my practice, although I continue to prescribe both oral and transdermal HT, a high percentage of my prescriptions are for transdermal formulations. For women who have an elevated baseline risk of VTE (especially overweight and obese women), I emphasize the safety benefits of transdermal HT in my counseling.

FDA APPROVES A NEW ORAL DRUG FOR VULVAR AND VAGINAL ATROPHY

Portman DJ, Bachmann GA, Simon JA; the Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy [published online ahead of print January 28, 2013]. Menopause. doi:10.1097/gme.0b013e318279ba64.

Simon JA, Lin VH, Radovich C, Bachmann GA. The Ospemifene Study Group. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause. 2013;20(4):418–427.

In February 2013, the US Food and Drug Administration (FDA) approved ospemifene (Osphena), an orally administered, tissue-selective estrogen agonist/antagonist, for the treatment of dyspareunia caused by vulvar and vaginal atrophy (VVA) in menopausal women. As with its pharmacologic relatives tamoxifen and raloxifene, ospemifene acts as an estrogen agonist in some tissues and an estrogen antagonist in others. In clinical trials, ospemifene has been found to reduce pain with sexual intercourse and increase vaginal mucosal maturation and vaginal pH to a greater extent than placebo.

Contraindications listed in package labeling for ospemifene include estrogen-dependent neoplasia, VTE (or a history of VTE), stroke, and myocardial infarction (or a history of it).

Although ospemifene acts as an estrogen agonist on the endometrium, no cases of endometrial cancer were noted in clinical ­trials, the longest of which was 12 months.

Adverse reactions most frequently reported in clinical trials were hot flushes (7.5% with ospemifene vs 2.6% with placebo), vaginal discharge (3.8% vs 0.3%), and muscle spasms  (3.2% vs 0.9%).

VVA has reached epidemic proportions
Although most women expect to continue their sexual lives during postmenopause, fewer of them are using hormone therapy. The result is an epidemic of symptomatic VVA. Against this backdrop, new treatment options represent good news for women.

Ospemifene may have special appeal for symptomatic women who prefer not to use vaginal cream, tablets, or the vaginal ring. However, in contrast with vaginal estrogen therapy, ospemifene increases hot flushes. In addition, like tamoxifen and raloxifene, it may increase the risk of VTE.

What this EVIDENCE means for practice
Package labeling recommends that clinicians consider adding a progestin to prevent endometrial neoplasia in women with an intact uterus using ospemifene, and that endometrial monitoring also be considered in long-term users. As with all menopausal women, any vaginal bleeding in a woman using ospemifene should be evaluated.
The use of vaginal or systemic estrogen is contraindicated in women with a history of breast cancer. As the ospemifene package label indicates, the drug has not been studied adequately in women with breast cancer; therefore, the FDA advises against the use of ospemifene in women with known or suspected breast cancer or a history of the malignancy.

UNOPPOSED ESTROGEN AND COMBINATION HORMONE THERAPY HAVE DISTINCTLY DIFFERENT EFFECTS ON THE BREAST

Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.

As I reported in this Update last year, a key finding of the WHI estrogen-only arm was a persistently reduced risk of invasive breast cancer among women without a uterus who used unopposed oral conjugated equine estrogen (CEE) for a median of 5.9 years.⁷ Since then, WHI investigators have reported additional details about breast cancer incidence and mortality after a median follow-up of 11.8 years.

They found CEE to be associated with a lower incidence of invasive breast cancer than placebo (annual incidence, 0.27% vs 0.35%; HR, 0.77; P = .02). The level of protection against breast cancer associated with CEE did not vary by duration of use during the intervention or postintervention phases. The incidence of breast cancer was even lower (HR, 0.68) when the analysis was restricted to patients most adherent to the study medication.

Among women given a diagnosis of breast cancer, both overall and breast cancer–related mortality were significantly lower in the CEE arm (HR, 0.62 and 0.37, respectively).

Detection bias is unlikely
Although many observational studies have reported a modestly elevated risk of breast cancer in women who use estrogen therapy, their findings could reflect detection bias. That is, women who use any HT tend to have more contact with clinicians and, as a result, may undergo more screening mammograms than nonusers. In the WHI randomized  trial, however, screening frequencies were similar among CEE and placebo users during and following the intervention phase.

What this EVIDENCE means for practice
These findings should reassure women who use estrogen to manage menopausal symptoms or prevent osteoporosis after hysterectomy that this therapy does not increase the risk of breast cancer.
The findings also underscore the importance of distinguishing between estrogen-only and estrogen-progestin therapy as we help our patients make sound decisions about HT.

NEW DATA SUPPORT THE PRACTICE OF OVARIAN CONSERVATION DURING BENIGN HYSTERECTOMY

Parker WH, Feskanich D, Broder MS, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study. Obstet Gynecol. 2013;121(4):709–716.

Perera HK, Ananth CV, Richards CA, et al. Variation in ovarian conservation in women undergoing hysterectomy for benign indications. Obstet Gynecol. 2013;121(4):717–726.

In recent years, studies have documented the health risks of routine bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign indications. The body of evidence of the potential risks of BSO continues to expand, with publication, in April 2013, of two large analyses.

In the first analysis, investigators from the Nurses’ Health Study (NHS), a large prospective cohort, extended follow-up to 28 years. Among more than 30,000 participating nurses who underwent hysterectomy for benign indications, 16.8% of those who underwent BSO died during follow-up, compared with 13.3% of those with ovarian conservation (hazard ratio [HR], 1.13; 95% CI, 1.06–1.21).

BSO was associated with a lower risk of fatal ovarian cancer and, if performed before age 47.5 years, a lower risk of breast cancer as well. However, at all ages, BSO was associated with higher other cause-specific deaths (coronary artery disease, stroke, lung cancer, colorectal malignancy) as well as all-cause mortality. Similar increases in overall and breast cancer deaths were associated with BSO regardless of family history (sibling or mother) of breast or ovarian cancer.

Among women younger than age 50 who had never used estrogen therapy at the time of BSO, the surgery was associated with significantly increased all-cause mortality (HR, 1.41; 95% CI, 1.04–1.92). However, BSO before age 50 was not associated with significantly higher all-cause mortality in current or previous users of estrogen (HR, 1.05; 95% CI, 0.94–1.17).

Ovarian conservation is more common in younger women
In the second large analysis published this year, Perera and colleagues used records that include approximately 15% of all US hospital discharges to explore recent practices with respect to ovarian conservation at the time of hysterectomy for benign indications. They found that, among more than 750,000 women who underwent hysterectomy between 2000 and 2010, the ovaries were conserved in 53.6% of cases.

Ovarian conservation was more common in younger women, as it was practiced in 74.3% of cases involving women younger than age 40 and in 31% of cases involving women aged 60 to 64 years.

Ovarian conservation was also more common in recent hysterectomies than in surgeries performed more remotely in time.

It is heartening to observe that US gynecologists are practicing ovarian conservation more often at the time of hysterectomy for benign indications. The new analysis from the NHS supports this practice unless the patient has a mutation (BRCA, Lynch) that substantially increases her risk of ovarian cancer.

What this EVIDENCE means for practice
Unless contraindications apply, ObGyns should encourage women who undergo BSO before age 50 to use HT, at least until they reach the normal age of spontaneous menopause.
Clinicians who are considering performing elective BSO at the time of hysterectomy despite this guidance should recognize that in the aftermath of the WHI, and in the absence of contraindications,it may not be wise to perform BSO in women younger than age 50, since many women currently are reluctant to use estrogen therapy.

SWEDISH COHORT CONFIRMS THE ILL EFFECTS OF EARLY MENOPAUSE

Svejme O, Ahlborg HG, Nilsson JA, Karlsson MK. Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. BJOG. 2012;119(7):810–816.

Although early menopause has been linked to osteoporosis and fragility fractures, most studies documenting this association have been cross-sectional and retrospective, raising concerns about recall bias (inaccurate recall of when menopause occurred).

In 1977, investigators began a study of women living in Malmö, Sweden, who were born in 1929. This ethnically homogeneous (white, Northern European) cohort of 390 women (age 48 at enrollment) underwent bone mineral density (BMD) assessment and were stratified into two groups:

• early menopause – those who entered menopause before age 47
• late menopause – those who became menopausal at or after age 47.

At age 77, 198 of the 298 surviving participants underwent BMD reassessment. Fracture history and mortality were documented at the study’s end in 2011.

BMD measurement at age 77 revealed osteoporosis in 56% of women with early menopause, compared with 30% of those with late menopause (P = .01). The incidence of fragility fractures per 1,000 person-years was 19.4 in the early menopause group, compared with 11.6 for late menopause (P = .01). The death rate during the 34-year follow-up was 52.4% for the early menopause group, compared with 35.2% for late menopause (P = .01). Twenty-two percent of women with early menopause had used HT, compared with 10% of those with late menopause (P  = .05).

Because it tracked health and mortality over multiple decades, this prospective, population-based study is particularly credible.

The use of HT was uncommon among women in this cohort.

What this EVIDENCE means for practice
Given our current understanding of the efficacy of HT in lowering the risk of osteoporotic fractures in menopausal women and reducing coronary artery disease and overall mortality among women in their 50s (or within 10 years of the onset of menopause), it is important to advise women who undergo early menopause to use HT unless they have specific contraindications.^8,9

PROGESTIN THERAPY MAY NOT IMPAIR MOOD, AFTER ALL

Rogines-Velo MP, Heberle AE, Joffe H. Effect of medroxyprogesterone on depressive symptoms in depressed and nondepressed perimenopausal and postmenopausal women after discontinuation of transdermal estradiol therapy. Menopause. 2012;19(4):471–475.

Although many ObGyns have noted anecdotally that progestin therapy precipitates negative mood reactions in some menopausal women, data addressing this issue have been scarce and inconsistent.

Rogines-Velo and colleagues analyzed the results of two short-term trials involving perimenopausal and postmenopausal women. One trial enrolled 52 nondepressed women, and the other enrolled 72 women with clinical depression. Participants were randomly allocated to transdermal estradiol or placebo for 2 or 3 months.

In both trials, women in the estradiol group who had a uterus received medroxyprogesterone acetate (MPA; 10 mg daily) for an additional 2 weeks to prevent endometrial hyperplasia. Depressive symptoms were assessed using the Beck Depression Inventory at study entry, after estradiol therapy, and again at the conclusion of MPA treatment.

Among women who received estradiol, 24 of 26 nondepressed women and 14 of 21 depressed women completed the course of MPA. Estradiol therapy was associated with mood improvement in both trials, with greater improvement among depressed women (P = .02). Subsequent use of MPA did not affect mood significantly in either depressed or nondepressed women, even after adjustment for educational status and presence of vasomotor symptoms.

What this EVIDENCE means for practice
Although considerable anecdotal experience suggests that progestational treatment can cause mood deterioration in some women, this effect had not been studied in depressed populations.^10,11 The two short-term trials on which this report is based confirm that estrogen has a positive effect on mood. Their findings suggest that progestin need not be withheld from depressed women on the assumption that it will worsen mood.

Ten years have passed since the Women’s Health Initiative (WHI) investigators published initial findings from the estrogen-progestin arm, shaking up the field of menopause management and leading to a sharp decline in the number of prescriptions being written for hormone therapy (HT). Over the course of the ensuing decade, numerous studies have filled in gaps in our understanding of the menopausal transition and the decades that follow—studies that have been detailed in OBG Management in this Update in Menopause and other articles. In this installment of the Update, I review:

• two studies that address the lower risk of venous thromboembolism (VTE) when transdermal HT is prescribed rather than oral estrogen
• the characteristics of a new oral medication to treat vulvar and vaginal atrophy
• a study highlighting the distinct effects on the breast of unopposed estrogen and combination estrogen-progestin HT
• two reports on ovarian conservation at the time of hysterectomy for benign indications
• a study from Sweden on the health impact of early menopause
• a closer look at the mood effects—or lack of them—of progestin therapy.

In addition, JoAnn E. Manson, MD, DrPH, NCMP, weighs in on what we have learned from the WHI and the Kronos Early Estrogen Prevention Study (KEEPS).

ACCUMULATING EVIDENCE POINTS TO A LOWER RISK OF VTE WITH TRANSDERMAL VERSUS ORAL HT

American College of Obstetricians and Gynecologists. Committee Opinion #556: Postmenopausal estrogen therapy: Route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121(4):887–890.

Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost. 2013;11(1):124–131.

Sweetland S, Beral V, Balkwill A, et al; The Million Women Study Collaborators. Venous thromboembolism risk in relation to use of different types of ­postmenopausal hormone therapy in a large prospective study [published online ahead of print September 10, 2012]. J Thromb Haemost. doi:10.1111/j.1538-7836.2012.04919.x.

The estrogen-progestin arm of the WHI clarified the most statistically prominent risk associated with combination HT: a higher incidence of VTE in women ­allocated to oral conjugated equine estrogen and medroxyprogesterone acetate (MPA).¹

Although no randomized trials have been large enough to compare the safety of oral versus transdermal HT with respect to VTE in a statistically meaningful manner, the issue has been investigated in observational (case-control and cohort) studies. In past Updates in Menopause, I have detailed studies from France,^2,3 the United Kingdom,⁴ and the United States,⁵ each of which has suggested that, in contrast with oral HT, transdermal HT does not increase the risk of VTE.

One British study also indicated that while oral estrogen therapy slightly increased the risk of stroke (as demonstrated by the WHI), transdermal estradiol at a dose of 0.05 mg or less did not.⁶ In 2012, two additional observational reports—one from the United Kingdom and one from Holland—provided additional data confirming the safety of transdermal HT with respect to thrombosis.

Sweetland and colleagues drew from a large population
Using data from the massive British Million Women’s Study (MWS), investigators compared the risk of VTE between oral and transdermal HT. Of 1,058,259 postmenopausal women followed in the MWS cohort, 36% were current HT users. Of current users, 23% were using oral and 14% were using transdermal HT.

The risk of VTE—including deep venous thrombosis and pulmonary embolism—was significantly elevated with the use of oral HT, with a relative risk (RR) of 1.42, compared with nonuse of HT (95% confidence interval [CI], 1.21–1.66).

The risk of VTE was not elevated among users of transdermal therapy (RR, 0.82; 95% CI, 0.54–1.06).

Roach and colleagues studied VTE among 1,000 HT users
In a large case-control study from the Netherlands, investigators identified 1,082 cases of VTE among women older than age 50. Women who used oral estrogen-progestin HT had four times the risk of VTE, compared with nonusers. Although oral unopposed estrogen therapy was also associated with an elevated risk of VTE, this risk was lower than with combination HT and appeared to be dose-dependent.

In contrast, the risk of VTE associated with transdermal estrogen therapy was almost identical to the risk observed in nonusers.

With the addition of these two new studies, there are now six observational studies that agree that transdermal estrogen is safer than oral estrogen with respect to the risk of VTE.^2–5

ACOG weighs in
In April 2013, ACOG published a Committee Opinion on the route of administration of HT and the risk of VTE, stating: “When prescribing estrogen therapy, the gynecologist should take into consideration the possible thrombosis-sparing properties of transdermal forms of estrogen therapy.”

What this EVIDENCE means for practice
Although the data comparing the risk of VTE between oral and transdermal estrogen is observational, my perspective is that it would be inappropriate to wait for randomized trials before informing our patients that transdermal estrogen appears to be safer than the oral route. Given the costs, logistical challenges (including likely low adherence to study medications) and time involved, we are unlikely to see randomized trials of HT large enough to more definitively compare the risks and benefits between oral and transdermal HT.
In my practice, although I continue to prescribe both oral and transdermal HT, a high percentage of my prescriptions are for transdermal formulations. For women who have an elevated baseline risk of VTE (especially overweight and obese women), I emphasize the safety benefits of transdermal HT in my counseling.

FDA APPROVES A NEW ORAL DRUG FOR VULVAR AND VAGINAL ATROPHY

Portman DJ, Bachmann GA, Simon JA; the Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy [published online ahead of print January 28, 2013]. Menopause. doi:10.1097/gme.0b013e318279ba64.

Simon JA, Lin VH, Radovich C, Bachmann GA. The Ospemifene Study Group. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause. 2013;20(4):418–427.

In February 2013, the US Food and Drug Administration (FDA) approved ospemifene (Osphena), an orally administered, tissue-selective estrogen agonist/antagonist, for the treatment of dyspareunia caused by vulvar and vaginal atrophy (VVA) in menopausal women. As with its pharmacologic relatives tamoxifen and raloxifene, ospemifene acts as an estrogen agonist in some tissues and an estrogen antagonist in others. In clinical trials, ospemifene has been found to reduce pain with sexual intercourse and increase vaginal mucosal maturation and vaginal pH to a greater extent than placebo.

Contraindications listed in package labeling for ospemifene include estrogen-dependent neoplasia, VTE (or a history of VTE), stroke, and myocardial infarction (or a history of it).

Although ospemifene acts as an estrogen agonist on the endometrium, no cases of endometrial cancer were noted in clinical ­trials, the longest of which was 12 months.

Adverse reactions most frequently reported in clinical trials were hot flushes (7.5% with ospemifene vs 2.6% with placebo), vaginal discharge (3.8% vs 0.3%), and muscle spasms  (3.2% vs 0.9%).

VVA has reached epidemic proportions
Although most women expect to continue their sexual lives during postmenopause, fewer of them are using hormone therapy. The result is an epidemic of symptomatic VVA. Against this backdrop, new treatment options represent good news for women.

Ospemifene may have special appeal for symptomatic women who prefer not to use vaginal cream, tablets, or the vaginal ring. However, in contrast with vaginal estrogen therapy, ospemifene increases hot flushes. In addition, like tamoxifen and raloxifene, it may increase the risk of VTE.

What this EVIDENCE means for practice
Package labeling recommends that clinicians consider adding a progestin to prevent endometrial neoplasia in women with an intact uterus using ospemifene, and that endometrial monitoring also be considered in long-term users. As with all menopausal women, any vaginal bleeding in a woman using ospemifene should be evaluated.
The use of vaginal or systemic estrogen is contraindicated in women with a history of breast cancer. As the ospemifene package label indicates, the drug has not been studied adequately in women with breast cancer; therefore, the FDA advises against the use of ospemifene in women with known or suspected breast cancer or a history of the malignancy.

UNOPPOSED ESTROGEN AND COMBINATION HORMONE THERAPY HAVE DISTINCTLY DIFFERENT EFFECTS ON THE BREAST

Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.

As I reported in this Update last year, a key finding of the WHI estrogen-only arm was a persistently reduced risk of invasive breast cancer among women without a uterus who used unopposed oral conjugated equine estrogen (CEE) for a median of 5.9 years.⁷ Since then, WHI investigators have reported additional details about breast cancer incidence and mortality after a median follow-up of 11.8 years.

They found CEE to be associated with a lower incidence of invasive breast cancer than placebo (annual incidence, 0.27% vs 0.35%; HR, 0.77; P = .02). The level of protection against breast cancer associated with CEE did not vary by duration of use during the intervention or postintervention phases. The incidence of breast cancer was even lower (HR, 0.68) when the analysis was restricted to patients most adherent to the study medication.

Among women given a diagnosis of breast cancer, both overall and breast cancer–related mortality were significantly lower in the CEE arm (HR, 0.62 and 0.37, respectively).

Detection bias is unlikely
Although many observational studies have reported a modestly elevated risk of breast cancer in women who use estrogen therapy, their findings could reflect detection bias. That is, women who use any HT tend to have more contact with clinicians and, as a result, may undergo more screening mammograms than nonusers. In the WHI randomized  trial, however, screening frequencies were similar among CEE and placebo users during and following the intervention phase.

What this EVIDENCE means for practice
These findings should reassure women who use estrogen to manage menopausal symptoms or prevent osteoporosis after hysterectomy that this therapy does not increase the risk of breast cancer.
The findings also underscore the importance of distinguishing between estrogen-only and estrogen-progestin therapy as we help our patients make sound decisions about HT.

NEW DATA SUPPORT THE PRACTICE OF OVARIAN CONSERVATION DURING BENIGN HYSTERECTOMY

Parker WH, Feskanich D, Broder MS, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study. Obstet Gynecol. 2013;121(4):709–716.

Perera HK, Ananth CV, Richards CA, et al. Variation in ovarian conservation in women undergoing hysterectomy for benign indications. Obstet Gynecol. 2013;121(4):717–726.

In recent years, studies have documented the health risks of routine bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy for benign indications. The body of evidence of the potential risks of BSO continues to expand, with publication, in April 2013, of two large analyses.

In the first analysis, investigators from the Nurses’ Health Study (NHS), a large prospective cohort, extended follow-up to 28 years. Among more than 30,000 participating nurses who underwent hysterectomy for benign indications, 16.8% of those who underwent BSO died during follow-up, compared with 13.3% of those with ovarian conservation (hazard ratio [HR], 1.13; 95% CI, 1.06–1.21).

BSO was associated with a lower risk of fatal ovarian cancer and, if performed before age 47.5 years, a lower risk of breast cancer as well. However, at all ages, BSO was associated with higher other cause-specific deaths (coronary artery disease, stroke, lung cancer, colorectal malignancy) as well as all-cause mortality. Similar increases in overall and breast cancer deaths were associated with BSO regardless of family history (sibling or mother) of breast or ovarian cancer.

Among women younger than age 50 who had never used estrogen therapy at the time of BSO, the surgery was associated with significantly increased all-cause mortality (HR, 1.41; 95% CI, 1.04–1.92). However, BSO before age 50 was not associated with significantly higher all-cause mortality in current or previous users of estrogen (HR, 1.05; 95% CI, 0.94–1.17).

Ovarian conservation is more common in younger women
In the second large analysis published this year, Perera and colleagues used records that include approximately 15% of all US hospital discharges to explore recent practices with respect to ovarian conservation at the time of hysterectomy for benign indications. They found that, among more than 750,000 women who underwent hysterectomy between 2000 and 2010, the ovaries were conserved in 53.6% of cases.

Ovarian conservation was more common in younger women, as it was practiced in 74.3% of cases involving women younger than age 40 and in 31% of cases involving women aged 60 to 64 years.

Ovarian conservation was also more common in recent hysterectomies than in surgeries performed more remotely in time.

It is heartening to observe that US gynecologists are practicing ovarian conservation more often at the time of hysterectomy for benign indications. The new analysis from the NHS supports this practice unless the patient has a mutation (BRCA, Lynch) that substantially increases her risk of ovarian cancer.

What this EVIDENCE means for practice
Unless contraindications apply, ObGyns should encourage women who undergo BSO before age 50 to use HT, at least until they reach the normal age of spontaneous menopause.
Clinicians who are considering performing elective BSO at the time of hysterectomy despite this guidance should recognize that in the aftermath of the WHI, and in the absence of contraindications,it may not be wise to perform BSO in women younger than age 50, since many women currently are reluctant to use estrogen therapy.

SWEDISH COHORT CONFIRMS THE ILL EFFECTS OF EARLY MENOPAUSE

Svejme O, Ahlborg HG, Nilsson JA, Karlsson MK. Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. BJOG. 2012;119(7):810–816.

Although early menopause has been linked to osteoporosis and fragility fractures, most studies documenting this association have been cross-sectional and retrospective, raising concerns about recall bias (inaccurate recall of when menopause occurred).

In 1977, investigators began a study of women living in Malmö, Sweden, who were born in 1929. This ethnically homogeneous (white, Northern European) cohort of 390 women (age 48 at enrollment) underwent bone mineral density (BMD) assessment and were stratified into two groups:

• early menopause – those who entered menopause before age 47
• late menopause – those who became menopausal at or after age 47.

At age 77, 198 of the 298 surviving participants underwent BMD reassessment. Fracture history and mortality were documented at the study’s end in 2011.

BMD measurement at age 77 revealed osteoporosis in 56% of women with early menopause, compared with 30% of those with late menopause (P = .01). The incidence of fragility fractures per 1,000 person-years was 19.4 in the early menopause group, compared with 11.6 for late menopause (P = .01). The death rate during the 34-year follow-up was 52.4% for the early menopause group, compared with 35.2% for late menopause (P = .01). Twenty-two percent of women with early menopause had used HT, compared with 10% of those with late menopause (P  = .05).

Because it tracked health and mortality over multiple decades, this prospective, population-based study is particularly credible.

The use of HT was uncommon among women in this cohort.

What this EVIDENCE means for practice
Given our current understanding of the efficacy of HT in lowering the risk of osteoporotic fractures in menopausal women and reducing coronary artery disease and overall mortality among women in their 50s (or within 10 years of the onset of menopause), it is important to advise women who undergo early menopause to use HT unless they have specific contraindications.^8,9

PROGESTIN THERAPY MAY NOT IMPAIR MOOD, AFTER ALL

Rogines-Velo MP, Heberle AE, Joffe H. Effect of medroxyprogesterone on depressive symptoms in depressed and nondepressed perimenopausal and postmenopausal women after discontinuation of transdermal estradiol therapy. Menopause. 2012;19(4):471–475.

Although many ObGyns have noted anecdotally that progestin therapy precipitates negative mood reactions in some menopausal women, data addressing this issue have been scarce and inconsistent.

Rogines-Velo and colleagues analyzed the results of two short-term trials involving perimenopausal and postmenopausal women. One trial enrolled 52 nondepressed women, and the other enrolled 72 women with clinical depression. Participants were randomly allocated to transdermal estradiol or placebo for 2 or 3 months.

In both trials, women in the estradiol group who had a uterus received medroxyprogesterone acetate (MPA; 10 mg daily) for an additional 2 weeks to prevent endometrial hyperplasia. Depressive symptoms were assessed using the Beck Depression Inventory at study entry, after estradiol therapy, and again at the conclusion of MPA treatment.

Among women who received estradiol, 24 of 26 nondepressed women and 14 of 21 depressed women completed the course of MPA. Estradiol therapy was associated with mood improvement in both trials, with greater improvement among depressed women (P = .02). Subsequent use of MPA did not affect mood significantly in either depressed or nondepressed women, even after adjustment for educational status and presence of vasomotor symptoms.

What this EVIDENCE means for practice
Although considerable anecdotal experience suggests that progestational treatment can cause mood deterioration in some women, this effect had not been studied in depressed populations.^10,11 The two short-term trials on which this report is based confirm that estrogen has a positive effect on mood. Their findings suggest that progestin need not be withheld from depressed women on the assumption that it will worsen mood.

Breast augmentation is one of the most commonly performed plastic surgery procedures. It is important for primary care providers who perform clinical breast exams to be well versed in complications that can occur after the immediate postsurgical period and to prepare patients with augmented breasts for the likelihood of requiring a secondary procedure at some time.

Breast augmentation continues to rank as the procedure most commonly performed by US plastic surgeons. According to data from the American Society of Plastic Surgeons,¹ 307,000 breast augmentation procedures were performed in the US in 2011—a 4% increase from the previous year. Breast implants are not permanent devices, and most patients can expect to undergo a secondary procedure during their lifetime.²

Hematomas and infections associated with breast augmentation usually occur within two to 14 days following surgery, while the patient is still under the care of the plastic surgeon.^2,3 For long-term complications, however, patients are likely to consult their primary care or gynecologic provider. Thus, it is important that any clinician who performs clinical breast exams be well versed in the complications, both local and systemic, that can occur after the immediate postsurgical period in patients who have undergone breast augmentation.

Common Complications of Breast Enhancement
Complications after breast augmentation are not uncommon. They can occur in women with either silicone gel– or saline-filled implants; conflicting incidence rates for capsular contracture (the most common local complication^3,4) have been reported following insertion of silicone gel–filled implants, compared with saline implants.^5,6 It has been noted, however, that prospective data comparing the two implant types are lacking in the literature.⁷

Complications can be categorized as either local or systemic. In addition to capsular contracture, local complications (which are more common) include implant rupture or deflation, and implant rippling or wrinkling.

Systemic complications may include anaplastic large-cell lymphoma, a rare but serious complication that is currently under study for its potential association with breast implants⁸ (see third article in this series, “Anaplastic Large-Cell Lymphoma”^9-14). Other systemic sequelae include autoimmune disorders, connective tissue disease, and fibrositis/fibromyalgia conditions; these conditions can only be addressed in an article of greater scope.

In 2006, breast implant manufacturers were mandated to conduct postapproval studies regarding the devices’ safety¹⁵ (see fourth article in this series, “History of Breast Implant Regulation,”^2,15-20). Findings from these studies can facilitate primary care providers’ management of patients who have augmented breasts.

Capsular Contracture
Capsular contracture occurs with frequencies ranging from 1.9% to 2.3%.⁸ As a result of the immune response to any foreign body, collagen fibers form and weave around the prosthetic device once it is implanted. For reasons not completely understood, these fibers can begin to tighten over time. As the capsule continues to tighten and harden, the implant is then compressed, resulting in breast pain and deformity.

The degree of capsular contracture is categorized according to Baker’s classification system regarding implant position and breast firmness postaugmentation.^2,21 A Baker’s grade I designation implies that the modified breast is soft and looks normal. Grade II describes a breast that is slightly firm upon exam but looks completely normal. In grade III, the breast is firm and has taken on an abnormal appearance. In grade IV, the breast looks abnormal and is firm on examination, with the patient describing significant pain.

Some researchers believe that capsular contracture develops because of a subclinical bacterial infection, while others suggest that silicone leakage may be the cause.^6,22,23 A patient who is diagnosed with a hematoma during the postoperative period is at increased risk for capsular contracture, and one who has been treated previously for capsular contracture has a significant risk for recurrence.^2,24

Capsular contracture is usually treated surgically by a capsulectomy or a capsulotomy. Currently, the preferred procedure is an open capsulectomy to remove the implant, surgically excise the entire capsule, and replace the implant.⁴

Implant Deflation, Rupture
Most ruptures of implants (whether they are used cosmetically or for reconstruction) occur between 10 and 15 years after implantation.^3,25 Incidence of implant removal by 10 years postsurgery ranges from 21% to 32% for silicone gel–filled implants, depending on the specific implant model.¹⁷

Saline implant deflation is relatively easy to detect because it presents with a rapid decrease in breast size on the affected side. Ruptures of silicone gel–filled implants, by contrast, can go undetected for years—hence the term silent rupture applied in this circumstance.³ If a rupture is detected, the faulty breast implant is removed and returned to the manufacturer for investigation.

If surgical instrumentation leads to a puncture during saline gel–filled implant surgery, it is usually noticed immediately. A silicone gel–filled implant can also be punctured during the implantation procedure, often with no obvious signs of the rupture.

Rupture of a silicone gel–filled implant may be intracapsular or extracapsular. In intracapsular ruptures, the contents of the implant remain within the capsule that has formed around the implant. Extracapsular ruptures involve migration of the silicone material outside the capsule.³ Current-generation silicone implants are increasingly biodurable, thereby reducing the risk for silicone migration.^26,27

MRI is currently considered the study of choice to detect silent rupture of a silicone gel–filled implant.²⁸ As primary care providers should be aware, the FDA recommends that women with silicone gel–filled implants undergo MRI screening three years after implantation and every two years thereafter to assess the implants’ integrity.¹⁷ This applies to all age-groups and does not replace screening mammography requirements for breast cancer.

While mammography is ideal for detecting extracapsular silicone implant ruptures, it fails to detect intracapsular implant rupture consistently.²⁹ Breast ultrasound cannot effectively detect ruptures in the posterior portion of the implant and cannot evaluate the chest wall. Thus, MRI, with its high spatial resolution and marked contrast between implants and natural breast tissue, is considered most effective in detecting either intracapsular or extracapsular ruptures.^3,28,29

Despite earlier reports that implant rupture could prompt an immunologic reaction, giving rise to autoimmune or related diseases, subsequent studies reveal “no association between silicone gel–filled breast implants and connective tissue disease, breast cancer, or reproductive problems.”¹⁷ Apart from a relatively low risk for silicone migration, implant rupture has been deemed relatively harmless.³⁰

Implant Wrinkling, Folding
Implant wrinkling visible to the naked eye can mar the aesthetic appearance of an augmented breast. In some cases, the wrinkled implant may be detected only by palpation. Causes of wrinkling include:

• Thin skin and insufficient natural breast tissue, especially in the lower outer pole

• Subglandular placement of the implant, which allows less coverage over the implant than submuscular placement; and

• Use of saline-filled or textured-surface implants.

Because saline has a lower viscosity than silicone, it may allow lower-pole expansion and settling—and hence, wrinkling. Insufficient filling in saline implants may contribute to the problem, in addition to palpable shell folding, palpable shifts of filler material, sloshing, and other compromised aesthetic results.^3,31

In rare cases, wrinkling over thin skin can cause implant extrusion. Additionally, the friction created as the shell rubs against itself can cause implant deflation or even rupture due to the development of a “hot spot.”

Options to address implant wrinkling are to replace saline-filled implants with silicone gel–filled implants or to revise placement of the implant from the subglandular to the submuscular location. Use of acellular dermal matrix can help reinforce existing breast tissue, especially when placed in the lower pole of the affected breast.^32,33

Anaplastic Large-Cell Lymphoma
Of rising concern is a possible association between certain breast implants (ie, textured vs nontextured implants; silicone vs saline implants) and anaplastic large-cell lymphoma (ALCL).^9-13 RAND Health¹⁴ sponsored a study conducted by 10 multidisciplinary experts, who agreed on the following points:

(1) A positive association exists between breast implants and ALCL, with the actual number of cases probably underrecognized.

(2) Any recurrent, clinically evident seroma developing longer than six months after breast implantation should be aspirated for cytologic analysis.

(3) Anaplastic lymphoma kinase (ALK)–negative ALCL that develops in the vicinity of breast implants is distinct from systemic ALK-negative ALCL, is clinically indolent disease, and has a favorable prognosis.

(4) Management of ALCL requires removal of the involved implant and capsule (a strategy that is likely to prevent recurrence) and evaluation for the disease at other sites.

(5) Adjuvant radiation or chemotherapy need not be offered to women with capsule-confined disease.^13,14

Currently, the FDA has called for further research, concluding, “it is not possible to confirm with statistical certainty that breast implants cause ALCL.”¹¹

Because occurrence of ALCL is rare, the absolute risk for the disease may be extremely low. However, primary care providers who detect a seroma or note increased size in one augmented breast over another six months or longer after an augmentation procedure are advised to refer the patient to a plastic surgeon or other appropriate specialist.¹¹

All cases of confirmed ALCL in women with breast implants should be reported to [email protected]. This is a registry begun by the FDA, in conjunction with the Plastic Surgery Foundation and the American Society of Plastic Surgeons, to gather data about ALCL in women with breast implants.

History of Breast Implant Regulation
Silicone gel–filled implants, introduced in the US in 1962, were classified as moderate-risk (Class II) medical devices when Congress passed the 1976 Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act.¹⁷ In the 1980s, concerns regarding the safety of breast implants led to extensive studies. Data from the FDA’s surveillance systems and published case reports led the FDA to upgrade silicone breast implants to a Class III device (presenting “a potential unreasonable risk of illness or injury”), which requires premarket approval.¹⁶

In 1992, the FDA removed silicone breast implants from the market for primary augmentation purposes due to persistent concerns about patient safety. From 1992 to 2006, silicone breast implants remained available only for breast reconstruction after mastectomy, correction of congenital deformities, or replacement of existing implants.¹⁷ Women who agreed to undergo breast augmentation with silicone gel–filled implants were enrolled in safety studies conducted by the implant manufacturers. Saline implants remained on the market with no limitations on use, but additional studies on these implants were also ordered.

In 1999, the Institute of Medicine (IOM) released a report, “Safety of Silicone Breast Implants,”¹⁸ which more clearly delineated the complications associated with silicone gel–filled implant use. The authors concluded that local complications, including implant rupture and capsular contracture, were the primary associated safety issues. Furthermore, the authors of the IOM report found no causal relationship between silicone gel–filled implants and systemic diseases, such as autoimmune disorders or cancer.^2,18

In 2006, the FDA restored approval of silicone gel–filled implants, based largely on core studies conducted by the implant manufacturers.^15,19,20 “Despite frequent local complications and adverse outcomes,” it was noted, “the FDA determined that the benefits and risks of breast implants were sufficiently understood for women to make informed decisions about their use.”¹⁷ The FDA required the manufacturers to continue with several postapproval studies.¹⁵

The complications and adverse outcomes most frequently observed in these studies were capsular contracture, reoperation, removal of implant, and implant rupture.¹⁷ Revision and reconstruction surgeries typically have higher complication rates than do primary augmentation surgeries.²

Less Common Complications
In synmastia, a rare but serious complication, the breasts become conjoined because the natural intermammary sulcus (the cleft between the breasts) is obliterated. Causative and contributing factors include aggressive medical resection of the breast, medial migration of either or both implants, selection of a breast implant that is too large for the chest wall, a history of multiple breast surgeries, and a chest wall deformity called pectus excavatum.³⁴ Treatment for synmastia is generally surgical. The main goals of surgical treatment are restoration of the initial presternal subcutaneous integrity and medial closure of the pocket.^34,35

Bottoming outsimply means descent of the breast implant on the chest wall sufficient to compromise the inframammary fold. Early bottoming out is most likely due to overdissection or insufficient dissection of the implant pocket, whereas later occurrence is generally attributed to the weight of the implant, compromised breast tissue, or poor skin quality. Surgical revision is needed to elevate and reinforce the inframammary fold. As in the case of implant wrinkling, acellular dermal matrix can be added to bolster breast tissue and prevent tissue thinning (and reduce the risk for implant extrusion).^32,33

Mondor’s cordsare firm, cord-like bands caused by superficial thrombophlebitis that can involve the lateral thoracic vein, thoracoepigastric vein, or superior epigastric vein.^36,37 This condition presents with abrupt-onset pain in the breast or chest wall, preceded by the appearance of a firm, tender cord. Mondor’s cords usually resolve spontaneously but may be treated with warm compresses, NSAIDs, and use of a supportive bra.³⁷

 Conclusion

Breast implants are among the most thoroughly studied medical devices. Although systemic complications are sensationalized in the media, local complications are much more prevalent. The primary care provider is often the first clinician to identify complications of breast augmentation, especially beyond the one-year postprocedure period. Thus, primary care providers must be aware of the local complications that may arise.

Anaplastic large-cell lymphoma is being studied as a possible complication of breast augmentation. Clinicians should be alert to possible development of a seroma six months or longer after an augmentation procedure.

References
1. 
13.8 million cosmetic plastic surgery procedures performed in 2011 [press release]. Arlington Heights, IL: American Society of Plastic Surgeons; February 9, 2012.

2. 
FDA. Medical devices: risks of breast implants (2013). www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/Breastimplants/ucm064106.htm. Accessed May 14, 2013.

3. 
Juanpere S, Perez E, Huc O, et al. Imaging of breast implants: a pictorial review. Insights Imaging. 2011;2:653-690.

4. 
Adams WP Jr. Capsular contracture: what is it? What causes it? How can it be prevented and managed? Clin Plast Surg. 2009;36:119-126.

5. 
El-Sheikh Y, Tutino R, Knight C, et al. Incidence of capsular contracture in silicone versus saline cosmetic augmentation mammoplasty: a meta-analysis. Can J Plast Surg. 2008;16:211-215.

6. 
Blount AL, Martin MD, Lineberry KD, et al. Capsular contracture rate in a low-risk population after primary augmentation mammaplasty. Aesthet Surg J. 2013;33:516-521.

7. 
Schaub TA, Ahmad J, Rohrich RJ. Capsular contracture with breast implants in the cosmetic patient: saline versus silicone—a systematic review of the literature. Plast Reconstr Surg. 2010;126:2140-2149.

8. 
Hvilsom GB, Hölmich LR, Henriksen TF, et al. Local complications after cosmetic breast augmentation: results from the Danish Registry for Plastic Surgery of the Breast. Plast Reconstr Surg. 2009;124:919-925.

9. 
Thompson PA, Lade S, Webster H, et al. Effusion-associated anaplastic large cell lymphoma of the breast: time for it to be defined as a distinct clinico-pathological entity. Haematologica. 2010;95:1977-1979.

10. 
Brody GS, Deapen D, Gill P, et al. T-cell non-Hodgkin’s anaplastic lymphoma associated with one style of breast implants. Presented at: American Society of Plastic Surgeons Annual Conference; March 20-23, 2010; San Antonio, Texas. Abstract 42.

11. 
FDA, Center for Devices and Radiological Health. Anaplastic large cell lymphoma (ALCL) in women with breast implants: preliminary FDA findings and analyses (2011). www.fda.gov/MedicalDevices/ProductsandMedical Procedures/ImplantsandProsthetics/BreastImplants/ucm239996.htm. Accessed May 14, 2013.

12. 
Carty MJ, Pribaz JJ, Antin JH, et al. A patient death attributable to implant-related primary anaplastic large cell lymphoma of the breast. Plast Reconstr Surg. 2011;128:112e-118e.

13. 
Kim B, Roth C, Young VL, et al. Anaplastic large cell lymphoma and breast implants: results from a structured expert consultation process. Plast Reconstr Surg. 2011;128:629-639.

14. 
Kim B, Roth CP, Chung KC, et al. Are breast implants linked to a rare form of lymphoma? www.rand.org/pubs/research_briefs/RB9584.html. Accessed May 14, 2013.

15. 
Silicone gel-filled breast implants approved. FDA Consum. 2007;41:8-9.

16. 
Johnson JA; Congressional Research Service. FDA regulation of medical devices (2012). www.fas.org/sgp/crs/misc/R42130.pdf. Accessed May 14, 2013.

17. 
FDA. Update on the safety of silicone gel–filled breast implants (2011). www.fda.gov/downloads/medicaldevices/productsandmedicalprocedures/implantsandprosthetics/breastimplants/UCM260090.pdf. Accessed May 14, 2013.

18. 
Bondurant S, Ernster V, Herdman R, eds; Committee on the Safety of Silicone Breast Implants, Division of Health Promotion and Disease Prevention, Institute of Medicine. Washington, DC: National Academy Press; 1999.

19. 
Spear SL, Hedén P. Allergan’s silicone gel breast implants. Expert Rev Med Devices. 2007;4:699-708.

20. 
Cunningham B. The Mentor core study on silicone MemoryGel breast implants. Plast Reconstr Surg. 2007;120(7 suppl 1):19S-32S.

21. 
Spear SL, Baker JL Jr. Classification of capsular contracture after prosthetic breast reconstruction. Plast Reconstr Surg. 1995;96:1119-1123.

22. 
Schreml S, Heine N, Eisenmann-Klein M, Pranti L. Bacterial colonization is of major relevance for high-grade capsular contracture after augmentation mammaplasty. Ann Plast Surg. 2007;59:126-130.

23. 
Siggelkow W, Faridi A, Spiritus K, et al. Histological analysis of silicone breast implant capsules and correlation with capsular contracture. Biomaterials. 2003;24:1101-1109.

24. 
Henriksen TF, Fryzek JP, Hölmich LR, et al. Surgical intervention and capsular contracture after breast augmentation: a prospective study of risk factors. Ann Plast Surg. 2005;54:343-351.

25. 
Amano Y, Aoki R, Kumita S, Kumazaki T. Silicone-selective multishot echo-planar imaging for rapid MRI survey of breast implants. Eur Radiol. 2007;17:1875-1878.

26. 
Maxwell GP, Van Natta BW, Murphy DK, et al. Natrelle style 410 form-stable silicone breast implants: core study results at 6 years. Aesthet Surg J. 2012;32:709-717.

27. 
Stevens WG, Harrington J, Alizadeh K, et al. Five-year follow-up data from the US clinical trial for Sientra’s U.S. Food and Drug Administration-approved Silimed^® brand round and shaped implants with high-strength silicone gel. Plast Reconstr Surg. 2012;130:973-981.

28. 
Hold PM, Alam S, Pilbrow WJ, et al. How should we investigate breast implant rupture? Breast J. 2012;18:253-256.

29. 
Everson LI, Parantainen H, Detlie T, et al. Diagnosis of breast implant rupture: imaging findings and relative efficacies of imaging techniques. AJR Am J Roentgenol. 1994;163:57-60.

30. 
Hölmich LR, Vejborg IM, Conrad C, et al. Untreated silicone breast implant rupture. Plast Reconstr Surg. 2004;114:204-214.

31. 
Dowden RV, Reisman NR. Breast implant overfill, optimal fill, and the standard of care. Plast Reconstr Surg. 1999;104:1185-1186.

32. 
Spear SL, Sinkin JC, Al-Attar A. Porcine acellular dermal matrix (Strattice™) in primary and revision cosmetic breast surgery. Plast Reconstr Surg. 2013;131:1140-1148.

33. 
Shestak KC. Acellular dermal matrix inlays to correct significant implant malposition in patients with compromised local tissues. Aesthet Surg J. 2011;31(7 suppl):85S-94S.

34. 
Spear SL, Bogue DP, Thomassen JM. Synmastia after breast augmentation. Plast Reconstr Surg. 2006;118(7 suppl):168S-171S.

35. 
Selvaggi G, Giordano S, Ishak L. Synmastia: prevention and correction. Ann Plast Surg. 2010;65:455-461.

36. 
Coscia J, Lance S, Wong M, Garcia J. Mondor’s thrombophlebitis 13 years after breast augmentation. Ann Plast Surg. 2012;68:336-337.

37. 
Dudrap E, Milliez PY, Auquit-Auckbur I, Bony-Rerolle S. Mondor’s disease and breast plastic surgery [in French]. Ann Chir Plast Esthet. 2010; 55:233-237.

Breast augmentation is one of the most commonly performed plastic surgery procedures. It is important for primary care providers who perform clinical breast exams to be well versed in complications that can occur after the immediate postsurgical period and to prepare patients with augmented breasts for the likelihood of requiring a secondary procedure at some time.

Breast augmentation continues to rank as the procedure most commonly performed by US plastic surgeons. According to data from the American Society of Plastic Surgeons,¹ 307,000 breast augmentation procedures were performed in the US in 2011—a 4% increase from the previous year. Breast implants are not permanent devices, and most patients can expect to undergo a secondary procedure during their lifetime.²

Hematomas and infections associated with breast augmentation usually occur within two to 14 days following surgery, while the patient is still under the care of the plastic surgeon.^2,3 For long-term complications, however, patients are likely to consult their primary care or gynecologic provider. Thus, it is important that any clinician who performs clinical breast exams be well versed in the complications, both local and systemic, that can occur after the immediate postsurgical period in patients who have undergone breast augmentation.

Common Complications of Breast Enhancement
Complications after breast augmentation are not uncommon. They can occur in women with either silicone gel– or saline-filled implants; conflicting incidence rates for capsular contracture (the most common local complication^3,4) have been reported following insertion of silicone gel–filled implants, compared with saline implants.^5,6 It has been noted, however, that prospective data comparing the two implant types are lacking in the literature.⁷

Complications can be categorized as either local or systemic. In addition to capsular contracture, local complications (which are more common) include implant rupture or deflation, and implant rippling or wrinkling.

Systemic complications may include anaplastic large-cell lymphoma, a rare but serious complication that is currently under study for its potential association with breast implants⁸ (see third article in this series, “Anaplastic Large-Cell Lymphoma”^9-14). Other systemic sequelae include autoimmune disorders, connective tissue disease, and fibrositis/fibromyalgia conditions; these conditions can only be addressed in an article of greater scope.

In 2006, breast implant manufacturers were mandated to conduct postapproval studies regarding the devices’ safety¹⁵ (see fourth article in this series, “History of Breast Implant Regulation,”^2,15-20). Findings from these studies can facilitate primary care providers’ management of patients who have augmented breasts.

Capsular Contracture
Capsular contracture occurs with frequencies ranging from 1.9% to 2.3%.⁸ As a result of the immune response to any foreign body, collagen fibers form and weave around the prosthetic device once it is implanted. For reasons not completely understood, these fibers can begin to tighten over time. As the capsule continues to tighten and harden, the implant is then compressed, resulting in breast pain and deformity.

The degree of capsular contracture is categorized according to Baker’s classification system regarding implant position and breast firmness postaugmentation.^2,21 A Baker’s grade I designation implies that the modified breast is soft and looks normal. Grade II describes a breast that is slightly firm upon exam but looks completely normal. In grade III, the breast is firm and has taken on an abnormal appearance. In grade IV, the breast looks abnormal and is firm on examination, with the patient describing significant pain.

Some researchers believe that capsular contracture develops because of a subclinical bacterial infection, while others suggest that silicone leakage may be the cause.^6,22,23 A patient who is diagnosed with a hematoma during the postoperative period is at increased risk for capsular contracture, and one who has been treated previously for capsular contracture has a significant risk for recurrence.^2,24

Capsular contracture is usually treated surgically by a capsulectomy or a capsulotomy. Currently, the preferred procedure is an open capsulectomy to remove the implant, surgically excise the entire capsule, and replace the implant.⁴

Implant Deflation, Rupture
Most ruptures of implants (whether they are used cosmetically or for reconstruction) occur between 10 and 15 years after implantation.^3,25 Incidence of implant removal by 10 years postsurgery ranges from 21% to 32% for silicone gel–filled implants, depending on the specific implant model.¹⁷

Saline implant deflation is relatively easy to detect because it presents with a rapid decrease in breast size on the affected side. Ruptures of silicone gel–filled implants, by contrast, can go undetected for years—hence the term silent rupture applied in this circumstance.³ If a rupture is detected, the faulty breast implant is removed and returned to the manufacturer for investigation.

If surgical instrumentation leads to a puncture during saline gel–filled implant surgery, it is usually noticed immediately. A silicone gel–filled implant can also be punctured during the implantation procedure, often with no obvious signs of the rupture.

Rupture of a silicone gel–filled implant may be intracapsular or extracapsular. In intracapsular ruptures, the contents of the implant remain within the capsule that has formed around the implant. Extracapsular ruptures involve migration of the silicone material outside the capsule.³ Current-generation silicone implants are increasingly biodurable, thereby reducing the risk for silicone migration.^26,27

MRI is currently considered the study of choice to detect silent rupture of a silicone gel–filled implant.²⁸ As primary care providers should be aware, the FDA recommends that women with silicone gel–filled implants undergo MRI screening three years after implantation and every two years thereafter to assess the implants’ integrity.¹⁷ This applies to all age-groups and does not replace screening mammography requirements for breast cancer.

While mammography is ideal for detecting extracapsular silicone implant ruptures, it fails to detect intracapsular implant rupture consistently.²⁹ Breast ultrasound cannot effectively detect ruptures in the posterior portion of the implant and cannot evaluate the chest wall. Thus, MRI, with its high spatial resolution and marked contrast between implants and natural breast tissue, is considered most effective in detecting either intracapsular or extracapsular ruptures.^3,28,29

Despite earlier reports that implant rupture could prompt an immunologic reaction, giving rise to autoimmune or related diseases, subsequent studies reveal “no association between silicone gel–filled breast implants and connective tissue disease, breast cancer, or reproductive problems.”¹⁷ Apart from a relatively low risk for silicone migration, implant rupture has been deemed relatively harmless.³⁰

Implant Wrinkling, Folding
Implant wrinkling visible to the naked eye can mar the aesthetic appearance of an augmented breast. In some cases, the wrinkled implant may be detected only by palpation. Causes of wrinkling include:

• Thin skin and insufficient natural breast tissue, especially in the lower outer pole

• Subglandular placement of the implant, which allows less coverage over the implant than submuscular placement; and

• Use of saline-filled or textured-surface implants.

Because saline has a lower viscosity than silicone, it may allow lower-pole expansion and settling—and hence, wrinkling. Insufficient filling in saline implants may contribute to the problem, in addition to palpable shell folding, palpable shifts of filler material, sloshing, and other compromised aesthetic results.^3,31

In rare cases, wrinkling over thin skin can cause implant extrusion. Additionally, the friction created as the shell rubs against itself can cause implant deflation or even rupture due to the development of a “hot spot.”

Options to address implant wrinkling are to replace saline-filled implants with silicone gel–filled implants or to revise placement of the implant from the subglandular to the submuscular location. Use of acellular dermal matrix can help reinforce existing breast tissue, especially when placed in the lower pole of the affected breast.^32,33

Anaplastic Large-Cell Lymphoma
Of rising concern is a possible association between certain breast implants (ie, textured vs nontextured implants; silicone vs saline implants) and anaplastic large-cell lymphoma (ALCL).^9-13 RAND Health¹⁴ sponsored a study conducted by 10 multidisciplinary experts, who agreed on the following points:

(1) A positive association exists between breast implants and ALCL, with the actual number of cases probably underrecognized.

(2) Any recurrent, clinically evident seroma developing longer than six months after breast implantation should be aspirated for cytologic analysis.

(3) Anaplastic lymphoma kinase (ALK)–negative ALCL that develops in the vicinity of breast implants is distinct from systemic ALK-negative ALCL, is clinically indolent disease, and has a favorable prognosis.

(4) Management of ALCL requires removal of the involved implant and capsule (a strategy that is likely to prevent recurrence) and evaluation for the disease at other sites.

(5) Adjuvant radiation or chemotherapy need not be offered to women with capsule-confined disease.^13,14

Currently, the FDA has called for further research, concluding, “it is not possible to confirm with statistical certainty that breast implants cause ALCL.”¹¹

Because occurrence of ALCL is rare, the absolute risk for the disease may be extremely low. However, primary care providers who detect a seroma or note increased size in one augmented breast over another six months or longer after an augmentation procedure are advised to refer the patient to a plastic surgeon or other appropriate specialist.¹¹

All cases of confirmed ALCL in women with breast implants should be reported to [email protected]. This is a registry begun by the FDA, in conjunction with the Plastic Surgery Foundation and the American Society of Plastic Surgeons, to gather data about ALCL in women with breast implants.

History of Breast Implant Regulation
Silicone gel–filled implants, introduced in the US in 1962, were classified as moderate-risk (Class II) medical devices when Congress passed the 1976 Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act.¹⁷ In the 1980s, concerns regarding the safety of breast implants led to extensive studies. Data from the FDA’s surveillance systems and published case reports led the FDA to upgrade silicone breast implants to a Class III device (presenting “a potential unreasonable risk of illness or injury”), which requires premarket approval.¹⁶

In 1992, the FDA removed silicone breast implants from the market for primary augmentation purposes due to persistent concerns about patient safety. From 1992 to 2006, silicone breast implants remained available only for breast reconstruction after mastectomy, correction of congenital deformities, or replacement of existing implants.¹⁷ Women who agreed to undergo breast augmentation with silicone gel–filled implants were enrolled in safety studies conducted by the implant manufacturers. Saline implants remained on the market with no limitations on use, but additional studies on these implants were also ordered.

In 1999, the Institute of Medicine (IOM) released a report, “Safety of Silicone Breast Implants,”¹⁸ which more clearly delineated the complications associated with silicone gel–filled implant use. The authors concluded that local complications, including implant rupture and capsular contracture, were the primary associated safety issues. Furthermore, the authors of the IOM report found no causal relationship between silicone gel–filled implants and systemic diseases, such as autoimmune disorders or cancer.^2,18

In 2006, the FDA restored approval of silicone gel–filled implants, based largely on core studies conducted by the implant manufacturers.^15,19,20 “Despite frequent local complications and adverse outcomes,” it was noted, “the FDA determined that the benefits and risks of breast implants were sufficiently understood for women to make informed decisions about their use.”¹⁷ The FDA required the manufacturers to continue with several postapproval studies.¹⁵

The complications and adverse outcomes most frequently observed in these studies were capsular contracture, reoperation, removal of implant, and implant rupture.¹⁷ Revision and reconstruction surgeries typically have higher complication rates than do primary augmentation surgeries.²

Less Common Complications
In synmastia, a rare but serious complication, the breasts become conjoined because the natural intermammary sulcus (the cleft between the breasts) is obliterated. Causative and contributing factors include aggressive medical resection of the breast, medial migration of either or both implants, selection of a breast implant that is too large for the chest wall, a history of multiple breast surgeries, and a chest wall deformity called pectus excavatum.³⁴ Treatment for synmastia is generally surgical. The main goals of surgical treatment are restoration of the initial presternal subcutaneous integrity and medial closure of the pocket.^34,35

Bottoming outsimply means descent of the breast implant on the chest wall sufficient to compromise the inframammary fold. Early bottoming out is most likely due to overdissection or insufficient dissection of the implant pocket, whereas later occurrence is generally attributed to the weight of the implant, compromised breast tissue, or poor skin quality. Surgical revision is needed to elevate and reinforce the inframammary fold. As in the case of implant wrinkling, acellular dermal matrix can be added to bolster breast tissue and prevent tissue thinning (and reduce the risk for implant extrusion).^32,33

Mondor’s cordsare firm, cord-like bands caused by superficial thrombophlebitis that can involve the lateral thoracic vein, thoracoepigastric vein, or superior epigastric vein.^36,37 This condition presents with abrupt-onset pain in the breast or chest wall, preceded by the appearance of a firm, tender cord. Mondor’s cords usually resolve spontaneously but may be treated with warm compresses, NSAIDs, and use of a supportive bra.³⁷

 Conclusion

Breast implants are among the most thoroughly studied medical devices. Although systemic complications are sensationalized in the media, local complications are much more prevalent. The primary care provider is often the first clinician to identify complications of breast augmentation, especially beyond the one-year postprocedure period. Thus, primary care providers must be aware of the local complications that may arise.

Anaplastic large-cell lymphoma is being studied as a possible complication of breast augmentation. Clinicians should be alert to possible development of a seroma six months or longer after an augmentation procedure.

References
1. 
13.8 million cosmetic plastic surgery procedures performed in 2011 [press release]. Arlington Heights, IL: American Society of Plastic Surgeons; February 9, 2012.

2. 
FDA. Medical devices: risks of breast implants (2013). www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/Breastimplants/ucm064106.htm. Accessed May 14, 2013.

3. 
Juanpere S, Perez E, Huc O, et al. Imaging of breast implants: a pictorial review. Insights Imaging. 2011;2:653-690.

4. 
Adams WP Jr. Capsular contracture: what is it? What causes it? How can it be prevented and managed? Clin Plast Surg. 2009;36:119-126.

5. 
El-Sheikh Y, Tutino R, Knight C, et al. Incidence of capsular contracture in silicone versus saline cosmetic augmentation mammoplasty: a meta-analysis. Can J Plast Surg. 2008;16:211-215.

6. 
Blount AL, Martin MD, Lineberry KD, et al. Capsular contracture rate in a low-risk population after primary augmentation mammaplasty. Aesthet Surg J. 2013;33:516-521.

7. 
Schaub TA, Ahmad J, Rohrich RJ. Capsular contracture with breast implants in the cosmetic patient: saline versus silicone—a systematic review of the literature. Plast Reconstr Surg. 2010;126:2140-2149.

8. 
Hvilsom GB, Hölmich LR, Henriksen TF, et al. Local complications after cosmetic breast augmentation: results from the Danish Registry for Plastic Surgery of the Breast. Plast Reconstr Surg. 2009;124:919-925.

9. 
Thompson PA, Lade S, Webster H, et al. Effusion-associated anaplastic large cell lymphoma of the breast: time for it to be defined as a distinct clinico-pathological entity. Haematologica. 2010;95:1977-1979.

10. 
Brody GS, Deapen D, Gill P, et al. T-cell non-Hodgkin’s anaplastic lymphoma associated with one style of breast implants. Presented at: American Society of Plastic Surgeons Annual Conference; March 20-23, 2010; San Antonio, Texas. Abstract 42.

11. 
FDA, Center for Devices and Radiological Health. Anaplastic large cell lymphoma (ALCL) in women with breast implants: preliminary FDA findings and analyses (2011). www.fda.gov/MedicalDevices/ProductsandMedical Procedures/ImplantsandProsthetics/BreastImplants/ucm239996.htm. Accessed May 14, 2013.

12. 
Carty MJ, Pribaz JJ, Antin JH, et al. A patient death attributable to implant-related primary anaplastic large cell lymphoma of the breast. Plast Reconstr Surg. 2011;128:112e-118e.

13. 
Kim B, Roth C, Young VL, et al. Anaplastic large cell lymphoma and breast implants: results from a structured expert consultation process. Plast Reconstr Surg. 2011;128:629-639.

14. 
Kim B, Roth CP, Chung KC, et al. Are breast implants linked to a rare form of lymphoma? www.rand.org/pubs/research_briefs/RB9584.html. Accessed May 14, 2013.

15. 
Silicone gel-filled breast implants approved. FDA Consum. 2007;41:8-9.

16. 
Johnson JA; Congressional Research Service. FDA regulation of medical devices (2012). www.fas.org/sgp/crs/misc/R42130.pdf. Accessed May 14, 2013.

17. 
FDA. Update on the safety of silicone gel–filled breast implants (2011). www.fda.gov/downloads/medicaldevices/productsandmedicalprocedures/implantsandprosthetics/breastimplants/UCM260090.pdf. Accessed May 14, 2013.

18. 
Bondurant S, Ernster V, Herdman R, eds; Committee on the Safety of Silicone Breast Implants, Division of Health Promotion and Disease Prevention, Institute of Medicine. Washington, DC: National Academy Press; 1999.

19. 
Spear SL, Hedén P. Allergan’s silicone gel breast implants. Expert Rev Med Devices. 2007;4:699-708.

20. 
Cunningham B. The Mentor core study on silicone MemoryGel breast implants. Plast Reconstr Surg. 2007;120(7 suppl 1):19S-32S.

21. 
Spear SL, Baker JL Jr. Classification of capsular contracture after prosthetic breast reconstruction. Plast Reconstr Surg. 1995;96:1119-1123.

22. 
Schreml S, Heine N, Eisenmann-Klein M, Pranti L. Bacterial colonization is of major relevance for high-grade capsular contracture after augmentation mammaplasty. Ann Plast Surg. 2007;59:126-130.

23. 
Siggelkow W, Faridi A, Spiritus K, et al. Histological analysis of silicone breast implant capsules and correlation with capsular contracture. Biomaterials. 2003;24:1101-1109.

24. 
Henriksen TF, Fryzek JP, Hölmich LR, et al. Surgical intervention and capsular contracture after breast augmentation: a prospective study of risk factors. Ann Plast Surg. 2005;54:343-351.

25. 
Amano Y, Aoki R, Kumita S, Kumazaki T. Silicone-selective multishot echo-planar imaging for rapid MRI survey of breast implants. Eur Radiol. 2007;17:1875-1878.

26. 
Maxwell GP, Van Natta BW, Murphy DK, et al. Natrelle style 410 form-stable silicone breast implants: core study results at 6 years. Aesthet Surg J. 2012;32:709-717.

27. 
Stevens WG, Harrington J, Alizadeh K, et al. Five-year follow-up data from the US clinical trial for Sientra’s U.S. Food and Drug Administration-approved Silimed^® brand round and shaped implants with high-strength silicone gel. Plast Reconstr Surg. 2012;130:973-981.

28. 
Hold PM, Alam S, Pilbrow WJ, et al. How should we investigate breast implant rupture? Breast J. 2012;18:253-256.

29. 
Everson LI, Parantainen H, Detlie T, et al. Diagnosis of breast implant rupture: imaging findings and relative efficacies of imaging techniques. AJR Am J Roentgenol. 1994;163:57-60.

30. 
Hölmich LR, Vejborg IM, Conrad C, et al. Untreated silicone breast implant rupture. Plast Reconstr Surg. 2004;114:204-214.

31. 
Dowden RV, Reisman NR. Breast implant overfill, optimal fill, and the standard of care. Plast Reconstr Surg. 1999;104:1185-1186.

32. 
Spear SL, Sinkin JC, Al-Attar A. Porcine acellular dermal matrix (Strattice™) in primary and revision cosmetic breast surgery. Plast Reconstr Surg. 2013;131:1140-1148.

33. 
Shestak KC. Acellular dermal matrix inlays to correct significant implant malposition in patients with compromised local tissues. Aesthet Surg J. 2011;31(7 suppl):85S-94S.

34. 
Spear SL, Bogue DP, Thomassen JM. Synmastia after breast augmentation. Plast Reconstr Surg. 2006;118(7 suppl):168S-171S.

35. 
Selvaggi G, Giordano S, Ishak L. Synmastia: prevention and correction. Ann Plast Surg. 2010;65:455-461.

36. 
Coscia J, Lance S, Wong M, Garcia J. Mondor’s thrombophlebitis 13 years after breast augmentation. Ann Plast Surg. 2012;68:336-337.

37. 
Dudrap E, Milliez PY, Auquit-Auckbur I, Bony-Rerolle S. Mondor’s disease and breast plastic surgery [in French]. Ann Chir Plast Esthet. 2010; 55:233-237.

Breast augmentation is one of the most commonly performed plastic surgery procedures. It is important for primary care providers who perform clinical breast exams to be well versed in complications that can occur after the immediate postsurgical period and to prepare patients with augmented breasts for the likelihood of requiring a secondary procedure at some time.

Breast augmentation continues to rank as the procedure most commonly performed by US plastic surgeons. According to data from the American Society of Plastic Surgeons,¹ 307,000 breast augmentation procedures were performed in the US in 2011—a 4% increase from the previous year. Breast implants are not permanent devices, and most patients can expect to undergo a secondary procedure during their lifetime.²

Hematomas and infections associated with breast augmentation usually occur within two to 14 days following surgery, while the patient is still under the care of the plastic surgeon.^2,3 For long-term complications, however, patients are likely to consult their primary care or gynecologic provider. Thus, it is important that any clinician who performs clinical breast exams be well versed in the complications, both local and systemic, that can occur after the immediate postsurgical period in patients who have undergone breast augmentation.

Common Complications of Breast Enhancement
Complications after breast augmentation are not uncommon. They can occur in women with either silicone gel– or saline-filled implants; conflicting incidence rates for capsular contracture (the most common local complication^3,4) have been reported following insertion of silicone gel–filled implants, compared with saline implants.^5,6 It has been noted, however, that prospective data comparing the two implant types are lacking in the literature.⁷

Complications can be categorized as either local or systemic. In addition to capsular contracture, local complications (which are more common) include implant rupture or deflation, and implant rippling or wrinkling.

Systemic complications may include anaplastic large-cell lymphoma, a rare but serious complication that is currently under study for its potential association with breast implants⁸ (see third article in this series, “Anaplastic Large-Cell Lymphoma”^9-14). Other systemic sequelae include autoimmune disorders, connective tissue disease, and fibrositis/fibromyalgia conditions; these conditions can only be addressed in an article of greater scope.

In 2006, breast implant manufacturers were mandated to conduct postapproval studies regarding the devices’ safety¹⁵ (see fourth article in this series, “History of Breast Implant Regulation,”^2,15-20). Findings from these studies can facilitate primary care providers’ management of patients who have augmented breasts.

Capsular Contracture
Capsular contracture occurs with frequencies ranging from 1.9% to 2.3%.⁸ As a result of the immune response to any foreign body, collagen fibers form and weave around the prosthetic device once it is implanted. For reasons not completely understood, these fibers can begin to tighten over time. As the capsule continues to tighten and harden, the implant is then compressed, resulting in breast pain and deformity.

The degree of capsular contracture is categorized according to Baker’s classification system regarding implant position and breast firmness postaugmentation.^2,21 A Baker’s grade I designation implies that the modified breast is soft and looks normal. Grade II describes a breast that is slightly firm upon exam but looks completely normal. In grade III, the breast is firm and has taken on an abnormal appearance. In grade IV, the breast looks abnormal and is firm on examination, with the patient describing significant pain.

Some researchers believe that capsular contracture develops because of a subclinical bacterial infection, while others suggest that silicone leakage may be the cause.^6,22,23 A patient who is diagnosed with a hematoma during the postoperative period is at increased risk for capsular contracture, and one who has been treated previously for capsular contracture has a significant risk for recurrence.^2,24

Capsular contracture is usually treated surgically by a capsulectomy or a capsulotomy. Currently, the preferred procedure is an open capsulectomy to remove the implant, surgically excise the entire capsule, and replace the implant.⁴

Implant Deflation, Rupture
Most ruptures of implants (whether they are used cosmetically or for reconstruction) occur between 10 and 15 years after implantation.^3,25 Incidence of implant removal by 10 years postsurgery ranges from 21% to 32% for silicone gel–filled implants, depending on the specific implant model.¹⁷

Saline implant deflation is relatively easy to detect because it presents with a rapid decrease in breast size on the affected side. Ruptures of silicone gel–filled implants, by contrast, can go undetected for years—hence the term silent rupture applied in this circumstance.³ If a rupture is detected, the faulty breast implant is removed and returned to the manufacturer for investigation.

If surgical instrumentation leads to a puncture during saline gel–filled implant surgery, it is usually noticed immediately. A silicone gel–filled implant can also be punctured during the implantation procedure, often with no obvious signs of the rupture.

Rupture of a silicone gel–filled implant may be intracapsular or extracapsular. In intracapsular ruptures, the contents of the implant remain within the capsule that has formed around the implant. Extracapsular ruptures involve migration of the silicone material outside the capsule.³ Current-generation silicone implants are increasingly biodurable, thereby reducing the risk for silicone migration.^26,27

MRI is currently considered the study of choice to detect silent rupture of a silicone gel–filled implant.²⁸ As primary care providers should be aware, the FDA recommends that women with silicone gel–filled implants undergo MRI screening three years after implantation and every two years thereafter to assess the implants’ integrity.¹⁷ This applies to all age-groups and does not replace screening mammography requirements for breast cancer.

While mammography is ideal for detecting extracapsular silicone implant ruptures, it fails to detect intracapsular implant rupture consistently.²⁹ Breast ultrasound cannot effectively detect ruptures in the posterior portion of the implant and cannot evaluate the chest wall. Thus, MRI, with its high spatial resolution and marked contrast between implants and natural breast tissue, is considered most effective in detecting either intracapsular or extracapsular ruptures.^3,28,29

Despite earlier reports that implant rupture could prompt an immunologic reaction, giving rise to autoimmune or related diseases, subsequent studies reveal “no association between silicone gel–filled breast implants and connective tissue disease, breast cancer, or reproductive problems.”¹⁷ Apart from a relatively low risk for silicone migration, implant rupture has been deemed relatively harmless.³⁰

Implant Wrinkling, Folding
Implant wrinkling visible to the naked eye can mar the aesthetic appearance of an augmented breast. In some cases, the wrinkled implant may be detected only by palpation. Causes of wrinkling include:

• Thin skin and insufficient natural breast tissue, especially in the lower outer pole

• Subglandular placement of the implant, which allows less coverage over the implant than submuscular placement; and

• Use of saline-filled or textured-surface implants.

Because saline has a lower viscosity than silicone, it may allow lower-pole expansion and settling—and hence, wrinkling. Insufficient filling in saline implants may contribute to the problem, in addition to palpable shell folding, palpable shifts of filler material, sloshing, and other compromised aesthetic results.^3,31

In rare cases, wrinkling over thin skin can cause implant extrusion. Additionally, the friction created as the shell rubs against itself can cause implant deflation or even rupture due to the development of a “hot spot.”

Options to address implant wrinkling are to replace saline-filled implants with silicone gel–filled implants or to revise placement of the implant from the subglandular to the submuscular location. Use of acellular dermal matrix can help reinforce existing breast tissue, especially when placed in the lower pole of the affected breast.^32,33

Anaplastic Large-Cell Lymphoma
Of rising concern is a possible association between certain breast implants (ie, textured vs nontextured implants; silicone vs saline implants) and anaplastic large-cell lymphoma (ALCL).^9-13 RAND Health¹⁴ sponsored a study conducted by 10 multidisciplinary experts, who agreed on the following points:

(1) A positive association exists between breast implants and ALCL, with the actual number of cases probably underrecognized.

(2) Any recurrent, clinically evident seroma developing longer than six months after breast implantation should be aspirated for cytologic analysis.

(3) Anaplastic lymphoma kinase (ALK)–negative ALCL that develops in the vicinity of breast implants is distinct from systemic ALK-negative ALCL, is clinically indolent disease, and has a favorable prognosis.

(4) Management of ALCL requires removal of the involved implant and capsule (a strategy that is likely to prevent recurrence) and evaluation for the disease at other sites.

(5) Adjuvant radiation or chemotherapy need not be offered to women with capsule-confined disease.^13,14

Currently, the FDA has called for further research, concluding, “it is not possible to confirm with statistical certainty that breast implants cause ALCL.”¹¹

Because occurrence of ALCL is rare, the absolute risk for the disease may be extremely low. However, primary care providers who detect a seroma or note increased size in one augmented breast over another six months or longer after an augmentation procedure are advised to refer the patient to a plastic surgeon or other appropriate specialist.¹¹

All cases of confirmed ALCL in women with breast implants should be reported to [email protected]. This is a registry begun by the FDA, in conjunction with the Plastic Surgery Foundation and the American Society of Plastic Surgeons, to gather data about ALCL in women with breast implants.

History of Breast Implant Regulation
Silicone gel–filled implants, introduced in the US in 1962, were classified as moderate-risk (Class II) medical devices when Congress passed the 1976 Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act.¹⁷ In the 1980s, concerns regarding the safety of breast implants led to extensive studies. Data from the FDA’s surveillance systems and published case reports led the FDA to upgrade silicone breast implants to a Class III device (presenting “a potential unreasonable risk of illness or injury”), which requires premarket approval.¹⁶

In 1992, the FDA removed silicone breast implants from the market for primary augmentation purposes due to persistent concerns about patient safety. From 1992 to 2006, silicone breast implants remained available only for breast reconstruction after mastectomy, correction of congenital deformities, or replacement of existing implants.¹⁷ Women who agreed to undergo breast augmentation with silicone gel–filled implants were enrolled in safety studies conducted by the implant manufacturers. Saline implants remained on the market with no limitations on use, but additional studies on these implants were also ordered.

In 1999, the Institute of Medicine (IOM) released a report, “Safety of Silicone Breast Implants,”¹⁸ which more clearly delineated the complications associated with silicone gel–filled implant use. The authors concluded that local complications, including implant rupture and capsular contracture, were the primary associated safety issues. Furthermore, the authors of the IOM report found no causal relationship between silicone gel–filled implants and systemic diseases, such as autoimmune disorders or cancer.^2,18

In 2006, the FDA restored approval of silicone gel–filled implants, based largely on core studies conducted by the implant manufacturers.^15,19,20 “Despite frequent local complications and adverse outcomes,” it was noted, “the FDA determined that the benefits and risks of breast implants were sufficiently understood for women to make informed decisions about their use.”¹⁷ The FDA required the manufacturers to continue with several postapproval studies.¹⁵

The complications and adverse outcomes most frequently observed in these studies were capsular contracture, reoperation, removal of implant, and implant rupture.¹⁷ Revision and reconstruction surgeries typically have higher complication rates than do primary augmentation surgeries.²

Less Common Complications
In synmastia, a rare but serious complication, the breasts become conjoined because the natural intermammary sulcus (the cleft between the breasts) is obliterated. Causative and contributing factors include aggressive medical resection of the breast, medial migration of either or both implants, selection of a breast implant that is too large for the chest wall, a history of multiple breast surgeries, and a chest wall deformity called pectus excavatum.³⁴ Treatment for synmastia is generally surgical. The main goals of surgical treatment are restoration of the initial presternal subcutaneous integrity and medial closure of the pocket.^34,35

Bottoming outsimply means descent of the breast implant on the chest wall sufficient to compromise the inframammary fold. Early bottoming out is most likely due to overdissection or insufficient dissection of the implant pocket, whereas later occurrence is generally attributed to the weight of the implant, compromised breast tissue, or poor skin quality. Surgical revision is needed to elevate and reinforce the inframammary fold. As in the case of implant wrinkling, acellular dermal matrix can be added to bolster breast tissue and prevent tissue thinning (and reduce the risk for implant extrusion).^32,33

Mondor’s cordsare firm, cord-like bands caused by superficial thrombophlebitis that can involve the lateral thoracic vein, thoracoepigastric vein, or superior epigastric vein.^36,37 This condition presents with abrupt-onset pain in the breast or chest wall, preceded by the appearance of a firm, tender cord. Mondor’s cords usually resolve spontaneously but may be treated with warm compresses, NSAIDs, and use of a supportive bra.³⁷

 Conclusion

Breast implants are among the most thoroughly studied medical devices. Although systemic complications are sensationalized in the media, local complications are much more prevalent. The primary care provider is often the first clinician to identify complications of breast augmentation, especially beyond the one-year postprocedure period. Thus, primary care providers must be aware of the local complications that may arise.

Anaplastic large-cell lymphoma is being studied as a possible complication of breast augmentation. Clinicians should be alert to possible development of a seroma six months or longer after an augmentation procedure.

References
1. 
13.8 million cosmetic plastic surgery procedures performed in 2011 [press release]. Arlington Heights, IL: American Society of Plastic Surgeons; February 9, 2012.

2. 
FDA. Medical devices: risks of breast implants (2013). www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/Breastimplants/ucm064106.htm. Accessed May 14, 2013.

3. 
Juanpere S, Perez E, Huc O, et al. Imaging of breast implants: a pictorial review. Insights Imaging. 2011;2:653-690.

4. 
Adams WP Jr. Capsular contracture: what is it? What causes it? How can it be prevented and managed? Clin Plast Surg. 2009;36:119-126.

5. 
El-Sheikh Y, Tutino R, Knight C, et al. Incidence of capsular contracture in silicone versus saline cosmetic augmentation mammoplasty: a meta-analysis. Can J Plast Surg. 2008;16:211-215.

6. 
Blount AL, Martin MD, Lineberry KD, et al. Capsular contracture rate in a low-risk population after primary augmentation mammaplasty. Aesthet Surg J. 2013;33:516-521.

7. 
Schaub TA, Ahmad J, Rohrich RJ. Capsular contracture with breast implants in the cosmetic patient: saline versus silicone—a systematic review of the literature. Plast Reconstr Surg. 2010;126:2140-2149.

8. 
Hvilsom GB, Hölmich LR, Henriksen TF, et al. Local complications after cosmetic breast augmentation: results from the Danish Registry for Plastic Surgery of the Breast. Plast Reconstr Surg. 2009;124:919-925.

9. 
Thompson PA, Lade S, Webster H, et al. Effusion-associated anaplastic large cell lymphoma of the breast: time for it to be defined as a distinct clinico-pathological entity. Haematologica. 2010;95:1977-1979.

10. 
Brody GS, Deapen D, Gill P, et al. T-cell non-Hodgkin’s anaplastic lymphoma associated with one style of breast implants. Presented at: American Society of Plastic Surgeons Annual Conference; March 20-23, 2010; San Antonio, Texas. Abstract 42.

11. 
FDA, Center for Devices and Radiological Health. Anaplastic large cell lymphoma (ALCL) in women with breast implants: preliminary FDA findings and analyses (2011). www.fda.gov/MedicalDevices/ProductsandMedical Procedures/ImplantsandProsthetics/BreastImplants/ucm239996.htm. Accessed May 14, 2013.

12. 
Carty MJ, Pribaz JJ, Antin JH, et al. A patient death attributable to implant-related primary anaplastic large cell lymphoma of the breast. Plast Reconstr Surg. 2011;128:112e-118e.

13. 
Kim B, Roth C, Young VL, et al. Anaplastic large cell lymphoma and breast implants: results from a structured expert consultation process. Plast Reconstr Surg. 2011;128:629-639.

14. 
Kim B, Roth CP, Chung KC, et al. Are breast implants linked to a rare form of lymphoma? www.rand.org/pubs/research_briefs/RB9584.html. Accessed May 14, 2013.

15. 
Silicone gel-filled breast implants approved. FDA Consum. 2007;41:8-9.

16. 
Johnson JA; Congressional Research Service. FDA regulation of medical devices (2012). www.fas.org/sgp/crs/misc/R42130.pdf. Accessed May 14, 2013.

17. 
FDA. Update on the safety of silicone gel–filled breast implants (2011). www.fda.gov/downloads/medicaldevices/productsandmedicalprocedures/implantsandprosthetics/breastimplants/UCM260090.pdf. Accessed May 14, 2013.

18. 
Bondurant S, Ernster V, Herdman R, eds; Committee on the Safety of Silicone Breast Implants, Division of Health Promotion and Disease Prevention, Institute of Medicine. Washington, DC: National Academy Press; 1999.

19. 
Spear SL, Hedén P. Allergan’s silicone gel breast implants. Expert Rev Med Devices. 2007;4:699-708.

20. 
Cunningham B. The Mentor core study on silicone MemoryGel breast implants. Plast Reconstr Surg. 2007;120(7 suppl 1):19S-32S.

21. 
Spear SL, Baker JL Jr. Classification of capsular contracture after prosthetic breast reconstruction. Plast Reconstr Surg. 1995;96:1119-1123.

22. 
Schreml S, Heine N, Eisenmann-Klein M, Pranti L. Bacterial colonization is of major relevance for high-grade capsular contracture after augmentation mammaplasty. Ann Plast Surg. 2007;59:126-130.

23. 
Siggelkow W, Faridi A, Spiritus K, et al. Histological analysis of silicone breast implant capsules and correlation with capsular contracture. Biomaterials. 2003;24:1101-1109.

24. 
Henriksen TF, Fryzek JP, Hölmich LR, et al. Surgical intervention and capsular contracture after breast augmentation: a prospective study of risk factors. Ann Plast Surg. 2005;54:343-351.

25. 
Amano Y, Aoki R, Kumita S, Kumazaki T. Silicone-selective multishot echo-planar imaging for rapid MRI survey of breast implants. Eur Radiol. 2007;17:1875-1878.

26. 
Maxwell GP, Van Natta BW, Murphy DK, et al. Natrelle style 410 form-stable silicone breast implants: core study results at 6 years. Aesthet Surg J. 2012;32:709-717.

27. 
Stevens WG, Harrington J, Alizadeh K, et al. Five-year follow-up data from the US clinical trial for Sientra’s U.S. Food and Drug Administration-approved Silimed^® brand round and shaped implants with high-strength silicone gel. Plast Reconstr Surg. 2012;130:973-981.

28. 
Hold PM, Alam S, Pilbrow WJ, et al. How should we investigate breast implant rupture? Breast J. 2012;18:253-256.

29. 
Everson LI, Parantainen H, Detlie T, et al. Diagnosis of breast implant rupture: imaging findings and relative efficacies of imaging techniques. AJR Am J Roentgenol. 1994;163:57-60.

30. 
Hölmich LR, Vejborg IM, Conrad C, et al. Untreated silicone breast implant rupture. Plast Reconstr Surg. 2004;114:204-214.

31. 
Dowden RV, Reisman NR. Breast implant overfill, optimal fill, and the standard of care. Plast Reconstr Surg. 1999;104:1185-1186.

32. 
Spear SL, Sinkin JC, Al-Attar A. Porcine acellular dermal matrix (Strattice™) in primary and revision cosmetic breast surgery. Plast Reconstr Surg. 2013;131:1140-1148.

33. 
Shestak KC. Acellular dermal matrix inlays to correct significant implant malposition in patients with compromised local tissues. Aesthet Surg J. 2011;31(7 suppl):85S-94S.

34. 
Spear SL, Bogue DP, Thomassen JM. Synmastia after breast augmentation. Plast Reconstr Surg. 2006;118(7 suppl):168S-171S.

35. 
Selvaggi G, Giordano S, Ishak L. Synmastia: prevention and correction. Ann Plast Surg. 2010;65:455-461.

36. 
Coscia J, Lance S, Wong M, Garcia J. Mondor’s thrombophlebitis 13 years after breast augmentation. Ann Plast Surg. 2012;68:336-337.

37. 
Dudrap E, Milliez PY, Auquit-Auckbur I, Bony-Rerolle S. Mondor’s disease and breast plastic surgery [in French]. Ann Chir Plast Esthet. 2010; 55:233-237.

With so many potential problems, and so many ways patients can react to them, it seems impossible to construct any sort of template for consistent, mutually satisfactory resolutions to patients' complaints. 

But it can be done, and it’s not as complex as it appears, once you realize that the vast majority of complaints have the same basic root: The patient’s expectations have not been met. Sometimes it’s your fault, sometimes the patient’s, and often a bit of both, but either way, the result is the same: You have an unhappy patient, and you must deal with it.

I have distilled this unpleasant duty down to a simple, three-part strategy:

• Discover which expectations went unmet and why.

• Agree on a solution.

• Learn from the experience, to prevent similar future complaints.

In most cases, this is not a job you should delegate. Unless the complaint is trivial or purely administrative, you should address it yourself. It’s what you would want if you were the complainant, and it’s often too important to trust to a subordinate.

At this point, you may be asking, "Why should I care?" Is the personal expenditure of your time and effort necessary to resolve complaints really worth it? Absolutely, because the old cliché is true: A satisfied patient will refer 5 new ones, but a dissatisfied one will frighten away 20 or more. Besides, if the complaint is significant and you don’t resolve it, the patient is likely to find someone who will; and chances are you won’t like their choice, or the eventual resolution.

Of course, the easiest way to deal with complaints is to prevent as many as possible in the first place. Try to nip unrealistic expectations in the bud. Take the time in advance to explain all treatments and procedures, and their most likely outcomes, in a clear and honest manner. And since even the most astute patients will not absorb everything you tell them, make liberal use of written handouts and other visual aids.

And, of course, document everything you have explained. Documentation is like garlic: There is no such thing as too much of it.

But despite your best efforts, there will always be complaints, and handling them is a skill set worth honing. The most important skill in that set is listening to the complaint. Before you can resolve a problem, you have to know what it is, and this is precisely the wrong time to make assumptions or jump to conclusions.

So listen to the entire complaint without interrupting, defending, or justifying. Angry patients don’t care why the problem occurred, and they are not interested in your side of the story. This is not about you, so listen and understand.

As you listen, the unmet expectations will become clear. When the patient is finished, I like to summarize the complaint in that context: "So, if I understand you correctly, you expected "X" to happen, but "Y" happened instead." If I’m wrong, I modify my summary until the patient agrees that I understand the problem.

Once you know the problem, you can talk about a solution. The patient usually has one in mind – additional treatment, a referral elsewhere, a fee adjustment, or sometimes simply an apology. Consider it.

If the patient’s solution is reasonable, by all means, agree to it; if it is unreasonable, try to offer a reasonable alternative. The temptation is to think more about protecting yourself than about making the patient happy, but that often leads to bigger problems. Don’t be defensive. Remember, this is not about you.

I am often asked if refunding a fee is a reasonable solution. Some patients (and lawyers) will interpret a refund as a tacit admission of guilt, so I generally try to avoid them. However, cancelling a small fee for an angry patient can be very prudent, and in my opinion that looks exactly like what it is: an honest effort to rectify the situation. But in general, free (or reduced-fee) additional materials or services are a better alternative than refunding money.

Once you have arrived at a mutually satisfactory solution, again, document everything, but consider reserving a "private" chart area for such documentation (unless it is a bona fide clinical issue) so that it won’t go out to referrers and other third parties with copies of your clinical notes. Also, consider having the patient sign off on the documentation, acknowledging that the complaint has been resolved.

Finally, always try to learn something from the experience. Ask yourself how you might prevent a repetition of the complaint, what you did that you can avoid doing next time, and how you might prevent unrealistic expectations in a similar future situation.

Above all, don’t take complaints personally – even when they are personal. It’s always worth remembering that no matter how hard you try, you can never please everyone.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J.

With so many potential problems, and so many ways patients can react to them, it seems impossible to construct any sort of template for consistent, mutually satisfactory resolutions to patients' complaints. 

But it can be done, and it’s not as complex as it appears, once you realize that the vast majority of complaints have the same basic root: The patient’s expectations have not been met. Sometimes it’s your fault, sometimes the patient’s, and often a bit of both, but either way, the result is the same: You have an unhappy patient, and you must deal with it.

I have distilled this unpleasant duty down to a simple, three-part strategy:

• Discover which expectations went unmet and why.

• Agree on a solution.

• Learn from the experience, to prevent similar future complaints.

In most cases, this is not a job you should delegate. Unless the complaint is trivial or purely administrative, you should address it yourself. It’s what you would want if you were the complainant, and it’s often too important to trust to a subordinate.

At this point, you may be asking, "Why should I care?" Is the personal expenditure of your time and effort necessary to resolve complaints really worth it? Absolutely, because the old cliché is true: A satisfied patient will refer 5 new ones, but a dissatisfied one will frighten away 20 or more. Besides, if the complaint is significant and you don’t resolve it, the patient is likely to find someone who will; and chances are you won’t like their choice, or the eventual resolution.

Of course, the easiest way to deal with complaints is to prevent as many as possible in the first place. Try to nip unrealistic expectations in the bud. Take the time in advance to explain all treatments and procedures, and their most likely outcomes, in a clear and honest manner. And since even the most astute patients will not absorb everything you tell them, make liberal use of written handouts and other visual aids.

And, of course, document everything you have explained. Documentation is like garlic: There is no such thing as too much of it.

But despite your best efforts, there will always be complaints, and handling them is a skill set worth honing. The most important skill in that set is listening to the complaint. Before you can resolve a problem, you have to know what it is, and this is precisely the wrong time to make assumptions or jump to conclusions.

So listen to the entire complaint without interrupting, defending, or justifying. Angry patients don’t care why the problem occurred, and they are not interested in your side of the story. This is not about you, so listen and understand.

As you listen, the unmet expectations will become clear. When the patient is finished, I like to summarize the complaint in that context: "So, if I understand you correctly, you expected "X" to happen, but "Y" happened instead." If I’m wrong, I modify my summary until the patient agrees that I understand the problem.

Once you know the problem, you can talk about a solution. The patient usually has one in mind – additional treatment, a referral elsewhere, a fee adjustment, or sometimes simply an apology. Consider it.

If the patient’s solution is reasonable, by all means, agree to it; if it is unreasonable, try to offer a reasonable alternative. The temptation is to think more about protecting yourself than about making the patient happy, but that often leads to bigger problems. Don’t be defensive. Remember, this is not about you.

I am often asked if refunding a fee is a reasonable solution. Some patients (and lawyers) will interpret a refund as a tacit admission of guilt, so I generally try to avoid them. However, cancelling a small fee for an angry patient can be very prudent, and in my opinion that looks exactly like what it is: an honest effort to rectify the situation. But in general, free (or reduced-fee) additional materials or services are a better alternative than refunding money.

Once you have arrived at a mutually satisfactory solution, again, document everything, but consider reserving a "private" chart area for such documentation (unless it is a bona fide clinical issue) so that it won’t go out to referrers and other third parties with copies of your clinical notes. Also, consider having the patient sign off on the documentation, acknowledging that the complaint has been resolved.

Finally, always try to learn something from the experience. Ask yourself how you might prevent a repetition of the complaint, what you did that you can avoid doing next time, and how you might prevent unrealistic expectations in a similar future situation.

Above all, don’t take complaints personally – even when they are personal. It’s always worth remembering that no matter how hard you try, you can never please everyone.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J.

With so many potential problems, and so many ways patients can react to them, it seems impossible to construct any sort of template for consistent, mutually satisfactory resolutions to patients' complaints. 

But it can be done, and it’s not as complex as it appears, once you realize that the vast majority of complaints have the same basic root: The patient’s expectations have not been met. Sometimes it’s your fault, sometimes the patient’s, and often a bit of both, but either way, the result is the same: You have an unhappy patient, and you must deal with it.

I have distilled this unpleasant duty down to a simple, three-part strategy:

• Discover which expectations went unmet and why.

• Agree on a solution.

• Learn from the experience, to prevent similar future complaints.

In most cases, this is not a job you should delegate. Unless the complaint is trivial or purely administrative, you should address it yourself. It’s what you would want if you were the complainant, and it’s often too important to trust to a subordinate.

At this point, you may be asking, "Why should I care?" Is the personal expenditure of your time and effort necessary to resolve complaints really worth it? Absolutely, because the old cliché is true: A satisfied patient will refer 5 new ones, but a dissatisfied one will frighten away 20 or more. Besides, if the complaint is significant and you don’t resolve it, the patient is likely to find someone who will; and chances are you won’t like their choice, or the eventual resolution.

Of course, the easiest way to deal with complaints is to prevent as many as possible in the first place. Try to nip unrealistic expectations in the bud. Take the time in advance to explain all treatments and procedures, and their most likely outcomes, in a clear and honest manner. And since even the most astute patients will not absorb everything you tell them, make liberal use of written handouts and other visual aids.

And, of course, document everything you have explained. Documentation is like garlic: There is no such thing as too much of it.

But despite your best efforts, there will always be complaints, and handling them is a skill set worth honing. The most important skill in that set is listening to the complaint. Before you can resolve a problem, you have to know what it is, and this is precisely the wrong time to make assumptions or jump to conclusions.

So listen to the entire complaint without interrupting, defending, or justifying. Angry patients don’t care why the problem occurred, and they are not interested in your side of the story. This is not about you, so listen and understand.

As you listen, the unmet expectations will become clear. When the patient is finished, I like to summarize the complaint in that context: "So, if I understand you correctly, you expected "X" to happen, but "Y" happened instead." If I’m wrong, I modify my summary until the patient agrees that I understand the problem.

Once you know the problem, you can talk about a solution. The patient usually has one in mind – additional treatment, a referral elsewhere, a fee adjustment, or sometimes simply an apology. Consider it.

If the patient’s solution is reasonable, by all means, agree to it; if it is unreasonable, try to offer a reasonable alternative. The temptation is to think more about protecting yourself than about making the patient happy, but that often leads to bigger problems. Don’t be defensive. Remember, this is not about you.

I am often asked if refunding a fee is a reasonable solution. Some patients (and lawyers) will interpret a refund as a tacit admission of guilt, so I generally try to avoid them. However, cancelling a small fee for an angry patient can be very prudent, and in my opinion that looks exactly like what it is: an honest effort to rectify the situation. But in general, free (or reduced-fee) additional materials or services are a better alternative than refunding money.

Once you have arrived at a mutually satisfactory solution, again, document everything, but consider reserving a "private" chart area for such documentation (unless it is a bona fide clinical issue) so that it won’t go out to referrers and other third parties with copies of your clinical notes. Also, consider having the patient sign off on the documentation, acknowledging that the complaint has been resolved.

Finally, always try to learn something from the experience. Ask yourself how you might prevent a repetition of the complaint, what you did that you can avoid doing next time, and how you might prevent unrealistic expectations in a similar future situation.

Above all, don’t take complaints personally – even when they are personal. It’s always worth remembering that no matter how hard you try, you can never please everyone.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J.

A significant dissatisfier for both clinician and patient is that inhaled corticosteroids, commonly underutilized and potentially lifesaving medications, are almost never (if ever) covered at the lowest tier by insurance companies. We would select a first-tier medication if there were one that we could substitute for an ICS; but frequently there isn’t, so we can’t.

Because of this, patients may be financially motivated to simply stop the medication – especially if they perceive that they are on the lowest doses and believe the medication perhaps is not needed at all. Clinicians, meanwhile, are doing the balancing act of moving patients to the lowest doses in order to avoid side effects while maintaining optimal disease control.

So, what are the risks when patients stop using inhaled corticosteroids?

Dr. Matthew A. Rank of the Mayo Clinic, Rochester, Minn., and his colleagues recently published a systematic review of the literature to answer this question (J. Allergy Clin. Immunol. 2013;131:724-9). In this review, randomized, controlled clinical trials in which the study intervention was continuing or stopping low-dose ICSs were included. Studies had to have 4 or more weeks of a run-in with stable doses of ICSs to ensure a minimum period of asthma stability. Seven studies met inclusion criteria. Two studies were exclusively in children, and one was exclusively in adults.

Asthma exacerbations were more likely among patients who stopped ICSs, compared with those who did not (relative risk, 2.35; 95% CI: 1.88-2.92). The risk for an asthma exacerbation in the next 6 months on low-dose ICSs was 16% if patients continued taking the medications, and 38% if they stopped. For every five patients who stopped ICSs, one patient would be expected to have an asthma exacerbation in the next 6 months – which could have been prevented if steroids had been continued. The mean decrease in forced expiratory volume in 1 second associated with discontinued ICSs use was 130 mL.

Most patients can step down with ICSs if they are on long-acting beta-agonists. Expert panels have suggested that patients should be controlled for 3 months before stepping down therapy. Findings from this study further suggest that patients who discontinue low-dose ICSs are at an increased risk of asthma exacerbation.

We need to help our patients understand the risk of stopping low-dose ICSs and encourage them, as much as they are able, to stay on them.

Dr. Ebbert is professor of medicine and a primary care clinician at the Mayo Clinic in Rochester, Minn. He reported having no relevant financial conflicts. The opinions expressed are those of the author.

This column, "What Matters," appears regularly in Internal Medicine News.

A significant dissatisfier for both clinician and patient is that inhaled corticosteroids, commonly underutilized and potentially lifesaving medications, are almost never (if ever) covered at the lowest tier by insurance companies. We would select a first-tier medication if there were one that we could substitute for an ICS; but frequently there isn’t, so we can’t.

Because of this, patients may be financially motivated to simply stop the medication – especially if they perceive that they are on the lowest doses and believe the medication perhaps is not needed at all. Clinicians, meanwhile, are doing the balancing act of moving patients to the lowest doses in order to avoid side effects while maintaining optimal disease control.

So, what are the risks when patients stop using inhaled corticosteroids?

Dr. Matthew A. Rank of the Mayo Clinic, Rochester, Minn., and his colleagues recently published a systematic review of the literature to answer this question (J. Allergy Clin. Immunol. 2013;131:724-9). In this review, randomized, controlled clinical trials in which the study intervention was continuing or stopping low-dose ICSs were included. Studies had to have 4 or more weeks of a run-in with stable doses of ICSs to ensure a minimum period of asthma stability. Seven studies met inclusion criteria. Two studies were exclusively in children, and one was exclusively in adults.

Asthma exacerbations were more likely among patients who stopped ICSs, compared with those who did not (relative risk, 2.35; 95% CI: 1.88-2.92). The risk for an asthma exacerbation in the next 6 months on low-dose ICSs was 16% if patients continued taking the medications, and 38% if they stopped. For every five patients who stopped ICSs, one patient would be expected to have an asthma exacerbation in the next 6 months – which could have been prevented if steroids had been continued. The mean decrease in forced expiratory volume in 1 second associated with discontinued ICSs use was 130 mL.

Most patients can step down with ICSs if they are on long-acting beta-agonists. Expert panels have suggested that patients should be controlled for 3 months before stepping down therapy. Findings from this study further suggest that patients who discontinue low-dose ICSs are at an increased risk of asthma exacerbation.

We need to help our patients understand the risk of stopping low-dose ICSs and encourage them, as much as they are able, to stay on them.

Dr. Ebbert is professor of medicine and a primary care clinician at the Mayo Clinic in Rochester, Minn. He reported having no relevant financial conflicts. The opinions expressed are those of the author.

This column, "What Matters," appears regularly in Internal Medicine News.

A significant dissatisfier for both clinician and patient is that inhaled corticosteroids, commonly underutilized and potentially lifesaving medications, are almost never (if ever) covered at the lowest tier by insurance companies. We would select a first-tier medication if there were one that we could substitute for an ICS; but frequently there isn’t, so we can’t.

Because of this, patients may be financially motivated to simply stop the medication – especially if they perceive that they are on the lowest doses and believe the medication perhaps is not needed at all. Clinicians, meanwhile, are doing the balancing act of moving patients to the lowest doses in order to avoid side effects while maintaining optimal disease control.

So, what are the risks when patients stop using inhaled corticosteroids?

Dr. Matthew A. Rank of the Mayo Clinic, Rochester, Minn., and his colleagues recently published a systematic review of the literature to answer this question (J. Allergy Clin. Immunol. 2013;131:724-9). In this review, randomized, controlled clinical trials in which the study intervention was continuing or stopping low-dose ICSs were included. Studies had to have 4 or more weeks of a run-in with stable doses of ICSs to ensure a minimum period of asthma stability. Seven studies met inclusion criteria. Two studies were exclusively in children, and one was exclusively in adults.

Asthma exacerbations were more likely among patients who stopped ICSs, compared with those who did not (relative risk, 2.35; 95% CI: 1.88-2.92). The risk for an asthma exacerbation in the next 6 months on low-dose ICSs was 16% if patients continued taking the medications, and 38% if they stopped. For every five patients who stopped ICSs, one patient would be expected to have an asthma exacerbation in the next 6 months – which could have been prevented if steroids had been continued. The mean decrease in forced expiratory volume in 1 second associated with discontinued ICSs use was 130 mL.

Most patients can step down with ICSs if they are on long-acting beta-agonists. Expert panels have suggested that patients should be controlled for 3 months before stepping down therapy. Findings from this study further suggest that patients who discontinue low-dose ICSs are at an increased risk of asthma exacerbation.

We need to help our patients understand the risk of stopping low-dose ICSs and encourage them, as much as they are able, to stay on them.

Dr. Ebbert is professor of medicine and a primary care clinician at the Mayo Clinic in Rochester, Minn. He reported having no relevant financial conflicts. The opinions expressed are those of the author.

This column, "What Matters," appears regularly in Internal Medicine News.

Since the last Practice Alert update on the US Preventive Services Task Force (USPSTF) recommendations,¹ the Task Force released 16 final recommendations, through January of this year (TABLE).² However, none of these were level A recommendations and only 4 were level B. This is significant in that USPSTF level A and B recommendations must now be covered by health insurance plans without patient cost sharing as a result of a clause in the Affordable Care Act. There were 5 D recommendations (recommend against), and some of the tests that fell into this category are in common use. I discuss the B and D recommendations below.

TABLE
Recent recommendations from the USPSTF²

B recommendations

Encourage vitamin D supplementation and regular exercise to prevent falls in elderly
Falls in the elderly are a significant cause of morbidity and mortality. The Task Force found that between 30% and 40% of community-dwelling adults ≥65 years fall each year, and 5% to 10% of those who fall will sustain a fracture, head injury, or laceration.³ Those at highest risk have a history of falls, report mobility problems, have chronic diseases, use psychotropic medications, or have difficulty on a “get up and go” test, which involves rising from a sitting position in an arm chair, walking 10 feet, turning, walking back, and sitting down. If this activity takes more than 10 seconds, the risk of a fall is increased.³

Two interventions were found to be effective in preventing falls: vitamin D supplementation and regular exercise or physical therapy. Vitamin D enhances muscular strength and balance, and supplementation of 800 IU daily for 12 months can decrease the risk of a fall by 17%, with a number needed to treat (NNT) of 10 to prevent one fall.³ Exercise or physical therapy that focuses on gait and balance, strength or resistance training, or general fitness can reduce the risk of falls with an NNT of 16. Individuals who benefit the most are those at higher risk.³

As for multifactorial risk assessment and comprehensive management of risks to prevent falls, a pooled analysis of studies showed that these interventions do little to reduce falls and do not warrant routine use. The Task Force evaluated other interventions—vision correction, medication discontinuation, protein supplementation, education or counseling, and home hazard modification—but could not find sufficient evidence to recommend for or against them.

Screen for obesity in adults
The Task Force reaffirmed its recommendation to screen all adults for obesity and to offer intensive behavioral interventions to those with a body mass index of ≥30 kg/m². Helpful interventions include multiple behavioral management activities in group or individual sessions; setting weight-loss goals; improving diet or nutrition; physical activity sessions; addressing barriers to change; active use of self-monitoring; and strategizing ways to maintain lifestyle changes. High-intensity programs involve 12 to 26 sessions a year and result, on average, in a reduction of 6% of body weight.⁴

Counsel fair-skinned patients to minimize sun exposure
The Task Force now recommends counseling fair-skinned children, adolescents, and young adults (10-24 years of age) about reducing their exposure to ultraviolet (UV) radiation. UV radiation exposure occurs when outdoors in the sun, especially in the middle of the day; and when using artificial sources of UV light, such as an indoor tanning bed. Unprotected UV light exposure is a cause of skin cancer, especially when this exposure occurs in childhood or young adulthood.

Behaviors that protect from UV radiation exposure include using broad-spectrum sunscreen with a sun-protection factor of at least 15, wearing hats and protective clothing, avoiding the outdoors during midday hours (10 am-3 pm), and avoiding indoor tanning. Brief counseling offered in a primary care setting can increase protective behaviors in the targeted age group.

UV light exposure in adults is also linked to skin cancer, but the effectiveness of counseling in this population is less certain and the benefit from protective behaviors is less. In addition, almost all studies of skin cancer prevention have been conducted with fair-skinned subjects, so the Task Force limited this recommendation to those who have fair skin and are between the ages of 10 and 24.⁵

Screen for intimate partner violence
The USPSTF has changed its recommendation on screening women for intimate partner violence (IPV). Previously it said that the evidence was insufficient to make a recommendation. New evidence has since been published and the Task Force recommends that women of childbearing age (14-46 years, with most evidence for those over age 18) be screened using one of 6 screening tools found to have satisfactory performance characteristics.⁶ IPV means physical, sexual, or psychological abuse by a current or former partner or spouse, among heterosexual or same-sex couples. To learn more, see “Time to routinely screen for intimate partner violence?” (J Fam Pract. 2013;62:90-92).

Services found to be effective in preventing IPV include counseling, home visits, information cards, referrals to community services, and mentoring support provided by physicians or other health professionals.⁶

The evidence on screening for the prevention of elder abuse and abuse of vulnerable adults still remains insufficient for a recommendation.

D recommendations

No need for prostate cancer screening, or these other interventions
The list of new D recommendations (interventions that have no benefit or that cause more harm than benefit) includes:

• screening for ovarian and prostate cancer
• using estrogen or estrogen combined with progestin in postmenopausal women for the prevention of chronic conditions
• screening with resting or exercise electrocardiography for the prediction of coronary heart disease events in asymptomatic adults at low risk for such events.

The most controversial D recommendation is to avoid measuring prostate-specific antigen (PSA) to screen for prostate cancer. The Task Force has never endorsed use of the PSA test, previously stating that evidence was not of sufficient strength to recommend for or against it in men <75 years and recommending against it for older men. The evidence report conducted for the reconsideration of this topic provided sufficient evidence that the PSA test results in far more harm than benefit.

The troublesome C recommendation

Proceed with caution with these 2 interventions
The wording of level C recommendations has undergone revision once again. In recognition that some preventive services may benefit select patients—although the overall benefit in the population is small—the USPSTF now states that a C recommendation means that the Task Force “recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences.” This past year, 2 interventions fell into this category: multifactorial risk assessment and management to prevent falls in community dwelling elders, and counseling adults about a healthy diet and exercise to prevent cardiovascular disease (TABLE).²

Since the last Practice Alert update on the US Preventive Services Task Force (USPSTF) recommendations,¹ the Task Force released 16 final recommendations, through January of this year (TABLE).² However, none of these were level A recommendations and only 4 were level B. This is significant in that USPSTF level A and B recommendations must now be covered by health insurance plans without patient cost sharing as a result of a clause in the Affordable Care Act. There were 5 D recommendations (recommend against), and some of the tests that fell into this category are in common use. I discuss the B and D recommendations below.

TABLE
Recent recommendations from the USPSTF²

B recommendations

Encourage vitamin D supplementation and regular exercise to prevent falls in elderly
Falls in the elderly are a significant cause of morbidity and mortality. The Task Force found that between 30% and 40% of community-dwelling adults ≥65 years fall each year, and 5% to 10% of those who fall will sustain a fracture, head injury, or laceration.³ Those at highest risk have a history of falls, report mobility problems, have chronic diseases, use psychotropic medications, or have difficulty on a “get up and go” test, which involves rising from a sitting position in an arm chair, walking 10 feet, turning, walking back, and sitting down. If this activity takes more than 10 seconds, the risk of a fall is increased.³

Two interventions were found to be effective in preventing falls: vitamin D supplementation and regular exercise or physical therapy. Vitamin D enhances muscular strength and balance, and supplementation of 800 IU daily for 12 months can decrease the risk of a fall by 17%, with a number needed to treat (NNT) of 10 to prevent one fall.³ Exercise or physical therapy that focuses on gait and balance, strength or resistance training, or general fitness can reduce the risk of falls with an NNT of 16. Individuals who benefit the most are those at higher risk.³

As for multifactorial risk assessment and comprehensive management of risks to prevent falls, a pooled analysis of studies showed that these interventions do little to reduce falls and do not warrant routine use. The Task Force evaluated other interventions—vision correction, medication discontinuation, protein supplementation, education or counseling, and home hazard modification—but could not find sufficient evidence to recommend for or against them.

Screen for obesity in adults
The Task Force reaffirmed its recommendation to screen all adults for obesity and to offer intensive behavioral interventions to those with a body mass index of ≥30 kg/m². Helpful interventions include multiple behavioral management activities in group or individual sessions; setting weight-loss goals; improving diet or nutrition; physical activity sessions; addressing barriers to change; active use of self-monitoring; and strategizing ways to maintain lifestyle changes. High-intensity programs involve 12 to 26 sessions a year and result, on average, in a reduction of 6% of body weight.⁴

Counsel fair-skinned patients to minimize sun exposure
The Task Force now recommends counseling fair-skinned children, adolescents, and young adults (10-24 years of age) about reducing their exposure to ultraviolet (UV) radiation. UV radiation exposure occurs when outdoors in the sun, especially in the middle of the day; and when using artificial sources of UV light, such as an indoor tanning bed. Unprotected UV light exposure is a cause of skin cancer, especially when this exposure occurs in childhood or young adulthood.

Behaviors that protect from UV radiation exposure include using broad-spectrum sunscreen with a sun-protection factor of at least 15, wearing hats and protective clothing, avoiding the outdoors during midday hours (10 am-3 pm), and avoiding indoor tanning. Brief counseling offered in a primary care setting can increase protective behaviors in the targeted age group.

UV light exposure in adults is also linked to skin cancer, but the effectiveness of counseling in this population is less certain and the benefit from protective behaviors is less. In addition, almost all studies of skin cancer prevention have been conducted with fair-skinned subjects, so the Task Force limited this recommendation to those who have fair skin and are between the ages of 10 and 24.⁵

Screen for intimate partner violence
The USPSTF has changed its recommendation on screening women for intimate partner violence (IPV). Previously it said that the evidence was insufficient to make a recommendation. New evidence has since been published and the Task Force recommends that women of childbearing age (14-46 years, with most evidence for those over age 18) be screened using one of 6 screening tools found to have satisfactory performance characteristics.⁶ IPV means physical, sexual, or psychological abuse by a current or former partner or spouse, among heterosexual or same-sex couples. To learn more, see “Time to routinely screen for intimate partner violence?” (J Fam Pract. 2013;62:90-92).

Services found to be effective in preventing IPV include counseling, home visits, information cards, referrals to community services, and mentoring support provided by physicians or other health professionals.⁶

The evidence on screening for the prevention of elder abuse and abuse of vulnerable adults still remains insufficient for a recommendation.

D recommendations

No need for prostate cancer screening, or these other interventions
The list of new D recommendations (interventions that have no benefit or that cause more harm than benefit) includes:

• screening for ovarian and prostate cancer
• using estrogen or estrogen combined with progestin in postmenopausal women for the prevention of chronic conditions
• screening with resting or exercise electrocardiography for the prediction of coronary heart disease events in asymptomatic adults at low risk for such events.

The most controversial D recommendation is to avoid measuring prostate-specific antigen (PSA) to screen for prostate cancer. The Task Force has never endorsed use of the PSA test, previously stating that evidence was not of sufficient strength to recommend for or against it in men <75 years and recommending against it for older men. The evidence report conducted for the reconsideration of this topic provided sufficient evidence that the PSA test results in far more harm than benefit.

The troublesome C recommendation

Proceed with caution with these 2 interventions
The wording of level C recommendations has undergone revision once again. In recognition that some preventive services may benefit select patients—although the overall benefit in the population is small—the USPSTF now states that a C recommendation means that the Task Force “recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences.” This past year, 2 interventions fell into this category: multifactorial risk assessment and management to prevent falls in community dwelling elders, and counseling adults about a healthy diet and exercise to prevent cardiovascular disease (TABLE).²

Since the last Practice Alert update on the US Preventive Services Task Force (USPSTF) recommendations,¹ the Task Force released 16 final recommendations, through January of this year (TABLE).² However, none of these were level A recommendations and only 4 were level B. This is significant in that USPSTF level A and B recommendations must now be covered by health insurance plans without patient cost sharing as a result of a clause in the Affordable Care Act. There were 5 D recommendations (recommend against), and some of the tests that fell into this category are in common use. I discuss the B and D recommendations below.

TABLE
Recent recommendations from the USPSTF²

B recommendations

Encourage vitamin D supplementation and regular exercise to prevent falls in elderly
Falls in the elderly are a significant cause of morbidity and mortality. The Task Force found that between 30% and 40% of community-dwelling adults ≥65 years fall each year, and 5% to 10% of those who fall will sustain a fracture, head injury, or laceration.³ Those at highest risk have a history of falls, report mobility problems, have chronic diseases, use psychotropic medications, or have difficulty on a “get up and go” test, which involves rising from a sitting position in an arm chair, walking 10 feet, turning, walking back, and sitting down. If this activity takes more than 10 seconds, the risk of a fall is increased.³

Two interventions were found to be effective in preventing falls: vitamin D supplementation and regular exercise or physical therapy. Vitamin D enhances muscular strength and balance, and supplementation of 800 IU daily for 12 months can decrease the risk of a fall by 17%, with a number needed to treat (NNT) of 10 to prevent one fall.³ Exercise or physical therapy that focuses on gait and balance, strength or resistance training, or general fitness can reduce the risk of falls with an NNT of 16. Individuals who benefit the most are those at higher risk.³

As for multifactorial risk assessment and comprehensive management of risks to prevent falls, a pooled analysis of studies showed that these interventions do little to reduce falls and do not warrant routine use. The Task Force evaluated other interventions—vision correction, medication discontinuation, protein supplementation, education or counseling, and home hazard modification—but could not find sufficient evidence to recommend for or against them.

Screen for obesity in adults
The Task Force reaffirmed its recommendation to screen all adults for obesity and to offer intensive behavioral interventions to those with a body mass index of ≥30 kg/m². Helpful interventions include multiple behavioral management activities in group or individual sessions; setting weight-loss goals; improving diet or nutrition; physical activity sessions; addressing barriers to change; active use of self-monitoring; and strategizing ways to maintain lifestyle changes. High-intensity programs involve 12 to 26 sessions a year and result, on average, in a reduction of 6% of body weight.⁴

Counsel fair-skinned patients to minimize sun exposure
The Task Force now recommends counseling fair-skinned children, adolescents, and young adults (10-24 years of age) about reducing their exposure to ultraviolet (UV) radiation. UV radiation exposure occurs when outdoors in the sun, especially in the middle of the day; and when using artificial sources of UV light, such as an indoor tanning bed. Unprotected UV light exposure is a cause of skin cancer, especially when this exposure occurs in childhood or young adulthood.

Behaviors that protect from UV radiation exposure include using broad-spectrum sunscreen with a sun-protection factor of at least 15, wearing hats and protective clothing, avoiding the outdoors during midday hours (10 am-3 pm), and avoiding indoor tanning. Brief counseling offered in a primary care setting can increase protective behaviors in the targeted age group.

UV light exposure in adults is also linked to skin cancer, but the effectiveness of counseling in this population is less certain and the benefit from protective behaviors is less. In addition, almost all studies of skin cancer prevention have been conducted with fair-skinned subjects, so the Task Force limited this recommendation to those who have fair skin and are between the ages of 10 and 24.⁵

Screen for intimate partner violence
The USPSTF has changed its recommendation on screening women for intimate partner violence (IPV). Previously it said that the evidence was insufficient to make a recommendation. New evidence has since been published and the Task Force recommends that women of childbearing age (14-46 years, with most evidence for those over age 18) be screened using one of 6 screening tools found to have satisfactory performance characteristics.⁶ IPV means physical, sexual, or psychological abuse by a current or former partner or spouse, among heterosexual or same-sex couples. To learn more, see “Time to routinely screen for intimate partner violence?” (J Fam Pract. 2013;62:90-92).

Services found to be effective in preventing IPV include counseling, home visits, information cards, referrals to community services, and mentoring support provided by physicians or other health professionals.⁶

The evidence on screening for the prevention of elder abuse and abuse of vulnerable adults still remains insufficient for a recommendation.

D recommendations

No need for prostate cancer screening, or these other interventions
The list of new D recommendations (interventions that have no benefit or that cause more harm than benefit) includes:

• screening for ovarian and prostate cancer
• using estrogen or estrogen combined with progestin in postmenopausal women for the prevention of chronic conditions
• screening with resting or exercise electrocardiography for the prediction of coronary heart disease events in asymptomatic adults at low risk for such events.

The most controversial D recommendation is to avoid measuring prostate-specific antigen (PSA) to screen for prostate cancer. The Task Force has never endorsed use of the PSA test, previously stating that evidence was not of sufficient strength to recommend for or against it in men <75 years and recommending against it for older men. The evidence report conducted for the reconsideration of this topic provided sufficient evidence that the PSA test results in far more harm than benefit.

The troublesome C recommendation

Proceed with caution with these 2 interventions
The wording of level C recommendations has undergone revision once again. In recognition that some preventive services may benefit select patients—although the overall benefit in the population is small—the USPSTF now states that a C recommendation means that the Task Force “recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences.” This past year, 2 interventions fell into this category: multifactorial risk assessment and management to prevent falls in community dwelling elders, and counseling adults about a healthy diet and exercise to prevent cardiovascular disease (TABLE).²

Heparin-induced thrombocytopenia (HIT) is an immune-mediated drug reaction that requires prompt detection and treatment in order to minimize patient morbidity and mortality.¹ HIT is caused by the development of antibodies to platelet factor 4 (PF4), although it is important to note that not all patients who develop PF4 antibodies will experience the clinical syndrome of HIT.^2-4 In fact, about 50% of patients who undergo cardiovascular surgery develop PF4 antibodies, but only 1% to 2% of patients with antibodies actually experience HIT.^5-7 There is currently no explanation for the phenomenon of HIT.⁸

In 2012, with an intent to limit HIT-associated morbidity and mortality, the American College of Chest Physicians (ACCP) unveiled the ninth edition of its evidence-based practice guidelines for the detection of HIT and appropriate treatment.⁵ Much of the information provided in this article emerged from these guidelines.

Epidemiology

Of the 12 million patients treated each year with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH), 600,000 (0.5%) will develop HIT. Among these patients, 300,000 will develop thrombosis, and 90,000 will die. In 2009 alone, the HIT-associated cost to the US health care system was estimated at $100 million.¹

As growing numbers of patients require anticoagulation therapy, it becomes increasingly important for clinicians to understand the importance of screening for deep vein thrombosis (DVT), one of the two most common thromboses; the other is pulmonary embolism.^9,10 Continuing to administer heparin or warfarin to patients with undetected HIT predisposes them to severe complications, including venous and arterial thromboses and gangrenous skin lesions—which can result in loss of life and/or limb.^1,11,12

Risk Factors for HIT

Several factors influence a patient's risk for HIT, including the type and dosing regimen of the heparin being administered. Generally, the risk for HIT is about 10-fold in patients treated with UFH (3% to 5%), compared with those receiving LMWH (0.5%).^5,13 The risk for HIT is also greater in patients receiving UFH of bovine origin, compared with those taking porcine-derived UFH.^8,14,15

In a recent meta-analysis of postsurgical patients who underwent heparin thromboprophylaxis, those given LMWH had a 76% relative risk reduction for HIT, compared with patients taking UFH.¹⁶ The incidence of HIT increases among patients receiving LMWH if they have been treated with UFH within the previous 100 days.⁹ HIT onset may be delayed for several days in patients given heparin for the first time (or for the first time in several months), whereas previously exposed patients who have already developed antiheparin PF4 antibodies can experience severe HIT within hours.⁹

Patient-Specific Risk Factors

Certain patient characteristics also have an impact on HIT risk. For example, the risk for HIT is approximately doubled in women, compared with men,^1,5,15 and the incidence of HIT is greater in surgical patients than in medical patients.^7,17 Among surgical patients, 5% of orthopedic patients have been reported to develop HIT, compared with 3% of cardiac patients and 1% of patients undergoing surgery for vascular illnesses.¹ The reasons for these differences are poorly understood, but current theory focuses on the inflammatory response of individual patients and the degree of associated platelet activation.^2,12

 

 

Patient Presentation and History

The typical patient with HIT presents with a new or progressing thrombosis between days 5 and 14 of heparin therapy (with day 0 representing the day the first dose is administered); thrombosis can be venous or arterial, although venous thrombosis occurs much more frequently.^1,5,9,15 As patients rarely remain hospitalized for such a long period, it is imperative that providers in clinic and emergency settings obtain detailed histories for patients who present with thrombocytopenia and/or thrombosis. HIT should be suspected in any such patient whose history shows heparin use within the previous two weeks (even if the drug has been discontinued).¹⁵

Two forms of atypical HIT are rapid-onset HIT and delayed-onset HIT. Rapid-onset HIT is defined by a platelet count that falls within 24 hours of exposure to heparin. This form is usually associated with previous heparin exposure (ie, within the previous 100 days, but most commonly within the previous 30 days). Affected patients have already developed circulating antiheparin PF4 antibodies, causing an immediate reaction when the patient is re-exposed to the drug.^1,15

The less common delayed-onset HIT occurs in patients in whom heparin has been discontinued for as long as 40 days. Delayed-onset HIT carries the greatest risk for severe thrombosis.^1,15

Atypically, a patient may present with bleeding, skin necrosis, venous gangrene, or anaphylaxis,⁹ but skin necrosis at the site of heparin injection is strongly suggestive of HIT.¹²However, neither physical signs nor symptoms, nor a thrombotic event is required to make a diagnosis of HIT. In fact, the preference is for a diagnosis to be made before thrombosis formation.⁵

The major manifestation of HIT is thrombocytopenia itself^2,18(see "Laboratory Findings"). Nevertheless, if physical signs and symptoms are evident, they will be related to the thrombosis, and the components of the physical exam will proceed accordingly.

Laboratory Findings

Platelet count monitoring and HIT antibody testing are the laboratory tests most commonly used when HIT is suspected. Although 25% of patients with HIT will experience a thrombotic event before the platelet count falls, monitoring the platelet count is considered the most effective means to identify patients with HIT.⁵ HIT antibody testing is not recommended unless the health care provider has a strong suspicion for HIT.¹⁹

Thrombocytopenia is a common abnormality, especially in hospitalized patients, and its causes are numerous.¹¹ Table 1^1,5,9 lists the differential diagnosis that the clinician who suspects HIT should consider.

Nevertheless, the ACCP guidelines⁵ recommend platelet count monitoring for all patients receiving heparin, beginning on day 4 of heparin therapy, then continuing every two to three days until treatment day 14 or heparin discontinuation, whichever occurs first.^5,15 A platelet count decrease of 50% or more should raise a suspicion for HIT.¹⁵

The ACCP makes two principal exceptions to these recommendations.⁵ The first involves patients who have received UFH within the previous 100 days. These patients should undergo a baseline platelet count before heparin is administered, followed by a repeat platelet count within 24 hours. Any patient who experiences an anaphylactic reaction to UFH should undergo an immediate platelet count; a decrease in these patients is often transient.

The second exception pertains to medical and obstetric patients. Those receiving LMWH or UFH only to maintain line patency do not require platelet monitoring, as their risk for HIT is relatively low.^1,5

Laboratory Interpretation

In HIT, thrombocytopenia is defined as a platelet count below 150,000/mm³ or a platelet count reduction of 50% or more from baseline, even if the platelet count remains above 150,000/mm³.⁹ (The patient's baseline platelet count is defined as the highest count recorded in the previous two weeks.^1,5,15) The thrombocytopenia associated with HIT is rarely severe and can be easily overlooked.¹

Once the platelet count suggests a diagnosis of HIT, heparin-dependent antibodies can be identified through immunologic or functional assays.^1,9,15 Immunologic assays should be ordered immediately upon suspicion of HIT since they are simple tests with relatively rapid results. Immunologic assays detect immunoglobulin G (IgG), IgA, and IgM antibodies.⁹Though lacking in specificity, the immunologic assay is highly sensitive.^2,12,20 The most frequently used immunologic assay is the enzyme-linked immunosorbent assay (ELISA).^1,2,9,20The ELISA, which detects antiheparin PF4 antibodies, has a sensitivity greater than 97% but a specificity of only 74% to 86%.^8,12

Functional assays,which are technically demanding, test the ability of PF4 antibodies to activate platelets in the presence of heparin. The functional assay is used to confirm the diagnosis of HIT when a positive ELISA result is obtained.^1,9,15 Among the functional assays, the serotonin release assay (SRA) has been most completely studied. Though very expensive, the SRA is 89% to 100% specific in diagnosing HIT.^2,12

 

 

Diagnosis

The diagnosis of HIT is determined by combining clinical and serologic assessment. HIT should be suspected in any patient who is in day 5 to 14 of heparin therapy and experiences a drop in platelet count of at least 50%, or in whom a new thrombotic event occurs (even if the patient is no longer receiving heparin therapy). The interpretation of all diagnostic information must be made in the context of the patient's clinical probability of HIT.¹⁵

A scoring system referred to as the 4Ts (thrombocytopenia, timing of platelet fall, thrombosis or other sequelae, and test interpretation) is used to help determine the patient's probability of HIT^5,21,22 (similar to the scoring strategy shown in Table 2^2,11,23,24).

The patient diagnosed with HIT must be positive for HIT antibodies and meet at least one additional criterion:

• A platelet count decrease of 30% to 50% below baseline, regardless of the actual value

• A venous or arterial thrombosis

• A skin lesion at the heparin injection site; and/or

• An anaphylactic reaction after IV bolus administration of heparin.¹⁵

Treatment/Management

The goal in management of HIT is to reduce the likelihood, then the severity, of thrombosis.⁹ Treatment should be started as soon as HIT is suspected, before laboratory confirmation.²⁵ Treatment for HIT comprises two steps: stopping all exposure to heparin, and administering an alternative, non-heparin anticoagulant.

Discontinuation of Heparin Exposure

Stopping heparin exposure is the mainstay of treatment for HIT. This includes all potential sources of heparin exposure, including "flushes" that may be used to promote patency of central IV catheters, use of UFH-coated catheters, or addition of any heparin to total parenteral nutrition.^9,25

Use of a Non-Heparin Anticoagulant

In addition to discontinuation of all heparin exposure, the patient must be started on a non-heparin anticoagulant, whether or not thrombosis is present.²⁵ Forty percent to 50% of patients without thrombosis will develop a thrombosis within 30 days if alternative anticoagulation is not started.^12,18,26

The principal choices for a non-heparin anticoagulant are the direct thrombin inhibitors (DTIs): lepirudin, argatroban, and bivalirudin.^1,9,15,25,27 DTIs are the treatment of choice for patients with known or suspected HIT. The ACCP dosing guidelines for the DTIs are summarized in Table 3.^9,5,15,28

The factor Xa inhibitor fondaparinux, though FDA approved for DVT prophylaxis,¹¹ has not yet been systematically investigated for the treatment of HIT; thus, its use for this indication is considered off-label.²⁹ However, small studies have shown no cross-reactivity between fondaparinux and PF4 antibodies.³⁰ Due to the positive risk/benefit ratio, ease of use, and reduced need for monitoring in patients taking fondaparinux, it is considered an attractive alternative to DTIs that may receive approval in the near future.^12,18,20,29

Currently, the ACCP limits its recommendation of fondaparinux use to patients with a previous history of HIT who require anticoagulation for an acute thrombotic event unrelated to HIT (grade 2C recommendation).⁵

The vitamin K antagonist warfarin is absolutely contraindicated in patients with HIT until the platelet count is at least 150,000/mm³, due to the risk for warfarin-induced skin necrosis and venous gangrene.^9,15 If a patient is receiving warfarin at diagnosis, vitamin K (10 mg orally or 5 to 10 mg IV) should be administered.¹⁵

The patient should remain on the alternative non-heparin anticoagulant until the platelet count has stabilized at or above 150,000/mm³. Warfarin should then be started at a maximum of 5 mg/d.^2,5 The non-heparin anticoagulant and warfarin should be continued until a therapeutic international normalized ratio (INR) is reached and maintained for 48 hours, with a minimum 5-day overlap of the two medications. Once the non-heparin anticoagulant is discontinued, the INR should be reevaluated for remaining within the therapeutic range, as DTIs can elevate the INR.^2,5Warfarin should be continued for as long as four weeks, with frequent INR monitoring.¹⁵

 

 

Patient Education

The presence of PF4 antibodies is transient (50 to 80 days); however, concern persists regarding recurrent antibody development with subsequent heparin use. Thus, an alternative anticoagulant should be used whenever possible. Patients who have been diagnosed with HIT should be advised to inform future health care professionals regarding their need for alternative anticoagulation whenever possible.

Patients should also be made aware that when the risk for DTI-associated bleeding is too great (as in the case of cardiac surgery), heparin remains the anticoagulant of choice.^9,15

Conclusion

Heparin-induced thrombocytopenia is a transient development of antibodies to heparin. While the condition carries a high risk for morbidity and mortality, early detection and prompt treatment can greatly reduce the associated risk to life and limb.

References

1. Kanaan AO, Al-Homsi AS. Heparin-induced thrombocytopenia: pathophysiology, diagnosis, and review of pharmacotherapy. J Pharm Pract. 2009;22:149-157.

2. LaMuraglia GM, Houbballah R, Laposata M. The identification and management of heparin-induced thrombocytopenia in the vascular patient. J Vasc Surg. 2012;55:562-570.

3. Rauova L, Zhai L, Kowalska MA, et al. Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications. Blood. 2006;107:2346-2353.

4. Suvarna S, Espinasse B, Qi R, et al. Determinants of PF4/heparin immunogenicity. Blood. 2007;110:4253-4260.

5. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e495S-e530S.

6. Demma LJ, Winkler AM, Levy JH. A diagnosis of heparin-induced thrombocytopenia with combined clinical and laboratory methods in cardiothoracic surgical intensive care unit patients. Anesth Analg. 2011;113:697-702.

7. Demma LJ, Levy JH. Diagnosing heparin-induced thrombocytopenia in cardiac surgical patients: not as easy as you think. Anesth Analg. 2011;112:747-749.

8. Alaraj A, Wallace A, Tesoro E, et al. Heparin-induced thrombocytopenia: diagnosis and management. J Neurointervent Surg. 2010;2:371-378.

9. Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. N Engl J Med. 2006;355:809-817.

10. Sud S, Mittmann N, Cook DJ, et al. Screening and prevention of venous thromboembolism in critically ill patients: a decision analysis and economic evaluation. Am J Resp Crit Care Med. 2011;184:1289-1298.

11. Shaikh N. Heparin-induced thrombocytopenia. J Emerg Trauma Shock. 2011;14:97-102.

12. Cuker A. Heparin-induced thrombocytopenia: present and future. J Thromb Thrombolysis. 2011;31:353-366.

13. Locke CSF, Dooley J, Gerber J. Rates of clinically apparent heparin-induced thrombocytopenia for unfractionated heparin vs low molecular weight heparin in non-surgical patients are low and similar. Thromb J. 2005;3:4.

14. Cuker A. Recent advances in heparin-induced thrombocytopenia. Curr Opin Hematol. 2011;18:315-322.

15. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest. 2008;133(6 suppl):340S-380S.

16. Junqueira DR, Perini E, Penholati RR, Carvalho MG. Unfractionated heparin versus low molecular weight heparin for avoiding heparin-induced thrombocytopenia in postoperative patients. Cochrane Database Syst Rev. 2012;9:CD007557.

17. Berry C, Tcherniantchouk O, Ley EJ, et al. Overdiagnosis of heparin-induced thrombocytopenia in surgical ICU patients. J Am Coll Surg. 2011;213:10-17.

18. Cuker A. Current and emerging therapeutics for heparin-induced thrombocytopenia. Semin Thromb Hemost. 2012;38:31-37.

19. Warkentin TE. New approaches to the diagnosis of heparin-induced thrombocytopenia. Chest. 2005;127(2 suppl):35S-45S.

20. Fennessy-Cooney M. Heparin-induced thrombocytopenia. Nurse Pract. 2011;36:31-37.

21. Bryant A, Low J, Austin S, Joseph JE. Timely diagnosis and management of heparin-induced thrombocytopenia in a frequent request, low incidence single centre using clinical 4T's score and particle gel immunoassay. Br J Haematol. 2008;143:721-726.

22. Lo GK, Juhl D, Warkentin TE, et al. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4:759-765.

23. Wirth SM, Macaulay TE, Armistead JA, et al. Evaluation of a clinical scoring scale to direct early appropriate therapy in heparin-induced thrombocytopenia. J Oncol Pharm Pract. 2010;16:161-166.

24. Yoon JH, Jang IK. Heparin-induced thrombocytopenia in cardiovascular patients: pathophysiology, diagnosis, and treatment. Cardiol Rev. 2011;19:143-153.

25. Bartholomew JR. Heparin-induced thrombocytopenia: 2008 update. Curr Treat Options Cardiovasc Med. 2008;10:117-127.

26. Warkentin TE. Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia. Arch Pathol Lab Med. 2002;126:1415-1423.

27. Badger NO. Fondaparinux (Arixtra^®), a safe alternative for the treatment of patients with heparin-induced thrombocytopenia? J Pharm Pract. 2010;23:235-238.

28. Petros S. Lepirudin in the management of patients with heparin-induced thrombocytopenia. Biologics. 2008;2:481-490.

29. Warkentin TE. How I diagnose and manage HIT. Hematology Am Soc Hematol Educ Program. 2011;2011:143-149.

30. Papadopoulos S, Flynn JD, Lewis DA. Fondaparinux as a treatment option for heparin-induced thrombocytopenia. Pharmacotherapy. 2007; 27:921-926.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated drug reaction that requires prompt detection and treatment in order to minimize patient morbidity and mortality.¹ HIT is caused by the development of antibodies to platelet factor 4 (PF4), although it is important to note that not all patients who develop PF4 antibodies will experience the clinical syndrome of HIT.^2-4 In fact, about 50% of patients who undergo cardiovascular surgery develop PF4 antibodies, but only 1% to 2% of patients with antibodies actually experience HIT.^5-7 There is currently no explanation for the phenomenon of HIT.⁸

In 2012, with an intent to limit HIT-associated morbidity and mortality, the American College of Chest Physicians (ACCP) unveiled the ninth edition of its evidence-based practice guidelines for the detection of HIT and appropriate treatment.⁵ Much of the information provided in this article emerged from these guidelines.

Epidemiology

Of the 12 million patients treated each year with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH), 600,000 (0.5%) will develop HIT. Among these patients, 300,000 will develop thrombosis, and 90,000 will die. In 2009 alone, the HIT-associated cost to the US health care system was estimated at $100 million.¹

As growing numbers of patients require anticoagulation therapy, it becomes increasingly important for clinicians to understand the importance of screening for deep vein thrombosis (DVT), one of the two most common thromboses; the other is pulmonary embolism.^9,10 Continuing to administer heparin or warfarin to patients with undetected HIT predisposes them to severe complications, including venous and arterial thromboses and gangrenous skin lesions—which can result in loss of life and/or limb.^1,11,12

Risk Factors for HIT

Several factors influence a patient's risk for HIT, including the type and dosing regimen of the heparin being administered. Generally, the risk for HIT is about 10-fold in patients treated with UFH (3% to 5%), compared with those receiving LMWH (0.5%).^5,13 The risk for HIT is also greater in patients receiving UFH of bovine origin, compared with those taking porcine-derived UFH.^8,14,15

In a recent meta-analysis of postsurgical patients who underwent heparin thromboprophylaxis, those given LMWH had a 76% relative risk reduction for HIT, compared with patients taking UFH.¹⁶ The incidence of HIT increases among patients receiving LMWH if they have been treated with UFH within the previous 100 days.⁹ HIT onset may be delayed for several days in patients given heparin for the first time (or for the first time in several months), whereas previously exposed patients who have already developed antiheparin PF4 antibodies can experience severe HIT within hours.⁹

Patient-Specific Risk Factors

Certain patient characteristics also have an impact on HIT risk. For example, the risk for HIT is approximately doubled in women, compared with men,^1,5,15 and the incidence of HIT is greater in surgical patients than in medical patients.^7,17 Among surgical patients, 5% of orthopedic patients have been reported to develop HIT, compared with 3% of cardiac patients and 1% of patients undergoing surgery for vascular illnesses.¹ The reasons for these differences are poorly understood, but current theory focuses on the inflammatory response of individual patients and the degree of associated platelet activation.^2,12

 

 

Patient Presentation and History

The typical patient with HIT presents with a new or progressing thrombosis between days 5 and 14 of heparin therapy (with day 0 representing the day the first dose is administered); thrombosis can be venous or arterial, although venous thrombosis occurs much more frequently.^1,5,9,15 As patients rarely remain hospitalized for such a long period, it is imperative that providers in clinic and emergency settings obtain detailed histories for patients who present with thrombocytopenia and/or thrombosis. HIT should be suspected in any such patient whose history shows heparin use within the previous two weeks (even if the drug has been discontinued).¹⁵

Two forms of atypical HIT are rapid-onset HIT and delayed-onset HIT. Rapid-onset HIT is defined by a platelet count that falls within 24 hours of exposure to heparin. This form is usually associated with previous heparin exposure (ie, within the previous 100 days, but most commonly within the previous 30 days). Affected patients have already developed circulating antiheparin PF4 antibodies, causing an immediate reaction when the patient is re-exposed to the drug.^1,15

The less common delayed-onset HIT occurs in patients in whom heparin has been discontinued for as long as 40 days. Delayed-onset HIT carries the greatest risk for severe thrombosis.^1,15

Atypically, a patient may present with bleeding, skin necrosis, venous gangrene, or anaphylaxis,⁹ but skin necrosis at the site of heparin injection is strongly suggestive of HIT.¹²However, neither physical signs nor symptoms, nor a thrombotic event is required to make a diagnosis of HIT. In fact, the preference is for a diagnosis to be made before thrombosis formation.⁵

The major manifestation of HIT is thrombocytopenia itself^2,18(see "Laboratory Findings"). Nevertheless, if physical signs and symptoms are evident, they will be related to the thrombosis, and the components of the physical exam will proceed accordingly.

Laboratory Findings

Platelet count monitoring and HIT antibody testing are the laboratory tests most commonly used when HIT is suspected. Although 25% of patients with HIT will experience a thrombotic event before the platelet count falls, monitoring the platelet count is considered the most effective means to identify patients with HIT.⁵ HIT antibody testing is not recommended unless the health care provider has a strong suspicion for HIT.¹⁹

Thrombocytopenia is a common abnormality, especially in hospitalized patients, and its causes are numerous.¹¹ Table 1^1,5,9 lists the differential diagnosis that the clinician who suspects HIT should consider.

Nevertheless, the ACCP guidelines⁵ recommend platelet count monitoring for all patients receiving heparin, beginning on day 4 of heparin therapy, then continuing every two to three days until treatment day 14 or heparin discontinuation, whichever occurs first.^5,15 A platelet count decrease of 50% or more should raise a suspicion for HIT.¹⁵

The ACCP makes two principal exceptions to these recommendations.⁵ The first involves patients who have received UFH within the previous 100 days. These patients should undergo a baseline platelet count before heparin is administered, followed by a repeat platelet count within 24 hours. Any patient who experiences an anaphylactic reaction to UFH should undergo an immediate platelet count; a decrease in these patients is often transient.

The second exception pertains to medical and obstetric patients. Those receiving LMWH or UFH only to maintain line patency do not require platelet monitoring, as their risk for HIT is relatively low.^1,5

Laboratory Interpretation

In HIT, thrombocytopenia is defined as a platelet count below 150,000/mm³ or a platelet count reduction of 50% or more from baseline, even if the platelet count remains above 150,000/mm³.⁹ (The patient's baseline platelet count is defined as the highest count recorded in the previous two weeks.^1,5,15) The thrombocytopenia associated with HIT is rarely severe and can be easily overlooked.¹

Once the platelet count suggests a diagnosis of HIT, heparin-dependent antibodies can be identified through immunologic or functional assays.^1,9,15 Immunologic assays should be ordered immediately upon suspicion of HIT since they are simple tests with relatively rapid results. Immunologic assays detect immunoglobulin G (IgG), IgA, and IgM antibodies.⁹Though lacking in specificity, the immunologic assay is highly sensitive.^2,12,20 The most frequently used immunologic assay is the enzyme-linked immunosorbent assay (ELISA).^1,2,9,20The ELISA, which detects antiheparin PF4 antibodies, has a sensitivity greater than 97% but a specificity of only 74% to 86%.^8,12

Functional assays,which are technically demanding, test the ability of PF4 antibodies to activate platelets in the presence of heparin. The functional assay is used to confirm the diagnosis of HIT when a positive ELISA result is obtained.^1,9,15 Among the functional assays, the serotonin release assay (SRA) has been most completely studied. Though very expensive, the SRA is 89% to 100% specific in diagnosing HIT.^2,12

 

 

Diagnosis

The diagnosis of HIT is determined by combining clinical and serologic assessment. HIT should be suspected in any patient who is in day 5 to 14 of heparin therapy and experiences a drop in platelet count of at least 50%, or in whom a new thrombotic event occurs (even if the patient is no longer receiving heparin therapy). The interpretation of all diagnostic information must be made in the context of the patient's clinical probability of HIT.¹⁵

A scoring system referred to as the 4Ts (thrombocytopenia, timing of platelet fall, thrombosis or other sequelae, and test interpretation) is used to help determine the patient's probability of HIT^5,21,22 (similar to the scoring strategy shown in Table 2^2,11,23,24).

The patient diagnosed with HIT must be positive for HIT antibodies and meet at least one additional criterion:

• A platelet count decrease of 30% to 50% below baseline, regardless of the actual value

• A venous or arterial thrombosis

• A skin lesion at the heparin injection site; and/or

• An anaphylactic reaction after IV bolus administration of heparin.¹⁵

Treatment/Management

The goal in management of HIT is to reduce the likelihood, then the severity, of thrombosis.⁹ Treatment should be started as soon as HIT is suspected, before laboratory confirmation.²⁵ Treatment for HIT comprises two steps: stopping all exposure to heparin, and administering an alternative, non-heparin anticoagulant.

Discontinuation of Heparin Exposure

Stopping heparin exposure is the mainstay of treatment for HIT. This includes all potential sources of heparin exposure, including "flushes" that may be used to promote patency of central IV catheters, use of UFH-coated catheters, or addition of any heparin to total parenteral nutrition.^9,25

Use of a Non-Heparin Anticoagulant

In addition to discontinuation of all heparin exposure, the patient must be started on a non-heparin anticoagulant, whether or not thrombosis is present.²⁵ Forty percent to 50% of patients without thrombosis will develop a thrombosis within 30 days if alternative anticoagulation is not started.^12,18,26

The principal choices for a non-heparin anticoagulant are the direct thrombin inhibitors (DTIs): lepirudin, argatroban, and bivalirudin.^1,9,15,25,27 DTIs are the treatment of choice for patients with known or suspected HIT. The ACCP dosing guidelines for the DTIs are summarized in Table 3.^9,5,15,28

The factor Xa inhibitor fondaparinux, though FDA approved for DVT prophylaxis,¹¹ has not yet been systematically investigated for the treatment of HIT; thus, its use for this indication is considered off-label.²⁹ However, small studies have shown no cross-reactivity between fondaparinux and PF4 antibodies.³⁰ Due to the positive risk/benefit ratio, ease of use, and reduced need for monitoring in patients taking fondaparinux, it is considered an attractive alternative to DTIs that may receive approval in the near future.^12,18,20,29

Currently, the ACCP limits its recommendation of fondaparinux use to patients with a previous history of HIT who require anticoagulation for an acute thrombotic event unrelated to HIT (grade 2C recommendation).⁵

The vitamin K antagonist warfarin is absolutely contraindicated in patients with HIT until the platelet count is at least 150,000/mm³, due to the risk for warfarin-induced skin necrosis and venous gangrene.^9,15 If a patient is receiving warfarin at diagnosis, vitamin K (10 mg orally or 5 to 10 mg IV) should be administered.¹⁵

The patient should remain on the alternative non-heparin anticoagulant until the platelet count has stabilized at or above 150,000/mm³. Warfarin should then be started at a maximum of 5 mg/d.^2,5 The non-heparin anticoagulant and warfarin should be continued until a therapeutic international normalized ratio (INR) is reached and maintained for 48 hours, with a minimum 5-day overlap of the two medications. Once the non-heparin anticoagulant is discontinued, the INR should be reevaluated for remaining within the therapeutic range, as DTIs can elevate the INR.^2,5Warfarin should be continued for as long as four weeks, with frequent INR monitoring.¹⁵

 

 

Patient Education

The presence of PF4 antibodies is transient (50 to 80 days); however, concern persists regarding recurrent antibody development with subsequent heparin use. Thus, an alternative anticoagulant should be used whenever possible. Patients who have been diagnosed with HIT should be advised to inform future health care professionals regarding their need for alternative anticoagulation whenever possible.

Patients should also be made aware that when the risk for DTI-associated bleeding is too great (as in the case of cardiac surgery), heparin remains the anticoagulant of choice.^9,15

Conclusion

Heparin-induced thrombocytopenia is a transient development of antibodies to heparin. While the condition carries a high risk for morbidity and mortality, early detection and prompt treatment can greatly reduce the associated risk to life and limb.

References

1. Kanaan AO, Al-Homsi AS. Heparin-induced thrombocytopenia: pathophysiology, diagnosis, and review of pharmacotherapy. J Pharm Pract. 2009;22:149-157.

2. LaMuraglia GM, Houbballah R, Laposata M. The identification and management of heparin-induced thrombocytopenia in the vascular patient. J Vasc Surg. 2012;55:562-570.

3. Rauova L, Zhai L, Kowalska MA, et al. Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications. Blood. 2006;107:2346-2353.

4. Suvarna S, Espinasse B, Qi R, et al. Determinants of PF4/heparin immunogenicity. Blood. 2007;110:4253-4260.

5. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e495S-e530S.

6. Demma LJ, Winkler AM, Levy JH. A diagnosis of heparin-induced thrombocytopenia with combined clinical and laboratory methods in cardiothoracic surgical intensive care unit patients. Anesth Analg. 2011;113:697-702.

7. Demma LJ, Levy JH. Diagnosing heparin-induced thrombocytopenia in cardiac surgical patients: not as easy as you think. Anesth Analg. 2011;112:747-749.

8. Alaraj A, Wallace A, Tesoro E, et al. Heparin-induced thrombocytopenia: diagnosis and management. J Neurointervent Surg. 2010;2:371-378.

9. Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. N Engl J Med. 2006;355:809-817.

10. Sud S, Mittmann N, Cook DJ, et al. Screening and prevention of venous thromboembolism in critically ill patients: a decision analysis and economic evaluation. Am J Resp Crit Care Med. 2011;184:1289-1298.

11. Shaikh N. Heparin-induced thrombocytopenia. J Emerg Trauma Shock. 2011;14:97-102.

12. Cuker A. Heparin-induced thrombocytopenia: present and future. J Thromb Thrombolysis. 2011;31:353-366.

13. Locke CSF, Dooley J, Gerber J. Rates of clinically apparent heparin-induced thrombocytopenia for unfractionated heparin vs low molecular weight heparin in non-surgical patients are low and similar. Thromb J. 2005;3:4.

14. Cuker A. Recent advances in heparin-induced thrombocytopenia. Curr Opin Hematol. 2011;18:315-322.

15. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest. 2008;133(6 suppl):340S-380S.

16. Junqueira DR, Perini E, Penholati RR, Carvalho MG. Unfractionated heparin versus low molecular weight heparin for avoiding heparin-induced thrombocytopenia in postoperative patients. Cochrane Database Syst Rev. 2012;9:CD007557.

17. Berry C, Tcherniantchouk O, Ley EJ, et al. Overdiagnosis of heparin-induced thrombocytopenia in surgical ICU patients. J Am Coll Surg. 2011;213:10-17.

18. Cuker A. Current and emerging therapeutics for heparin-induced thrombocytopenia. Semin Thromb Hemost. 2012;38:31-37.

19. Warkentin TE. New approaches to the diagnosis of heparin-induced thrombocytopenia. Chest. 2005;127(2 suppl):35S-45S.

20. Fennessy-Cooney M. Heparin-induced thrombocytopenia. Nurse Pract. 2011;36:31-37.

21. Bryant A, Low J, Austin S, Joseph JE. Timely diagnosis and management of heparin-induced thrombocytopenia in a frequent request, low incidence single centre using clinical 4T's score and particle gel immunoassay. Br J Haematol. 2008;143:721-726.

22. Lo GK, Juhl D, Warkentin TE, et al. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4:759-765.

23. Wirth SM, Macaulay TE, Armistead JA, et al. Evaluation of a clinical scoring scale to direct early appropriate therapy in heparin-induced thrombocytopenia. J Oncol Pharm Pract. 2010;16:161-166.

24. Yoon JH, Jang IK. Heparin-induced thrombocytopenia in cardiovascular patients: pathophysiology, diagnosis, and treatment. Cardiol Rev. 2011;19:143-153.

25. Bartholomew JR. Heparin-induced thrombocytopenia: 2008 update. Curr Treat Options Cardiovasc Med. 2008;10:117-127.

26. Warkentin TE. Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia. Arch Pathol Lab Med. 2002;126:1415-1423.

27. Badger NO. Fondaparinux (Arixtra^®), a safe alternative for the treatment of patients with heparin-induced thrombocytopenia? J Pharm Pract. 2010;23:235-238.

28. Petros S. Lepirudin in the management of patients with heparin-induced thrombocytopenia. Biologics. 2008;2:481-490.

29. Warkentin TE. How I diagnose and manage HIT. Hematology Am Soc Hematol Educ Program. 2011;2011:143-149.

30. Papadopoulos S, Flynn JD, Lewis DA. Fondaparinux as a treatment option for heparin-induced thrombocytopenia. Pharmacotherapy. 2007; 27:921-926.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated drug reaction that requires prompt detection and treatment in order to minimize patient morbidity and mortality.¹ HIT is caused by the development of antibodies to platelet factor 4 (PF4), although it is important to note that not all patients who develop PF4 antibodies will experience the clinical syndrome of HIT.^2-4 In fact, about 50% of patients who undergo cardiovascular surgery develop PF4 antibodies, but only 1% to 2% of patients with antibodies actually experience HIT.^5-7 There is currently no explanation for the phenomenon of HIT.⁸

In 2012, with an intent to limit HIT-associated morbidity and mortality, the American College of Chest Physicians (ACCP) unveiled the ninth edition of its evidence-based practice guidelines for the detection of HIT and appropriate treatment.⁵ Much of the information provided in this article emerged from these guidelines.

Epidemiology

Of the 12 million patients treated each year with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH), 600,000 (0.5%) will develop HIT. Among these patients, 300,000 will develop thrombosis, and 90,000 will die. In 2009 alone, the HIT-associated cost to the US health care system was estimated at $100 million.¹

As growing numbers of patients require anticoagulation therapy, it becomes increasingly important for clinicians to understand the importance of screening for deep vein thrombosis (DVT), one of the two most common thromboses; the other is pulmonary embolism.^9,10 Continuing to administer heparin or warfarin to patients with undetected HIT predisposes them to severe complications, including venous and arterial thromboses and gangrenous skin lesions—which can result in loss of life and/or limb.^1,11,12

Risk Factors for HIT

Several factors influence a patient's risk for HIT, including the type and dosing regimen of the heparin being administered. Generally, the risk for HIT is about 10-fold in patients treated with UFH (3% to 5%), compared with those receiving LMWH (0.5%).^5,13 The risk for HIT is also greater in patients receiving UFH of bovine origin, compared with those taking porcine-derived UFH.^8,14,15

In a recent meta-analysis of postsurgical patients who underwent heparin thromboprophylaxis, those given LMWH had a 76% relative risk reduction for HIT, compared with patients taking UFH.¹⁶ The incidence of HIT increases among patients receiving LMWH if they have been treated with UFH within the previous 100 days.⁹ HIT onset may be delayed for several days in patients given heparin for the first time (or for the first time in several months), whereas previously exposed patients who have already developed antiheparin PF4 antibodies can experience severe HIT within hours.⁹

Patient-Specific Risk Factors

Certain patient characteristics also have an impact on HIT risk. For example, the risk for HIT is approximately doubled in women, compared with men,^1,5,15 and the incidence of HIT is greater in surgical patients than in medical patients.^7,17 Among surgical patients, 5% of orthopedic patients have been reported to develop HIT, compared with 3% of cardiac patients and 1% of patients undergoing surgery for vascular illnesses.¹ The reasons for these differences are poorly understood, but current theory focuses on the inflammatory response of individual patients and the degree of associated platelet activation.^2,12

 

 

Patient Presentation and History

The typical patient with HIT presents with a new or progressing thrombosis between days 5 and 14 of heparin therapy (with day 0 representing the day the first dose is administered); thrombosis can be venous or arterial, although venous thrombosis occurs much more frequently.^1,5,9,15 As patients rarely remain hospitalized for such a long period, it is imperative that providers in clinic and emergency settings obtain detailed histories for patients who present with thrombocytopenia and/or thrombosis. HIT should be suspected in any such patient whose history shows heparin use within the previous two weeks (even if the drug has been discontinued).¹⁵

Two forms of atypical HIT are rapid-onset HIT and delayed-onset HIT. Rapid-onset HIT is defined by a platelet count that falls within 24 hours of exposure to heparin. This form is usually associated with previous heparin exposure (ie, within the previous 100 days, but most commonly within the previous 30 days). Affected patients have already developed circulating antiheparin PF4 antibodies, causing an immediate reaction when the patient is re-exposed to the drug.^1,15

The less common delayed-onset HIT occurs in patients in whom heparin has been discontinued for as long as 40 days. Delayed-onset HIT carries the greatest risk for severe thrombosis.^1,15

Atypically, a patient may present with bleeding, skin necrosis, venous gangrene, or anaphylaxis,⁹ but skin necrosis at the site of heparin injection is strongly suggestive of HIT.¹²However, neither physical signs nor symptoms, nor a thrombotic event is required to make a diagnosis of HIT. In fact, the preference is for a diagnosis to be made before thrombosis formation.⁵

The major manifestation of HIT is thrombocytopenia itself^2,18(see "Laboratory Findings"). Nevertheless, if physical signs and symptoms are evident, they will be related to the thrombosis, and the components of the physical exam will proceed accordingly.

Laboratory Findings

Platelet count monitoring and HIT antibody testing are the laboratory tests most commonly used when HIT is suspected. Although 25% of patients with HIT will experience a thrombotic event before the platelet count falls, monitoring the platelet count is considered the most effective means to identify patients with HIT.⁵ HIT antibody testing is not recommended unless the health care provider has a strong suspicion for HIT.¹⁹

Thrombocytopenia is a common abnormality, especially in hospitalized patients, and its causes are numerous.¹¹ Table 1^1,5,9 lists the differential diagnosis that the clinician who suspects HIT should consider.

Nevertheless, the ACCP guidelines⁵ recommend platelet count monitoring for all patients receiving heparin, beginning on day 4 of heparin therapy, then continuing every two to three days until treatment day 14 or heparin discontinuation, whichever occurs first.^5,15 A platelet count decrease of 50% or more should raise a suspicion for HIT.¹⁵

The ACCP makes two principal exceptions to these recommendations.⁵ The first involves patients who have received UFH within the previous 100 days. These patients should undergo a baseline platelet count before heparin is administered, followed by a repeat platelet count within 24 hours. Any patient who experiences an anaphylactic reaction to UFH should undergo an immediate platelet count; a decrease in these patients is often transient.

The second exception pertains to medical and obstetric patients. Those receiving LMWH or UFH only to maintain line patency do not require platelet monitoring, as their risk for HIT is relatively low.^1,5

Laboratory Interpretation

In HIT, thrombocytopenia is defined as a platelet count below 150,000/mm³ or a platelet count reduction of 50% or more from baseline, even if the platelet count remains above 150,000/mm³.⁹ (The patient's baseline platelet count is defined as the highest count recorded in the previous two weeks.^1,5,15) The thrombocytopenia associated with HIT is rarely severe and can be easily overlooked.¹

Once the platelet count suggests a diagnosis of HIT, heparin-dependent antibodies can be identified through immunologic or functional assays.^1,9,15 Immunologic assays should be ordered immediately upon suspicion of HIT since they are simple tests with relatively rapid results. Immunologic assays detect immunoglobulin G (IgG), IgA, and IgM antibodies.⁹Though lacking in specificity, the immunologic assay is highly sensitive.^2,12,20 The most frequently used immunologic assay is the enzyme-linked immunosorbent assay (ELISA).^1,2,9,20The ELISA, which detects antiheparin PF4 antibodies, has a sensitivity greater than 97% but a specificity of only 74% to 86%.^8,12

Functional assays,which are technically demanding, test the ability of PF4 antibodies to activate platelets in the presence of heparin. The functional assay is used to confirm the diagnosis of HIT when a positive ELISA result is obtained.^1,9,15 Among the functional assays, the serotonin release assay (SRA) has been most completely studied. Though very expensive, the SRA is 89% to 100% specific in diagnosing HIT.^2,12

 

 

Diagnosis

The diagnosis of HIT is determined by combining clinical and serologic assessment. HIT should be suspected in any patient who is in day 5 to 14 of heparin therapy and experiences a drop in platelet count of at least 50%, or in whom a new thrombotic event occurs (even if the patient is no longer receiving heparin therapy). The interpretation of all diagnostic information must be made in the context of the patient's clinical probability of HIT.¹⁵

A scoring system referred to as the 4Ts (thrombocytopenia, timing of platelet fall, thrombosis or other sequelae, and test interpretation) is used to help determine the patient's probability of HIT^5,21,22 (similar to the scoring strategy shown in Table 2^2,11,23,24).

The patient diagnosed with HIT must be positive for HIT antibodies and meet at least one additional criterion:

• A platelet count decrease of 30% to 50% below baseline, regardless of the actual value

• A venous or arterial thrombosis

• A skin lesion at the heparin injection site; and/or

• An anaphylactic reaction after IV bolus administration of heparin.¹⁵

Treatment/Management

The goal in management of HIT is to reduce the likelihood, then the severity, of thrombosis.⁹ Treatment should be started as soon as HIT is suspected, before laboratory confirmation.²⁵ Treatment for HIT comprises two steps: stopping all exposure to heparin, and administering an alternative, non-heparin anticoagulant.

Discontinuation of Heparin Exposure

Stopping heparin exposure is the mainstay of treatment for HIT. This includes all potential sources of heparin exposure, including "flushes" that may be used to promote patency of central IV catheters, use of UFH-coated catheters, or addition of any heparin to total parenteral nutrition.^9,25

Use of a Non-Heparin Anticoagulant

In addition to discontinuation of all heparin exposure, the patient must be started on a non-heparin anticoagulant, whether or not thrombosis is present.²⁵ Forty percent to 50% of patients without thrombosis will develop a thrombosis within 30 days if alternative anticoagulation is not started.^12,18,26

The principal choices for a non-heparin anticoagulant are the direct thrombin inhibitors (DTIs): lepirudin, argatroban, and bivalirudin.^1,9,15,25,27 DTIs are the treatment of choice for patients with known or suspected HIT. The ACCP dosing guidelines for the DTIs are summarized in Table 3.^9,5,15,28

The factor Xa inhibitor fondaparinux, though FDA approved for DVT prophylaxis,¹¹ has not yet been systematically investigated for the treatment of HIT; thus, its use for this indication is considered off-label.²⁹ However, small studies have shown no cross-reactivity between fondaparinux and PF4 antibodies.³⁰ Due to the positive risk/benefit ratio, ease of use, and reduced need for monitoring in patients taking fondaparinux, it is considered an attractive alternative to DTIs that may receive approval in the near future.^12,18,20,29

Currently, the ACCP limits its recommendation of fondaparinux use to patients with a previous history of HIT who require anticoagulation for an acute thrombotic event unrelated to HIT (grade 2C recommendation).⁵

The vitamin K antagonist warfarin is absolutely contraindicated in patients with HIT until the platelet count is at least 150,000/mm³, due to the risk for warfarin-induced skin necrosis and venous gangrene.^9,15 If a patient is receiving warfarin at diagnosis, vitamin K (10 mg orally or 5 to 10 mg IV) should be administered.¹⁵

The patient should remain on the alternative non-heparin anticoagulant until the platelet count has stabilized at or above 150,000/mm³. Warfarin should then be started at a maximum of 5 mg/d.^2,5 The non-heparin anticoagulant and warfarin should be continued until a therapeutic international normalized ratio (INR) is reached and maintained for 48 hours, with a minimum 5-day overlap of the two medications. Once the non-heparin anticoagulant is discontinued, the INR should be reevaluated for remaining within the therapeutic range, as DTIs can elevate the INR.^2,5Warfarin should be continued for as long as four weeks, with frequent INR monitoring.¹⁵

 

 

Patient Education

The presence of PF4 antibodies is transient (50 to 80 days); however, concern persists regarding recurrent antibody development with subsequent heparin use. Thus, an alternative anticoagulant should be used whenever possible. Patients who have been diagnosed with HIT should be advised to inform future health care professionals regarding their need for alternative anticoagulation whenever possible.

Patients should also be made aware that when the risk for DTI-associated bleeding is too great (as in the case of cardiac surgery), heparin remains the anticoagulant of choice.^9,15

Conclusion

Heparin-induced thrombocytopenia is a transient development of antibodies to heparin. While the condition carries a high risk for morbidity and mortality, early detection and prompt treatment can greatly reduce the associated risk to life and limb.

References

1. Kanaan AO, Al-Homsi AS. Heparin-induced thrombocytopenia: pathophysiology, diagnosis, and review of pharmacotherapy. J Pharm Pract. 2009;22:149-157.

2. LaMuraglia GM, Houbballah R, Laposata M. The identification and management of heparin-induced thrombocytopenia in the vascular patient. J Vasc Surg. 2012;55:562-570.

3. Rauova L, Zhai L, Kowalska MA, et al. Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications. Blood. 2006;107:2346-2353.

4. Suvarna S, Espinasse B, Qi R, et al. Determinants of PF4/heparin immunogenicity. Blood. 2007;110:4253-4260.

5. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e495S-e530S.

6. Demma LJ, Winkler AM, Levy JH. A diagnosis of heparin-induced thrombocytopenia with combined clinical and laboratory methods in cardiothoracic surgical intensive care unit patients. Anesth Analg. 2011;113:697-702.

7. Demma LJ, Levy JH. Diagnosing heparin-induced thrombocytopenia in cardiac surgical patients: not as easy as you think. Anesth Analg. 2011;112:747-749.

8. Alaraj A, Wallace A, Tesoro E, et al. Heparin-induced thrombocytopenia: diagnosis and management. J Neurointervent Surg. 2010;2:371-378.

9. Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. N Engl J Med. 2006;355:809-817.

10. Sud S, Mittmann N, Cook DJ, et al. Screening and prevention of venous thromboembolism in critically ill patients: a decision analysis and economic evaluation. Am J Resp Crit Care Med. 2011;184:1289-1298.

11. Shaikh N. Heparin-induced thrombocytopenia. J Emerg Trauma Shock. 2011;14:97-102.

12. Cuker A. Heparin-induced thrombocytopenia: present and future. J Thromb Thrombolysis. 2011;31:353-366.

13. Locke CSF, Dooley J, Gerber J. Rates of clinically apparent heparin-induced thrombocytopenia for unfractionated heparin vs low molecular weight heparin in non-surgical patients are low and similar. Thromb J. 2005;3:4.

14. Cuker A. Recent advances in heparin-induced thrombocytopenia. Curr Opin Hematol. 2011;18:315-322.

15. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest. 2008;133(6 suppl):340S-380S.

16. Junqueira DR, Perini E, Penholati RR, Carvalho MG. Unfractionated heparin versus low molecular weight heparin for avoiding heparin-induced thrombocytopenia in postoperative patients. Cochrane Database Syst Rev. 2012;9:CD007557.

17. Berry C, Tcherniantchouk O, Ley EJ, et al. Overdiagnosis of heparin-induced thrombocytopenia in surgical ICU patients. J Am Coll Surg. 2011;213:10-17.

18. Cuker A. Current and emerging therapeutics for heparin-induced thrombocytopenia. Semin Thromb Hemost. 2012;38:31-37.

19. Warkentin TE. New approaches to the diagnosis of heparin-induced thrombocytopenia. Chest. 2005;127(2 suppl):35S-45S.

20. Fennessy-Cooney M. Heparin-induced thrombocytopenia. Nurse Pract. 2011;36:31-37.

21. Bryant A, Low J, Austin S, Joseph JE. Timely diagnosis and management of heparin-induced thrombocytopenia in a frequent request, low incidence single centre using clinical 4T's score and particle gel immunoassay. Br J Haematol. 2008;143:721-726.

22. Lo GK, Juhl D, Warkentin TE, et al. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4:759-765.

23. Wirth SM, Macaulay TE, Armistead JA, et al. Evaluation of a clinical scoring scale to direct early appropriate therapy in heparin-induced thrombocytopenia. J Oncol Pharm Pract. 2010;16:161-166.

24. Yoon JH, Jang IK. Heparin-induced thrombocytopenia in cardiovascular patients: pathophysiology, diagnosis, and treatment. Cardiol Rev. 2011;19:143-153.

25. Bartholomew JR. Heparin-induced thrombocytopenia: 2008 update. Curr Treat Options Cardiovasc Med. 2008;10:117-127.

26. Warkentin TE. Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia. Arch Pathol Lab Med. 2002;126:1415-1423.

27. Badger NO. Fondaparinux (Arixtra^®), a safe alternative for the treatment of patients with heparin-induced thrombocytopenia? J Pharm Pract. 2010;23:235-238.

28. Petros S. Lepirudin in the management of patients with heparin-induced thrombocytopenia. Biologics. 2008;2:481-490.

29. Warkentin TE. How I diagnose and manage HIT. Hematology Am Soc Hematol Educ Program. 2011;2011:143-149.

30. Papadopoulos S, Flynn JD, Lewis DA. Fondaparinux as a treatment option for heparin-induced thrombocytopenia. Pharmacotherapy. 2007; 27:921-926.

This is the second article in the series, "Heparin-Induced Thrombocytopenia." The remaining articles are Introduction; Diagnosis; Treatment/Management; and References.

Patient Presentation and History

The typical patient with HIT presents with a new or progressing thrombosis between days 5 and 14 of heparin therapy (with day 0 representing the day the first dose is administered); thrombosis can be venous or arterial, although venous thrombosis occurs much more frequently.^1,5,9,15 As patients rarely remain hospitalized for such a long period, it is imperative that providers in clinic and emergency settings obtain detailed histories for patients who present with thrombocytopenia and/or thrombosis. HIT should be suspected in any such patient whose history shows heparin use within the previous two weeks (even if the drug has been discontinued).¹⁵

Two forms of atypical HIT are rapid-onset HIT and delayed-onset HIT. Rapid-onset HIT is defined by a platelet count that falls within 24 hours of exposure to heparin. This form is usually associated with previous heparin exposure (ie, within the previous 100 days, but most commonly within the previous 30 days). Affected patients have already developed circulating antiheparin PF4 antibodies, causing an immediate reaction when the patient is re-exposed to the drug.^1,15

The less common delayed-onset HIT occurs in patients in whom heparin has been discontinued for as long as 40 days. Delayed-onset HIT carries the greatest risk for severe thrombosis.^1,15

Physical Examination

Atypically, a patient may present with bleeding, skin necrosis, venous gangrene, or anaphylaxis,⁹ but skin necrosis at the site of heparin injection is strongly suggestive of HIT.¹² However, neither physical signs nor symptoms, nor a thrombotic event is required to make a diagnosis of HIT. In fact, the preference is for a diagnosis to be made before thrombosis formation.⁵

The major manifestation of HIT is thrombocytopenia itself^2,18 (see "Laboratory Findings"). Nevertheless, if physical signs and symptoms are evident, they will be related to the thrombosis, and the components of the physical exam will proceed accordingly.

Laboratory Findings

Platelet count monitoring and HIT antibody testing are the laboratory tests most commonly used when HIT is suspected. Although 25% of patients with HIT will experience a thrombotic event before the platelet count falls, monitoring the platelet count is considered the most effective means to identify patients with HIT.⁵ HIT antibody testing is not recommended unless the health care provider has a strong suspicion for HIT.¹⁹

Thrombocytopenia is a common abnormality, especially in hospitalized patients, and its causes are numerous.¹¹ Table 1^1,5,9 lists the differential diagnosis that the clinician who suspects HIT should consider.

Nevertheless, the ACCP guidelines⁵ recommend platelet count monitoring for all patients receiving heparin, beginning on day 4 of heparin therapy, then continuing every two to three days until treatment day 14 or heparin discontinuation, whichever occurs first.^5,15 A platelet count decrease of 50% or more should raise a suspicion for HIT.¹⁵

The ACCP makes two principal exceptions to these recommendations.⁵ The first involves patients who have received UFH within the previous 100 days. These patients should undergo a baseline platelet count before heparin is administered, followed by a repeat platelet count within 24 hours. Any patient who experiences an anaphylactic reaction to UFH should undergo an immediate platelet count; a decrease in these patients is often transient.

The second exception pertains to medical and obstetric patients. Those receiving LMWH or UFH only to maintain line patency do not require platelet monitoring, as their risk for HIT is relatively low.^1,5

Laboratory Interpretation

In HIT, thrombocytopenia is defined as a platelet count below 150,000/mm³ or a platelet count reduction of 50% or more from baseline, even if the platelet count remains above 150,000/mm³.⁹ (The patient's baseline platelet count is defined as the highest count recorded in the previous two weeks.^1,5,15) The thrombocytopenia associated with HIT is rarely severe and can be easily overlooked.¹

Once the platelet count suggests a diagnosis of HIT, heparin-dependent antibodies can be identified through immunologic or functional assays.^1,9,15 Immunologic assays should be ordered immediately upon suspicion of HIT since they are simple tests with relatively rapid results. Immunologic assays detect immunoglobulin G (IgG), IgA, and IgM antibodies.⁹ Though lacking in specificity, the immunologic assay is highly sensitive.^2,12,20 The most frequently used immunologic assay is the enzyme-linked immunosorbent assay (ELISA).^1,2,9,20 The ELISA, which detects antiheparin PF4 antibodies, has a sensitivity greater than 97% but a specificity of only 74% to 86%.^8,12

Functional assays,which are technically demanding, test the ability of PF4 antibodies to activate platelets in the presence of heparin. The functional assay is used to confirm the diagnosis of HIT when a positive ELISA result is obtained.^1,9,15 Among the functional assays, the serotonin release assay (SRA) has been most completely studied. Though very expensive, the SRA is 89% to 100% specific in diagnosing HIT.^2,12

This is the second article in the series, "Heparin-Induced Thrombocytopenia." The remaining articles are Introduction; Diagnosis; Treatment/Management; and References.

This is the second article in the series, "Heparin-Induced Thrombocytopenia." The remaining articles are Introduction; Diagnosis; Treatment/Management; and References.

Patient Presentation and History

The typical patient with HIT presents with a new or progressing thrombosis between days 5 and 14 of heparin therapy (with day 0 representing the day the first dose is administered); thrombosis can be venous or arterial, although venous thrombosis occurs much more frequently.^1,5,9,15 As patients rarely remain hospitalized for such a long period, it is imperative that providers in clinic and emergency settings obtain detailed histories for patients who present with thrombocytopenia and/or thrombosis. HIT should be suspected in any such patient whose history shows heparin use within the previous two weeks (even if the drug has been discontinued).¹⁵

Two forms of atypical HIT are rapid-onset HIT and delayed-onset HIT. Rapid-onset HIT is defined by a platelet count that falls within 24 hours of exposure to heparin. This form is usually associated with previous heparin exposure (ie, within the previous 100 days, but most commonly within the previous 30 days). Affected patients have already developed circulating antiheparin PF4 antibodies, causing an immediate reaction when the patient is re-exposed to the drug.^1,15

The less common delayed-onset HIT occurs in patients in whom heparin has been discontinued for as long as 40 days. Delayed-onset HIT carries the greatest risk for severe thrombosis.^1,15

Physical Examination

Atypically, a patient may present with bleeding, skin necrosis, venous gangrene, or anaphylaxis,⁹ but skin necrosis at the site of heparin injection is strongly suggestive of HIT.¹² However, neither physical signs nor symptoms, nor a thrombotic event is required to make a diagnosis of HIT. In fact, the preference is for a diagnosis to be made before thrombosis formation.⁵

The major manifestation of HIT is thrombocytopenia itself^2,18 (see "Laboratory Findings"). Nevertheless, if physical signs and symptoms are evident, they will be related to the thrombosis, and the components of the physical exam will proceed accordingly.

Laboratory Findings

Platelet count monitoring and HIT antibody testing are the laboratory tests most commonly used when HIT is suspected. Although 25% of patients with HIT will experience a thrombotic event before the platelet count falls, monitoring the platelet count is considered the most effective means to identify patients with HIT.⁵ HIT antibody testing is not recommended unless the health care provider has a strong suspicion for HIT.¹⁹

Thrombocytopenia is a common abnormality, especially in hospitalized patients, and its causes are numerous.¹¹ Table 1^1,5,9 lists the differential diagnosis that the clinician who suspects HIT should consider.

Nevertheless, the ACCP guidelines⁵ recommend platelet count monitoring for all patients receiving heparin, beginning on day 4 of heparin therapy, then continuing every two to three days until treatment day 14 or heparin discontinuation, whichever occurs first.^5,15 A platelet count decrease of 50% or more should raise a suspicion for HIT.¹⁵

The ACCP makes two principal exceptions to these recommendations.⁵ The first involves patients who have received UFH within the previous 100 days. These patients should undergo a baseline platelet count before heparin is administered, followed by a repeat platelet count within 24 hours. Any patient who experiences an anaphylactic reaction to UFH should undergo an immediate platelet count; a decrease in these patients is often transient.

The second exception pertains to medical and obstetric patients. Those receiving LMWH or UFH only to maintain line patency do not require platelet monitoring, as their risk for HIT is relatively low.^1,5

Laboratory Interpretation

In HIT, thrombocytopenia is defined as a platelet count below 150,000/mm³ or a platelet count reduction of 50% or more from baseline, even if the platelet count remains above 150,000/mm³.⁹ (The patient's baseline platelet count is defined as the highest count recorded in the previous two weeks.^1,5,15) The thrombocytopenia associated with HIT is rarely severe and can be easily overlooked.¹

Once the platelet count suggests a diagnosis of HIT, heparin-dependent antibodies can be identified through immunologic or functional assays.^1,9,15 Immunologic assays should be ordered immediately upon suspicion of HIT since they are simple tests with relatively rapid results. Immunologic assays detect immunoglobulin G (IgG), IgA, and IgM antibodies.⁹ Though lacking in specificity, the immunologic assay is highly sensitive.^2,12,20 The most frequently used immunologic assay is the enzyme-linked immunosorbent assay (ELISA).^1,2,9,20 The ELISA, which detects antiheparin PF4 antibodies, has a sensitivity greater than 97% but a specificity of only 74% to 86%.^8,12

Functional assays,which are technically demanding, test the ability of PF4 antibodies to activate platelets in the presence of heparin. The functional assay is used to confirm the diagnosis of HIT when a positive ELISA result is obtained.^1,9,15 Among the functional assays, the serotonin release assay (SRA) has been most completely studied. Though very expensive, the SRA is 89% to 100% specific in diagnosing HIT.^2,12

This is the second article in the series, "Heparin-Induced Thrombocytopenia." The remaining articles are Introduction; Diagnosis; Treatment/Management; and References.

This is the second article in the series, "Heparin-Induced Thrombocytopenia." The remaining articles are Introduction; Diagnosis; Treatment/Management; and References.

Patient Presentation and History

The typical patient with HIT presents with a new or progressing thrombosis between days 5 and 14 of heparin therapy (with day 0 representing the day the first dose is administered); thrombosis can be venous or arterial, although venous thrombosis occurs much more frequently.^1,5,9,15 As patients rarely remain hospitalized for such a long period, it is imperative that providers in clinic and emergency settings obtain detailed histories for patients who present with thrombocytopenia and/or thrombosis. HIT should be suspected in any such patient whose history shows heparin use within the previous two weeks (even if the drug has been discontinued).¹⁵

Two forms of atypical HIT are rapid-onset HIT and delayed-onset HIT. Rapid-onset HIT is defined by a platelet count that falls within 24 hours of exposure to heparin. This form is usually associated with previous heparin exposure (ie, within the previous 100 days, but most commonly within the previous 30 days). Affected patients have already developed circulating antiheparin PF4 antibodies, causing an immediate reaction when the patient is re-exposed to the drug.^1,15

The less common delayed-onset HIT occurs in patients in whom heparin has been discontinued for as long as 40 days. Delayed-onset HIT carries the greatest risk for severe thrombosis.^1,15

Physical Examination

Atypically, a patient may present with bleeding, skin necrosis, venous gangrene, or anaphylaxis,⁹ but skin necrosis at the site of heparin injection is strongly suggestive of HIT.¹² However, neither physical signs nor symptoms, nor a thrombotic event is required to make a diagnosis of HIT. In fact, the preference is for a diagnosis to be made before thrombosis formation.⁵

The major manifestation of HIT is thrombocytopenia itself^2,18 (see "Laboratory Findings"). Nevertheless, if physical signs and symptoms are evident, they will be related to the thrombosis, and the components of the physical exam will proceed accordingly.

Laboratory Findings

Platelet count monitoring and HIT antibody testing are the laboratory tests most commonly used when HIT is suspected. Although 25% of patients with HIT will experience a thrombotic event before the platelet count falls, monitoring the platelet count is considered the most effective means to identify patients with HIT.⁵ HIT antibody testing is not recommended unless the health care provider has a strong suspicion for HIT.¹⁹

Thrombocytopenia is a common abnormality, especially in hospitalized patients, and its causes are numerous.¹¹ Table 1^1,5,9 lists the differential diagnosis that the clinician who suspects HIT should consider.

Nevertheless, the ACCP guidelines⁵ recommend platelet count monitoring for all patients receiving heparin, beginning on day 4 of heparin therapy, then continuing every two to three days until treatment day 14 or heparin discontinuation, whichever occurs first.^5,15 A platelet count decrease of 50% or more should raise a suspicion for HIT.¹⁵

The ACCP makes two principal exceptions to these recommendations.⁵ The first involves patients who have received UFH within the previous 100 days. These patients should undergo a baseline platelet count before heparin is administered, followed by a repeat platelet count within 24 hours. Any patient who experiences an anaphylactic reaction to UFH should undergo an immediate platelet count; a decrease in these patients is often transient.

The second exception pertains to medical and obstetric patients. Those receiving LMWH or UFH only to maintain line patency do not require platelet monitoring, as their risk for HIT is relatively low.^1,5

Laboratory Interpretation

In HIT, thrombocytopenia is defined as a platelet count below 150,000/mm³ or a platelet count reduction of 50% or more from baseline, even if the platelet count remains above 150,000/mm³.⁹ (The patient's baseline platelet count is defined as the highest count recorded in the previous two weeks.^1,5,15) The thrombocytopenia associated with HIT is rarely severe and can be easily overlooked.¹

Once the platelet count suggests a diagnosis of HIT, heparin-dependent antibodies can be identified through immunologic or functional assays.^1,9,15 Immunologic assays should be ordered immediately upon suspicion of HIT since they are simple tests with relatively rapid results. Immunologic assays detect immunoglobulin G (IgG), IgA, and IgM antibodies.⁹ Though lacking in specificity, the immunologic assay is highly sensitive.^2,12,20 The most frequently used immunologic assay is the enzyme-linked immunosorbent assay (ELISA).^1,2,9,20 The ELISA, which detects antiheparin PF4 antibodies, has a sensitivity greater than 97% but a specificity of only 74% to 86%.^8,12

Functional assays,which are technically demanding, test the ability of PF4 antibodies to activate platelets in the presence of heparin. The functional assay is used to confirm the diagnosis of HIT when a positive ELISA result is obtained.^1,9,15 Among the functional assays, the serotonin release assay (SRA) has been most completely studied. Though very expensive, the SRA is 89% to 100% specific in diagnosing HIT.^2,12

This is the second article in the series, "Heparin-Induced Thrombocytopenia." The remaining articles are Introduction; Diagnosis; Treatment/Management; and References.