Clinical Review

Knee osteoarthritis (KOA), a common disabling disease with a high impact on quality of life, has a large societal cost. Yet no procedure halts progressive degeneration of the osteoarthritic knee joint.^1,2

According to Barry,³ mesenchymal stem cells (MSCs) differentiate into many different connective tissue cells, including cartilage. MSCs can be isolated from bone marrow, skeletal muscle, fat, and synovium. MSCs are multipotent cells with the capacity for self-renewal. Therefore, adult MSCs may regenerate tissues damaged by disease. In OA, the proliferative capacity and ability to differentiate are reduced in MSCs. Intra-articular injections of MSCs (MSC therapy) could repair progressively degenerated knee cartilage.

This review article summarizes the knowledge on the role of intra-articular injections of MSCs in the treatment of KOA, based on studies published in PubMed and the Cochrane Library. The article also reviews the methodology and results of the animal and clinical studies published so far on the topic.

Materials and Methods

PubMed (Medline) and the Cochrane Library were searched for literature on the role of MSC therapy in treating KOA. The key words used were stem cells and knee osteoarthritis. The period searched was from when these search engines began until January 31, 2014. One hundred thirty-five articles (including negative studies) were found, but only the 25 deeply focused on the topic were reviewed. The Figure shows the flow diagram of this study.

Results

Several experimental models of KOA have shown that MSC therapy can delay progressive degeneration of the knee joint (Appendix 1).^4-15 Using a rabbit massive meniscal defect model, Hatsushika and colleagues¹³ found that a single intra-articular injection of synovial MSCs into the knee adhered around the meniscal defect and promoted meniscal regeneration. Park and colleagues¹⁴ conducted an experimental study in dogs—the first demonstrating regional and systemic safety and systemic immunomodulatory effects of repeated local delivery of allogeneic MSCs in vivo. Regarding the observed systemic immunomodulatory effects, clinical and pathologic examinations revealed no severe consequences of repeated MSC transplantations. Results of mixed leukocyte reactions demonstrated suppression of T-cell proliferation after MSC transplantations.

Of the human studies published so far, only 3 were prospective randomized trials (level II evidence) included in the Cochrane Library (Appendix 2).^16-18 Varma and colleagues¹⁶ found that intra-articular injections of MSCs considerably improved overall KOA outcome scores. Fifty patients with mild to moderate KOA were divided into 2 groups. Group A underwent arthroscopic débridement, and group B had buffy coat (MSC concentrate) injection and arthroscopic débridement. Patients were assessed on the basis of their visual analog scale (VAS) pain scores and osteoarthritis outcome scores.

Wong and colleagues¹⁷ analyzed 56 knees in 56 patients (mean age, 51 years) with unicompartmental KOA and genu varum. Patients were randomly assigned to 2 groups, MSC and control. All patients underwent high tibial osteotomy (HTO) and microfracture. Patients in the MSC group received intra-articular injection of cultured MSCs with hyaluronic acid (HA) 3 weeks after surgery. Patients in the control group received only HA. The primary outcome measure was International Knee Documentation Committee (IKDC) score 6 months, 1 year, and 2 years after surgery. Secondary outcome measures were Tegner and Lysholm clinical scores and 1-year postoperative Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores. Both treatment arms achieved improvements in Tegner, Lysholm, and IKDC scores. After adjustment for age, baseline scores, and time of evaluation, the MSC group had significantly better scores. One year after surgery, magnetic resonance imaging (MRI) scans showed significantly better MOCART scores for the MSC group. Intra-articular injection of MSCs appeared to be effective in improving short-term clinical and MOCART outcomes in patients who underwent HTO and microfracture for varus knees with cartilage defects.

Saw and colleagues¹⁸ compared histologic and MRI evaluation of articular cartilage regeneration in patients with chondral lesions treated by arthroscopic subchondral drilling followed by postoperative intra-articular injections of HA with and without peripheral blood stem cells (PBSCs). Fifty patients (ages, 18-50 years) with International Cartilage Repair Society grades 3 and 4 lesions of the knee joint underwent arthroscopic subchondral drilling; 25 patients were randomized to the intervention group (HA + PBSC) and 25 to the control group (HA). Both groups received 5 weekly injections starting 1 week after surgery. Three additional injections of either HA + PBSC or HA only were given at weekly intervals 6 months after surgery. After arthroscopic subchondral drilling into grades 3 and 4 chondral lesions, postoperative intra-articular injections of autologous PBSC combined with HA resulted in improved quality of articular cartilage repair over the same treatment without PBSC.

The other human studies analyzed had a low level of evidence (grade IV, case series) but found that intra-articular injections of MSCs reduced pain and improved function in patients with KOA over the short term, 1 year (Appendix 3).^19-25

Discussion

This review aimed to define the role of MSC therapy in the treatment of KOA. MSC therapy has yielded encouraging outcomes in experimental models of KOA.^4-15 These experimental studies have suggested that MSCs can halt cartilage degeneration in KOA. So far, however, only 3 human studies with grade II evidence (randomized prospective trials) have been reported on the role of MSCs in KOA, but results of these studies have suggested that MSCs can reduce pain and improve function.^16-18

Previous reviews of the literature^1,2 have analyzed the role of MSC therapy in KOA. Barry and Murphy¹ reported that several early-stage clinical trials, initiated or under way in 2013, were testing MSC delivery as an intra-articular injection into the knee, but optimal dose and vehicle were yet to be established. Filardo and colleagues² reported that, despite growing interest in this biological approach to cartilage regeneration, knowledge on the topic is still preliminary, as shown by the prevalence of preclinical studies and the presence of low-quality clinical studies.

Study design weakness prevents effective comparison of the efficacy of MSC therapy with that of other treatments for relief of pain and other outcomes in KOA. The consistency of evidence of the clinical studies is low because of many uncontrolled variables.^1-3

Conclusion

The results of MSC therapy in KOA are encouraging. However, optimal dose and vehicle are yet to be established.¹ Knowledge on this topic is still preliminary. Many aspects have to be optimized, and further randomized controlled trials are needed to support the potential of this biological treatment for cartilage repair and to evaluate advantages and disadvantages with respect to the available treatments. The relative short duration of these studies is also a limitation for the technique at present.

Knee osteoarthritis (KOA), a common disabling disease with a high impact on quality of life, has a large societal cost. Yet no procedure halts progressive degeneration of the osteoarthritic knee joint.^1,2

According to Barry,³ mesenchymal stem cells (MSCs) differentiate into many different connective tissue cells, including cartilage. MSCs can be isolated from bone marrow, skeletal muscle, fat, and synovium. MSCs are multipotent cells with the capacity for self-renewal. Therefore, adult MSCs may regenerate tissues damaged by disease. In OA, the proliferative capacity and ability to differentiate are reduced in MSCs. Intra-articular injections of MSCs (MSC therapy) could repair progressively degenerated knee cartilage.

This review article summarizes the knowledge on the role of intra-articular injections of MSCs in the treatment of KOA, based on studies published in PubMed and the Cochrane Library. The article also reviews the methodology and results of the animal and clinical studies published so far on the topic.

Materials and Methods

PubMed (Medline) and the Cochrane Library were searched for literature on the role of MSC therapy in treating KOA. The key words used were stem cells and knee osteoarthritis. The period searched was from when these search engines began until January 31, 2014. One hundred thirty-five articles (including negative studies) were found, but only the 25 deeply focused on the topic were reviewed. The Figure shows the flow diagram of this study.

Results

Several experimental models of KOA have shown that MSC therapy can delay progressive degeneration of the knee joint (Appendix 1).^4-15 Using a rabbit massive meniscal defect model, Hatsushika and colleagues¹³ found that a single intra-articular injection of synovial MSCs into the knee adhered around the meniscal defect and promoted meniscal regeneration. Park and colleagues¹⁴ conducted an experimental study in dogs—the first demonstrating regional and systemic safety and systemic immunomodulatory effects of repeated local delivery of allogeneic MSCs in vivo. Regarding the observed systemic immunomodulatory effects, clinical and pathologic examinations revealed no severe consequences of repeated MSC transplantations. Results of mixed leukocyte reactions demonstrated suppression of T-cell proliferation after MSC transplantations.

Of the human studies published so far, only 3 were prospective randomized trials (level II evidence) included in the Cochrane Library (Appendix 2).^16-18 Varma and colleagues¹⁶ found that intra-articular injections of MSCs considerably improved overall KOA outcome scores. Fifty patients with mild to moderate KOA were divided into 2 groups. Group A underwent arthroscopic débridement, and group B had buffy coat (MSC concentrate) injection and arthroscopic débridement. Patients were assessed on the basis of their visual analog scale (VAS) pain scores and osteoarthritis outcome scores.

Wong and colleagues¹⁷ analyzed 56 knees in 56 patients (mean age, 51 years) with unicompartmental KOA and genu varum. Patients were randomly assigned to 2 groups, MSC and control. All patients underwent high tibial osteotomy (HTO) and microfracture. Patients in the MSC group received intra-articular injection of cultured MSCs with hyaluronic acid (HA) 3 weeks after surgery. Patients in the control group received only HA. The primary outcome measure was International Knee Documentation Committee (IKDC) score 6 months, 1 year, and 2 years after surgery. Secondary outcome measures were Tegner and Lysholm clinical scores and 1-year postoperative Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores. Both treatment arms achieved improvements in Tegner, Lysholm, and IKDC scores. After adjustment for age, baseline scores, and time of evaluation, the MSC group had significantly better scores. One year after surgery, magnetic resonance imaging (MRI) scans showed significantly better MOCART scores for the MSC group. Intra-articular injection of MSCs appeared to be effective in improving short-term clinical and MOCART outcomes in patients who underwent HTO and microfracture for varus knees with cartilage defects.

Saw and colleagues¹⁸ compared histologic and MRI evaluation of articular cartilage regeneration in patients with chondral lesions treated by arthroscopic subchondral drilling followed by postoperative intra-articular injections of HA with and without peripheral blood stem cells (PBSCs). Fifty patients (ages, 18-50 years) with International Cartilage Repair Society grades 3 and 4 lesions of the knee joint underwent arthroscopic subchondral drilling; 25 patients were randomized to the intervention group (HA + PBSC) and 25 to the control group (HA). Both groups received 5 weekly injections starting 1 week after surgery. Three additional injections of either HA + PBSC or HA only were given at weekly intervals 6 months after surgery. After arthroscopic subchondral drilling into grades 3 and 4 chondral lesions, postoperative intra-articular injections of autologous PBSC combined with HA resulted in improved quality of articular cartilage repair over the same treatment without PBSC.

The other human studies analyzed had a low level of evidence (grade IV, case series) but found that intra-articular injections of MSCs reduced pain and improved function in patients with KOA over the short term, 1 year (Appendix 3).^19-25

Discussion

This review aimed to define the role of MSC therapy in the treatment of KOA. MSC therapy has yielded encouraging outcomes in experimental models of KOA.^4-15 These experimental studies have suggested that MSCs can halt cartilage degeneration in KOA. So far, however, only 3 human studies with grade II evidence (randomized prospective trials) have been reported on the role of MSCs in KOA, but results of these studies have suggested that MSCs can reduce pain and improve function.^16-18

Previous reviews of the literature^1,2 have analyzed the role of MSC therapy in KOA. Barry and Murphy¹ reported that several early-stage clinical trials, initiated or under way in 2013, were testing MSC delivery as an intra-articular injection into the knee, but optimal dose and vehicle were yet to be established. Filardo and colleagues² reported that, despite growing interest in this biological approach to cartilage regeneration, knowledge on the topic is still preliminary, as shown by the prevalence of preclinical studies and the presence of low-quality clinical studies.

Study design weakness prevents effective comparison of the efficacy of MSC therapy with that of other treatments for relief of pain and other outcomes in KOA. The consistency of evidence of the clinical studies is low because of many uncontrolled variables.^1-3

Conclusion

The results of MSC therapy in KOA are encouraging. However, optimal dose and vehicle are yet to be established.¹ Knowledge on this topic is still preliminary. Many aspects have to be optimized, and further randomized controlled trials are needed to support the potential of this biological treatment for cartilage repair and to evaluate advantages and disadvantages with respect to the available treatments. The relative short duration of these studies is also a limitation for the technique at present.

Knee osteoarthritis (KOA), a common disabling disease with a high impact on quality of life, has a large societal cost. Yet no procedure halts progressive degeneration of the osteoarthritic knee joint.^1,2

According to Barry,³ mesenchymal stem cells (MSCs) differentiate into many different connective tissue cells, including cartilage. MSCs can be isolated from bone marrow, skeletal muscle, fat, and synovium. MSCs are multipotent cells with the capacity for self-renewal. Therefore, adult MSCs may regenerate tissues damaged by disease. In OA, the proliferative capacity and ability to differentiate are reduced in MSCs. Intra-articular injections of MSCs (MSC therapy) could repair progressively degenerated knee cartilage.

This review article summarizes the knowledge on the role of intra-articular injections of MSCs in the treatment of KOA, based on studies published in PubMed and the Cochrane Library. The article also reviews the methodology and results of the animal and clinical studies published so far on the topic.

Materials and Methods

PubMed (Medline) and the Cochrane Library were searched for literature on the role of MSC therapy in treating KOA. The key words used were stem cells and knee osteoarthritis. The period searched was from when these search engines began until January 31, 2014. One hundred thirty-five articles (including negative studies) were found, but only the 25 deeply focused on the topic were reviewed. The Figure shows the flow diagram of this study.

Results

Several experimental models of KOA have shown that MSC therapy can delay progressive degeneration of the knee joint (Appendix 1).^4-15 Using a rabbit massive meniscal defect model, Hatsushika and colleagues¹³ found that a single intra-articular injection of synovial MSCs into the knee adhered around the meniscal defect and promoted meniscal regeneration. Park and colleagues¹⁴ conducted an experimental study in dogs—the first demonstrating regional and systemic safety and systemic immunomodulatory effects of repeated local delivery of allogeneic MSCs in vivo. Regarding the observed systemic immunomodulatory effects, clinical and pathologic examinations revealed no severe consequences of repeated MSC transplantations. Results of mixed leukocyte reactions demonstrated suppression of T-cell proliferation after MSC transplantations.

Of the human studies published so far, only 3 were prospective randomized trials (level II evidence) included in the Cochrane Library (Appendix 2).^16-18 Varma and colleagues¹⁶ found that intra-articular injections of MSCs considerably improved overall KOA outcome scores. Fifty patients with mild to moderate KOA were divided into 2 groups. Group A underwent arthroscopic débridement, and group B had buffy coat (MSC concentrate) injection and arthroscopic débridement. Patients were assessed on the basis of their visual analog scale (VAS) pain scores and osteoarthritis outcome scores.

Wong and colleagues¹⁷ analyzed 56 knees in 56 patients (mean age, 51 years) with unicompartmental KOA and genu varum. Patients were randomly assigned to 2 groups, MSC and control. All patients underwent high tibial osteotomy (HTO) and microfracture. Patients in the MSC group received intra-articular injection of cultured MSCs with hyaluronic acid (HA) 3 weeks after surgery. Patients in the control group received only HA. The primary outcome measure was International Knee Documentation Committee (IKDC) score 6 months, 1 year, and 2 years after surgery. Secondary outcome measures were Tegner and Lysholm clinical scores and 1-year postoperative Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores. Both treatment arms achieved improvements in Tegner, Lysholm, and IKDC scores. After adjustment for age, baseline scores, and time of evaluation, the MSC group had significantly better scores. One year after surgery, magnetic resonance imaging (MRI) scans showed significantly better MOCART scores for the MSC group. Intra-articular injection of MSCs appeared to be effective in improving short-term clinical and MOCART outcomes in patients who underwent HTO and microfracture for varus knees with cartilage defects.

Saw and colleagues¹⁸ compared histologic and MRI evaluation of articular cartilage regeneration in patients with chondral lesions treated by arthroscopic subchondral drilling followed by postoperative intra-articular injections of HA with and without peripheral blood stem cells (PBSCs). Fifty patients (ages, 18-50 years) with International Cartilage Repair Society grades 3 and 4 lesions of the knee joint underwent arthroscopic subchondral drilling; 25 patients were randomized to the intervention group (HA + PBSC) and 25 to the control group (HA). Both groups received 5 weekly injections starting 1 week after surgery. Three additional injections of either HA + PBSC or HA only were given at weekly intervals 6 months after surgery. After arthroscopic subchondral drilling into grades 3 and 4 chondral lesions, postoperative intra-articular injections of autologous PBSC combined with HA resulted in improved quality of articular cartilage repair over the same treatment without PBSC.

The other human studies analyzed had a low level of evidence (grade IV, case series) but found that intra-articular injections of MSCs reduced pain and improved function in patients with KOA over the short term, 1 year (Appendix 3).^19-25

Discussion

This review aimed to define the role of MSC therapy in the treatment of KOA. MSC therapy has yielded encouraging outcomes in experimental models of KOA.^4-15 These experimental studies have suggested that MSCs can halt cartilage degeneration in KOA. So far, however, only 3 human studies with grade II evidence (randomized prospective trials) have been reported on the role of MSCs in KOA, but results of these studies have suggested that MSCs can reduce pain and improve function.^16-18

Previous reviews of the literature^1,2 have analyzed the role of MSC therapy in KOA. Barry and Murphy¹ reported that several early-stage clinical trials, initiated or under way in 2013, were testing MSC delivery as an intra-articular injection into the knee, but optimal dose and vehicle were yet to be established. Filardo and colleagues² reported that, despite growing interest in this biological approach to cartilage regeneration, knowledge on the topic is still preliminary, as shown by the prevalence of preclinical studies and the presence of low-quality clinical studies.

Study design weakness prevents effective comparison of the efficacy of MSC therapy with that of other treatments for relief of pain and other outcomes in KOA. The consistency of evidence of the clinical studies is low because of many uncontrolled variables.^1-3

Conclusion

The results of MSC therapy in KOA are encouraging. However, optimal dose and vehicle are yet to be established.¹ Knowledge on this topic is still preliminary. Many aspects have to be optimized, and further randomized controlled trials are needed to support the potential of this biological treatment for cartilage repair and to evaluate advantages and disadvantages with respect to the available treatments. The relative short duration of these studies is also a limitation for the technique at present.

Gynecologists are “first-line” providers for the diagnosis and treatment of osteoporosis in women. Lest you doubt the importance of this fact, consider that there are more osteoporotic fractures annually in the United States than all myocardial infarctions, strokes, breast cancers, and gynecologic malignancies combined. It is our duty to stay abreast of current developments in the diagnosis and treatment of this potentially devastating skeletal disorder as our patients live longer and longer.

In this article, I present recent studies on:

• the use of conjugated estrogens and bazedoxifene (Duavee) to manage hot flashes and menopausal bone loss
• the need for adequate levels of vitamin D to maintain bone and overall health, with sunlight exposure remaining a viable option
• a reinterpretation of the findings on estrogen and fracture risk from the Women’s Health Initiative (WHI)
• the effects of selective serotonin reuptake inhibitors (SSRIs) on bone mineral density (BMD)
• development of blosozumab, a new agent in the fight against osteoporosis and fracture.

FIRST TISSUE-SELECTIVE ESTROGEN COMPLEX PROTECTS AGAINST BONE LOSS WITHOUT AFFECTING ENDOMETRIAL AND BREAST TISSUE

Komm BS, Mirkin S, Jenkins SN. Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss. ­Steroids. 2014;90:71–81.

Pinkerton JV, Harvey JA, Lindsay R, et al; SMART-5 Investigators. Effects of bazedoxifene/conjugated ­estrogens on the endometrium and bone: a randomized trial. J Clin Endocrinol Metab. 2014;99(2):e189–e198.

Conjugated estrogens combined with the selective estrogen receptor modulator (SERM) bazedoxifene (Duavee) are a new option to alleviate menopausal symptoms and prevent postmenopausal bone loss. The rationale for development of the tissue-selective estrogen complex (TSEC) was to combine the benefits of conjugated estrogens with the SERM’s ability to offset estrogenic stimulation of the endometrium and breast.

TSECs offer a progestin-free alternative to traditional hormone therapy for women with a uterus. In preclinical studies, investigators found evidence to support bazedoxifene as the SERM of choice and demonstrated that, by combining it with conjugated estrogens, they could provide an optimal balance of estrogen-receptor agonist/antagonist activity, compared with other potential TSEC pairings. Clinical study results confirmed the efficacy of this combination in maintaining bone mass.

Given separately, conjugated estrogens and bazedoxifene each protect against the loss of BMD and help prevent fracture in postmenopausal women.

Findings in key populations
Komm and colleagues describe substudies of the Selective estrogens, Menopause, and Response to Therapy (SMART) trials to evaluate the combination of conjugated estrogens and SERMs to prevent osteoporosis in postmenopausal women with a uterus. One SMART-1 trial included two osteoporosis prevention substudies that evaluated the combination of conjugated estrogens and bazedoxifene in different subpopulations:

• women more than 5 years past the last menstrual period with a lumbar spine or hip BMD T-score between –1 and –2.5 plus one other risk factor for osteoporosis (n = 1,454)
• women 1 to 5 years past their last menstrual period (the interval during which bone loss is greatest) with at least one risk factor for osteoporosis (n = 861).

All doses of conjugated estrogens and bazedoxifene significantly increased the adjusted mean percentage of change in BMD of the lumbar spine from baseline to 24 months (a primary endpoint), compared with placebo, which was associated with decreases in BMD (P<.001). Findings were similar for total hip BMD.

In a separate study, Pinkerton and colleagues found that the dose of conjugated estrogens (0.45 mg) and bazedoxifene (20 mg) approved by the US Food and Drug Administration does not cause a change in breast density or thickness of the endometrium, nor does it increase breast pain, compared with placebo.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This newly available TSEC—a combination of conjugated estrogens (0.45 mg) and bazedoxifene (20 mg)—is an effective, well-tolerated alternative to traditional estrogen-progestin hormone therapy for relief of menopausal symptoms and prevention of osteoporosis in postmenopausal women with a uterus.

DON’T EXCLUDE SUNLIGHT FROM THE BONE–HEALTH EQUATION

Holick MF. Sunlight, ultraviolet radiation, vitamin D, and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2014;810:1–16.

Many people think of vitamin D as the “sunshine vitamin.” During exposure to sunlight, ultraviolet photons enter the skin and convert 7-dehydrocholesterol to previtamin D3, which, in turn, is converted to vitamin D3.

Throughout most of human history, people have depended on sunlight for vitamin D. Variables such as skin pigmentation, sunscreen use, aging, time of day, season, and latitude dramatically affect previtamin synthesis.

Although vitamin D deficiency was thought to have been conquered, it is now recognized that more than 50% of the world’s population is at risk for vitamin D insufficiency or low levels of 25-hydroxyvitamin D. Among the reasons are inadequate fortification of foods with vitamin D and a misconception that most balanced diets contain adequate vitamin D.

Deficiency of this vitamin causes growth retardation and rickets in children and osteomalacia in adults and can precipitate and exacerbate osteopenia or osteoporosis and increase the risk of fracture in adults.

Some evidence also suggests that vitamin D deficiency may have other serious consequences, including an increased risk for common cancers and autoimmune, infectious, and cardiovascular diseases.

In this review, Holick argues that we need to remind our patients of the beneficial effects of moderate sunlight.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
There is no question that sufficient levels of vitamin D are vital to bone health, and perhaps to overall health in numerous other organ systems as well. The pendulum of our concern over skin cancers may have moved too far in the direction of sun avoidance. In reality, moderate sunlight as a source of vitamin D is still appropriate for many of our patients.

WHEN IT COMES TO ESTROGEN AND BONE, BENEFITS OUTWEIGH RISKS

de Villiers TJ. 8th Pieter van Keep Memorial Lecture. Estrogen and bone: have we completed a full circle? [published online ahead of print September 22, 2014]. Climacteric. 2014;17(suppl 2):4–7. doi:10.3109/13697137.2014.953047.

In the WHI estrogen-progestin arm, fracture rates were reported as hazard ratios:

• hip fracture, 0.66 (95% confidence interval [CI], 0.45–0.98)
• clinical vertebral fracture, 0.66 (95% CI, 0.44–0.98)
• nonvertebral fractures, 0.77 (95% CI, 0.69–0.86).

In the estrogen-only arm of the WHI, reductions in the rates of fracture were reported as percentages and were similar:

• 39% reduction in hip fracture, compared with placebo
• 38% reduction in clinical vertebral fracture
• 21% reduction in total fractures.

All of these reductions were statistically significant.

Despite the excellent anti-fracture efficacy demonstrated in the WHI, investigators concluded that the risks of hormone therapy outweighed the benefits in the general postmenopausal population.

Why we should reconsider estrogen for bone health
In his presidential address to the International Menopause Society (cited above), de Villiers observed that, in the WHI:

• Only clinical fractures were recorded. Unlike all other fracture trials, routine radiographs were not obtained to record morphometric fractures. This decision, he believes (and I concur), led to a significant understatement of estrogen’s protective effects against vertebral fracture.
• The general population studied had a low risk of fracture, with an average spinal T-score of –1.3. This, too, contributed to an understatement of estrogen’s protective effects, compared with the findings of other randomized controlled trials involving patients at much higher risk.
• From a bone-centric point of view, the WHI findings represent a favorable ratio of benefits to risks.

No bone-active drugs are completely free of potential adverse effects and restrictions, many of which become apparent only after FDA approval and general use of the drug. Bisphosphonates have been implicated in atrial fibrillation, osteonecrosis of the jaw, and atypical femur shaft fracture after extended use. Like estrogen, SERMs can increase the risk of death from deep venous thrombosis and stroke.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Estrogen is the only agent proved to be effective against all types of osteoporotic fractures during primary analysis of a large randomized controlled trial. This efficacy is of special importance for the patient with osteopenia who is at risk for fracture. Estrogen remains a serious option for the prevention of postmenopausal bone loss and osteoporosis-related fractures, especially in younger patients. Individualization of therapy is key.

COUNSEL SSRI AND SNRI USERS THAT BMD MAY DECLINE OVER THE LONG TERM

Ak E, Bulut SD, Bulut S, et al. Evaluation of the effect of selective serotonin reuptake inhibitors on bone mineral density: an observational cross-sectional study [published online ahead of print September 4, 2014]. ­Osteoporos Int. doi:10.10007/s00198-014-2859-2.

Moura C, Bernatsky S, Ambrahamowicz M, et al. Antidepressant use and 10-year incident fracture risk: the population-based Canadian Multicentre Osteoporosis Study (CaMoS). Osteoporos Int. 2014;25(5):1473–1481.

Bruyère O, Reginster J-V. Osteoporosis in patients taking selective serotonin reuptake inhibitors: a focus on fracture outcome [published online ahead of print August 5, 2014]. Endocrine. doi:10.1007/s12020-014-0357-0.

Evidence from longitudinal, cross-­sectional, and prospective cohort studies suggests that the use of antidepressants at therapeutic doses is associated with a reduction in BMD and an increase in the risk of falls and fracture. These associations have been demonstrated in several distinct populations using various study designs, and with bone density, bone loss, or fractures as outcomes. They remain consistent even after adjustment for confounding variables such as age, body mass index, lifestyle factors such as alcohol and tobacco use, and fracture history.

Ak and colleagues recruited 60 patients given a diagnosis of generalized anxiety disorder and treated with paroxetine, sertraline, or citalopram for at least 12 months, comparing their BMD with that of 40 healthy volunteers. BMD was measured by dual-energy x-ray absorptiometry at the femoral and lumbar regions. BMD of the L2–L4 vertebrae, total lumbar vertebrae, and femoral intertrochanteric region, as well as total femoral Z-scores and femoral Ward’s region T-scores, were lower in the treatment group (P<.05). There was a significant negative correlation between the duration of treatment and the change in BMD values.

Moura and colleagues reviewed data from a large prospective Canadian cohort to assess the association between SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), and fracture in adults aged 50 and older. They used the Canadian Multicentre Osteoporosis Study (CaMos), a prospective, randomly selected, population-based community cohort.

Among 6,645 subjects, 192 (2.9%) were using SSRIs or SNRIs, or both, at baseline. During the 10-year study period, 978 participants (14.7%) experienced at least one fragility fracture. SSRI/SNRI use was associated with an increased risk of fragility fracture (hazard ratio [HR], 1.88; 95% CI, 1.48–2.39). After controlling for multiple risk factors, previous falls, and BMD of the hip and lumbar bone, the adjusted hazard ratio for current SSRI/SNRI use remained elevated (HR, 1.68; 95% CI, 1.32–2.14). The authors concluded that these results lend additional support to an association between SSRI/SNRI use and fragility fractures.

A few possible underlying mechanisms support the biological plausibility of these observations. One explanation is that increased fracture risk is mediated simply by falling. Another explanation could involve the influence of serotonin on bone. Besides their effects on balance, SSRIs may influence bone turnover and BMD. Whatever the mechanism, sufficient evidence exists to warrant the addition of SSRIs to the list of medications that contribute to osteoporosis.

Antidepressant use is not listed as a secondary cause of osteoporosis in the FRAX algorithm. Because the association between SSRI use and fracture risk appears to be independent of BMD, it may be useful to consider the possibility of including it in FRAX.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Consider BMD assessment for patients who take an SSRI, or who take an SSRI and have additional risk factors for fracture. Given the body of data on this issue, it seems appropriate to expect providers of SSRIs to conduct at least some discussion of bone health with patients.

IN THE PIPELINE: A HIGHLY EFFECTIVE AGENT TARGETING SCLEROSTIN

Recker R, Benson C, Matsumoto T, et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density [published online ahead of print September 5, 2014]. J Bone Miner Res. doi:10.1002/jbmr.2351.

Sclerostin is a protein secreted by osteocytes that negatively regulates the formation of mineralized bone matrix and bone mass. Recker and colleagues conducted a randomized, double-blind, placebo-
controlled, multicenter, phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin. The year-long trial involved 120 postmenopausal women with low BMD (lumbar spine T-score, –2.0 to –3.5) who were randomly allocated to:

• subcutaneous blosozumab 180 mg every 4 weeks
• subcutaneous blosozumab 180 mg every 2 weeks
• subcutaneous blosozumab 270 mg every 2 weeks
• placebo.

All groups also received calcium and vitamin D and underwent serial measurement of spine and hip BMD and testing of biochemical markers of bone turnover. The mean age was 65.8 years, and the mean lumbar spine T-score was –2.8.

Women treated with blosozumab experienced statistically significant, dose-related increases in spine, femoral neck, and total hip BMD, compared with placebo. In the highest dose group, BMD increased 17.7% from baseline at the spine and 6.2% at the total hip. Biochemical markers of bone ­formation increased rapidly during treatment with blosozumab, trending toward pretreatment levels by the study’s end. CTX, a biochemical marker of bone resorption, decreased early during blosozumab treatment to a concentration lower than that in the placebo group by 2 weeks, and it remained low throughout treatment.

Mild injection-site reactions were reported more frequently with blosozumab than with placebo.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Although blosozumab is not yet available, clinicians should be aware of the potential of sclerostin-antibody therapies like it. Such therapies appear to have substantial anabolic effects on the skeleton and may become promising agents in the treatment of osteoporosis.

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

Gynecologists are “first-line” providers for the diagnosis and treatment of osteoporosis in women. Lest you doubt the importance of this fact, consider that there are more osteoporotic fractures annually in the United States than all myocardial infarctions, strokes, breast cancers, and gynecologic malignancies combined. It is our duty to stay abreast of current developments in the diagnosis and treatment of this potentially devastating skeletal disorder as our patients live longer and longer.

In this article, I present recent studies on:

• the use of conjugated estrogens and bazedoxifene (Duavee) to manage hot flashes and menopausal bone loss
• the need for adequate levels of vitamin D to maintain bone and overall health, with sunlight exposure remaining a viable option
• a reinterpretation of the findings on estrogen and fracture risk from the Women’s Health Initiative (WHI)
• the effects of selective serotonin reuptake inhibitors (SSRIs) on bone mineral density (BMD)
• development of blosozumab, a new agent in the fight against osteoporosis and fracture.

FIRST TISSUE-SELECTIVE ESTROGEN COMPLEX PROTECTS AGAINST BONE LOSS WITHOUT AFFECTING ENDOMETRIAL AND BREAST TISSUE

Komm BS, Mirkin S, Jenkins SN. Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss. ­Steroids. 2014;90:71–81.

Pinkerton JV, Harvey JA, Lindsay R, et al; SMART-5 Investigators. Effects of bazedoxifene/conjugated ­estrogens on the endometrium and bone: a randomized trial. J Clin Endocrinol Metab. 2014;99(2):e189–e198.

Conjugated estrogens combined with the selective estrogen receptor modulator (SERM) bazedoxifene (Duavee) are a new option to alleviate menopausal symptoms and prevent postmenopausal bone loss. The rationale for development of the tissue-selective estrogen complex (TSEC) was to combine the benefits of conjugated estrogens with the SERM’s ability to offset estrogenic stimulation of the endometrium and breast.

TSECs offer a progestin-free alternative to traditional hormone therapy for women with a uterus. In preclinical studies, investigators found evidence to support bazedoxifene as the SERM of choice and demonstrated that, by combining it with conjugated estrogens, they could provide an optimal balance of estrogen-receptor agonist/antagonist activity, compared with other potential TSEC pairings. Clinical study results confirmed the efficacy of this combination in maintaining bone mass.

Given separately, conjugated estrogens and bazedoxifene each protect against the loss of BMD and help prevent fracture in postmenopausal women.

Findings in key populations
Komm and colleagues describe substudies of the Selective estrogens, Menopause, and Response to Therapy (SMART) trials to evaluate the combination of conjugated estrogens and SERMs to prevent osteoporosis in postmenopausal women with a uterus. One SMART-1 trial included two osteoporosis prevention substudies that evaluated the combination of conjugated estrogens and bazedoxifene in different subpopulations:

• women more than 5 years past the last menstrual period with a lumbar spine or hip BMD T-score between –1 and –2.5 plus one other risk factor for osteoporosis (n = 1,454)
• women 1 to 5 years past their last menstrual period (the interval during which bone loss is greatest) with at least one risk factor for osteoporosis (n = 861).

All doses of conjugated estrogens and bazedoxifene significantly increased the adjusted mean percentage of change in BMD of the lumbar spine from baseline to 24 months (a primary endpoint), compared with placebo, which was associated with decreases in BMD (P<.001). Findings were similar for total hip BMD.

In a separate study, Pinkerton and colleagues found that the dose of conjugated estrogens (0.45 mg) and bazedoxifene (20 mg) approved by the US Food and Drug Administration does not cause a change in breast density or thickness of the endometrium, nor does it increase breast pain, compared with placebo.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This newly available TSEC—a combination of conjugated estrogens (0.45 mg) and bazedoxifene (20 mg)—is an effective, well-tolerated alternative to traditional estrogen-progestin hormone therapy for relief of menopausal symptoms and prevention of osteoporosis in postmenopausal women with a uterus.

DON’T EXCLUDE SUNLIGHT FROM THE BONE–HEALTH EQUATION

Holick MF. Sunlight, ultraviolet radiation, vitamin D, and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2014;810:1–16.

Many people think of vitamin D as the “sunshine vitamin.” During exposure to sunlight, ultraviolet photons enter the skin and convert 7-dehydrocholesterol to previtamin D3, which, in turn, is converted to vitamin D3.

Throughout most of human history, people have depended on sunlight for vitamin D. Variables such as skin pigmentation, sunscreen use, aging, time of day, season, and latitude dramatically affect previtamin synthesis.

Although vitamin D deficiency was thought to have been conquered, it is now recognized that more than 50% of the world’s population is at risk for vitamin D insufficiency or low levels of 25-hydroxyvitamin D. Among the reasons are inadequate fortification of foods with vitamin D and a misconception that most balanced diets contain adequate vitamin D.

Deficiency of this vitamin causes growth retardation and rickets in children and osteomalacia in adults and can precipitate and exacerbate osteopenia or osteoporosis and increase the risk of fracture in adults.

Some evidence also suggests that vitamin D deficiency may have other serious consequences, including an increased risk for common cancers and autoimmune, infectious, and cardiovascular diseases.

In this review, Holick argues that we need to remind our patients of the beneficial effects of moderate sunlight.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
There is no question that sufficient levels of vitamin D are vital to bone health, and perhaps to overall health in numerous other organ systems as well. The pendulum of our concern over skin cancers may have moved too far in the direction of sun avoidance. In reality, moderate sunlight as a source of vitamin D is still appropriate for many of our patients.

WHEN IT COMES TO ESTROGEN AND BONE, BENEFITS OUTWEIGH RISKS

de Villiers TJ. 8th Pieter van Keep Memorial Lecture. Estrogen and bone: have we completed a full circle? [published online ahead of print September 22, 2014]. Climacteric. 2014;17(suppl 2):4–7. doi:10.3109/13697137.2014.953047.

In the WHI estrogen-progestin arm, fracture rates were reported as hazard ratios:

• hip fracture, 0.66 (95% confidence interval [CI], 0.45–0.98)
• clinical vertebral fracture, 0.66 (95% CI, 0.44–0.98)
• nonvertebral fractures, 0.77 (95% CI, 0.69–0.86).

In the estrogen-only arm of the WHI, reductions in the rates of fracture were reported as percentages and were similar:

• 39% reduction in hip fracture, compared with placebo
• 38% reduction in clinical vertebral fracture
• 21% reduction in total fractures.

All of these reductions were statistically significant.

Despite the excellent anti-fracture efficacy demonstrated in the WHI, investigators concluded that the risks of hormone therapy outweighed the benefits in the general postmenopausal population.

Why we should reconsider estrogen for bone health
In his presidential address to the International Menopause Society (cited above), de Villiers observed that, in the WHI:

• Only clinical fractures were recorded. Unlike all other fracture trials, routine radiographs were not obtained to record morphometric fractures. This decision, he believes (and I concur), led to a significant understatement of estrogen’s protective effects against vertebral fracture.
• The general population studied had a low risk of fracture, with an average spinal T-score of –1.3. This, too, contributed to an understatement of estrogen’s protective effects, compared with the findings of other randomized controlled trials involving patients at much higher risk.
• From a bone-centric point of view, the WHI findings represent a favorable ratio of benefits to risks.

No bone-active drugs are completely free of potential adverse effects and restrictions, many of which become apparent only after FDA approval and general use of the drug. Bisphosphonates have been implicated in atrial fibrillation, osteonecrosis of the jaw, and atypical femur shaft fracture after extended use. Like estrogen, SERMs can increase the risk of death from deep venous thrombosis and stroke.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Estrogen is the only agent proved to be effective against all types of osteoporotic fractures during primary analysis of a large randomized controlled trial. This efficacy is of special importance for the patient with osteopenia who is at risk for fracture. Estrogen remains a serious option for the prevention of postmenopausal bone loss and osteoporosis-related fractures, especially in younger patients. Individualization of therapy is key.

COUNSEL SSRI AND SNRI USERS THAT BMD MAY DECLINE OVER THE LONG TERM

Ak E, Bulut SD, Bulut S, et al. Evaluation of the effect of selective serotonin reuptake inhibitors on bone mineral density: an observational cross-sectional study [published online ahead of print September 4, 2014]. ­Osteoporos Int. doi:10.10007/s00198-014-2859-2.

Moura C, Bernatsky S, Ambrahamowicz M, et al. Antidepressant use and 10-year incident fracture risk: the population-based Canadian Multicentre Osteoporosis Study (CaMoS). Osteoporos Int. 2014;25(5):1473–1481.

Bruyère O, Reginster J-V. Osteoporosis in patients taking selective serotonin reuptake inhibitors: a focus on fracture outcome [published online ahead of print August 5, 2014]. Endocrine. doi:10.1007/s12020-014-0357-0.

Evidence from longitudinal, cross-­sectional, and prospective cohort studies suggests that the use of antidepressants at therapeutic doses is associated with a reduction in BMD and an increase in the risk of falls and fracture. These associations have been demonstrated in several distinct populations using various study designs, and with bone density, bone loss, or fractures as outcomes. They remain consistent even after adjustment for confounding variables such as age, body mass index, lifestyle factors such as alcohol and tobacco use, and fracture history.

Ak and colleagues recruited 60 patients given a diagnosis of generalized anxiety disorder and treated with paroxetine, sertraline, or citalopram for at least 12 months, comparing their BMD with that of 40 healthy volunteers. BMD was measured by dual-energy x-ray absorptiometry at the femoral and lumbar regions. BMD of the L2–L4 vertebrae, total lumbar vertebrae, and femoral intertrochanteric region, as well as total femoral Z-scores and femoral Ward’s region T-scores, were lower in the treatment group (P<.05). There was a significant negative correlation between the duration of treatment and the change in BMD values.

Moura and colleagues reviewed data from a large prospective Canadian cohort to assess the association between SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), and fracture in adults aged 50 and older. They used the Canadian Multicentre Osteoporosis Study (CaMos), a prospective, randomly selected, population-based community cohort.

Among 6,645 subjects, 192 (2.9%) were using SSRIs or SNRIs, or both, at baseline. During the 10-year study period, 978 participants (14.7%) experienced at least one fragility fracture. SSRI/SNRI use was associated with an increased risk of fragility fracture (hazard ratio [HR], 1.88; 95% CI, 1.48–2.39). After controlling for multiple risk factors, previous falls, and BMD of the hip and lumbar bone, the adjusted hazard ratio for current SSRI/SNRI use remained elevated (HR, 1.68; 95% CI, 1.32–2.14). The authors concluded that these results lend additional support to an association between SSRI/SNRI use and fragility fractures.

A few possible underlying mechanisms support the biological plausibility of these observations. One explanation is that increased fracture risk is mediated simply by falling. Another explanation could involve the influence of serotonin on bone. Besides their effects on balance, SSRIs may influence bone turnover and BMD. Whatever the mechanism, sufficient evidence exists to warrant the addition of SSRIs to the list of medications that contribute to osteoporosis.

Antidepressant use is not listed as a secondary cause of osteoporosis in the FRAX algorithm. Because the association between SSRI use and fracture risk appears to be independent of BMD, it may be useful to consider the possibility of including it in FRAX.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Consider BMD assessment for patients who take an SSRI, or who take an SSRI and have additional risk factors for fracture. Given the body of data on this issue, it seems appropriate to expect providers of SSRIs to conduct at least some discussion of bone health with patients.

IN THE PIPELINE: A HIGHLY EFFECTIVE AGENT TARGETING SCLEROSTIN

Recker R, Benson C, Matsumoto T, et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density [published online ahead of print September 5, 2014]. J Bone Miner Res. doi:10.1002/jbmr.2351.

Sclerostin is a protein secreted by osteocytes that negatively regulates the formation of mineralized bone matrix and bone mass. Recker and colleagues conducted a randomized, double-blind, placebo-
controlled, multicenter, phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin. The year-long trial involved 120 postmenopausal women with low BMD (lumbar spine T-score, –2.0 to –3.5) who were randomly allocated to:

• subcutaneous blosozumab 180 mg every 4 weeks
• subcutaneous blosozumab 180 mg every 2 weeks
• subcutaneous blosozumab 270 mg every 2 weeks
• placebo.

All groups also received calcium and vitamin D and underwent serial measurement of spine and hip BMD and testing of biochemical markers of bone turnover. The mean age was 65.8 years, and the mean lumbar spine T-score was –2.8.

Women treated with blosozumab experienced statistically significant, dose-related increases in spine, femoral neck, and total hip BMD, compared with placebo. In the highest dose group, BMD increased 17.7% from baseline at the spine and 6.2% at the total hip. Biochemical markers of bone ­formation increased rapidly during treatment with blosozumab, trending toward pretreatment levels by the study’s end. CTX, a biochemical marker of bone resorption, decreased early during blosozumab treatment to a concentration lower than that in the placebo group by 2 weeks, and it remained low throughout treatment.

Mild injection-site reactions were reported more frequently with blosozumab than with placebo.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Although blosozumab is not yet available, clinicians should be aware of the potential of sclerostin-antibody therapies like it. Such therapies appear to have substantial anabolic effects on the skeleton and may become promising agents in the treatment of osteoporosis.

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

Gynecologists are “first-line” providers for the diagnosis and treatment of osteoporosis in women. Lest you doubt the importance of this fact, consider that there are more osteoporotic fractures annually in the United States than all myocardial infarctions, strokes, breast cancers, and gynecologic malignancies combined. It is our duty to stay abreast of current developments in the diagnosis and treatment of this potentially devastating skeletal disorder as our patients live longer and longer.

In this article, I present recent studies on:

• the use of conjugated estrogens and bazedoxifene (Duavee) to manage hot flashes and menopausal bone loss
• the need for adequate levels of vitamin D to maintain bone and overall health, with sunlight exposure remaining a viable option
• a reinterpretation of the findings on estrogen and fracture risk from the Women’s Health Initiative (WHI)
• the effects of selective serotonin reuptake inhibitors (SSRIs) on bone mineral density (BMD)
• development of blosozumab, a new agent in the fight against osteoporosis and fracture.

FIRST TISSUE-SELECTIVE ESTROGEN COMPLEX PROTECTS AGAINST BONE LOSS WITHOUT AFFECTING ENDOMETRIAL AND BREAST TISSUE

Komm BS, Mirkin S, Jenkins SN. Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss. ­Steroids. 2014;90:71–81.

Pinkerton JV, Harvey JA, Lindsay R, et al; SMART-5 Investigators. Effects of bazedoxifene/conjugated ­estrogens on the endometrium and bone: a randomized trial. J Clin Endocrinol Metab. 2014;99(2):e189–e198.

Conjugated estrogens combined with the selective estrogen receptor modulator (SERM) bazedoxifene (Duavee) are a new option to alleviate menopausal symptoms and prevent postmenopausal bone loss. The rationale for development of the tissue-selective estrogen complex (TSEC) was to combine the benefits of conjugated estrogens with the SERM’s ability to offset estrogenic stimulation of the endometrium and breast.

TSECs offer a progestin-free alternative to traditional hormone therapy for women with a uterus. In preclinical studies, investigators found evidence to support bazedoxifene as the SERM of choice and demonstrated that, by combining it with conjugated estrogens, they could provide an optimal balance of estrogen-receptor agonist/antagonist activity, compared with other potential TSEC pairings. Clinical study results confirmed the efficacy of this combination in maintaining bone mass.

Given separately, conjugated estrogens and bazedoxifene each protect against the loss of BMD and help prevent fracture in postmenopausal women.

Findings in key populations
Komm and colleagues describe substudies of the Selective estrogens, Menopause, and Response to Therapy (SMART) trials to evaluate the combination of conjugated estrogens and SERMs to prevent osteoporosis in postmenopausal women with a uterus. One SMART-1 trial included two osteoporosis prevention substudies that evaluated the combination of conjugated estrogens and bazedoxifene in different subpopulations:

• women more than 5 years past the last menstrual period with a lumbar spine or hip BMD T-score between –1 and –2.5 plus one other risk factor for osteoporosis (n = 1,454)
• women 1 to 5 years past their last menstrual period (the interval during which bone loss is greatest) with at least one risk factor for osteoporosis (n = 861).

All doses of conjugated estrogens and bazedoxifene significantly increased the adjusted mean percentage of change in BMD of the lumbar spine from baseline to 24 months (a primary endpoint), compared with placebo, which was associated with decreases in BMD (P<.001). Findings were similar for total hip BMD.

In a separate study, Pinkerton and colleagues found that the dose of conjugated estrogens (0.45 mg) and bazedoxifene (20 mg) approved by the US Food and Drug Administration does not cause a change in breast density or thickness of the endometrium, nor does it increase breast pain, compared with placebo.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
This newly available TSEC—a combination of conjugated estrogens (0.45 mg) and bazedoxifene (20 mg)—is an effective, well-tolerated alternative to traditional estrogen-progestin hormone therapy for relief of menopausal symptoms and prevention of osteoporosis in postmenopausal women with a uterus.

DON’T EXCLUDE SUNLIGHT FROM THE BONE–HEALTH EQUATION

Holick MF. Sunlight, ultraviolet radiation, vitamin D, and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2014;810:1–16.

Many people think of vitamin D as the “sunshine vitamin.” During exposure to sunlight, ultraviolet photons enter the skin and convert 7-dehydrocholesterol to previtamin D3, which, in turn, is converted to vitamin D3.

Throughout most of human history, people have depended on sunlight for vitamin D. Variables such as skin pigmentation, sunscreen use, aging, time of day, season, and latitude dramatically affect previtamin synthesis.

Although vitamin D deficiency was thought to have been conquered, it is now recognized that more than 50% of the world’s population is at risk for vitamin D insufficiency or low levels of 25-hydroxyvitamin D. Among the reasons are inadequate fortification of foods with vitamin D and a misconception that most balanced diets contain adequate vitamin D.

Deficiency of this vitamin causes growth retardation and rickets in children and osteomalacia in adults and can precipitate and exacerbate osteopenia or osteoporosis and increase the risk of fracture in adults.

Some evidence also suggests that vitamin D deficiency may have other serious consequences, including an increased risk for common cancers and autoimmune, infectious, and cardiovascular diseases.

In this review, Holick argues that we need to remind our patients of the beneficial effects of moderate sunlight.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
There is no question that sufficient levels of vitamin D are vital to bone health, and perhaps to overall health in numerous other organ systems as well. The pendulum of our concern over skin cancers may have moved too far in the direction of sun avoidance. In reality, moderate sunlight as a source of vitamin D is still appropriate for many of our patients.

WHEN IT COMES TO ESTROGEN AND BONE, BENEFITS OUTWEIGH RISKS

de Villiers TJ. 8th Pieter van Keep Memorial Lecture. Estrogen and bone: have we completed a full circle? [published online ahead of print September 22, 2014]. Climacteric. 2014;17(suppl 2):4–7. doi:10.3109/13697137.2014.953047.

In the WHI estrogen-progestin arm, fracture rates were reported as hazard ratios:

• hip fracture, 0.66 (95% confidence interval [CI], 0.45–0.98)
• clinical vertebral fracture, 0.66 (95% CI, 0.44–0.98)
• nonvertebral fractures, 0.77 (95% CI, 0.69–0.86).

In the estrogen-only arm of the WHI, reductions in the rates of fracture were reported as percentages and were similar:

• 39% reduction in hip fracture, compared with placebo
• 38% reduction in clinical vertebral fracture
• 21% reduction in total fractures.

All of these reductions were statistically significant.

Despite the excellent anti-fracture efficacy demonstrated in the WHI, investigators concluded that the risks of hormone therapy outweighed the benefits in the general postmenopausal population.

Why we should reconsider estrogen for bone health
In his presidential address to the International Menopause Society (cited above), de Villiers observed that, in the WHI:

• Only clinical fractures were recorded. Unlike all other fracture trials, routine radiographs were not obtained to record morphometric fractures. This decision, he believes (and I concur), led to a significant understatement of estrogen’s protective effects against vertebral fracture.
• The general population studied had a low risk of fracture, with an average spinal T-score of –1.3. This, too, contributed to an understatement of estrogen’s protective effects, compared with the findings of other randomized controlled trials involving patients at much higher risk.
• From a bone-centric point of view, the WHI findings represent a favorable ratio of benefits to risks.

No bone-active drugs are completely free of potential adverse effects and restrictions, many of which become apparent only after FDA approval and general use of the drug. Bisphosphonates have been implicated in atrial fibrillation, osteonecrosis of the jaw, and atypical femur shaft fracture after extended use. Like estrogen, SERMs can increase the risk of death from deep venous thrombosis and stroke.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Estrogen is the only agent proved to be effective against all types of osteoporotic fractures during primary analysis of a large randomized controlled trial. This efficacy is of special importance for the patient with osteopenia who is at risk for fracture. Estrogen remains a serious option for the prevention of postmenopausal bone loss and osteoporosis-related fractures, especially in younger patients. Individualization of therapy is key.

COUNSEL SSRI AND SNRI USERS THAT BMD MAY DECLINE OVER THE LONG TERM

Ak E, Bulut SD, Bulut S, et al. Evaluation of the effect of selective serotonin reuptake inhibitors on bone mineral density: an observational cross-sectional study [published online ahead of print September 4, 2014]. ­Osteoporos Int. doi:10.10007/s00198-014-2859-2.

Moura C, Bernatsky S, Ambrahamowicz M, et al. Antidepressant use and 10-year incident fracture risk: the population-based Canadian Multicentre Osteoporosis Study (CaMoS). Osteoporos Int. 2014;25(5):1473–1481.

Bruyère O, Reginster J-V. Osteoporosis in patients taking selective serotonin reuptake inhibitors: a focus on fracture outcome [published online ahead of print August 5, 2014]. Endocrine. doi:10.1007/s12020-014-0357-0.

Evidence from longitudinal, cross-­sectional, and prospective cohort studies suggests that the use of antidepressants at therapeutic doses is associated with a reduction in BMD and an increase in the risk of falls and fracture. These associations have been demonstrated in several distinct populations using various study designs, and with bone density, bone loss, or fractures as outcomes. They remain consistent even after adjustment for confounding variables such as age, body mass index, lifestyle factors such as alcohol and tobacco use, and fracture history.

Ak and colleagues recruited 60 patients given a diagnosis of generalized anxiety disorder and treated with paroxetine, sertraline, or citalopram for at least 12 months, comparing their BMD with that of 40 healthy volunteers. BMD was measured by dual-energy x-ray absorptiometry at the femoral and lumbar regions. BMD of the L2–L4 vertebrae, total lumbar vertebrae, and femoral intertrochanteric region, as well as total femoral Z-scores and femoral Ward’s region T-scores, were lower in the treatment group (P<.05). There was a significant negative correlation between the duration of treatment and the change in BMD values.

Moura and colleagues reviewed data from a large prospective Canadian cohort to assess the association between SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), and fracture in adults aged 50 and older. They used the Canadian Multicentre Osteoporosis Study (CaMos), a prospective, randomly selected, population-based community cohort.

Among 6,645 subjects, 192 (2.9%) were using SSRIs or SNRIs, or both, at baseline. During the 10-year study period, 978 participants (14.7%) experienced at least one fragility fracture. SSRI/SNRI use was associated with an increased risk of fragility fracture (hazard ratio [HR], 1.88; 95% CI, 1.48–2.39). After controlling for multiple risk factors, previous falls, and BMD of the hip and lumbar bone, the adjusted hazard ratio for current SSRI/SNRI use remained elevated (HR, 1.68; 95% CI, 1.32–2.14). The authors concluded that these results lend additional support to an association between SSRI/SNRI use and fragility fractures.

A few possible underlying mechanisms support the biological plausibility of these observations. One explanation is that increased fracture risk is mediated simply by falling. Another explanation could involve the influence of serotonin on bone. Besides their effects on balance, SSRIs may influence bone turnover and BMD. Whatever the mechanism, sufficient evidence exists to warrant the addition of SSRIs to the list of medications that contribute to osteoporosis.

Antidepressant use is not listed as a secondary cause of osteoporosis in the FRAX algorithm. Because the association between SSRI use and fracture risk appears to be independent of BMD, it may be useful to consider the possibility of including it in FRAX.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Consider BMD assessment for patients who take an SSRI, or who take an SSRI and have additional risk factors for fracture. Given the body of data on this issue, it seems appropriate to expect providers of SSRIs to conduct at least some discussion of bone health with patients.

IN THE PIPELINE: A HIGHLY EFFECTIVE AGENT TARGETING SCLEROSTIN

Recker R, Benson C, Matsumoto T, et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density [published online ahead of print September 5, 2014]. J Bone Miner Res. doi:10.1002/jbmr.2351.

Sclerostin is a protein secreted by osteocytes that negatively regulates the formation of mineralized bone matrix and bone mass. Recker and colleagues conducted a randomized, double-blind, placebo-
controlled, multicenter, phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin. The year-long trial involved 120 postmenopausal women with low BMD (lumbar spine T-score, –2.0 to –3.5) who were randomly allocated to:

• subcutaneous blosozumab 180 mg every 4 weeks
• subcutaneous blosozumab 180 mg every 2 weeks
• subcutaneous blosozumab 270 mg every 2 weeks
• placebo.

All groups also received calcium and vitamin D and underwent serial measurement of spine and hip BMD and testing of biochemical markers of bone turnover. The mean age was 65.8 years, and the mean lumbar spine T-score was –2.8.

Women treated with blosozumab experienced statistically significant, dose-related increases in spine, femoral neck, and total hip BMD, compared with placebo. In the highest dose group, BMD increased 17.7% from baseline at the spine and 6.2% at the total hip. Biochemical markers of bone ­formation increased rapidly during treatment with blosozumab, trending toward pretreatment levels by the study’s end. CTX, a biochemical marker of bone resorption, decreased early during blosozumab treatment to a concentration lower than that in the placebo group by 2 weeks, and it remained low throughout treatment.

Mild injection-site reactions were reported more frequently with blosozumab than with placebo.

WHAT THIS EVIDENCE MEANS FOR PRACTICE
Although blosozumab is not yet available, clinicians should be aware of the potential of sclerostin-antibody therapies like it. Such therapies appear to have substantial anabolic effects on the skeleton and may become promising agents in the treatment of osteoporosis.

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

Hospitals usually put patients who have had methicillin-resistant Staphylococcus aureus (MRSA) in isolation. However, researchers who conducted a 9-month pilot project at Christiana Care Health System in Newark, Delaware, say that many patients admitted with a history of MRSA colonization are isolated unnecessarily. They suggest that screening patients first is both cost-effective and better for the patients.

When surveyed, patients said the isolation made them feel stigmatized, contaminated, neglected, and distressed. One patient felt “treated like a plague victim.” The researchers also found that > 80% of the patients on the MRSA list were put at needless risk, especially when they roomed with another patient who had an active MRSA infection.

In the study, 7 medical-surgical units admitted 211 patients who were listed as MRSA positive (MRSA+) but who had not had a positive MRSA culture for ≥ 12 months. Of these patients, 23% did not complete the screening process, because they were discharged or were receiving antibiotics. Of the patients who did complete screening, only 32 (20%) were still colonized.

Thirteen of the 32 patients placed in contact isolation said the isolation had affected their hospital stay. Some felt they had fewer visitors because of the isolation; that the isolation measures were “off-putting” and “inconvenient” for visitors. They also felt they were treated differently by staff. Nine patients reported emotional distress, saying they felt uncomfortable and worried about their MRSA+ status.

The researchers used culture-based screening with CHROMagar MRSA plates rather than real-time polymerase chain reaction (PCR) screening. But cultures are less sensitive than is PCR screening, they say, and require a longer turnaround time, which can mean patients are not able to complete screening or may be erroneously removed from isolation. After the study was done, the researchers’ hospital switched to PCR assay screening.

Another potential area for improvement: Only 14 of the MRSA+ patients were aware that their previous MRSA diagnosis would remain on their patient record, and only 11 reported that they were given instructions for follow-up care after their discharge from the hospital where the diagnosis was first made.

The annual cost of screening for the 7 medical-surgical units was projected to be about $7,700. The cost associated with unnecessary isolation reached nearly $109,000 per year.

Source
Goldsack JC, DeRitter C, Power M, et al. Am J Infect Contr. 2014;42(10):1039-1043.
doi: 10.1016/j.ajic.2014.07.011.

Hospitals usually put patients who have had methicillin-resistant Staphylococcus aureus (MRSA) in isolation. However, researchers who conducted a 9-month pilot project at Christiana Care Health System in Newark, Delaware, say that many patients admitted with a history of MRSA colonization are isolated unnecessarily. They suggest that screening patients first is both cost-effective and better for the patients.

When surveyed, patients said the isolation made them feel stigmatized, contaminated, neglected, and distressed. One patient felt “treated like a plague victim.” The researchers also found that > 80% of the patients on the MRSA list were put at needless risk, especially when they roomed with another patient who had an active MRSA infection.

In the study, 7 medical-surgical units admitted 211 patients who were listed as MRSA positive (MRSA+) but who had not had a positive MRSA culture for ≥ 12 months. Of these patients, 23% did not complete the screening process, because they were discharged or were receiving antibiotics. Of the patients who did complete screening, only 32 (20%) were still colonized.

Thirteen of the 32 patients placed in contact isolation said the isolation had affected their hospital stay. Some felt they had fewer visitors because of the isolation; that the isolation measures were “off-putting” and “inconvenient” for visitors. They also felt they were treated differently by staff. Nine patients reported emotional distress, saying they felt uncomfortable and worried about their MRSA+ status.

The researchers used culture-based screening with CHROMagar MRSA plates rather than real-time polymerase chain reaction (PCR) screening. But cultures are less sensitive than is PCR screening, they say, and require a longer turnaround time, which can mean patients are not able to complete screening or may be erroneously removed from isolation. After the study was done, the researchers’ hospital switched to PCR assay screening.

Another potential area for improvement: Only 14 of the MRSA+ patients were aware that their previous MRSA diagnosis would remain on their patient record, and only 11 reported that they were given instructions for follow-up care after their discharge from the hospital where the diagnosis was first made.

The annual cost of screening for the 7 medical-surgical units was projected to be about $7,700. The cost associated with unnecessary isolation reached nearly $109,000 per year.

Source
Goldsack JC, DeRitter C, Power M, et al. Am J Infect Contr. 2014;42(10):1039-1043.
doi: 10.1016/j.ajic.2014.07.011.

Hospitals usually put patients who have had methicillin-resistant Staphylococcus aureus (MRSA) in isolation. However, researchers who conducted a 9-month pilot project at Christiana Care Health System in Newark, Delaware, say that many patients admitted with a history of MRSA colonization are isolated unnecessarily. They suggest that screening patients first is both cost-effective and better for the patients.

When surveyed, patients said the isolation made them feel stigmatized, contaminated, neglected, and distressed. One patient felt “treated like a plague victim.” The researchers also found that > 80% of the patients on the MRSA list were put at needless risk, especially when they roomed with another patient who had an active MRSA infection.

In the study, 7 medical-surgical units admitted 211 patients who were listed as MRSA positive (MRSA+) but who had not had a positive MRSA culture for ≥ 12 months. Of these patients, 23% did not complete the screening process, because they were discharged or were receiving antibiotics. Of the patients who did complete screening, only 32 (20%) were still colonized.

Thirteen of the 32 patients placed in contact isolation said the isolation had affected their hospital stay. Some felt they had fewer visitors because of the isolation; that the isolation measures were “off-putting” and “inconvenient” for visitors. They also felt they were treated differently by staff. Nine patients reported emotional distress, saying they felt uncomfortable and worried about their MRSA+ status.

The researchers used culture-based screening with CHROMagar MRSA plates rather than real-time polymerase chain reaction (PCR) screening. But cultures are less sensitive than is PCR screening, they say, and require a longer turnaround time, which can mean patients are not able to complete screening or may be erroneously removed from isolation. After the study was done, the researchers’ hospital switched to PCR assay screening.

Another potential area for improvement: Only 14 of the MRSA+ patients were aware that their previous MRSA diagnosis would remain on their patient record, and only 11 reported that they were given instructions for follow-up care after their discharge from the hospital where the diagnosis was first made.

The annual cost of screening for the 7 medical-surgical units was projected to be about $7,700. The cost associated with unnecessary isolation reached nearly $109,000 per year.

Source
Goldsack JC, DeRitter C, Power M, et al. Am J Infect Contr. 2014;42(10):1039-1043.
doi: 10.1016/j.ajic.2014.07.011.

Nephrotic syndrome may raise the risk of cancer by > 70%—and has a “noteworthy” association with certain cancers—according to researchers from Aarhus University Hospital, in Denmark, Dartmouth Medical School, in Hanover, New Hampshire, and University of North Carolina, Chapel Hill.

Case reports and case series have long suggested that nephrotic syndrome and occult cancer are linked, the researchers say. For instance, one study found a more than double cancer risk during the 15 years after diagnosis with membranous nephropathy. In that study, as many as 21% of patients were diagnosed with cancer during a median follow-up of 6.2 years. The high risk might be explained by the focus on membranous nephropathy, a condition known to be associated with cancer, the researchers say. But the studies were very small and lacked comparison groups. Moreover, there have been no formal epidemiologic studies in a population-based setting.

In this study, the researchers analyzed data from about 7.8 million people in the Danish National Registry of Patients, estimating the 5-year risk of incident cancer in the 4,293 patients with nephrotic syndrome. The researchers found a 4.7% 5-year risk of any cancer, with the highest risk for lung cancer, multiple myeloma, and prostate cancer. Over the entire follow-up period, 196 cancers were “expected,” but 338 cancers were observed. The elevated risk was highest during the first 6 months after nephrotic syndrome was diagnosed, but remained elevated through the long-term follow-up.

Five-year mortality rates were 68.5% for patients with nephrotic syndrome, compared with 63.4% in patients without nephrotic syndrome. At 1 year, mortality was 40.8% (95% confidence interval [CI], 35.7-46.4) in patients with nephrotic syndrome, and 38.4% (95% CI, 36.0-40.8) in those without. The impact of nephrotic syndrome on 1-year mortality was most pronounced in patients with hematologic malignancy. After adjusting for age, gender, and comorbidity, the researchers found a hazard ratio of 1.2 for mortality in patients with cancer following nephrotic syndrome, with the most pronounced effect in those with localized cancer.

Despite a low absolute risk of most cancers, the researchers conclude, their findings suggest that clinical workups might logically focus on lung cancer and multiple myeloma when there is a suspicion of co-occurring signs or symptoms in patients with nephrotic syndrome.

Source
Christiansen CF, Onega T, Sværke C, et al. Am J Med. 2014;127(9):871-877.
doi: 10.1016/j.amjmed.2014.05.002.

Nephrotic syndrome may raise the risk of cancer by > 70%—and has a “noteworthy” association with certain cancers—according to researchers from Aarhus University Hospital, in Denmark, Dartmouth Medical School, in Hanover, New Hampshire, and University of North Carolina, Chapel Hill.

Case reports and case series have long suggested that nephrotic syndrome and occult cancer are linked, the researchers say. For instance, one study found a more than double cancer risk during the 15 years after diagnosis with membranous nephropathy. In that study, as many as 21% of patients were diagnosed with cancer during a median follow-up of 6.2 years. The high risk might be explained by the focus on membranous nephropathy, a condition known to be associated with cancer, the researchers say. But the studies were very small and lacked comparison groups. Moreover, there have been no formal epidemiologic studies in a population-based setting.

In this study, the researchers analyzed data from about 7.8 million people in the Danish National Registry of Patients, estimating the 5-year risk of incident cancer in the 4,293 patients with nephrotic syndrome. The researchers found a 4.7% 5-year risk of any cancer, with the highest risk for lung cancer, multiple myeloma, and prostate cancer. Over the entire follow-up period, 196 cancers were “expected,” but 338 cancers were observed. The elevated risk was highest during the first 6 months after nephrotic syndrome was diagnosed, but remained elevated through the long-term follow-up.

Five-year mortality rates were 68.5% for patients with nephrotic syndrome, compared with 63.4% in patients without nephrotic syndrome. At 1 year, mortality was 40.8% (95% confidence interval [CI], 35.7-46.4) in patients with nephrotic syndrome, and 38.4% (95% CI, 36.0-40.8) in those without. The impact of nephrotic syndrome on 1-year mortality was most pronounced in patients with hematologic malignancy. After adjusting for age, gender, and comorbidity, the researchers found a hazard ratio of 1.2 for mortality in patients with cancer following nephrotic syndrome, with the most pronounced effect in those with localized cancer.

Despite a low absolute risk of most cancers, the researchers conclude, their findings suggest that clinical workups might logically focus on lung cancer and multiple myeloma when there is a suspicion of co-occurring signs or symptoms in patients with nephrotic syndrome.

Source
Christiansen CF, Onega T, Sværke C, et al. Am J Med. 2014;127(9):871-877.
doi: 10.1016/j.amjmed.2014.05.002.

Nephrotic syndrome may raise the risk of cancer by > 70%—and has a “noteworthy” association with certain cancers—according to researchers from Aarhus University Hospital, in Denmark, Dartmouth Medical School, in Hanover, New Hampshire, and University of North Carolina, Chapel Hill.

Case reports and case series have long suggested that nephrotic syndrome and occult cancer are linked, the researchers say. For instance, one study found a more than double cancer risk during the 15 years after diagnosis with membranous nephropathy. In that study, as many as 21% of patients were diagnosed with cancer during a median follow-up of 6.2 years. The high risk might be explained by the focus on membranous nephropathy, a condition known to be associated with cancer, the researchers say. But the studies were very small and lacked comparison groups. Moreover, there have been no formal epidemiologic studies in a population-based setting.

In this study, the researchers analyzed data from about 7.8 million people in the Danish National Registry of Patients, estimating the 5-year risk of incident cancer in the 4,293 patients with nephrotic syndrome. The researchers found a 4.7% 5-year risk of any cancer, with the highest risk for lung cancer, multiple myeloma, and prostate cancer. Over the entire follow-up period, 196 cancers were “expected,” but 338 cancers were observed. The elevated risk was highest during the first 6 months after nephrotic syndrome was diagnosed, but remained elevated through the long-term follow-up.

Five-year mortality rates were 68.5% for patients with nephrotic syndrome, compared with 63.4% in patients without nephrotic syndrome. At 1 year, mortality was 40.8% (95% confidence interval [CI], 35.7-46.4) in patients with nephrotic syndrome, and 38.4% (95% CI, 36.0-40.8) in those without. The impact of nephrotic syndrome on 1-year mortality was most pronounced in patients with hematologic malignancy. After adjusting for age, gender, and comorbidity, the researchers found a hazard ratio of 1.2 for mortality in patients with cancer following nephrotic syndrome, with the most pronounced effect in those with localized cancer.

Despite a low absolute risk of most cancers, the researchers conclude, their findings suggest that clinical workups might logically focus on lung cancer and multiple myeloma when there is a suspicion of co-occurring signs or symptoms in patients with nephrotic syndrome.

Source
Christiansen CF, Onega T, Sværke C, et al. Am J Med. 2014;127(9):871-877.
doi: 10.1016/j.amjmed.2014.05.002.

Much of my practice has focused on the treatment of menopausal women, but which of my patients can benefit from this particular combination of conjugated estrogen (CE) 0.45 mg plus bazedoxifene (BZA) 20 mg? I asked Dr Pinkerton this question, and more.

WHICH PATIENTS CAN BENEFIT MOST?
Dr Pinkerton: CE/BZA was tested in healthy postmenopausal women with a uterus who are at risk for bone loss and were reporting 50 or more moderate to severe hot flashes per week. The combination of CE and BZA is a good choice for women who have bothersome menopausal symptoms: hot flashes, night sweats, and sleep disruption or symptomatic vulvovaginal atrophy (VVA)—although it’s not approved for VVA.

Efficacy and safety data show that compared with placebo
• CE/BZA decreases the frequency and severity of hot flashes at 12 weeks, and those decreases are maintained at 12 months.^1,2
• Women taking CE/BZA have greater improvements in sleep, with both decreased sleep disturbance and time to fall asleep.³
• CE/BZA maintained or prevented lumbar spine and hip bone loss in postmenopausal women at risk for osteoporosis.^1,4,5

Although fracture data were not captured and the drug was not tested in osteoporotic women, study results showed bone loss prevention at 12 months, which was sustained at 24 months. The improvement in bone mineral density from baseline was about 1% to 1.5%. This was compared with a bone loss of 1.8% in women taking placebo.

In clinical studies, women taking CE/BZA versus placebo also reported a lower incidence of painful intercourse⁶ and some improvement in health-related quality of life and treatment satisfaction.^7,8

In short, CE/BZA is a good option for symptomatic menopausal women with a uterus who have bothersome hot flashes, night sweats, and sleep disruptions and want to prevent bone loss.

WHAT ABOUT ADVERSE EFFECTS?
Dr Pinkerton: In general, CE/BZA has a favorable safety and tolerability profile, with an overall incidence of adverse events similar to placebo. The rates of cardiovascular and cerebrovascular events, cancers (breast, endometrial, and ovarian), and mortality are comparable to placebo in two-year trials. These data are limited; studies have been conducted in healthy postmenopausal women. Future studies need to define the full risk profile, particularly among overweight or obese women and different ethnic groups, as well as for longer-term use.

IS THERE A ROLE AMONG WOMEN WITH BREAST CANCER?
Dr Pinkerton: CE/BZA has not been tested in women at risk for or who have a history of breast cancer. In preclinical trials of up to two years’ duration, involving healthy postmenopausal women, the rates for breast cancer with CE/BZA were similar to placebo. There are no long-term data, however, and there are no data in women at risk for breast cancer. I recommend that women who have or are at high risk for breast cancer consider nonhormonal treatment options.^9–11

HAS THERE BEEN AN ASSOCIATED INCREASE IN BREAST DENSITY WITH CE/BZA?
Dr Pinkerton: No. Data from two randomized clinical trials showed that the breast density changes with 12-month CE/BZA treatment were similar to placebo—which is markedly different from comparisons of placebo and combination estrogen-progestin therapy (EPT), where EPT increased breast density. If indeed this lack of an association translates into fewer breast cancers, it would be wonderful, but we do not have long-term data. We can tell our patients that using CE/BZA has not been shown to increase the risk for breast cancer, at least up to two years.

Continue for differences from traditional EPT >>

WHAT MAKES CE/BZA DIFFERENT FROM TRADITIONAL EPT?
Dr Pinkerton: There are two exciting differences:
   • The incidences of breast pain and tenderness were found to be similar to placebo and were significantly lower than those with the comparator EPT (conjugated estrogens 0.45 mg plus medroxyprogesterone acetate [CE/MPA] 1.5 mg).^9,10,12
   • Bleeding and spotting rates were significantly lower than those found with CE/MPA.¹³
In addition, high rates of amenorrhea have been found—comparable to placebo.¹³

CE/BZA is similar to traditional EPT in several ways. For instance, compared with placebo, at two years, CE/BZA was not found to increase the incidence of endometrial hyperplasia, endometrial thickness (increase from baseline was < 1 mm and comparable to placebo), or endometrial cancers.¹⁴ Lastly, similar to EPT, there is probably a twofold risk for venous thromboembolism (VTE) with BZA 20 mg alone.¹⁵ Importantly, there has been no additive effect on VTE risk when combining CE with BZA; however, we will need longer studies, in older women, to fully evaluate this risk.¹

Overall, in symptomatic postmenopausal women with a uterus, randomized controlled data show the same improvement with CE/BZA as that seen with traditional oral EPTs, with improvements in hot flashes; night sweats, with fewer sleep disruptions; and prevention of bone loss. In addition, the changes in cholesterol (an increase in triglyceride levels) and effect on the vagina are the same. Yet, CE/BZA appears to have a neutral effect on the breast and protects against endometrial hyperplasia and endometrial cancer without causing bleeding.^9,10 CE/BZA’s VTE and stroke risks are expected to be similar to traditional oral EPT.

Therefore, the major benefit of CE/BZA for women who have a uterus is the lack of significant breast tenderness, lack of changes in breast density, and lack of vaginal bleeding that is often seen with traditional EPT.¹²

THEN, IS PROGESTOGEN THE HARMFUL AGENT IN TRADITIONAL HT OPTIONS?
Dr Pinkerton: There is evidence that estrogen plus progestogen therapy has more risk for breast cancer than estrogen alone. But in women who have a uterus, you need to protect against uterine cancer so, up until now, the only option was to add progestogen. Some studies suggest the risk for breast cancer may differ depending on the type of progestogen. So it’s a laudable goal to try to protect the endometrium without using a progestogen.

GIVEN ITS SAFETY PROFILE, DO YOU SEE CE/BZA BEING INDICATED FOR WOMEN WITHOUT A UTERUS?
Dr Pinkerton: CE/BZA has been tested only in women with a uterus; there is no indication for using it in hysterectomized women. In the future, unless trial data show a benefit to hysterectomized women—by a reduction in breast cancer compared with estrogen alone—there would be no reason to add BZA to the CE for these women. You would just use CE or another type of estrogen alone.

DO YOU ANTICIPATE BZA BEING USED ALONE?
Dr Pinkerton: For treating osteoporosis in postmenopausal women at increased risk for fracture, BZA alone has greater benefits than risks. It is approved in other countries to prevent or treat osteoporosis. In 2008, Wyeth received an approval letter from the FDA for BZA alone but, for whatever reason, the drug was not brought to market. BZA reduces the number of new lumbar spine fractures by 4% (vs 2% for placebo), with efficacy better in those with a higher risk for fractures. Like raloxifene, it has not been shown effective at reducing nonvertebral fractures, although it maintains spinal bone density.¹⁶

BZA available as monotherapy could tempt clinicians to pair it with other estrogens. We must recognize that the combination of the specific estrogen and BZA dose and type need to be balanced to provide endometrial hyperplasia protection. It would not be safe or effective to take BZA as a selective estrogen-receptor modulator and pair it with any other untested systemic estrogen. I do not anticipate, in this country, that BZA will become available as monotherapy, however.

NEW OPTIONS ARE WELCOME
Dr Moore: Novel strategies for clinicians to optimally treat menopausal symptoms are always welcome. I look forward to more data from the SMART trials on CE/BZA and to moving forward as we gain experience with using this new treatment option.

REFERENCES
1. Lobo RA, Pinkerton JV, Gass ML, et al. Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic bone parameters and overall safety profile. Fertil Steril. 2009;92(3):1025–1038.

2. Pinkerton JV, Utian WH, Constantine GD, et al. Relief of vasomotor symptoms with the tissue-selective estrogen complex containing bazedoxifene/conjugated estrogens. Menopause. 2009;16(6): 1116–1124.

3. Pinkerton JV, Pan K, Abraham L, et al. Sleep parameters and health-related quality of life with bazedoxifene/conjugated estrogens. Menopause. 2014;21(3):252–259.

4. Lindsay R, Gallagher JC, Kagan R, et al. Efficacy of tissue-selective estrogen complex (TSEC) of bazedoxifene/conjugated estrogens (BZA/CE) for osteoporosis prevention in at-risk postmenopausal women. Fertil Steril. 2009;92(3):1045–1052.

5. Pinkerton JV, Harvey JA, Lindsay R, et al; SMART-5 Investigators. Effects of bazedoxifene/conjugated estrogens on the endometrium and bone.
J Clin Endocrinol Metab. 2014;99(2):E189–E198.

6. Kagan R, Williams RS, Pan K, Mirkin S, Pickar JH. A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estrogens (BZA/CE) for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women. Menopause. 2010;17(2):281–289.

7. Utian W, Yu H, Bobula J, et al. Bazedoxifene/conjugated estrogens and quality of life in postmenopausal women. Maturitas. 2009;63(4):
329–335.

8. Abraham L, Pinkerton JV, Messig M, et al. Menopause-specific quality of life across varying menopausal populations with conjugated estrogens/bazedoxifene. Maturitas. 2014;78(3):212–218.

9. Harvey JA, Pinkerton JV, Baracat EC, et al. Breast density changes in a randomized controlled trial evaluating bazedoxifene/conjugated estrogens. Menopause. 2013;20:(2)138–145.

10. Pinkerton JV, Harvey JA, Pan K, et al. Breast effects of bazedoxifene-conjugated estrogens. Obstet Gynecol. 2013;121(5):959–968.

11. Kaunitz AM. When should a menopausal woman discontinue hormone therapy? OBG Manag. 2014;26(2):59–65.

12. Pinkerton JV, Pickar JH, Racketa J, Mirkin S. Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention. Climacteric. 2012;15:(5)411–418.

13. Archer DF, Lewis V, Carr BR, et al. Bazedoxifene/conjugated estrogens (BZA/CE): incidence of uterine bleeding in postmenopausal women. Fertil Steril. 2009;92:1039–1044.

14. Pickar JH, Yeh I-T, Bachmann G, Speroff L. Endometrial effects of a tissue selective estrogen complex (TSEC) containing bazedoxifene/conjugated estrogens as a menopausal therapy. Fertil Steril. 2009; 92(3):1018–1024.

15. Mirkin S, Komm BS. Tissue-selective estrogen complexes for postmenopausal women. Maturitas. 2013;76(3):213–220.

16. Ellis AG, Reginster JY, Luo X, et al. Bazedoxifene versus oral bisphosphonates for the prevention of nonvertebral fractures in postmenopausal women with osteoporosis at higher risk of fracture. Value Health. 2014;17(4):424–432.

Much of my practice has focused on the treatment of menopausal women, but which of my patients can benefit from this particular combination of conjugated estrogen (CE) 0.45 mg plus bazedoxifene (BZA) 20 mg? I asked Dr Pinkerton this question, and more.

WHICH PATIENTS CAN BENEFIT MOST?
Dr Pinkerton: CE/BZA was tested in healthy postmenopausal women with a uterus who are at risk for bone loss and were reporting 50 or more moderate to severe hot flashes per week. The combination of CE and BZA is a good choice for women who have bothersome menopausal symptoms: hot flashes, night sweats, and sleep disruption or symptomatic vulvovaginal atrophy (VVA)—although it’s not approved for VVA.

Efficacy and safety data show that compared with placebo
• CE/BZA decreases the frequency and severity of hot flashes at 12 weeks, and those decreases are maintained at 12 months.^1,2
• Women taking CE/BZA have greater improvements in sleep, with both decreased sleep disturbance and time to fall asleep.³
• CE/BZA maintained or prevented lumbar spine and hip bone loss in postmenopausal women at risk for osteoporosis.^1,4,5

Although fracture data were not captured and the drug was not tested in osteoporotic women, study results showed bone loss prevention at 12 months, which was sustained at 24 months. The improvement in bone mineral density from baseline was about 1% to 1.5%. This was compared with a bone loss of 1.8% in women taking placebo.

In clinical studies, women taking CE/BZA versus placebo also reported a lower incidence of painful intercourse⁶ and some improvement in health-related quality of life and treatment satisfaction.^7,8

In short, CE/BZA is a good option for symptomatic menopausal women with a uterus who have bothersome hot flashes, night sweats, and sleep disruptions and want to prevent bone loss.

WHAT ABOUT ADVERSE EFFECTS?
Dr Pinkerton: In general, CE/BZA has a favorable safety and tolerability profile, with an overall incidence of adverse events similar to placebo. The rates of cardiovascular and cerebrovascular events, cancers (breast, endometrial, and ovarian), and mortality are comparable to placebo in two-year trials. These data are limited; studies have been conducted in healthy postmenopausal women. Future studies need to define the full risk profile, particularly among overweight or obese women and different ethnic groups, as well as for longer-term use.

IS THERE A ROLE AMONG WOMEN WITH BREAST CANCER?
Dr Pinkerton: CE/BZA has not been tested in women at risk for or who have a history of breast cancer. In preclinical trials of up to two years’ duration, involving healthy postmenopausal women, the rates for breast cancer with CE/BZA were similar to placebo. There are no long-term data, however, and there are no data in women at risk for breast cancer. I recommend that women who have or are at high risk for breast cancer consider nonhormonal treatment options.^9–11

HAS THERE BEEN AN ASSOCIATED INCREASE IN BREAST DENSITY WITH CE/BZA?
Dr Pinkerton: No. Data from two randomized clinical trials showed that the breast density changes with 12-month CE/BZA treatment were similar to placebo—which is markedly different from comparisons of placebo and combination estrogen-progestin therapy (EPT), where EPT increased breast density. If indeed this lack of an association translates into fewer breast cancers, it would be wonderful, but we do not have long-term data. We can tell our patients that using CE/BZA has not been shown to increase the risk for breast cancer, at least up to two years.

Continue for differences from traditional EPT >>

WHAT MAKES CE/BZA DIFFERENT FROM TRADITIONAL EPT?
Dr Pinkerton: There are two exciting differences:
   • The incidences of breast pain and tenderness were found to be similar to placebo and were significantly lower than those with the comparator EPT (conjugated estrogens 0.45 mg plus medroxyprogesterone acetate [CE/MPA] 1.5 mg).^9,10,12
   • Bleeding and spotting rates were significantly lower than those found with CE/MPA.¹³
In addition, high rates of amenorrhea have been found—comparable to placebo.¹³

CE/BZA is similar to traditional EPT in several ways. For instance, compared with placebo, at two years, CE/BZA was not found to increase the incidence of endometrial hyperplasia, endometrial thickness (increase from baseline was < 1 mm and comparable to placebo), or endometrial cancers.¹⁴ Lastly, similar to EPT, there is probably a twofold risk for venous thromboembolism (VTE) with BZA 20 mg alone.¹⁵ Importantly, there has been no additive effect on VTE risk when combining CE with BZA; however, we will need longer studies, in older women, to fully evaluate this risk.¹

Overall, in symptomatic postmenopausal women with a uterus, randomized controlled data show the same improvement with CE/BZA as that seen with traditional oral EPTs, with improvements in hot flashes; night sweats, with fewer sleep disruptions; and prevention of bone loss. In addition, the changes in cholesterol (an increase in triglyceride levels) and effect on the vagina are the same. Yet, CE/BZA appears to have a neutral effect on the breast and protects against endometrial hyperplasia and endometrial cancer without causing bleeding.^9,10 CE/BZA’s VTE and stroke risks are expected to be similar to traditional oral EPT.

Therefore, the major benefit of CE/BZA for women who have a uterus is the lack of significant breast tenderness, lack of changes in breast density, and lack of vaginal bleeding that is often seen with traditional EPT.¹²

THEN, IS PROGESTOGEN THE HARMFUL AGENT IN TRADITIONAL HT OPTIONS?
Dr Pinkerton: There is evidence that estrogen plus progestogen therapy has more risk for breast cancer than estrogen alone. But in women who have a uterus, you need to protect against uterine cancer so, up until now, the only option was to add progestogen. Some studies suggest the risk for breast cancer may differ depending on the type of progestogen. So it’s a laudable goal to try to protect the endometrium without using a progestogen.

GIVEN ITS SAFETY PROFILE, DO YOU SEE CE/BZA BEING INDICATED FOR WOMEN WITHOUT A UTERUS?
Dr Pinkerton: CE/BZA has been tested only in women with a uterus; there is no indication for using it in hysterectomized women. In the future, unless trial data show a benefit to hysterectomized women—by a reduction in breast cancer compared with estrogen alone—there would be no reason to add BZA to the CE for these women. You would just use CE or another type of estrogen alone.

DO YOU ANTICIPATE BZA BEING USED ALONE?
Dr Pinkerton: For treating osteoporosis in postmenopausal women at increased risk for fracture, BZA alone has greater benefits than risks. It is approved in other countries to prevent or treat osteoporosis. In 2008, Wyeth received an approval letter from the FDA for BZA alone but, for whatever reason, the drug was not brought to market. BZA reduces the number of new lumbar spine fractures by 4% (vs 2% for placebo), with efficacy better in those with a higher risk for fractures. Like raloxifene, it has not been shown effective at reducing nonvertebral fractures, although it maintains spinal bone density.¹⁶

BZA available as monotherapy could tempt clinicians to pair it with other estrogens. We must recognize that the combination of the specific estrogen and BZA dose and type need to be balanced to provide endometrial hyperplasia protection. It would not be safe or effective to take BZA as a selective estrogen-receptor modulator and pair it with any other untested systemic estrogen. I do not anticipate, in this country, that BZA will become available as monotherapy, however.

NEW OPTIONS ARE WELCOME
Dr Moore: Novel strategies for clinicians to optimally treat menopausal symptoms are always welcome. I look forward to more data from the SMART trials on CE/BZA and to moving forward as we gain experience with using this new treatment option.

REFERENCES
1. Lobo RA, Pinkerton JV, Gass ML, et al. Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic bone parameters and overall safety profile. Fertil Steril. 2009;92(3):1025–1038.

2. Pinkerton JV, Utian WH, Constantine GD, et al. Relief of vasomotor symptoms with the tissue-selective estrogen complex containing bazedoxifene/conjugated estrogens. Menopause. 2009;16(6): 1116–1124.

3. Pinkerton JV, Pan K, Abraham L, et al. Sleep parameters and health-related quality of life with bazedoxifene/conjugated estrogens. Menopause. 2014;21(3):252–259.

4. Lindsay R, Gallagher JC, Kagan R, et al. Efficacy of tissue-selective estrogen complex (TSEC) of bazedoxifene/conjugated estrogens (BZA/CE) for osteoporosis prevention in at-risk postmenopausal women. Fertil Steril. 2009;92(3):1045–1052.

5. Pinkerton JV, Harvey JA, Lindsay R, et al; SMART-5 Investigators. Effects of bazedoxifene/conjugated estrogens on the endometrium and bone.
J Clin Endocrinol Metab. 2014;99(2):E189–E198.

6. Kagan R, Williams RS, Pan K, Mirkin S, Pickar JH. A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estrogens (BZA/CE) for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women. Menopause. 2010;17(2):281–289.

7. Utian W, Yu H, Bobula J, et al. Bazedoxifene/conjugated estrogens and quality of life in postmenopausal women. Maturitas. 2009;63(4):
329–335.

8. Abraham L, Pinkerton JV, Messig M, et al. Menopause-specific quality of life across varying menopausal populations with conjugated estrogens/bazedoxifene. Maturitas. 2014;78(3):212–218.

9. Harvey JA, Pinkerton JV, Baracat EC, et al. Breast density changes in a randomized controlled trial evaluating bazedoxifene/conjugated estrogens. Menopause. 2013;20:(2)138–145.

10. Pinkerton JV, Harvey JA, Pan K, et al. Breast effects of bazedoxifene-conjugated estrogens. Obstet Gynecol. 2013;121(5):959–968.

11. Kaunitz AM. When should a menopausal woman discontinue hormone therapy? OBG Manag. 2014;26(2):59–65.

12. Pinkerton JV, Pickar JH, Racketa J, Mirkin S. Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention. Climacteric. 2012;15:(5)411–418.

13. Archer DF, Lewis V, Carr BR, et al. Bazedoxifene/conjugated estrogens (BZA/CE): incidence of uterine bleeding in postmenopausal women. Fertil Steril. 2009;92:1039–1044.

14. Pickar JH, Yeh I-T, Bachmann G, Speroff L. Endometrial effects of a tissue selective estrogen complex (TSEC) containing bazedoxifene/conjugated estrogens as a menopausal therapy. Fertil Steril. 2009; 92(3):1018–1024.

15. Mirkin S, Komm BS. Tissue-selective estrogen complexes for postmenopausal women. Maturitas. 2013;76(3):213–220.

16. Ellis AG, Reginster JY, Luo X, et al. Bazedoxifene versus oral bisphosphonates for the prevention of nonvertebral fractures in postmenopausal women with osteoporosis at higher risk of fracture. Value Health. 2014;17(4):424–432.

Much of my practice has focused on the treatment of menopausal women, but which of my patients can benefit from this particular combination of conjugated estrogen (CE) 0.45 mg plus bazedoxifene (BZA) 20 mg? I asked Dr Pinkerton this question, and more.

WHICH PATIENTS CAN BENEFIT MOST?
Dr Pinkerton: CE/BZA was tested in healthy postmenopausal women with a uterus who are at risk for bone loss and were reporting 50 or more moderate to severe hot flashes per week. The combination of CE and BZA is a good choice for women who have bothersome menopausal symptoms: hot flashes, night sweats, and sleep disruption or symptomatic vulvovaginal atrophy (VVA)—although it’s not approved for VVA.

Efficacy and safety data show that compared with placebo
• CE/BZA decreases the frequency and severity of hot flashes at 12 weeks, and those decreases are maintained at 12 months.^1,2
• Women taking CE/BZA have greater improvements in sleep, with both decreased sleep disturbance and time to fall asleep.³
• CE/BZA maintained or prevented lumbar spine and hip bone loss in postmenopausal women at risk for osteoporosis.^1,4,5

Although fracture data were not captured and the drug was not tested in osteoporotic women, study results showed bone loss prevention at 12 months, which was sustained at 24 months. The improvement in bone mineral density from baseline was about 1% to 1.5%. This was compared with a bone loss of 1.8% in women taking placebo.

In clinical studies, women taking CE/BZA versus placebo also reported a lower incidence of painful intercourse⁶ and some improvement in health-related quality of life and treatment satisfaction.^7,8

In short, CE/BZA is a good option for symptomatic menopausal women with a uterus who have bothersome hot flashes, night sweats, and sleep disruptions and want to prevent bone loss.

WHAT ABOUT ADVERSE EFFECTS?
Dr Pinkerton: In general, CE/BZA has a favorable safety and tolerability profile, with an overall incidence of adverse events similar to placebo. The rates of cardiovascular and cerebrovascular events, cancers (breast, endometrial, and ovarian), and mortality are comparable to placebo in two-year trials. These data are limited; studies have been conducted in healthy postmenopausal women. Future studies need to define the full risk profile, particularly among overweight or obese women and different ethnic groups, as well as for longer-term use.

IS THERE A ROLE AMONG WOMEN WITH BREAST CANCER?
Dr Pinkerton: CE/BZA has not been tested in women at risk for or who have a history of breast cancer. In preclinical trials of up to two years’ duration, involving healthy postmenopausal women, the rates for breast cancer with CE/BZA were similar to placebo. There are no long-term data, however, and there are no data in women at risk for breast cancer. I recommend that women who have or are at high risk for breast cancer consider nonhormonal treatment options.^9–11

HAS THERE BEEN AN ASSOCIATED INCREASE IN BREAST DENSITY WITH CE/BZA?
Dr Pinkerton: No. Data from two randomized clinical trials showed that the breast density changes with 12-month CE/BZA treatment were similar to placebo—which is markedly different from comparisons of placebo and combination estrogen-progestin therapy (EPT), where EPT increased breast density. If indeed this lack of an association translates into fewer breast cancers, it would be wonderful, but we do not have long-term data. We can tell our patients that using CE/BZA has not been shown to increase the risk for breast cancer, at least up to two years.

Continue for differences from traditional EPT >>

WHAT MAKES CE/BZA DIFFERENT FROM TRADITIONAL EPT?
Dr Pinkerton: There are two exciting differences:
   • The incidences of breast pain and tenderness were found to be similar to placebo and were significantly lower than those with the comparator EPT (conjugated estrogens 0.45 mg plus medroxyprogesterone acetate [CE/MPA] 1.5 mg).^9,10,12
   • Bleeding and spotting rates were significantly lower than those found with CE/MPA.¹³
In addition, high rates of amenorrhea have been found—comparable to placebo.¹³

CE/BZA is similar to traditional EPT in several ways. For instance, compared with placebo, at two years, CE/BZA was not found to increase the incidence of endometrial hyperplasia, endometrial thickness (increase from baseline was < 1 mm and comparable to placebo), or endometrial cancers.¹⁴ Lastly, similar to EPT, there is probably a twofold risk for venous thromboembolism (VTE) with BZA 20 mg alone.¹⁵ Importantly, there has been no additive effect on VTE risk when combining CE with BZA; however, we will need longer studies, in older women, to fully evaluate this risk.¹

Overall, in symptomatic postmenopausal women with a uterus, randomized controlled data show the same improvement with CE/BZA as that seen with traditional oral EPTs, with improvements in hot flashes; night sweats, with fewer sleep disruptions; and prevention of bone loss. In addition, the changes in cholesterol (an increase in triglyceride levels) and effect on the vagina are the same. Yet, CE/BZA appears to have a neutral effect on the breast and protects against endometrial hyperplasia and endometrial cancer without causing bleeding.^9,10 CE/BZA’s VTE and stroke risks are expected to be similar to traditional oral EPT.

Therefore, the major benefit of CE/BZA for women who have a uterus is the lack of significant breast tenderness, lack of changes in breast density, and lack of vaginal bleeding that is often seen with traditional EPT.¹²

THEN, IS PROGESTOGEN THE HARMFUL AGENT IN TRADITIONAL HT OPTIONS?
Dr Pinkerton: There is evidence that estrogen plus progestogen therapy has more risk for breast cancer than estrogen alone. But in women who have a uterus, you need to protect against uterine cancer so, up until now, the only option was to add progestogen. Some studies suggest the risk for breast cancer may differ depending on the type of progestogen. So it’s a laudable goal to try to protect the endometrium without using a progestogen.

GIVEN ITS SAFETY PROFILE, DO YOU SEE CE/BZA BEING INDICATED FOR WOMEN WITHOUT A UTERUS?
Dr Pinkerton: CE/BZA has been tested only in women with a uterus; there is no indication for using it in hysterectomized women. In the future, unless trial data show a benefit to hysterectomized women—by a reduction in breast cancer compared with estrogen alone—there would be no reason to add BZA to the CE for these women. You would just use CE or another type of estrogen alone.

DO YOU ANTICIPATE BZA BEING USED ALONE?
Dr Pinkerton: For treating osteoporosis in postmenopausal women at increased risk for fracture, BZA alone has greater benefits than risks. It is approved in other countries to prevent or treat osteoporosis. In 2008, Wyeth received an approval letter from the FDA for BZA alone but, for whatever reason, the drug was not brought to market. BZA reduces the number of new lumbar spine fractures by 4% (vs 2% for placebo), with efficacy better in those with a higher risk for fractures. Like raloxifene, it has not been shown effective at reducing nonvertebral fractures, although it maintains spinal bone density.¹⁶

BZA available as monotherapy could tempt clinicians to pair it with other estrogens. We must recognize that the combination of the specific estrogen and BZA dose and type need to be balanced to provide endometrial hyperplasia protection. It would not be safe or effective to take BZA as a selective estrogen-receptor modulator and pair it with any other untested systemic estrogen. I do not anticipate, in this country, that BZA will become available as monotherapy, however.

NEW OPTIONS ARE WELCOME
Dr Moore: Novel strategies for clinicians to optimally treat menopausal symptoms are always welcome. I look forward to more data from the SMART trials on CE/BZA and to moving forward as we gain experience with using this new treatment option.

REFERENCES
1. Lobo RA, Pinkerton JV, Gass ML, et al. Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic bone parameters and overall safety profile. Fertil Steril. 2009;92(3):1025–1038.

2. Pinkerton JV, Utian WH, Constantine GD, et al. Relief of vasomotor symptoms with the tissue-selective estrogen complex containing bazedoxifene/conjugated estrogens. Menopause. 2009;16(6): 1116–1124.

3. Pinkerton JV, Pan K, Abraham L, et al. Sleep parameters and health-related quality of life with bazedoxifene/conjugated estrogens. Menopause. 2014;21(3):252–259.

4. Lindsay R, Gallagher JC, Kagan R, et al. Efficacy of tissue-selective estrogen complex (TSEC) of bazedoxifene/conjugated estrogens (BZA/CE) for osteoporosis prevention in at-risk postmenopausal women. Fertil Steril. 2009;92(3):1045–1052.

5. Pinkerton JV, Harvey JA, Lindsay R, et al; SMART-5 Investigators. Effects of bazedoxifene/conjugated estrogens on the endometrium and bone.
J Clin Endocrinol Metab. 2014;99(2):E189–E198.

6. Kagan R, Williams RS, Pan K, Mirkin S, Pickar JH. A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estrogens (BZA/CE) for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women. Menopause. 2010;17(2):281–289.

7. Utian W, Yu H, Bobula J, et al. Bazedoxifene/conjugated estrogens and quality of life in postmenopausal women. Maturitas. 2009;63(4):
329–335.

8. Abraham L, Pinkerton JV, Messig M, et al. Menopause-specific quality of life across varying menopausal populations with conjugated estrogens/bazedoxifene. Maturitas. 2014;78(3):212–218.

9. Harvey JA, Pinkerton JV, Baracat EC, et al. Breast density changes in a randomized controlled trial evaluating bazedoxifene/conjugated estrogens. Menopause. 2013;20:(2)138–145.

10. Pinkerton JV, Harvey JA, Pan K, et al. Breast effects of bazedoxifene-conjugated estrogens. Obstet Gynecol. 2013;121(5):959–968.

11. Kaunitz AM. When should a menopausal woman discontinue hormone therapy? OBG Manag. 2014;26(2):59–65.

12. Pinkerton JV, Pickar JH, Racketa J, Mirkin S. Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention. Climacteric. 2012;15:(5)411–418.

13. Archer DF, Lewis V, Carr BR, et al. Bazedoxifene/conjugated estrogens (BZA/CE): incidence of uterine bleeding in postmenopausal women. Fertil Steril. 2009;92:1039–1044.

14. Pickar JH, Yeh I-T, Bachmann G, Speroff L. Endometrial effects of a tissue selective estrogen complex (TSEC) containing bazedoxifene/conjugated estrogens as a menopausal therapy. Fertil Steril. 2009; 92(3):1018–1024.

15. Mirkin S, Komm BS. Tissue-selective estrogen complexes for postmenopausal women. Maturitas. 2013;76(3):213–220.

16. Ellis AG, Reginster JY, Luo X, et al. Bazedoxifene versus oral bisphosphonates for the prevention of nonvertebral fractures in postmenopausal women with osteoporosis at higher risk of fracture. Value Health. 2014;17(4):424–432.

Public health officials in El Paso, Texas, reported in September 2014 that more than 850 infants and 43 health care workers (HCW) at Providence Memorial Hospital may have been exposed to tuberculosis (TB) by a nurse with active infection. In collaboration with the CDC, the hospital administrators and local and state health officials advised potentially exposed individuals and their families to be screened for TB. According to press reports, five infants tested positive for TB and were to be treated.^1,2 This news report highlights the importance of maintaining infection control protocols in health care facilities throughout the United States to reduce the risk for TB transmission.

SCREENING HEALTH CARE WORKERS
In the US, reported cases of TB, a treatable and curable disease, have declined since 1993. A total of 9,582 cases were reported in 2013, with 536 deaths due to TB reported in 2011 (the most recent year for which this data is available).³

Even though TB is on the decline worldwide,⁴ HCWs remain at increased risk for infection, confirming that TB is an occupational disease.⁵ It is imperative that health care facilities have effective infection control plans in place, primarily to reduce the risk for transmission of TB to HCWs.

This article reviews the available TB screening tests, CDC recommendations, parameters for evaluating test performance, and recent studies that lend support to the superiority of interferon-γ (IFN-γ) release assays (IGRAs) over tuberculin skin tests (TSTs) as part of HCW screening and infection control for TB. Primary care clinicians need to know about the status of these tests not only because we are HCWs ourselves, but because we are often responsible for the safety of other HCWs in our workplaces.

TB SCREENING TESTS
Diagnosing latent tuberculosis infection (LTBI) is key to overall control of the disease, since treatment decreases risk for conversion to active disease. Until recently, the diagnosis of LTBI relied on the TST, despite its limitations (see discussion under “Accuracy”). Now, immune-based blood tests hold promise for improving LTBI diagnosis.

Tuberculin skin test
In 1934, Florence Seibert developed what is known today as the purified protein derivative (PPD) test, which was adopted as the standard in the US in 1941.⁶ For 60 years, the PPD TST was the only screening method for Mycobacterium tuberculosis infection. It involves the intradermal injection of PPD; a hypersensitivity response leads to a cutaneous induration at the injection site after 48 to 72 hours.⁷Hence, the TST is a two-step test, requiring a follow-up visit for the result to be read.

Although strongly predictive of TB, the TST may result in false-positive test results in those previously immunized with the Bacille Calmette-Guerin (BCG) vaccine (a WHO-recommended childhood vaccination against TB, widely used outside the US),⁸ and in those exposed to certain nontuberculous mycobacteria such as M bovis and M africana.⁹ Test results may also be false negative in immunocompromised patients.⁹

Interferon-γ release assays
With the goal of developing a more specific and sensitive test for TB infection, IGRAs were developed in the mid-1990s as a new tool to detect active and latent TB infection.¹⁰ The first IGRA test for TB received FDA approval in 2001.¹¹ There are currently two FDA-approved IGRAs—QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB—in use.

QuantiFERON-TB Gold In-Tube test. The QFT-GIT measures cell-mediated immune responses to antigens that simulate mycobacterial proteins. Requiring only one patient visit, whole blood is collected in three different tubes (negative control, TB antigen, and mitogen [positive] control), each containing a single antigen.¹² After 16 to 24 hours in a temperature-controlled environment, the tubes are centrifuged to separate the plasma. IFN-γ levels are measured in each tube to calculate the test result.

T-SPOT.TB test. Using one blood sample, the T-SPOT.TB test captures IFN-γ produced by activated T-cells in response to stimulation by two M tuberculosis antigens. Addition of a substrate produces dark blue spots; the number of spots indicates the quantity of M tuberculosis-sensitive effector T-cells in the peripheral blood. A positive result is eight or more spots; a negative result is fewer than four spots, and a borderline result is five to seven spots.¹³ Unlike the QFT-GIT, the T-SPOT.TB has a “borderline” interpretation category.

See the Table for a comparison of the TST, QFT-GIT, and T-SPOT.TB tests for TB screening.

Continue for CDC guidelines >>

CDC GUIDELINES
Subject to state and federal regulations and Occupational Safety and Health Administration (OSHA) directives, the CDC states that the goals of a TB infection control plan are
• Prompt detection of suspected or confirmed TB infection
• Airborne precautions implemented to reduce risk for TB transmission in areas in which exposure can occur
• Treatment of persons with suspected or confirmed TB.¹⁴

TB screening for HCWs has historically been a challenge in that, for new hires, the CDC recommends a baseline two-step process (meaning up to four visits) when TST is used.¹⁵ This is because TST-tested individuals may test false negative, even if they have LTBI, if many years have passed since their infection was acquired. As a result, guidelines for baseline testing are that, if the initial TST is negative, TST should be repeated one to three weeks later. If the person is in fact infected with TB, the first TST may stimulate the immune system’s ability to react to the TB antigens and elicit a positive or “boosted” response to the second test.

The above figure has been corrected from the print version as of December 16, 2014.

The 2005 guidelines recommended screening new-hire HCWs with either a baseline two-step TST or with one blood assay for M tuberculosis. After the introduction of the QFT-GIT and T-SPOT.TB tests, the CDC included them in its updated 2010 guidelines and indicated that either IGRAs or TSTs may be used in HCW surveillance programs for occupational exposure to M tuberculosis (see Figure).^15,16 The algorithm clearly illustrates how the use of IGRAs in place of TSTs streamlines the process of HCW TB screening.¹⁷

EVALUATION OF TESTS
Given the stringent nature of the CDC’s TB infection control goals, it is essential that health care facilities use the most effective and efficient means for timely and thorough screening of HCWs for TB. When evaluating the available tests, the following factors must be considered: accuracy and reproducibility of test results; impact on results when testing is repeated frequently; interpretation of discordant test results; and specificity, sensitivity, and identification of appropriate test cutoff values so that a positive result signifies a new TB infection (ie, conversion, a change from a documented negative to positive test result within a two-year period) rather than a false positive; and costs.^18,19

Accuracy
Unlike TSTs, IGRAs do not produce false-positive results in individuals vaccinated with BCG or in those infected with most nontuberculous mycobacteria.^9,16 Neither TSTs nor IGRAs, however, can distinguish between active and latent TB infection.¹⁹ If either test is positive, a chest radiograph is indicated. If the x-ray reveals abnormalities in the lungs, a sputum smear to detect acid-fast-bacilli (AFB), of which M tuberculosis is one, is indicative of TB. Nuclear acid amplification testing of a respiratory specimen ­provides rapid laboratory confirmation, but a positive culture for M tuberculosis confirms the ­diagnosis.²²

Specificity and sensitivity
Pai, Zwerling, and Menzies conducted a meta-analysis of 38 studies of TB testing. Most of the studies were small and had limitations, such as the lack of a gold standard test for the diagnosis of LTBI and variable TST methods and cutoff values. Nevertheless, the researchers were able to conclude that IGRAs are significantly more specific than TST and are unaffected by BCG vaccination. Although the sensitivity of IGRAs and TST is inconsistent across test populations, T-SPOT.TB appears to have greater sensitivity than QFT-GIT or TST.²³

Further, TST is subject to variability in administration and interpretation, and cut points for TST positivity vary internationally.⁹ In contrast, the ­T-SPOT.TB test specifies a borderline result zone. According to the CDC, this increases test accuracy by classifying results near the cut point, making a subsequent test conversion from negative to positive more likely to represent newly acquired infection.¹⁶

On the other hand, some studies of IGRAs have found unexpectedly high rates of initial positive results and conversions among HCWs in low-risk settings that are later determined to be false positives.²⁴ However, as noted previously, TSTs are also subject to false-positive results. In addition, the definition of an IGRA conversion is less stringent than the TST conversion definition, which may result in more IGRA conversions.¹⁶

Discordant results
Zwerling et al conducted a systematic review of all studies in which IGRAs were used for HCW screening to summarize their performance in cross-sectional and serial testing settings. The prevalence of positive IGRAs was found to be lower than that of positive TSTs. This difference was significant in low- and moderate-TB incidence settings but not in high-incidence settings. A positive association was reported between positive IGRA test results and occupational risk factors, including work in high-risk wards, TB clinics, and geriatric care, as well as length of employment.¹⁸

According to Mancuso et al, discordance of results between the TST and IGRAs in populations with low LTBI prevalence suggests that most positive test results are in fact false positives in these populations.²⁵ Although IGRAs were designed to increase specificity, the authors found that IGRA specificity was no better than the specificity of TST. Without a gold standard for detecting M tuberculosis infection, assessing the true significance of discordance between TST and IGRAs is difficult. Further research is needed to determine the significance of test discordance, to obtain data on progression to active TB, and to better define appropriate cut points for interpreting IGRA results.²⁵

Costs
The primary impediment to the widespread use of IGRAs has been cost, which is approximately three times that of a TST.²⁴

Eralp et al studied the cost-effectiveness of IGRAs versus TST for screening for active LTBI in HCWs by using healthy life-years gained—defined as the number of TB cases avoided, yielding an increase in life expectancy—as the benefit metric rather than quality-adjusted life-years. Because testing is completed with a single visit, use of IGRAs increases compliance while minimizing resources needed for a second visit and eliminating loss to follow-up. Also notable is that IGRA testing takes place in a laboratory, where costs can be held in check with focused expertise and optimized staffing structures. The authors concluded that incremental IGRA costs per healthy life-year gained were justified.¹⁹

Until publication of the SWITCH (Screening health care Workers with IGRA vs. TST: impact on Costs and adHerence to testing) study in 2012, cost-effectiveness studies had shown inconsistent results. This study, conducted by The Johns Hopkins University (JHU) employee health department, was the first of its kind in the US to systematically analyze test performance and labor costs for TB screening of HCWs. The results showed that the time required to administer a TST is one of the costliest elements. For a sizeable institution such as JHU, TST screening cost more than $1.3 million annually, equivalent to approximately $73 per person; in contrast, IGRA screening amounted to less than $55 per person.²⁶

Further research
The association between IGRA test conversion in HCWs and the risk for active TB disease has not been demonstrated.¹⁶ However, this is also true of TSTs²⁷ and further research is needed in this area. Research is also needed to determine the significance of TSA-IGRA results discordance and to better define cut points for IGRA interpretation.²⁵ In addition, more study of factors related to serial (periodic or ongoing) TB testing—which are very important within the context of HCW screening—is needed. As an example, serial TB testing may reveal trends in test conversions and can identify areas of concern within a health care facility. Unfortunately, current CDC recommendations do not provide specific guidelines for serial IGRA testing, such as guidance for accurate interpretation of IGRA results within a serial testing context.¹⁶ These areas should be addressed in future CDC updates.

Continue for conclusion >>

CONCLUSION
Occupational health professionals are continuously evaluating how to improve surveillance programs and reduce HCWs’ time away from work. Within this context, four advantages IGRAs offer include
• Elimination of a two-step TST for new hires (which requires up to four separate visits)
• No false-positive results caused by previous BCG vaccination or exposure to most nontuberculous mycobacteria
• Significantly improved HCW compliance because screening requires only one visit
• Cost effectiveness.

From an occupational health perspective, these are significant advantages that support the use of IGRAs to screen HCW for TB.

REFERENCES
1. Wilson J. Five babies test positive for TB in Texas. CNN. September 30, 2014. www.cnn.com/2014/09/29/health/babies-test-positive-tb/index.html. Accessed November 12, 2014.

2. Bailey J. 700 babies exposed to TB at Texas Hospital. Atlanta Journal Constitution. September 22, 2014. www.ajc.com/news/lifestyles/health/700-babies-exposed-TB-texas-hospital/nhRmC/. Accessed November 12, 2014.

3. CDC. Reported tuberculosis in the United States, 2013. www.cdc.gov/tb/statistics/reports/2013/pdf/report2013.pdf. Accessed October 23, 2014.

4. World Health Organization. Global tuberculosis report 2014. www.who.int/tb/publications/global_report/en/. Accessed November 12, 2014.

5. Baussano I, Nunn P, Williams B, et al. Tuberculosis among health care workers. Emerg Infect Dis. 2011;17(3):488-494.

6. Yang H, Kruh-Garcia NA, Dobos KM. Purified protein derivatives of tuberculin: past, present, and future. FEMS Immunol Med Microbiol. 2012;66(3):273-280.

7. Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect Dis. 1993;17(6):968-975.

8. World Health Organization. Recommendations for vaccine administration. www.who.int/immunization/policy/Immunization_routine_table1.pdf. Accessed November 12, 2014.

9. Al-Orainey IO. Diagnosis of latent tuberculosis: can we do better? Ann Thorac Med. 2009;4(1):5-9.

10. Desem N, Jones SL. Development of a human gamma interferon enzyme immunoassay and comparison with tuberculin skin testing for detection of Mycobacterium tuberculosis infection. Clin Diagn Lab Immunol. 1998;5(4): 531-536.

11. FDA. QuantiFERON-TB - P010033. www.fda.gov/MedicalDevices/Products andMedicalProcedures/DeviceApprovalsandClearances/Recently-Approved Devices/ucm084025.htm. Accessed November 12, 2014.

12. QuantiFERON-TB Gold In-Tube Test [package insert]. www.quantiferon.com/irm/content/PI/QFT/2PK/US.pdf. Accessed November 12, 2014.

13. T-SPOT.TB [package insert]. Marlborough, MA. Oxford Immunotec, Inc. www.tspot.com/wp-content/uploads/2012/01/PI-TB-US-v4.pdf. Accessed November 12, 2014.

14. CDC. Fact sheet: infection control in health-care settings. www.cdc.gov/tb/publications/factsheets/prevention/ichcs.htm. Accessed November 12, 2014.

15. Jensen PA, Lambert LA, Iademarco MF, Ridzon R; CDC. Guidelines for preventing the transmission of Mycobacterium TB in health-care settings, 2005. MMWR Recomm Rep. 2005;54(RR-17):1-141.

16. Mazurek GH, Jereb J, Vernon A, et al; IGRA Expert Committee, CDC. Updated guidelines for using interferon γ release assays to detect Mycobacterium TB infection: United States, 2010. MMWR Recomm Rep. 2010;59(RR-5):1-25.

17. CDC. Latent tuberculosis infection: a guide for primary health care providers. www.cdc.gov/tb/publications/ltbi/diagnosis.htm. Accessed November 3, 2014.

18. Zwerling A, van den Hof S, Scholten J, et al. Interferon-γ release assays for TB screening of healthcare workers: a systematic review. Thorax. 2012;67(1): 62-70.

19. Eralp MN, Scholtes S, Martell G, et al. Screening of healthcare workers for TB: development and validation of a new health economic model to inform practice. BMJ Open. 2012;2:e000630.

20. FDA. FDA permits marketing of first US test labeled for simultaneous detection of tuberculosis bacteria and resistance to the antibiotic rifampin [press release]. July 25, 2013.

21. CDC. Availability of an assay for detecting Mycobacterium TB, including rifampin-resistant strains, and considerations for its use: United States, 2013 [published correction appears in MMWR Morb Mortal Wkly Rep. 2013;62(45):906]. MMWR Morb Mortal Wkly Rep. 2013;62(41):821-827.

22. CDC. Fact sheet: diagnosis of tuberculosis disease. www.cdc.gov/tb/publica tions/factsheets/testing/diagnosis.htm. Accessed November 12, 2014.

23. Pai M, Zwerling A, Menzies D. Systematic review: T-cell–based assays for the diagnosis of latent TB infection: an update. Ann Intern Med. 2008;149(3): 177-184.

24. LoBue PA, Castro KG. Is it time to replace the tuberculin skin test with a blood test? JAMA. 2012;308(3):241-242.

25. Mancuso JD, Mazurek GH, Tribble D, et al. Discordance among commercially available diagnostics for latent TB infection. Am J Respir Crit Care Med. 2012;185(4):427-434.

26. Wrighton-Smith P, Sneed L, Humphrey F, et al. Screening health care workers with interferon-γ release assay versus tuberculin skin test: impact on costs and adherence to testing (the SWITCH study). J Occup Environ Med. 2012;54(7):806-815.

27. World Health Organization. Use of tuberculosis interferon-gamma release assays (IGRAs) in low- and middle-income countries. www.who.int/tb/
features_archive/policy_statement_igra_oct2011.pdf. Accessed November 12, 2014.

Public health officials in El Paso, Texas, reported in September 2014 that more than 850 infants and 43 health care workers (HCW) at Providence Memorial Hospital may have been exposed to tuberculosis (TB) by a nurse with active infection. In collaboration with the CDC, the hospital administrators and local and state health officials advised potentially exposed individuals and their families to be screened for TB. According to press reports, five infants tested positive for TB and were to be treated.^1,2 This news report highlights the importance of maintaining infection control protocols in health care facilities throughout the United States to reduce the risk for TB transmission.

SCREENING HEALTH CARE WORKERS
In the US, reported cases of TB, a treatable and curable disease, have declined since 1993. A total of 9,582 cases were reported in 2013, with 536 deaths due to TB reported in 2011 (the most recent year for which this data is available).³

Even though TB is on the decline worldwide,⁴ HCWs remain at increased risk for infection, confirming that TB is an occupational disease.⁵ It is imperative that health care facilities have effective infection control plans in place, primarily to reduce the risk for transmission of TB to HCWs.

This article reviews the available TB screening tests, CDC recommendations, parameters for evaluating test performance, and recent studies that lend support to the superiority of interferon-γ (IFN-γ) release assays (IGRAs) over tuberculin skin tests (TSTs) as part of HCW screening and infection control for TB. Primary care clinicians need to know about the status of these tests not only because we are HCWs ourselves, but because we are often responsible for the safety of other HCWs in our workplaces.

TB SCREENING TESTS
Diagnosing latent tuberculosis infection (LTBI) is key to overall control of the disease, since treatment decreases risk for conversion to active disease. Until recently, the diagnosis of LTBI relied on the TST, despite its limitations (see discussion under “Accuracy”). Now, immune-based blood tests hold promise for improving LTBI diagnosis.

Tuberculin skin test
In 1934, Florence Seibert developed what is known today as the purified protein derivative (PPD) test, which was adopted as the standard in the US in 1941.⁶ For 60 years, the PPD TST was the only screening method for Mycobacterium tuberculosis infection. It involves the intradermal injection of PPD; a hypersensitivity response leads to a cutaneous induration at the injection site after 48 to 72 hours.⁷Hence, the TST is a two-step test, requiring a follow-up visit for the result to be read.

Although strongly predictive of TB, the TST may result in false-positive test results in those previously immunized with the Bacille Calmette-Guerin (BCG) vaccine (a WHO-recommended childhood vaccination against TB, widely used outside the US),⁸ and in those exposed to certain nontuberculous mycobacteria such as M bovis and M africana.⁹ Test results may also be false negative in immunocompromised patients.⁹

Interferon-γ release assays
With the goal of developing a more specific and sensitive test for TB infection, IGRAs were developed in the mid-1990s as a new tool to detect active and latent TB infection.¹⁰ The first IGRA test for TB received FDA approval in 2001.¹¹ There are currently two FDA-approved IGRAs—QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB—in use.

QuantiFERON-TB Gold In-Tube test. The QFT-GIT measures cell-mediated immune responses to antigens that simulate mycobacterial proteins. Requiring only one patient visit, whole blood is collected in three different tubes (negative control, TB antigen, and mitogen [positive] control), each containing a single antigen.¹² After 16 to 24 hours in a temperature-controlled environment, the tubes are centrifuged to separate the plasma. IFN-γ levels are measured in each tube to calculate the test result.

T-SPOT.TB test. Using one blood sample, the T-SPOT.TB test captures IFN-γ produced by activated T-cells in response to stimulation by two M tuberculosis antigens. Addition of a substrate produces dark blue spots; the number of spots indicates the quantity of M tuberculosis-sensitive effector T-cells in the peripheral blood. A positive result is eight or more spots; a negative result is fewer than four spots, and a borderline result is five to seven spots.¹³ Unlike the QFT-GIT, the T-SPOT.TB has a “borderline” interpretation category.

See the Table for a comparison of the TST, QFT-GIT, and T-SPOT.TB tests for TB screening.

Continue for CDC guidelines >>

CDC GUIDELINES
Subject to state and federal regulations and Occupational Safety and Health Administration (OSHA) directives, the CDC states that the goals of a TB infection control plan are
• Prompt detection of suspected or confirmed TB infection
• Airborne precautions implemented to reduce risk for TB transmission in areas in which exposure can occur
• Treatment of persons with suspected or confirmed TB.¹⁴

TB screening for HCWs has historically been a challenge in that, for new hires, the CDC recommends a baseline two-step process (meaning up to four visits) when TST is used.¹⁵ This is because TST-tested individuals may test false negative, even if they have LTBI, if many years have passed since their infection was acquired. As a result, guidelines for baseline testing are that, if the initial TST is negative, TST should be repeated one to three weeks later. If the person is in fact infected with TB, the first TST may stimulate the immune system’s ability to react to the TB antigens and elicit a positive or “boosted” response to the second test.

The above figure has been corrected from the print version as of December 16, 2014.

The 2005 guidelines recommended screening new-hire HCWs with either a baseline two-step TST or with one blood assay for M tuberculosis. After the introduction of the QFT-GIT and T-SPOT.TB tests, the CDC included them in its updated 2010 guidelines and indicated that either IGRAs or TSTs may be used in HCW surveillance programs for occupational exposure to M tuberculosis (see Figure).^15,16 The algorithm clearly illustrates how the use of IGRAs in place of TSTs streamlines the process of HCW TB screening.¹⁷

EVALUATION OF TESTS
Given the stringent nature of the CDC’s TB infection control goals, it is essential that health care facilities use the most effective and efficient means for timely and thorough screening of HCWs for TB. When evaluating the available tests, the following factors must be considered: accuracy and reproducibility of test results; impact on results when testing is repeated frequently; interpretation of discordant test results; and specificity, sensitivity, and identification of appropriate test cutoff values so that a positive result signifies a new TB infection (ie, conversion, a change from a documented negative to positive test result within a two-year period) rather than a false positive; and costs.^18,19

Accuracy
Unlike TSTs, IGRAs do not produce false-positive results in individuals vaccinated with BCG or in those infected with most nontuberculous mycobacteria.^9,16 Neither TSTs nor IGRAs, however, can distinguish between active and latent TB infection.¹⁹ If either test is positive, a chest radiograph is indicated. If the x-ray reveals abnormalities in the lungs, a sputum smear to detect acid-fast-bacilli (AFB), of which M tuberculosis is one, is indicative of TB. Nuclear acid amplification testing of a respiratory specimen ­provides rapid laboratory confirmation, but a positive culture for M tuberculosis confirms the ­diagnosis.²²

Specificity and sensitivity
Pai, Zwerling, and Menzies conducted a meta-analysis of 38 studies of TB testing. Most of the studies were small and had limitations, such as the lack of a gold standard test for the diagnosis of LTBI and variable TST methods and cutoff values. Nevertheless, the researchers were able to conclude that IGRAs are significantly more specific than TST and are unaffected by BCG vaccination. Although the sensitivity of IGRAs and TST is inconsistent across test populations, T-SPOT.TB appears to have greater sensitivity than QFT-GIT or TST.²³

Further, TST is subject to variability in administration and interpretation, and cut points for TST positivity vary internationally.⁹ In contrast, the ­T-SPOT.TB test specifies a borderline result zone. According to the CDC, this increases test accuracy by classifying results near the cut point, making a subsequent test conversion from negative to positive more likely to represent newly acquired infection.¹⁶

On the other hand, some studies of IGRAs have found unexpectedly high rates of initial positive results and conversions among HCWs in low-risk settings that are later determined to be false positives.²⁴ However, as noted previously, TSTs are also subject to false-positive results. In addition, the definition of an IGRA conversion is less stringent than the TST conversion definition, which may result in more IGRA conversions.¹⁶

Discordant results
Zwerling et al conducted a systematic review of all studies in which IGRAs were used for HCW screening to summarize their performance in cross-sectional and serial testing settings. The prevalence of positive IGRAs was found to be lower than that of positive TSTs. This difference was significant in low- and moderate-TB incidence settings but not in high-incidence settings. A positive association was reported between positive IGRA test results and occupational risk factors, including work in high-risk wards, TB clinics, and geriatric care, as well as length of employment.¹⁸

According to Mancuso et al, discordance of results between the TST and IGRAs in populations with low LTBI prevalence suggests that most positive test results are in fact false positives in these populations.²⁵ Although IGRAs were designed to increase specificity, the authors found that IGRA specificity was no better than the specificity of TST. Without a gold standard for detecting M tuberculosis infection, assessing the true significance of discordance between TST and IGRAs is difficult. Further research is needed to determine the significance of test discordance, to obtain data on progression to active TB, and to better define appropriate cut points for interpreting IGRA results.²⁵

Costs
The primary impediment to the widespread use of IGRAs has been cost, which is approximately three times that of a TST.²⁴

Eralp et al studied the cost-effectiveness of IGRAs versus TST for screening for active LTBI in HCWs by using healthy life-years gained—defined as the number of TB cases avoided, yielding an increase in life expectancy—as the benefit metric rather than quality-adjusted life-years. Because testing is completed with a single visit, use of IGRAs increases compliance while minimizing resources needed for a second visit and eliminating loss to follow-up. Also notable is that IGRA testing takes place in a laboratory, where costs can be held in check with focused expertise and optimized staffing structures. The authors concluded that incremental IGRA costs per healthy life-year gained were justified.¹⁹

Until publication of the SWITCH (Screening health care Workers with IGRA vs. TST: impact on Costs and adHerence to testing) study in 2012, cost-effectiveness studies had shown inconsistent results. This study, conducted by The Johns Hopkins University (JHU) employee health department, was the first of its kind in the US to systematically analyze test performance and labor costs for TB screening of HCWs. The results showed that the time required to administer a TST is one of the costliest elements. For a sizeable institution such as JHU, TST screening cost more than $1.3 million annually, equivalent to approximately $73 per person; in contrast, IGRA screening amounted to less than $55 per person.²⁶

Further research
The association between IGRA test conversion in HCWs and the risk for active TB disease has not been demonstrated.¹⁶ However, this is also true of TSTs²⁷ and further research is needed in this area. Research is also needed to determine the significance of TSA-IGRA results discordance and to better define cut points for IGRA interpretation.²⁵ In addition, more study of factors related to serial (periodic or ongoing) TB testing—which are very important within the context of HCW screening—is needed. As an example, serial TB testing may reveal trends in test conversions and can identify areas of concern within a health care facility. Unfortunately, current CDC recommendations do not provide specific guidelines for serial IGRA testing, such as guidance for accurate interpretation of IGRA results within a serial testing context.¹⁶ These areas should be addressed in future CDC updates.

Continue for conclusion >>

CONCLUSION
Occupational health professionals are continuously evaluating how to improve surveillance programs and reduce HCWs’ time away from work. Within this context, four advantages IGRAs offer include
• Elimination of a two-step TST for new hires (which requires up to four separate visits)
• No false-positive results caused by previous BCG vaccination or exposure to most nontuberculous mycobacteria
• Significantly improved HCW compliance because screening requires only one visit
• Cost effectiveness.

From an occupational health perspective, these are significant advantages that support the use of IGRAs to screen HCW for TB.

REFERENCES
1. Wilson J. Five babies test positive for TB in Texas. CNN. September 30, 2014. www.cnn.com/2014/09/29/health/babies-test-positive-tb/index.html. Accessed November 12, 2014.

2. Bailey J. 700 babies exposed to TB at Texas Hospital. Atlanta Journal Constitution. September 22, 2014. www.ajc.com/news/lifestyles/health/700-babies-exposed-TB-texas-hospital/nhRmC/. Accessed November 12, 2014.

3. CDC. Reported tuberculosis in the United States, 2013. www.cdc.gov/tb/statistics/reports/2013/pdf/report2013.pdf. Accessed October 23, 2014.

4. World Health Organization. Global tuberculosis report 2014. www.who.int/tb/publications/global_report/en/. Accessed November 12, 2014.

5. Baussano I, Nunn P, Williams B, et al. Tuberculosis among health care workers. Emerg Infect Dis. 2011;17(3):488-494.

6. Yang H, Kruh-Garcia NA, Dobos KM. Purified protein derivatives of tuberculin: past, present, and future. FEMS Immunol Med Microbiol. 2012;66(3):273-280.

7. Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect Dis. 1993;17(6):968-975.

8. World Health Organization. Recommendations for vaccine administration. www.who.int/immunization/policy/Immunization_routine_table1.pdf. Accessed November 12, 2014.

9. Al-Orainey IO. Diagnosis of latent tuberculosis: can we do better? Ann Thorac Med. 2009;4(1):5-9.

10. Desem N, Jones SL. Development of a human gamma interferon enzyme immunoassay and comparison with tuberculin skin testing for detection of Mycobacterium tuberculosis infection. Clin Diagn Lab Immunol. 1998;5(4): 531-536.

11. FDA. QuantiFERON-TB - P010033. www.fda.gov/MedicalDevices/Products andMedicalProcedures/DeviceApprovalsandClearances/Recently-Approved Devices/ucm084025.htm. Accessed November 12, 2014.

12. QuantiFERON-TB Gold In-Tube Test [package insert]. www.quantiferon.com/irm/content/PI/QFT/2PK/US.pdf. Accessed November 12, 2014.

13. T-SPOT.TB [package insert]. Marlborough, MA. Oxford Immunotec, Inc. www.tspot.com/wp-content/uploads/2012/01/PI-TB-US-v4.pdf. Accessed November 12, 2014.

14. CDC. Fact sheet: infection control in health-care settings. www.cdc.gov/tb/publications/factsheets/prevention/ichcs.htm. Accessed November 12, 2014.

15. Jensen PA, Lambert LA, Iademarco MF, Ridzon R; CDC. Guidelines for preventing the transmission of Mycobacterium TB in health-care settings, 2005. MMWR Recomm Rep. 2005;54(RR-17):1-141.

16. Mazurek GH, Jereb J, Vernon A, et al; IGRA Expert Committee, CDC. Updated guidelines for using interferon γ release assays to detect Mycobacterium TB infection: United States, 2010. MMWR Recomm Rep. 2010;59(RR-5):1-25.

17. CDC. Latent tuberculosis infection: a guide for primary health care providers. www.cdc.gov/tb/publications/ltbi/diagnosis.htm. Accessed November 3, 2014.

18. Zwerling A, van den Hof S, Scholten J, et al. Interferon-γ release assays for TB screening of healthcare workers: a systematic review. Thorax. 2012;67(1): 62-70.

19. Eralp MN, Scholtes S, Martell G, et al. Screening of healthcare workers for TB: development and validation of a new health economic model to inform practice. BMJ Open. 2012;2:e000630.

20. FDA. FDA permits marketing of first US test labeled for simultaneous detection of tuberculosis bacteria and resistance to the antibiotic rifampin [press release]. July 25, 2013.

21. CDC. Availability of an assay for detecting Mycobacterium TB, including rifampin-resistant strains, and considerations for its use: United States, 2013 [published correction appears in MMWR Morb Mortal Wkly Rep. 2013;62(45):906]. MMWR Morb Mortal Wkly Rep. 2013;62(41):821-827.

22. CDC. Fact sheet: diagnosis of tuberculosis disease. www.cdc.gov/tb/publica tions/factsheets/testing/diagnosis.htm. Accessed November 12, 2014.

23. Pai M, Zwerling A, Menzies D. Systematic review: T-cell–based assays for the diagnosis of latent TB infection: an update. Ann Intern Med. 2008;149(3): 177-184.

24. LoBue PA, Castro KG. Is it time to replace the tuberculin skin test with a blood test? JAMA. 2012;308(3):241-242.

25. Mancuso JD, Mazurek GH, Tribble D, et al. Discordance among commercially available diagnostics for latent TB infection. Am J Respir Crit Care Med. 2012;185(4):427-434.

26. Wrighton-Smith P, Sneed L, Humphrey F, et al. Screening health care workers with interferon-γ release assay versus tuberculin skin test: impact on costs and adherence to testing (the SWITCH study). J Occup Environ Med. 2012;54(7):806-815.

27. World Health Organization. Use of tuberculosis interferon-gamma release assays (IGRAs) in low- and middle-income countries. www.who.int/tb/
features_archive/policy_statement_igra_oct2011.pdf. Accessed November 12, 2014.

Public health officials in El Paso, Texas, reported in September 2014 that more than 850 infants and 43 health care workers (HCW) at Providence Memorial Hospital may have been exposed to tuberculosis (TB) by a nurse with active infection. In collaboration with the CDC, the hospital administrators and local and state health officials advised potentially exposed individuals and their families to be screened for TB. According to press reports, five infants tested positive for TB and were to be treated.^1,2 This news report highlights the importance of maintaining infection control protocols in health care facilities throughout the United States to reduce the risk for TB transmission.

SCREENING HEALTH CARE WORKERS
In the US, reported cases of TB, a treatable and curable disease, have declined since 1993. A total of 9,582 cases were reported in 2013, with 536 deaths due to TB reported in 2011 (the most recent year for which this data is available).³

Even though TB is on the decline worldwide,⁴ HCWs remain at increased risk for infection, confirming that TB is an occupational disease.⁵ It is imperative that health care facilities have effective infection control plans in place, primarily to reduce the risk for transmission of TB to HCWs.

This article reviews the available TB screening tests, CDC recommendations, parameters for evaluating test performance, and recent studies that lend support to the superiority of interferon-γ (IFN-γ) release assays (IGRAs) over tuberculin skin tests (TSTs) as part of HCW screening and infection control for TB. Primary care clinicians need to know about the status of these tests not only because we are HCWs ourselves, but because we are often responsible for the safety of other HCWs in our workplaces.

TB SCREENING TESTS
Diagnosing latent tuberculosis infection (LTBI) is key to overall control of the disease, since treatment decreases risk for conversion to active disease. Until recently, the diagnosis of LTBI relied on the TST, despite its limitations (see discussion under “Accuracy”). Now, immune-based blood tests hold promise for improving LTBI diagnosis.

Tuberculin skin test
In 1934, Florence Seibert developed what is known today as the purified protein derivative (PPD) test, which was adopted as the standard in the US in 1941.⁶ For 60 years, the PPD TST was the only screening method for Mycobacterium tuberculosis infection. It involves the intradermal injection of PPD; a hypersensitivity response leads to a cutaneous induration at the injection site after 48 to 72 hours.⁷Hence, the TST is a two-step test, requiring a follow-up visit for the result to be read.

Although strongly predictive of TB, the TST may result in false-positive test results in those previously immunized with the Bacille Calmette-Guerin (BCG) vaccine (a WHO-recommended childhood vaccination against TB, widely used outside the US),⁸ and in those exposed to certain nontuberculous mycobacteria such as M bovis and M africana.⁹ Test results may also be false negative in immunocompromised patients.⁹

Interferon-γ release assays
With the goal of developing a more specific and sensitive test for TB infection, IGRAs were developed in the mid-1990s as a new tool to detect active and latent TB infection.¹⁰ The first IGRA test for TB received FDA approval in 2001.¹¹ There are currently two FDA-approved IGRAs—QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB—in use.

QuantiFERON-TB Gold In-Tube test. The QFT-GIT measures cell-mediated immune responses to antigens that simulate mycobacterial proteins. Requiring only one patient visit, whole blood is collected in three different tubes (negative control, TB antigen, and mitogen [positive] control), each containing a single antigen.¹² After 16 to 24 hours in a temperature-controlled environment, the tubes are centrifuged to separate the plasma. IFN-γ levels are measured in each tube to calculate the test result.

T-SPOT.TB test. Using one blood sample, the T-SPOT.TB test captures IFN-γ produced by activated T-cells in response to stimulation by two M tuberculosis antigens. Addition of a substrate produces dark blue spots; the number of spots indicates the quantity of M tuberculosis-sensitive effector T-cells in the peripheral blood. A positive result is eight or more spots; a negative result is fewer than four spots, and a borderline result is five to seven spots.¹³ Unlike the QFT-GIT, the T-SPOT.TB has a “borderline” interpretation category.

See the Table for a comparison of the TST, QFT-GIT, and T-SPOT.TB tests for TB screening.

Continue for CDC guidelines >>

CDC GUIDELINES
Subject to state and federal regulations and Occupational Safety and Health Administration (OSHA) directives, the CDC states that the goals of a TB infection control plan are
• Prompt detection of suspected or confirmed TB infection
• Airborne precautions implemented to reduce risk for TB transmission in areas in which exposure can occur
• Treatment of persons with suspected or confirmed TB.¹⁴

TB screening for HCWs has historically been a challenge in that, for new hires, the CDC recommends a baseline two-step process (meaning up to four visits) when TST is used.¹⁵ This is because TST-tested individuals may test false negative, even if they have LTBI, if many years have passed since their infection was acquired. As a result, guidelines for baseline testing are that, if the initial TST is negative, TST should be repeated one to three weeks later. If the person is in fact infected with TB, the first TST may stimulate the immune system’s ability to react to the TB antigens and elicit a positive or “boosted” response to the second test.

The above figure has been corrected from the print version as of December 16, 2014.

The 2005 guidelines recommended screening new-hire HCWs with either a baseline two-step TST or with one blood assay for M tuberculosis. After the introduction of the QFT-GIT and T-SPOT.TB tests, the CDC included them in its updated 2010 guidelines and indicated that either IGRAs or TSTs may be used in HCW surveillance programs for occupational exposure to M tuberculosis (see Figure).^15,16 The algorithm clearly illustrates how the use of IGRAs in place of TSTs streamlines the process of HCW TB screening.¹⁷

EVALUATION OF TESTS
Given the stringent nature of the CDC’s TB infection control goals, it is essential that health care facilities use the most effective and efficient means for timely and thorough screening of HCWs for TB. When evaluating the available tests, the following factors must be considered: accuracy and reproducibility of test results; impact on results when testing is repeated frequently; interpretation of discordant test results; and specificity, sensitivity, and identification of appropriate test cutoff values so that a positive result signifies a new TB infection (ie, conversion, a change from a documented negative to positive test result within a two-year period) rather than a false positive; and costs.^18,19

Accuracy
Unlike TSTs, IGRAs do not produce false-positive results in individuals vaccinated with BCG or in those infected with most nontuberculous mycobacteria.^9,16 Neither TSTs nor IGRAs, however, can distinguish between active and latent TB infection.¹⁹ If either test is positive, a chest radiograph is indicated. If the x-ray reveals abnormalities in the lungs, a sputum smear to detect acid-fast-bacilli (AFB), of which M tuberculosis is one, is indicative of TB. Nuclear acid amplification testing of a respiratory specimen ­provides rapid laboratory confirmation, but a positive culture for M tuberculosis confirms the ­diagnosis.²²

Specificity and sensitivity
Pai, Zwerling, and Menzies conducted a meta-analysis of 38 studies of TB testing. Most of the studies were small and had limitations, such as the lack of a gold standard test for the diagnosis of LTBI and variable TST methods and cutoff values. Nevertheless, the researchers were able to conclude that IGRAs are significantly more specific than TST and are unaffected by BCG vaccination. Although the sensitivity of IGRAs and TST is inconsistent across test populations, T-SPOT.TB appears to have greater sensitivity than QFT-GIT or TST.²³

Further, TST is subject to variability in administration and interpretation, and cut points for TST positivity vary internationally.⁹ In contrast, the ­T-SPOT.TB test specifies a borderline result zone. According to the CDC, this increases test accuracy by classifying results near the cut point, making a subsequent test conversion from negative to positive more likely to represent newly acquired infection.¹⁶

On the other hand, some studies of IGRAs have found unexpectedly high rates of initial positive results and conversions among HCWs in low-risk settings that are later determined to be false positives.²⁴ However, as noted previously, TSTs are also subject to false-positive results. In addition, the definition of an IGRA conversion is less stringent than the TST conversion definition, which may result in more IGRA conversions.¹⁶

Discordant results
Zwerling et al conducted a systematic review of all studies in which IGRAs were used for HCW screening to summarize their performance in cross-sectional and serial testing settings. The prevalence of positive IGRAs was found to be lower than that of positive TSTs. This difference was significant in low- and moderate-TB incidence settings but not in high-incidence settings. A positive association was reported between positive IGRA test results and occupational risk factors, including work in high-risk wards, TB clinics, and geriatric care, as well as length of employment.¹⁸

According to Mancuso et al, discordance of results between the TST and IGRAs in populations with low LTBI prevalence suggests that most positive test results are in fact false positives in these populations.²⁵ Although IGRAs were designed to increase specificity, the authors found that IGRA specificity was no better than the specificity of TST. Without a gold standard for detecting M tuberculosis infection, assessing the true significance of discordance between TST and IGRAs is difficult. Further research is needed to determine the significance of test discordance, to obtain data on progression to active TB, and to better define appropriate cut points for interpreting IGRA results.²⁵

Costs
The primary impediment to the widespread use of IGRAs has been cost, which is approximately three times that of a TST.²⁴

Eralp et al studied the cost-effectiveness of IGRAs versus TST for screening for active LTBI in HCWs by using healthy life-years gained—defined as the number of TB cases avoided, yielding an increase in life expectancy—as the benefit metric rather than quality-adjusted life-years. Because testing is completed with a single visit, use of IGRAs increases compliance while minimizing resources needed for a second visit and eliminating loss to follow-up. Also notable is that IGRA testing takes place in a laboratory, where costs can be held in check with focused expertise and optimized staffing structures. The authors concluded that incremental IGRA costs per healthy life-year gained were justified.¹⁹

Until publication of the SWITCH (Screening health care Workers with IGRA vs. TST: impact on Costs and adHerence to testing) study in 2012, cost-effectiveness studies had shown inconsistent results. This study, conducted by The Johns Hopkins University (JHU) employee health department, was the first of its kind in the US to systematically analyze test performance and labor costs for TB screening of HCWs. The results showed that the time required to administer a TST is one of the costliest elements. For a sizeable institution such as JHU, TST screening cost more than $1.3 million annually, equivalent to approximately $73 per person; in contrast, IGRA screening amounted to less than $55 per person.²⁶

Further research
The association between IGRA test conversion in HCWs and the risk for active TB disease has not been demonstrated.¹⁶ However, this is also true of TSTs²⁷ and further research is needed in this area. Research is also needed to determine the significance of TSA-IGRA results discordance and to better define cut points for IGRA interpretation.²⁵ In addition, more study of factors related to serial (periodic or ongoing) TB testing—which are very important within the context of HCW screening—is needed. As an example, serial TB testing may reveal trends in test conversions and can identify areas of concern within a health care facility. Unfortunately, current CDC recommendations do not provide specific guidelines for serial IGRA testing, such as guidance for accurate interpretation of IGRA results within a serial testing context.¹⁶ These areas should be addressed in future CDC updates.

Continue for conclusion >>

CONCLUSION
Occupational health professionals are continuously evaluating how to improve surveillance programs and reduce HCWs’ time away from work. Within this context, four advantages IGRAs offer include
• Elimination of a two-step TST for new hires (which requires up to four separate visits)
• No false-positive results caused by previous BCG vaccination or exposure to most nontuberculous mycobacteria
• Significantly improved HCW compliance because screening requires only one visit
• Cost effectiveness.

From an occupational health perspective, these are significant advantages that support the use of IGRAs to screen HCW for TB.

REFERENCES
1. Wilson J. Five babies test positive for TB in Texas. CNN. September 30, 2014. www.cnn.com/2014/09/29/health/babies-test-positive-tb/index.html. Accessed November 12, 2014.

2. Bailey J. 700 babies exposed to TB at Texas Hospital. Atlanta Journal Constitution. September 22, 2014. www.ajc.com/news/lifestyles/health/700-babies-exposed-TB-texas-hospital/nhRmC/. Accessed November 12, 2014.

3. CDC. Reported tuberculosis in the United States, 2013. www.cdc.gov/tb/statistics/reports/2013/pdf/report2013.pdf. Accessed October 23, 2014.

4. World Health Organization. Global tuberculosis report 2014. www.who.int/tb/publications/global_report/en/. Accessed November 12, 2014.

5. Baussano I, Nunn P, Williams B, et al. Tuberculosis among health care workers. Emerg Infect Dis. 2011;17(3):488-494.

6. Yang H, Kruh-Garcia NA, Dobos KM. Purified protein derivatives of tuberculin: past, present, and future. FEMS Immunol Med Microbiol. 2012;66(3):273-280.

7. Huebner RE, Schein MF, Bass JB Jr. The tuberculin skin test. Clin Infect Dis. 1993;17(6):968-975.

8. World Health Organization. Recommendations for vaccine administration. www.who.int/immunization/policy/Immunization_routine_table1.pdf. Accessed November 12, 2014.

9. Al-Orainey IO. Diagnosis of latent tuberculosis: can we do better? Ann Thorac Med. 2009;4(1):5-9.

10. Desem N, Jones SL. Development of a human gamma interferon enzyme immunoassay and comparison with tuberculin skin testing for detection of Mycobacterium tuberculosis infection. Clin Diagn Lab Immunol. 1998;5(4): 531-536.

11. FDA. QuantiFERON-TB - P010033. www.fda.gov/MedicalDevices/Products andMedicalProcedures/DeviceApprovalsandClearances/Recently-Approved Devices/ucm084025.htm. Accessed November 12, 2014.

12. QuantiFERON-TB Gold In-Tube Test [package insert]. www.quantiferon.com/irm/content/PI/QFT/2PK/US.pdf. Accessed November 12, 2014.

13. T-SPOT.TB [package insert]. Marlborough, MA. Oxford Immunotec, Inc. www.tspot.com/wp-content/uploads/2012/01/PI-TB-US-v4.pdf. Accessed November 12, 2014.

14. CDC. Fact sheet: infection control in health-care settings. www.cdc.gov/tb/publications/factsheets/prevention/ichcs.htm. Accessed November 12, 2014.

15. Jensen PA, Lambert LA, Iademarco MF, Ridzon R; CDC. Guidelines for preventing the transmission of Mycobacterium TB in health-care settings, 2005. MMWR Recomm Rep. 2005;54(RR-17):1-141.

16. Mazurek GH, Jereb J, Vernon A, et al; IGRA Expert Committee, CDC. Updated guidelines for using interferon γ release assays to detect Mycobacterium TB infection: United States, 2010. MMWR Recomm Rep. 2010;59(RR-5):1-25.

17. CDC. Latent tuberculosis infection: a guide for primary health care providers. www.cdc.gov/tb/publications/ltbi/diagnosis.htm. Accessed November 3, 2014.

18. Zwerling A, van den Hof S, Scholten J, et al. Interferon-γ release assays for TB screening of healthcare workers: a systematic review. Thorax. 2012;67(1): 62-70.

19. Eralp MN, Scholtes S, Martell G, et al. Screening of healthcare workers for TB: development and validation of a new health economic model to inform practice. BMJ Open. 2012;2:e000630.

20. FDA. FDA permits marketing of first US test labeled for simultaneous detection of tuberculosis bacteria and resistance to the antibiotic rifampin [press release]. July 25, 2013.

21. CDC. Availability of an assay for detecting Mycobacterium TB, including rifampin-resistant strains, and considerations for its use: United States, 2013 [published correction appears in MMWR Morb Mortal Wkly Rep. 2013;62(45):906]. MMWR Morb Mortal Wkly Rep. 2013;62(41):821-827.

22. CDC. Fact sheet: diagnosis of tuberculosis disease. www.cdc.gov/tb/publica tions/factsheets/testing/diagnosis.htm. Accessed November 12, 2014.

23. Pai M, Zwerling A, Menzies D. Systematic review: T-cell–based assays for the diagnosis of latent TB infection: an update. Ann Intern Med. 2008;149(3): 177-184.

24. LoBue PA, Castro KG. Is it time to replace the tuberculin skin test with a blood test? JAMA. 2012;308(3):241-242.

25. Mancuso JD, Mazurek GH, Tribble D, et al. Discordance among commercially available diagnostics for latent TB infection. Am J Respir Crit Care Med. 2012;185(4):427-434.

26. Wrighton-Smith P, Sneed L, Humphrey F, et al. Screening health care workers with interferon-γ release assay versus tuberculin skin test: impact on costs and adherence to testing (the SWITCH study). J Occup Environ Med. 2012;54(7):806-815.

27. World Health Organization. Use of tuberculosis interferon-gamma release assays (IGRAs) in low- and middle-income countries. www.who.int/tb/
features_archive/policy_statement_igra_oct2011.pdf. Accessed November 12, 2014.

Heart failure (HF) continues to grow as a significant health problem in the U.S., accounting for 1.1 million hospitalizations annually.¹ About 5.8 million Americans have HF, and 670,000 new cases are diagnosed each year.¹ The prevalence of HF increases with age. Persons aged > 65 years comprise the largest group of patients hospitalized for the condition. Heart failure-related hospitalizations place a major financial burden on patients, caregivers, and the national health care system. In 2010, the estimated cost of health care for HF was $35 billion with hospitalizations accounting for 1% to 2% of the total annual health care costs.^1-3 Furthermore, > 50% of patients with HF are rehospitalized before their first outpatient follow-up.⁴

To ensure patients are ready for discharge, HF guidelines recommend specific interventions for all hospitalized patients. These recommendations include successful transition from IV to oral diuretic therapy as well as the initiation of a ß-blocker and an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB) in stable patients with a left ventricular ejection fraction (LVEF) < 40% and without contraindications. Additionally, patients and their caregivers should receive comprehensive discharge instructions regarding medications, the importance of adherence and regular follow-up, sodium and fluid restriction, weight monitoring, physical activity, and a plan for worsening symptoms. When available, assistance with the hospital-to-home transition should also be provided.^5,6

Heart Failure Measures

Recognizing common factors essential to HF care, the Joint Commission has implemented HF core measures that all U.S. hospitals are required to meet to maintain accreditation status. These guideline-supported measures include receipt of diet, weight, and medication instructions; measured or scheduled assessment of LVEF; ACE-I or an ARB prescribed in patients with LVEF < 40%; and smoking cessation counseling before discharge for all patients with HF.

In addition to HF core measures, 30-day HF readmission rates have also become available to the general public as another hospital quality indicator. In 2009, the Centers for Medicare & Medicaid Services began publicly reporting 30-day HF readmission rates for Medicare patients. A CMS report indicated a 24.8% national 30-day HF readmission rate from July 1, 2007, through June 30, 2010.⁷ Unfortunately, even with the increased quality improvement effort, national HF rehospitalization rates have remained relatively steady in recent years.³

The VA health care system has a growing number of veterans with HF, and it is the leading discharge diagnosis in patients treated at VA hospitals. The number of HF-related hospitalizations at the VA health care system increased from just over 74,000 in fiscal year 2002 to 96,000 in 2009.⁸

To advance the care of veterans with HF and implement best practices, the VA launched the Chronic HF-Quality Enhancement Research Initiative (CHF-QUERI). The major goals of this initiative are to reduce hospitalization rates, increase use of life-prolonging care, empower patients and their caregivers in self-management, and improve appropriateness of HF therapies and tests. As part of its efforts, CHF-QUERI launched the HF Provider Network (HF Network), involving more than 712 VA health care providers (as of July 2014 there were more than 900 providers) committed to improving HF management throughout the entire VA health care system. The HF Network has already put into practice several quality improvement initiatives.

The National Hospital to Home initiative led by the American College of Cardiology and the Institute for Healthcare Improvement was launched throughout the VA system in January 2010.⁹ The main goal of this initiative is to reduce all-cause hospital readmission rates in patients with a discharge diagnosis of HF by improving medication management, early follow-up after discharge, and symptom management.

The Jesse Brown VAMC (JBVAMC) is an active participant of the Hospital to Home initiative, embracing the goals of reducing HF readmission rates and improving the transition of veterans from inpatient to outpatient care. The JBVAMC also has been successfully meeting or exceeding HF core measures except for providing discharge instructions. In May 2011, 91% of patients received discharge instructions, falling just slightly below the 93% target goal. Despite the implementation of HF care improvement initiatives and successful core measure performance, from July 1, 2007, to June 30, 2010, the average HF 30-day readmission rate at JBVAMC was reported to be 28.4%, compared with the national average of 24.8%. Additionally, the average readmission rate for fiscal year 2011 was 31% at JBVAMC, showing a further increase in readmission rates.

The cost of a hospital bed at JBVAMC ranges from about $2,000 to $5,000 per day. According to the American Heart Association’s Get With the Guidelines-HF registry, the mean hospital length of stay for HF in 2009 was 5.5 days.¹ Consequently, HF hospitalizations could potentially cost JBVAMC nearly $7 million annually. Therefore, HF readmissions not only affect patients and caregivers, but also represent a financial burden for JBVAMC. 

METHODS

The purpose of this study was to identify factors contributing to the high HF readmission rates in veterans enrolled at JBVAMC. This study was an Institutional Review Board and VA Research and Development Committee-approved retrospective, electronic chart review of patients with an ICD-9 principal discharge diagnosis code for HF and hospitalization for HF exacerbation anytime between October 1, 2010, and March 1, 2011. A patient chart was reviewed for 6 months after inclusion. A report was generated to identify patients discharged from JBVAMC with a principal discharge diagnosis of HF between October 1, 2010, and March 1, 2011, using the following ICD-9 HF codes: 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 428.0, 428.1, 428.20, 428.21, 428.22, 428.23, 428.30, 428.31, 428.32, 428.33, 428.40, 428.41, 428.42, 428.43, and 428.9.

Patients were included if aged  ≥ 18 years with one of the ICD-9 HF codes as the principal discharge diagnosis within the study period. Patients were excluded from the study if transferred to or from an outside hospital, discharged without an ICD-9 principal diagnosis code for HF, electively admitted for HF, not treated for HF during hospitalization, left the hospital against medical advice, had chart documentation with comfort measures only, were discharged/transferred to hospice, had active HF medications listed under non-VA medications in the electronic medication profile, or did not receive follow-up at JBVAMC. Study participants were included in the study once, which was classified as their index HF hospitalization, and were followed for 6 months thereafter.

The primary endpoint was the difference in patient characteristics between 2 groups of patients: those readmitted for HF within 30 days of the index hospitalization and those readmitted after 30 days or not at all.

The study had multiple secondary endpoints. One was the difference in patient characteristics between 2 groups of patients: those readmitted for HF within 90 days of the index hospitalization and those readmitted after 90 days or not at all. Another secondary endpoint was the difference in patient characteristics between 2 groups of patients: those with ≥ 2 readmissions for HF within 6 months and those with < 2 HF readmissions within 6 months. Additional secondary endpoints included percentage of patients readmitted for HF within 30 days of the index HF hospitalization, time to readmission if applicable, time to death if applicable, and average number of readmissions per patient within 6 months.

Index data collected included age, gender, ethnicity, prior diagnosis of HF, date of diagnosis, hospitalization for HF within 30 days of the index HF admission, in-hospital cardiac arrest, comorbid conditions, systolic blood pressure (BP), heart rate, respiratory rate, weight, serum sodium, blood urea nitrogen, serum creatinine, hematocrit, and glucose. For this study, comorbid conditions gathered were diabetes mellitus, coronary artery disease, prior percutaneous coronary intervention, aortic stenosis, stroke, chronic obstructive pulmonary disease, and dementia.

Medication profiles were reviewed at the time of admission to determine whether the patient was prescribed an ACE-I/ARB, ß-blocker, diuretic, hydralazine and isosorbide dinitrate, aldosterone antagonist, digoxin, NSAIDs, nonvasoselective calcium channel blocker, and an antiarrhytmic other than amiodarone and dofetilide. Hospitalization data included the most recent LVEF, the number of days on oral diuretic therapy after stopping IV diuretics, the number of days admitted, and documentation of an in-person inpatient dietitian consultation.

Data collected at discharge included diet/weight/medication instructions, weight, BP,  American College of Cardiology/American Heart Association HF stage and New York Heart Association (NYHA) HF functional class, if documented. Discharge medication profiles were assessed for the number of medications (< 9 or ≥ 9), documentation of active prescriptions for an ACE-I/ARB and a ß-blocker (or contraindication documented), diuretic, hydralazine and isosorbide dinitrate, aldosterone antagonist, and digoxin. Other data collected were documentation of a scheduled follow-up appointment with primary care physician, urgent care, chronic HF (CHF) clinic, or cardiologist, and whether the patient was discharged to home, skilled nursing facility, shelter, or homeless. Additionally, if the patient was discharged on a diuretic, the dose was compared with the baseline diuretic. If the diuretic at discharge was different from the home diuretic, equivalent doses were used for comparison with that of the baseline diuretic.

Postdischarge data collection included telephone follow-up within 48 hours of discharge, medication compliance since the initial hospitalization, date of first outpatient follow-up after initial hospital discharge, enrollment in CHF clinic/CHF-PharmD/Care Coordination Home Telehealth (CCHT) program, outpatient dietitian consultations, and date of death if applicable. Medication adherence was defined as ≥ 80% of lowest percentage filled medication of all HF medications, determined by the refill history in the computerized patient record system (CPRS). First outpatient follow-up was defined as a visit in which HF was addressed in the assessment and plan.

If readmitted within the study period, data collection included the date of first nonelective hospital readmission for HF, BP, heart rate, weight, serum digoxin level, serum creatinine, serum potassium, and whether the patient was on a target dose of HF recommended medications (if LVEF < 40% and no contraindication). Heart failure recommended medications for which target doses are established include ACE-I/ARB and ß-blockers. For this study, target doses of ACE-Is were captopril 50 mg 3 times daily, enalapril 10 mg twice daily, fosinopril 40 mg daily, lisinopril 20 mg daily, ramipril 10 mg daily, and trandolapril 4 mg daily. Target doses for ARBs were candesartan 32 mg daily, losartan 50 mg daily, and valsartan 160 mg twice daily. ß-blocker target doses were bisoprolol 10 mg daily, carvedilol 25 mg twice daily (50 mg twice daily if patients’ weight was > 85 kg), and metoprolol succinate 200 mg daily.^5,6 A statistical analysis was not performed on the data.

RESULTS

A total of 137 patient charts were reviewed, and 109 patients were included in the study. Patients were excluded if they transferred to or from an outside hospital (n = 8), had no follow-up at JBVAMC (n = 8), left the hospital against medical advice (n = 4), were electively admitted (n = 4), were not treated for HF (n = 3), or only had comfort measures documented in the chart (n = 1). The patients included were predominantly male (99%) and African American (78%) and had a mean age of 70 years. The majority of the patients had a prior diagnosis of HF (87%) and a history of systolic HF (58%). Most patients were previously prescribed an ACE-I/ARB (83%) and a ß-blocker (76%) at the time of admission (Table 1).

Six patients were readmitted within 30 days of the index hospitalization, whereas 103 patients were readmitted after 30 days or not at all. With respect to secondary endpoints, there were 21 patients readmitted within 90 days of the index hospitalization, whereas 88 patients were readmitted after 90 days or not at all. Additionally, 6 patients were readmitted ≥ 2 times within 6 months of the index hospitalization, whereas 103 patients were readmitted < 2 times within 6 months.

Baseline characteristics seemed similar across the study groups, except a greater percentage of patients readmitted within 30 days of the index HF hospitalization had a prior history of systolic HF and were hospitalized for HF 30 days prior to the index hospitalization (Table 2). In addition, patients readmitted within 30 days tended to receive a shorter duration of oral diuretic therapy after discontinuation of IV diuretics (mean 0.2 days vs 1.1 days). Patients in this group with an LVEF < 40% were less likely to be discharged on an ACE-I/ARB (75% vs 95%) and a ß-blocker (50% vs 85%) than were the patients who were readmitted after 30 days or not at all. These trends continued for patients readmitted within 90 days of the index hospitalization and for those readmitted after 90 days or not at all. The mean length of stay for the index HF hospitalization was about 5 days and was comparable among all study groups.

From the evaluation of postdischarge characteristics, no patients readmitted within 30 days had a follow-up appointment scheduled with the CHF clinic. In comparison with patients readmitted after 30 days or not at all, more patients had follow-up at an urgent care clinic (33% vs 6%) or no follow-up appointment scheduled at the time of discharge (17% vs 2%). Half of all the patients with a scheduled follow-up missed their appointment. Additionally, medication adherence was lower (33% vs 80%), and none of the patients were enrolled in the CHF-PharmD clinic (0% vs 5%). A similar trend continued for the secondary endpoint groups (Table 3). Last, none of the study patients had an outpatient dietitian consultation.

On readmission, the majority of patients readmitted within 30 days were not on a target dose of an ACE-I/ARB (75%), and none were on a target dose of a ß-blocker. The same trend continued for the secondary endpoint groups. None of the study patients had a serum digoxin level > 0.9 ng/mL. However, serum digoxin level was not measured in all readmitted patients prescribed digoxin (Table 4).

In regard to other secondary endpoints, 6 patients (5.5%) were readmitted for HF within 30 days of the index HF hospitalization. The average number of readmissions per patient in 6 months was < 1, mean time to readmission was 85 days (n = 33), and mean time to death was 88 days (n = 5) when applicable.

DISCUSSION

Based on the trends observed in this study, multiple recommendations can be made to further improve the quality of care and reduce HF readmissions at JBVAMC. The medical center physicians currently use a discharge note template, which already includes sections such as HF discharge instructions and follow-up appointments. The template also prompts providers to prescribe an ACE-I in appropriate patients.

When JBVAMC providers are ready to enter discharge notes into the CPRS, they first select the discharge note template from available note template options. The electronic template contains spaces for the provider to enter a patient’s primary reason for hospitalization, date of admission, discharge medication list, specific or suggested dates for follow-up with outpatient provider(s), general diet/weight/medication instructions, a space to answer whether the patient has HF, a space to record NYHA HF class if applicable, and a space to record whether the patient is prescribed or will be prescribed an ACE-I if appropriate, or whether ACE-I is contraindicated. The providers are able to modify and add information to the discharge note template as they see appropriate.

The findings of this study suggest that modifying the existing discharge template to include additional provider prompts in a form of designated spaces asking for specific information may help improve HF care outcomes. If providers are prompted to answer whether an oral diuretic was continued for at least 24 hours after stopping IV diuretics for HF, adherence to the HF guideline-recommended duration of oral diuretic therapy may improve. Additionally, ß-blocker prescribing in appropriate systolic HF patients may increase if providers are prompted. To enhance continuity of care, the discharge note template may be modified to include a section in which the providers can document patients followed by outside providers. This can be done by incorporating a space in the discharge template to enter the patient’s non-VA provider information if applicable and may help further coordinate the care of such patients to ensure that they are not lost.

Furthermore, the discharge template may be modified to include a prompt to place a CHF clinic consult to increase provider awareness about the availability of CHF and CHF-PharmD clinics at JBVAMC. CHF and CHF-PharmD clinics collaborate to provide comprehensive care to HF patients. After an initial evaluation at the CHF clinic, patients are referred to the clinical pharmacist for further medication therapy management when necessary. Currently, the physicians are encouraged to refer HF patients to the CHF clinic after discharge, but not all providers know that such a service is available. The prompt within the discharge note template would provide CHF/CHF-PharmD clinic provider contact information, clinic times, and a link that would take the provider to an appropriate screen for placing the consult.

Limitations

There are several limitations to this study, including its retrospective design and small sample size. Another source of potential study limitation was the initial process for creating a study patient list. The study list was designed to use ICD-9 codes to capture readmissions only for HF and only at JBVAMC. This was achieved by specifying any of the HF ICD-9 codes as the principal discharge diagnosis. However, the providers may not have always used a HF specific ICD-9 code for the principal discharge diagnosis, even if a patient was admitted primarily for HF. The provider may have chosen another principal discharge diagnosis for which the patient received treatment during the hospitalization.

There are multiple ways to obtain HF patient lists, one includes using the diagnosis-related group codes instead of ICD-9 codes. Due to the way the patient list was obtained and an inherent possibility that some patients admitted for HF had a non-HF ICD-9 code recorded as their principal discharge diagnosis, some eligible patients may not have appeared on the generated list. Additionally, this study captured readmission rates for only HF whereas the national HF 30-day readmission rate represents all-cause readmissions for HF patients. This difference may be reflected in the low 30-day readmission rate observed.

Another possible limitation was the timing of the launch of the CHF-PharmD clinic and the initiative for telephone follow-up 48 hours postdischarge. The CHF-PharmD clinic was launched in April 2011, and the initiative for telephone follow-up 48 hours postdischarge began in January 2011. As the start dates fell within the study period, these services may not have been available to all patients. Therefore, the data describing patient enrollment in CHF-PharmD clinic and those who received postdischarge telephone follow-up may not accurately reflect current practice. Last, statistical tests were not used in the study data analysis leaving any differences found open to interpretation. To minimize these limitations, larger prospective studies with statistical analysis capturing all-cause readmissions are necessary to further evaluate patient characteristics that may be contributing to HF readmissions at JBVAMC.

Conclusions

In general, earlier and more frequent readmissions were more common in patients who were converted to oral diuretic therapy for < 24 hours before discharge and were not discharged on an ACE-I/ARB and a b-blocker when appropriate. Additionally, most of the readmitted patients had no follow-up scheduled at discharge, were nonadherent with medications and follow-up appointments, and were not enrolled in the CHF and/or CHF-PharmD clinic. The majority of patients with systolic HF were not at target doses of either the ACE-I/ARB or the ß-blocker when readmitted. Overall, JBVAMC had a low percentage of patients readmitted for HF within 30 days, but there is still room for improvement in reducing HF readmissions.

At the time of discharge, all JBVAMC patients receive printed instructions and recommendations for their care after hospitalization. The patient handout includes the most current medications, diet/weight/medication instructions, and actual or suggested dates for follow-up appointments and/or tests. It may enhance awareness regarding dietician services to patients if the current discharge instruction template can be modified to provide information regarding the outpatient dietitian class. This could include date, time, and location of classes as well as dietician contact information. (See Appendixes 1 and 2.)

When these recommendations have been implemented, further studies will be warranted to assess the impact of the interventions. 

Acknowledgments
The authors thank Ms. Yvette Bloodson for her assistance in generating the initial patient list.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Heart failure (HF) continues to grow as a significant health problem in the U.S., accounting for 1.1 million hospitalizations annually.¹ About 5.8 million Americans have HF, and 670,000 new cases are diagnosed each year.¹ The prevalence of HF increases with age. Persons aged > 65 years comprise the largest group of patients hospitalized for the condition. Heart failure-related hospitalizations place a major financial burden on patients, caregivers, and the national health care system. In 2010, the estimated cost of health care for HF was $35 billion with hospitalizations accounting for 1% to 2% of the total annual health care costs.^1-3 Furthermore, > 50% of patients with HF are rehospitalized before their first outpatient follow-up.⁴

To ensure patients are ready for discharge, HF guidelines recommend specific interventions for all hospitalized patients. These recommendations include successful transition from IV to oral diuretic therapy as well as the initiation of a ß-blocker and an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB) in stable patients with a left ventricular ejection fraction (LVEF) < 40% and without contraindications. Additionally, patients and their caregivers should receive comprehensive discharge instructions regarding medications, the importance of adherence and regular follow-up, sodium and fluid restriction, weight monitoring, physical activity, and a plan for worsening symptoms. When available, assistance with the hospital-to-home transition should also be provided.^5,6

Heart Failure Measures

Recognizing common factors essential to HF care, the Joint Commission has implemented HF core measures that all U.S. hospitals are required to meet to maintain accreditation status. These guideline-supported measures include receipt of diet, weight, and medication instructions; measured or scheduled assessment of LVEF; ACE-I or an ARB prescribed in patients with LVEF < 40%; and smoking cessation counseling before discharge for all patients with HF.

In addition to HF core measures, 30-day HF readmission rates have also become available to the general public as another hospital quality indicator. In 2009, the Centers for Medicare & Medicaid Services began publicly reporting 30-day HF readmission rates for Medicare patients. A CMS report indicated a 24.8% national 30-day HF readmission rate from July 1, 2007, through June 30, 2010.⁷ Unfortunately, even with the increased quality improvement effort, national HF rehospitalization rates have remained relatively steady in recent years.³

The VA health care system has a growing number of veterans with HF, and it is the leading discharge diagnosis in patients treated at VA hospitals. The number of HF-related hospitalizations at the VA health care system increased from just over 74,000 in fiscal year 2002 to 96,000 in 2009.⁸

To advance the care of veterans with HF and implement best practices, the VA launched the Chronic HF-Quality Enhancement Research Initiative (CHF-QUERI). The major goals of this initiative are to reduce hospitalization rates, increase use of life-prolonging care, empower patients and their caregivers in self-management, and improve appropriateness of HF therapies and tests. As part of its efforts, CHF-QUERI launched the HF Provider Network (HF Network), involving more than 712 VA health care providers (as of July 2014 there were more than 900 providers) committed to improving HF management throughout the entire VA health care system. The HF Network has already put into practice several quality improvement initiatives.

The National Hospital to Home initiative led by the American College of Cardiology and the Institute for Healthcare Improvement was launched throughout the VA system in January 2010.⁹ The main goal of this initiative is to reduce all-cause hospital readmission rates in patients with a discharge diagnosis of HF by improving medication management, early follow-up after discharge, and symptom management.

The Jesse Brown VAMC (JBVAMC) is an active participant of the Hospital to Home initiative, embracing the goals of reducing HF readmission rates and improving the transition of veterans from inpatient to outpatient care. The JBVAMC also has been successfully meeting or exceeding HF core measures except for providing discharge instructions. In May 2011, 91% of patients received discharge instructions, falling just slightly below the 93% target goal. Despite the implementation of HF care improvement initiatives and successful core measure performance, from July 1, 2007, to June 30, 2010, the average HF 30-day readmission rate at JBVAMC was reported to be 28.4%, compared with the national average of 24.8%. Additionally, the average readmission rate for fiscal year 2011 was 31% at JBVAMC, showing a further increase in readmission rates.

The cost of a hospital bed at JBVAMC ranges from about $2,000 to $5,000 per day. According to the American Heart Association’s Get With the Guidelines-HF registry, the mean hospital length of stay for HF in 2009 was 5.5 days.¹ Consequently, HF hospitalizations could potentially cost JBVAMC nearly $7 million annually. Therefore, HF readmissions not only affect patients and caregivers, but also represent a financial burden for JBVAMC. 

METHODS

The purpose of this study was to identify factors contributing to the high HF readmission rates in veterans enrolled at JBVAMC. This study was an Institutional Review Board and VA Research and Development Committee-approved retrospective, electronic chart review of patients with an ICD-9 principal discharge diagnosis code for HF and hospitalization for HF exacerbation anytime between October 1, 2010, and March 1, 2011. A patient chart was reviewed for 6 months after inclusion. A report was generated to identify patients discharged from JBVAMC with a principal discharge diagnosis of HF between October 1, 2010, and March 1, 2011, using the following ICD-9 HF codes: 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 428.0, 428.1, 428.20, 428.21, 428.22, 428.23, 428.30, 428.31, 428.32, 428.33, 428.40, 428.41, 428.42, 428.43, and 428.9.

Patients were included if aged  ≥ 18 years with one of the ICD-9 HF codes as the principal discharge diagnosis within the study period. Patients were excluded from the study if transferred to or from an outside hospital, discharged without an ICD-9 principal diagnosis code for HF, electively admitted for HF, not treated for HF during hospitalization, left the hospital against medical advice, had chart documentation with comfort measures only, were discharged/transferred to hospice, had active HF medications listed under non-VA medications in the electronic medication profile, or did not receive follow-up at JBVAMC. Study participants were included in the study once, which was classified as their index HF hospitalization, and were followed for 6 months thereafter.

The primary endpoint was the difference in patient characteristics between 2 groups of patients: those readmitted for HF within 30 days of the index hospitalization and those readmitted after 30 days or not at all.

The study had multiple secondary endpoints. One was the difference in patient characteristics between 2 groups of patients: those readmitted for HF within 90 days of the index hospitalization and those readmitted after 90 days or not at all. Another secondary endpoint was the difference in patient characteristics between 2 groups of patients: those with ≥ 2 readmissions for HF within 6 months and those with < 2 HF readmissions within 6 months. Additional secondary endpoints included percentage of patients readmitted for HF within 30 days of the index HF hospitalization, time to readmission if applicable, time to death if applicable, and average number of readmissions per patient within 6 months.

Index data collected included age, gender, ethnicity, prior diagnosis of HF, date of diagnosis, hospitalization for HF within 30 days of the index HF admission, in-hospital cardiac arrest, comorbid conditions, systolic blood pressure (BP), heart rate, respiratory rate, weight, serum sodium, blood urea nitrogen, serum creatinine, hematocrit, and glucose. For this study, comorbid conditions gathered were diabetes mellitus, coronary artery disease, prior percutaneous coronary intervention, aortic stenosis, stroke, chronic obstructive pulmonary disease, and dementia.

Medication profiles were reviewed at the time of admission to determine whether the patient was prescribed an ACE-I/ARB, ß-blocker, diuretic, hydralazine and isosorbide dinitrate, aldosterone antagonist, digoxin, NSAIDs, nonvasoselective calcium channel blocker, and an antiarrhytmic other than amiodarone and dofetilide. Hospitalization data included the most recent LVEF, the number of days on oral diuretic therapy after stopping IV diuretics, the number of days admitted, and documentation of an in-person inpatient dietitian consultation.

Data collected at discharge included diet/weight/medication instructions, weight, BP,  American College of Cardiology/American Heart Association HF stage and New York Heart Association (NYHA) HF functional class, if documented. Discharge medication profiles were assessed for the number of medications (< 9 or ≥ 9), documentation of active prescriptions for an ACE-I/ARB and a ß-blocker (or contraindication documented), diuretic, hydralazine and isosorbide dinitrate, aldosterone antagonist, and digoxin. Other data collected were documentation of a scheduled follow-up appointment with primary care physician, urgent care, chronic HF (CHF) clinic, or cardiologist, and whether the patient was discharged to home, skilled nursing facility, shelter, or homeless. Additionally, if the patient was discharged on a diuretic, the dose was compared with the baseline diuretic. If the diuretic at discharge was different from the home diuretic, equivalent doses were used for comparison with that of the baseline diuretic.

Postdischarge data collection included telephone follow-up within 48 hours of discharge, medication compliance since the initial hospitalization, date of first outpatient follow-up after initial hospital discharge, enrollment in CHF clinic/CHF-PharmD/Care Coordination Home Telehealth (CCHT) program, outpatient dietitian consultations, and date of death if applicable. Medication adherence was defined as ≥ 80% of lowest percentage filled medication of all HF medications, determined by the refill history in the computerized patient record system (CPRS). First outpatient follow-up was defined as a visit in which HF was addressed in the assessment and plan.

If readmitted within the study period, data collection included the date of first nonelective hospital readmission for HF, BP, heart rate, weight, serum digoxin level, serum creatinine, serum potassium, and whether the patient was on a target dose of HF recommended medications (if LVEF < 40% and no contraindication). Heart failure recommended medications for which target doses are established include ACE-I/ARB and ß-blockers. For this study, target doses of ACE-Is were captopril 50 mg 3 times daily, enalapril 10 mg twice daily, fosinopril 40 mg daily, lisinopril 20 mg daily, ramipril 10 mg daily, and trandolapril 4 mg daily. Target doses for ARBs were candesartan 32 mg daily, losartan 50 mg daily, and valsartan 160 mg twice daily. ß-blocker target doses were bisoprolol 10 mg daily, carvedilol 25 mg twice daily (50 mg twice daily if patients’ weight was > 85 kg), and metoprolol succinate 200 mg daily.^5,6 A statistical analysis was not performed on the data.

RESULTS

A total of 137 patient charts were reviewed, and 109 patients were included in the study. Patients were excluded if they transferred to or from an outside hospital (n = 8), had no follow-up at JBVAMC (n = 8), left the hospital against medical advice (n = 4), were electively admitted (n = 4), were not treated for HF (n = 3), or only had comfort measures documented in the chart (n = 1). The patients included were predominantly male (99%) and African American (78%) and had a mean age of 70 years. The majority of the patients had a prior diagnosis of HF (87%) and a history of systolic HF (58%). Most patients were previously prescribed an ACE-I/ARB (83%) and a ß-blocker (76%) at the time of admission (Table 1).

Six patients were readmitted within 30 days of the index hospitalization, whereas 103 patients were readmitted after 30 days or not at all. With respect to secondary endpoints, there were 21 patients readmitted within 90 days of the index hospitalization, whereas 88 patients were readmitted after 90 days or not at all. Additionally, 6 patients were readmitted ≥ 2 times within 6 months of the index hospitalization, whereas 103 patients were readmitted < 2 times within 6 months.

Baseline characteristics seemed similar across the study groups, except a greater percentage of patients readmitted within 30 days of the index HF hospitalization had a prior history of systolic HF and were hospitalized for HF 30 days prior to the index hospitalization (Table 2). In addition, patients readmitted within 30 days tended to receive a shorter duration of oral diuretic therapy after discontinuation of IV diuretics (mean 0.2 days vs 1.1 days). Patients in this group with an LVEF < 40% were less likely to be discharged on an ACE-I/ARB (75% vs 95%) and a ß-blocker (50% vs 85%) than were the patients who were readmitted after 30 days or not at all. These trends continued for patients readmitted within 90 days of the index hospitalization and for those readmitted after 90 days or not at all. The mean length of stay for the index HF hospitalization was about 5 days and was comparable among all study groups.

From the evaluation of postdischarge characteristics, no patients readmitted within 30 days had a follow-up appointment scheduled with the CHF clinic. In comparison with patients readmitted after 30 days or not at all, more patients had follow-up at an urgent care clinic (33% vs 6%) or no follow-up appointment scheduled at the time of discharge (17% vs 2%). Half of all the patients with a scheduled follow-up missed their appointment. Additionally, medication adherence was lower (33% vs 80%), and none of the patients were enrolled in the CHF-PharmD clinic (0% vs 5%). A similar trend continued for the secondary endpoint groups (Table 3). Last, none of the study patients had an outpatient dietitian consultation.

On readmission, the majority of patients readmitted within 30 days were not on a target dose of an ACE-I/ARB (75%), and none were on a target dose of a ß-blocker. The same trend continued for the secondary endpoint groups. None of the study patients had a serum digoxin level > 0.9 ng/mL. However, serum digoxin level was not measured in all readmitted patients prescribed digoxin (Table 4).

In regard to other secondary endpoints, 6 patients (5.5%) were readmitted for HF within 30 days of the index HF hospitalization. The average number of readmissions per patient in 6 months was < 1, mean time to readmission was 85 days (n = 33), and mean time to death was 88 days (n = 5) when applicable.

DISCUSSION

Based on the trends observed in this study, multiple recommendations can be made to further improve the quality of care and reduce HF readmissions at JBVAMC. The medical center physicians currently use a discharge note template, which already includes sections such as HF discharge instructions and follow-up appointments. The template also prompts providers to prescribe an ACE-I in appropriate patients.

When JBVAMC providers are ready to enter discharge notes into the CPRS, they first select the discharge note template from available note template options. The electronic template contains spaces for the provider to enter a patient’s primary reason for hospitalization, date of admission, discharge medication list, specific or suggested dates for follow-up with outpatient provider(s), general diet/weight/medication instructions, a space to answer whether the patient has HF, a space to record NYHA HF class if applicable, and a space to record whether the patient is prescribed or will be prescribed an ACE-I if appropriate, or whether ACE-I is contraindicated. The providers are able to modify and add information to the discharge note template as they see appropriate.

The findings of this study suggest that modifying the existing discharge template to include additional provider prompts in a form of designated spaces asking for specific information may help improve HF care outcomes. If providers are prompted to answer whether an oral diuretic was continued for at least 24 hours after stopping IV diuretics for HF, adherence to the HF guideline-recommended duration of oral diuretic therapy may improve. Additionally, ß-blocker prescribing in appropriate systolic HF patients may increase if providers are prompted. To enhance continuity of care, the discharge note template may be modified to include a section in which the providers can document patients followed by outside providers. This can be done by incorporating a space in the discharge template to enter the patient’s non-VA provider information if applicable and may help further coordinate the care of such patients to ensure that they are not lost.

Furthermore, the discharge template may be modified to include a prompt to place a CHF clinic consult to increase provider awareness about the availability of CHF and CHF-PharmD clinics at JBVAMC. CHF and CHF-PharmD clinics collaborate to provide comprehensive care to HF patients. After an initial evaluation at the CHF clinic, patients are referred to the clinical pharmacist for further medication therapy management when necessary. Currently, the physicians are encouraged to refer HF patients to the CHF clinic after discharge, but not all providers know that such a service is available. The prompt within the discharge note template would provide CHF/CHF-PharmD clinic provider contact information, clinic times, and a link that would take the provider to an appropriate screen for placing the consult.

Limitations

There are several limitations to this study, including its retrospective design and small sample size. Another source of potential study limitation was the initial process for creating a study patient list. The study list was designed to use ICD-9 codes to capture readmissions only for HF and only at JBVAMC. This was achieved by specifying any of the HF ICD-9 codes as the principal discharge diagnosis. However, the providers may not have always used a HF specific ICD-9 code for the principal discharge diagnosis, even if a patient was admitted primarily for HF. The provider may have chosen another principal discharge diagnosis for which the patient received treatment during the hospitalization.

There are multiple ways to obtain HF patient lists, one includes using the diagnosis-related group codes instead of ICD-9 codes. Due to the way the patient list was obtained and an inherent possibility that some patients admitted for HF had a non-HF ICD-9 code recorded as their principal discharge diagnosis, some eligible patients may not have appeared on the generated list. Additionally, this study captured readmission rates for only HF whereas the national HF 30-day readmission rate represents all-cause readmissions for HF patients. This difference may be reflected in the low 30-day readmission rate observed.

Another possible limitation was the timing of the launch of the CHF-PharmD clinic and the initiative for telephone follow-up 48 hours postdischarge. The CHF-PharmD clinic was launched in April 2011, and the initiative for telephone follow-up 48 hours postdischarge began in January 2011. As the start dates fell within the study period, these services may not have been available to all patients. Therefore, the data describing patient enrollment in CHF-PharmD clinic and those who received postdischarge telephone follow-up may not accurately reflect current practice. Last, statistical tests were not used in the study data analysis leaving any differences found open to interpretation. To minimize these limitations, larger prospective studies with statistical analysis capturing all-cause readmissions are necessary to further evaluate patient characteristics that may be contributing to HF readmissions at JBVAMC.

Conclusions

In general, earlier and more frequent readmissions were more common in patients who were converted to oral diuretic therapy for < 24 hours before discharge and were not discharged on an ACE-I/ARB and a b-blocker when appropriate. Additionally, most of the readmitted patients had no follow-up scheduled at discharge, were nonadherent with medications and follow-up appointments, and were not enrolled in the CHF and/or CHF-PharmD clinic. The majority of patients with systolic HF were not at target doses of either the ACE-I/ARB or the ß-blocker when readmitted. Overall, JBVAMC had a low percentage of patients readmitted for HF within 30 days, but there is still room for improvement in reducing HF readmissions.

At the time of discharge, all JBVAMC patients receive printed instructions and recommendations for their care after hospitalization. The patient handout includes the most current medications, diet/weight/medication instructions, and actual or suggested dates for follow-up appointments and/or tests. It may enhance awareness regarding dietician services to patients if the current discharge instruction template can be modified to provide information regarding the outpatient dietitian class. This could include date, time, and location of classes as well as dietician contact information. (See Appendixes 1 and 2.)

When these recommendations have been implemented, further studies will be warranted to assess the impact of the interventions. 

Acknowledgments
The authors thank Ms. Yvette Bloodson for her assistance in generating the initial patient list.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Heart failure (HF) continues to grow as a significant health problem in the U.S., accounting for 1.1 million hospitalizations annually.¹ About 5.8 million Americans have HF, and 670,000 new cases are diagnosed each year.¹ The prevalence of HF increases with age. Persons aged > 65 years comprise the largest group of patients hospitalized for the condition. Heart failure-related hospitalizations place a major financial burden on patients, caregivers, and the national health care system. In 2010, the estimated cost of health care for HF was $35 billion with hospitalizations accounting for 1% to 2% of the total annual health care costs.^1-3 Furthermore, > 50% of patients with HF are rehospitalized before their first outpatient follow-up.⁴

To ensure patients are ready for discharge, HF guidelines recommend specific interventions for all hospitalized patients. These recommendations include successful transition from IV to oral diuretic therapy as well as the initiation of a ß-blocker and an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB) in stable patients with a left ventricular ejection fraction (LVEF) < 40% and without contraindications. Additionally, patients and their caregivers should receive comprehensive discharge instructions regarding medications, the importance of adherence and regular follow-up, sodium and fluid restriction, weight monitoring, physical activity, and a plan for worsening symptoms. When available, assistance with the hospital-to-home transition should also be provided.^5,6

Heart Failure Measures

Recognizing common factors essential to HF care, the Joint Commission has implemented HF core measures that all U.S. hospitals are required to meet to maintain accreditation status. These guideline-supported measures include receipt of diet, weight, and medication instructions; measured or scheduled assessment of LVEF; ACE-I or an ARB prescribed in patients with LVEF < 40%; and smoking cessation counseling before discharge for all patients with HF.

In addition to HF core measures, 30-day HF readmission rates have also become available to the general public as another hospital quality indicator. In 2009, the Centers for Medicare & Medicaid Services began publicly reporting 30-day HF readmission rates for Medicare patients. A CMS report indicated a 24.8% national 30-day HF readmission rate from July 1, 2007, through June 30, 2010.⁷ Unfortunately, even with the increased quality improvement effort, national HF rehospitalization rates have remained relatively steady in recent years.³

The VA health care system has a growing number of veterans with HF, and it is the leading discharge diagnosis in patients treated at VA hospitals. The number of HF-related hospitalizations at the VA health care system increased from just over 74,000 in fiscal year 2002 to 96,000 in 2009.⁸

To advance the care of veterans with HF and implement best practices, the VA launched the Chronic HF-Quality Enhancement Research Initiative (CHF-QUERI). The major goals of this initiative are to reduce hospitalization rates, increase use of life-prolonging care, empower patients and their caregivers in self-management, and improve appropriateness of HF therapies and tests. As part of its efforts, CHF-QUERI launched the HF Provider Network (HF Network), involving more than 712 VA health care providers (as of July 2014 there were more than 900 providers) committed to improving HF management throughout the entire VA health care system. The HF Network has already put into practice several quality improvement initiatives.

The National Hospital to Home initiative led by the American College of Cardiology and the Institute for Healthcare Improvement was launched throughout the VA system in January 2010.⁹ The main goal of this initiative is to reduce all-cause hospital readmission rates in patients with a discharge diagnosis of HF by improving medication management, early follow-up after discharge, and symptom management.

The Jesse Brown VAMC (JBVAMC) is an active participant of the Hospital to Home initiative, embracing the goals of reducing HF readmission rates and improving the transition of veterans from inpatient to outpatient care. The JBVAMC also has been successfully meeting or exceeding HF core measures except for providing discharge instructions. In May 2011, 91% of patients received discharge instructions, falling just slightly below the 93% target goal. Despite the implementation of HF care improvement initiatives and successful core measure performance, from July 1, 2007, to June 30, 2010, the average HF 30-day readmission rate at JBVAMC was reported to be 28.4%, compared with the national average of 24.8%. Additionally, the average readmission rate for fiscal year 2011 was 31% at JBVAMC, showing a further increase in readmission rates.

The cost of a hospital bed at JBVAMC ranges from about $2,000 to $5,000 per day. According to the American Heart Association’s Get With the Guidelines-HF registry, the mean hospital length of stay for HF in 2009 was 5.5 days.¹ Consequently, HF hospitalizations could potentially cost JBVAMC nearly $7 million annually. Therefore, HF readmissions not only affect patients and caregivers, but also represent a financial burden for JBVAMC. 

METHODS

The purpose of this study was to identify factors contributing to the high HF readmission rates in veterans enrolled at JBVAMC. This study was an Institutional Review Board and VA Research and Development Committee-approved retrospective, electronic chart review of patients with an ICD-9 principal discharge diagnosis code for HF and hospitalization for HF exacerbation anytime between October 1, 2010, and March 1, 2011. A patient chart was reviewed for 6 months after inclusion. A report was generated to identify patients discharged from JBVAMC with a principal discharge diagnosis of HF between October 1, 2010, and March 1, 2011, using the following ICD-9 HF codes: 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 428.0, 428.1, 428.20, 428.21, 428.22, 428.23, 428.30, 428.31, 428.32, 428.33, 428.40, 428.41, 428.42, 428.43, and 428.9.

Patients were included if aged  ≥ 18 years with one of the ICD-9 HF codes as the principal discharge diagnosis within the study period. Patients were excluded from the study if transferred to or from an outside hospital, discharged without an ICD-9 principal diagnosis code for HF, electively admitted for HF, not treated for HF during hospitalization, left the hospital against medical advice, had chart documentation with comfort measures only, were discharged/transferred to hospice, had active HF medications listed under non-VA medications in the electronic medication profile, or did not receive follow-up at JBVAMC. Study participants were included in the study once, which was classified as their index HF hospitalization, and were followed for 6 months thereafter.

The primary endpoint was the difference in patient characteristics between 2 groups of patients: those readmitted for HF within 30 days of the index hospitalization and those readmitted after 30 days or not at all.

The study had multiple secondary endpoints. One was the difference in patient characteristics between 2 groups of patients: those readmitted for HF within 90 days of the index hospitalization and those readmitted after 90 days or not at all. Another secondary endpoint was the difference in patient characteristics between 2 groups of patients: those with ≥ 2 readmissions for HF within 6 months and those with < 2 HF readmissions within 6 months. Additional secondary endpoints included percentage of patients readmitted for HF within 30 days of the index HF hospitalization, time to readmission if applicable, time to death if applicable, and average number of readmissions per patient within 6 months.

Index data collected included age, gender, ethnicity, prior diagnosis of HF, date of diagnosis, hospitalization for HF within 30 days of the index HF admission, in-hospital cardiac arrest, comorbid conditions, systolic blood pressure (BP), heart rate, respiratory rate, weight, serum sodium, blood urea nitrogen, serum creatinine, hematocrit, and glucose. For this study, comorbid conditions gathered were diabetes mellitus, coronary artery disease, prior percutaneous coronary intervention, aortic stenosis, stroke, chronic obstructive pulmonary disease, and dementia.

Medication profiles were reviewed at the time of admission to determine whether the patient was prescribed an ACE-I/ARB, ß-blocker, diuretic, hydralazine and isosorbide dinitrate, aldosterone antagonist, digoxin, NSAIDs, nonvasoselective calcium channel blocker, and an antiarrhytmic other than amiodarone and dofetilide. Hospitalization data included the most recent LVEF, the number of days on oral diuretic therapy after stopping IV diuretics, the number of days admitted, and documentation of an in-person inpatient dietitian consultation.

Data collected at discharge included diet/weight/medication instructions, weight, BP,  American College of Cardiology/American Heart Association HF stage and New York Heart Association (NYHA) HF functional class, if documented. Discharge medication profiles were assessed for the number of medications (< 9 or ≥ 9), documentation of active prescriptions for an ACE-I/ARB and a ß-blocker (or contraindication documented), diuretic, hydralazine and isosorbide dinitrate, aldosterone antagonist, and digoxin. Other data collected were documentation of a scheduled follow-up appointment with primary care physician, urgent care, chronic HF (CHF) clinic, or cardiologist, and whether the patient was discharged to home, skilled nursing facility, shelter, or homeless. Additionally, if the patient was discharged on a diuretic, the dose was compared with the baseline diuretic. If the diuretic at discharge was different from the home diuretic, equivalent doses were used for comparison with that of the baseline diuretic.

Postdischarge data collection included telephone follow-up within 48 hours of discharge, medication compliance since the initial hospitalization, date of first outpatient follow-up after initial hospital discharge, enrollment in CHF clinic/CHF-PharmD/Care Coordination Home Telehealth (CCHT) program, outpatient dietitian consultations, and date of death if applicable. Medication adherence was defined as ≥ 80% of lowest percentage filled medication of all HF medications, determined by the refill history in the computerized patient record system (CPRS). First outpatient follow-up was defined as a visit in which HF was addressed in the assessment and plan.

If readmitted within the study period, data collection included the date of first nonelective hospital readmission for HF, BP, heart rate, weight, serum digoxin level, serum creatinine, serum potassium, and whether the patient was on a target dose of HF recommended medications (if LVEF < 40% and no contraindication). Heart failure recommended medications for which target doses are established include ACE-I/ARB and ß-blockers. For this study, target doses of ACE-Is were captopril 50 mg 3 times daily, enalapril 10 mg twice daily, fosinopril 40 mg daily, lisinopril 20 mg daily, ramipril 10 mg daily, and trandolapril 4 mg daily. Target doses for ARBs were candesartan 32 mg daily, losartan 50 mg daily, and valsartan 160 mg twice daily. ß-blocker target doses were bisoprolol 10 mg daily, carvedilol 25 mg twice daily (50 mg twice daily if patients’ weight was > 85 kg), and metoprolol succinate 200 mg daily.^5,6 A statistical analysis was not performed on the data.

RESULTS

A total of 137 patient charts were reviewed, and 109 patients were included in the study. Patients were excluded if they transferred to or from an outside hospital (n = 8), had no follow-up at JBVAMC (n = 8), left the hospital against medical advice (n = 4), were electively admitted (n = 4), were not treated for HF (n = 3), or only had comfort measures documented in the chart (n = 1). The patients included were predominantly male (99%) and African American (78%) and had a mean age of 70 years. The majority of the patients had a prior diagnosis of HF (87%) and a history of systolic HF (58%). Most patients were previously prescribed an ACE-I/ARB (83%) and a ß-blocker (76%) at the time of admission (Table 1).

Six patients were readmitted within 30 days of the index hospitalization, whereas 103 patients were readmitted after 30 days or not at all. With respect to secondary endpoints, there were 21 patients readmitted within 90 days of the index hospitalization, whereas 88 patients were readmitted after 90 days or not at all. Additionally, 6 patients were readmitted ≥ 2 times within 6 months of the index hospitalization, whereas 103 patients were readmitted < 2 times within 6 months.

Baseline characteristics seemed similar across the study groups, except a greater percentage of patients readmitted within 30 days of the index HF hospitalization had a prior history of systolic HF and were hospitalized for HF 30 days prior to the index hospitalization (Table 2). In addition, patients readmitted within 30 days tended to receive a shorter duration of oral diuretic therapy after discontinuation of IV diuretics (mean 0.2 days vs 1.1 days). Patients in this group with an LVEF < 40% were less likely to be discharged on an ACE-I/ARB (75% vs 95%) and a ß-blocker (50% vs 85%) than were the patients who were readmitted after 30 days or not at all. These trends continued for patients readmitted within 90 days of the index hospitalization and for those readmitted after 90 days or not at all. The mean length of stay for the index HF hospitalization was about 5 days and was comparable among all study groups.

From the evaluation of postdischarge characteristics, no patients readmitted within 30 days had a follow-up appointment scheduled with the CHF clinic. In comparison with patients readmitted after 30 days or not at all, more patients had follow-up at an urgent care clinic (33% vs 6%) or no follow-up appointment scheduled at the time of discharge (17% vs 2%). Half of all the patients with a scheduled follow-up missed their appointment. Additionally, medication adherence was lower (33% vs 80%), and none of the patients were enrolled in the CHF-PharmD clinic (0% vs 5%). A similar trend continued for the secondary endpoint groups (Table 3). Last, none of the study patients had an outpatient dietitian consultation.

On readmission, the majority of patients readmitted within 30 days were not on a target dose of an ACE-I/ARB (75%), and none were on a target dose of a ß-blocker. The same trend continued for the secondary endpoint groups. None of the study patients had a serum digoxin level > 0.9 ng/mL. However, serum digoxin level was not measured in all readmitted patients prescribed digoxin (Table 4).

In regard to other secondary endpoints, 6 patients (5.5%) were readmitted for HF within 30 days of the index HF hospitalization. The average number of readmissions per patient in 6 months was < 1, mean time to readmission was 85 days (n = 33), and mean time to death was 88 days (n = 5) when applicable.

DISCUSSION

Based on the trends observed in this study, multiple recommendations can be made to further improve the quality of care and reduce HF readmissions at JBVAMC. The medical center physicians currently use a discharge note template, which already includes sections such as HF discharge instructions and follow-up appointments. The template also prompts providers to prescribe an ACE-I in appropriate patients.

When JBVAMC providers are ready to enter discharge notes into the CPRS, they first select the discharge note template from available note template options. The electronic template contains spaces for the provider to enter a patient’s primary reason for hospitalization, date of admission, discharge medication list, specific or suggested dates for follow-up with outpatient provider(s), general diet/weight/medication instructions, a space to answer whether the patient has HF, a space to record NYHA HF class if applicable, and a space to record whether the patient is prescribed or will be prescribed an ACE-I if appropriate, or whether ACE-I is contraindicated. The providers are able to modify and add information to the discharge note template as they see appropriate.

The findings of this study suggest that modifying the existing discharge template to include additional provider prompts in a form of designated spaces asking for specific information may help improve HF care outcomes. If providers are prompted to answer whether an oral diuretic was continued for at least 24 hours after stopping IV diuretics for HF, adherence to the HF guideline-recommended duration of oral diuretic therapy may improve. Additionally, ß-blocker prescribing in appropriate systolic HF patients may increase if providers are prompted. To enhance continuity of care, the discharge note template may be modified to include a section in which the providers can document patients followed by outside providers. This can be done by incorporating a space in the discharge template to enter the patient’s non-VA provider information if applicable and may help further coordinate the care of such patients to ensure that they are not lost.

Furthermore, the discharge template may be modified to include a prompt to place a CHF clinic consult to increase provider awareness about the availability of CHF and CHF-PharmD clinics at JBVAMC. CHF and CHF-PharmD clinics collaborate to provide comprehensive care to HF patients. After an initial evaluation at the CHF clinic, patients are referred to the clinical pharmacist for further medication therapy management when necessary. Currently, the physicians are encouraged to refer HF patients to the CHF clinic after discharge, but not all providers know that such a service is available. The prompt within the discharge note template would provide CHF/CHF-PharmD clinic provider contact information, clinic times, and a link that would take the provider to an appropriate screen for placing the consult.

Limitations

There are several limitations to this study, including its retrospective design and small sample size. Another source of potential study limitation was the initial process for creating a study patient list. The study list was designed to use ICD-9 codes to capture readmissions only for HF and only at JBVAMC. This was achieved by specifying any of the HF ICD-9 codes as the principal discharge diagnosis. However, the providers may not have always used a HF specific ICD-9 code for the principal discharge diagnosis, even if a patient was admitted primarily for HF. The provider may have chosen another principal discharge diagnosis for which the patient received treatment during the hospitalization.

There are multiple ways to obtain HF patient lists, one includes using the diagnosis-related group codes instead of ICD-9 codes. Due to the way the patient list was obtained and an inherent possibility that some patients admitted for HF had a non-HF ICD-9 code recorded as their principal discharge diagnosis, some eligible patients may not have appeared on the generated list. Additionally, this study captured readmission rates for only HF whereas the national HF 30-day readmission rate represents all-cause readmissions for HF patients. This difference may be reflected in the low 30-day readmission rate observed.

Another possible limitation was the timing of the launch of the CHF-PharmD clinic and the initiative for telephone follow-up 48 hours postdischarge. The CHF-PharmD clinic was launched in April 2011, and the initiative for telephone follow-up 48 hours postdischarge began in January 2011. As the start dates fell within the study period, these services may not have been available to all patients. Therefore, the data describing patient enrollment in CHF-PharmD clinic and those who received postdischarge telephone follow-up may not accurately reflect current practice. Last, statistical tests were not used in the study data analysis leaving any differences found open to interpretation. To minimize these limitations, larger prospective studies with statistical analysis capturing all-cause readmissions are necessary to further evaluate patient characteristics that may be contributing to HF readmissions at JBVAMC.

Conclusions

In general, earlier and more frequent readmissions were more common in patients who were converted to oral diuretic therapy for < 24 hours before discharge and were not discharged on an ACE-I/ARB and a b-blocker when appropriate. Additionally, most of the readmitted patients had no follow-up scheduled at discharge, were nonadherent with medications and follow-up appointments, and were not enrolled in the CHF and/or CHF-PharmD clinic. The majority of patients with systolic HF were not at target doses of either the ACE-I/ARB or the ß-blocker when readmitted. Overall, JBVAMC had a low percentage of patients readmitted for HF within 30 days, but there is still room for improvement in reducing HF readmissions.

At the time of discharge, all JBVAMC patients receive printed instructions and recommendations for their care after hospitalization. The patient handout includes the most current medications, diet/weight/medication instructions, and actual or suggested dates for follow-up appointments and/or tests. It may enhance awareness regarding dietician services to patients if the current discharge instruction template can be modified to provide information regarding the outpatient dietitian class. This could include date, time, and location of classes as well as dietician contact information. (See Appendixes 1 and 2.)

When these recommendations have been implemented, further studies will be warranted to assess the impact of the interventions. 

Acknowledgments
The authors thank Ms. Yvette Bloodson for her assistance in generating the initial patient list.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Although the elevated risks and rates of veterans’ substance abuse patterns are well documented, little has been written about veterans’ use of designer drugs.^1-6 In recent months throughout Europe and the U.S., there has been a flurry of media attention for 2 classes of designer drugs: synthetic cathinones and synthetic cannabinoids.^7,8 In the U.S., the popularity of these drugs has surged, and a disproportionate amount of use of these 2 drug classes is coming from locations near military instillations.^9,10

The purpose of this article is to raise awareness regarding these 2 burgeoning designer drug classes and their impact on veterans. Designer drugs affecting vulnerable populations are not a new phenomenon, yet many providers are unfamiliar with the effects of these unique drugs of abuse on their veteran populations.^11-13

Many designer drugs begin their existence as variations of other addictive or psychoactive drugs. Others begin in laboratories as investigative research compounds that end up on the street, often promising a novel mind-altering experience as a “legal high.”^14-18 The Designer Drug Enforcement Act of 1986 was an initial attempt in the U.S. to define and control the early rise of copycat drugs that appeared on the streets and mimicked the effects of other illicit substances. More recent legislation enacted in the U.S. has imposed Schedule I controls on the manufacture, distribution, possession, importation, and exportation of these types of drugs, including both synthetic cathinones and synthetic cannabinoids. State laws are perennially in flux trying to keep up with the latest drug trends.^19-21

Similar efforts have been made by the European Union to control mephedrone, a synthetic cathinone, citing multiple fatalities, seizures, related crime, lack of medical use, and risk of dependence.²² Although uniform levels of control do not exist in Europe for synthetic cannabinoids, many countries have independently acted to limit their use.²³

In its recent World Drug Report 2013, the United Nations Office on Drugs and Crime documents its growing concern about the “new psychoactive substances” category of illicit recreational substances (in which synthetic cannabinoids and cathinones are included) that has increased by 50% since 2009.²⁴ Alone, this category now outnumbers the total number of substances controlled by international drug conventions.

The novelty and variability of designer drugs causes difficulties with detection and regulation. Innovative chemists can legally manufacture new versions of known molecules intended for illicit use with a rapidity that outpaces bureaucratic control. Local law enforcement officials may be unaware of the latest designer drug trends, stifling efforts at public education or restriction. Designer drugs are often deceptively packaged and are available in convenience stores, tobacco outlets, gas stations, pawnshops, tattoo parlors, and truck stops.^25-28 The Internet may be the singular reason, however, that designer drugs continue to be widely available to veterans.^11,18

Innumerable websites discuss, promote, and sell designer drugs or deceitfully market them as safe, legitimate household products (“not for human consumption”), which can be ordered online and shipped by commercial carriers.¹² Little accurate information is known about their effects or about the specific compounds they contain. When the recreational nature of the drugs is actually acknowledged, information on how the buyer can evade prosecution is often provided in tandem. The suppliers’ inventory of the drugs has been shown to be variable and inconsistent, and the product ingredients can be similarly unpredictable despite comparatively more stable naming and labeling.^14,29

In the clinical setting, a reliable patient drug history may not be available. This ensures that the diagnosis of designer drug use will be an exclusionary process involving routine laboratory work, physical examination, and at times electroencephalogram and/or neuroimaging. Psychiatric consultation is often useful in this setting. Routine immunoassay tests do not detect either synthetic cathinones or synthetic cannabinoids.³⁰

Both cannabinoids and cathinones can be identified using gas chromatography-mass spectroscopy (GC-MS) or liquid chromatography-mass spectroscopy (LC-MS). However, this technology is limited to specialized laboratories.^31,32 The laboratory results often are not immediately available, potentially limiting the tests’ use in emergency or inpatient settings, as the patient may have left the hospital by the time the results are available. Additionally, these drugs’ prevalence of use, while increasing, often does not justify the cost of these tests.

The inability to routinely detect metabolites in urine may increase the enticement of these drugs given the likelihood that active-duty personnel could use them surreptitiously. Further, these compounds are evolving and seemingly limitless in their variability, and there is often a paucity of pure reference materials. As such, it is impossible to guarantee reliable test results.

The following profiles of each of these drug classes will be accompanied by clinical cases depicting the drugs’ effects and how an affected veteran might present clinically. The severe effects of these novel agents illustrate the value in maintaining a functional knowledge base about emerging drug trends. The accuracy of diagnosis as well as the outcome of a veteran’s treatment may depend on the provider’s ability to identify the presence of a drug and manage its effects.

Synthetic Cathinones

Mr. H is a 28-year-old Iraq War veteran with a history of posttraumatic stress disorder (PTSD), alcohol abuse, and opioid dependence who presented for inpatient psychiatric admission after making suicidal statements to his wife in the context of 2 weeks of “bath salts” use. A family member initially introduced him to the drug. His first drug purchase had been 1 gram ($30) at a local movie rental store.

After discharge from the hospital, Mr. H began purchasing increasing amounts online with a credit card. Although he initially had been insufflating and inhaling the substance, he later began injecting it (dissolving it in tap water and loading it through a cotton filter in a syringe). The patient admitted to finding the drug significantly more addictive than any others he had used, and his use resulted in leaving his job and abandoning his family.

Severe cravings and depression were present between episodes of use. He spent $40,000 over 6 months of use. Insomnia lasted for several days, his appearance changed dramatically (including persistent skin infections), and he became paranoid, believing that everyone around him was an undercover police officer. He remained on medications for persistent anxiety. His daily drug cravings continued,
although he remained uncertain about the actual ingredients of bath salts.

Cathinone is a naturally occurring stimulant from the khat plant (Catha edulis), which grows indigenously in Egypt and on the Arabian Peninsula. The recreational and religious use of this plant has occurred for thousands of years, though it is not without risk: The chewing of the leaves containing natural cathinones has been associated with esophagitis, gastritis, oral keratosis, myocardial infarction, dilated cardiomyopathy, hypertension, cerebral ischemia, thromboembolism, diabetes, sexual dysfunction, duodenal ulcer, and hepatitis.^33,34

The stimulants known colloquially as bath salts are synthetic cathinones, which have become more widely available within the past 10 years: first in the Middle East, then Europe, and now in the U.S.^{5,9,10,14,19,25,35-41,44} Although the current rise in use has occurred in the past few years, the first documented abuse of synthetic cathinones in the U.S. dates to the early 1990s in Michigan.⁴²

Bath salts is the most common of the many names used to denote synthetic cathinones. The compounds have no utility when used as such but often are marketed as research chemicals, plant fertilizer, or shoe polish. It is this deliberate counterfeit of household product names that allows many distributors to avoid classifying the compounds according to the true, intended use. More appealing brand names may also be used to entice the user (Table 1).²⁵

Synthetic cathinones owe their popularity to similarities with cocaine and methamphetamine. They are sympathomimetic with synaptic increases of monoamines after use: Surges in norepinephrine and dopamine account for the stimulant qualities, and serotonergic changes mediate distinct psychoactive effects (Table 2).⁴⁰ Users are interested in the drugs for many of the same reasons that other recreational stimulants have appeal: euphoria, energy, empathy, heightened sexuality, sociability, and an overall intensification of senses. Synthetic cathinones have become preferred to cocaine for some users.⁴³

The drugs can be used via oral and anal routes. Using methods known as “bombing” or “keystering,” users deliver boluses of the powder wrapped in cigarette paper, which they swallow or insert into the rectum. Insufflation and IV injection are also common methods of administration with a quicker onset of action expected.⁴⁰ The prices of the drugs range from $25 to $50 per 500-mg packet (though the cost is increasing with more regulation). Users typically use 500 mg to 2 g in one session.

The 2 most commonly abused synthetic cathinones are mephedrone and MDPV (methylenedioxypyrovalerone). There is some regional variability about which ingredient is present; mephedrone tends to be more prevalent in Europe, whereas MDPV is noted to be more common in the U.S.^10,44

When ordering a laboratory test to evaluate for the presence of these drugs, a specific request should be given to the technicians to look for signals of MDPV (most common metabolite is dimethylenyl-methyl-MDPV), mephedrone (4-methylmethcathinone), 3-bromomethcathinone (3-BMC), or 3-fluoromethcathinone (fluphedrone).^45-48 The study testing (both in VA and civilian settings) for Mr. H was done by a commercial laboratory several states away where patented techniques can screen for more than 30 compounds via LC-MS. The laboratory offered bath salts panels for urine, serum/plasma, and blood samples.

Synthetic cathinones are dangerous, and as the body of medical literature continues to expand, reports of significant morbidity and death related to their use are appearing. The harmful effects of recreational synthetic cathinone use has been documented across the globe in the form of serotonin syndrome, intoxication delirium, hyperthermia and multi-organ failure, myocarditis, hypo-osmotic hyponatremia with encephalopathy, agitation, psychosis, and death after cardiac arrest.^{5,12,38,39,49-53} Published treatment methods are largely supportive with the available literature, suggesting that benzodiazepines, antipsychotics (both typical and atypical), restraints to maintain safety, and IV fluids may be indicated.^5,9,50

Synthetic Cannabinoids

Mr. W is a 58-year-old veteran with a history of alcohol dependence and PTSD who reported use of the synthetic cannabinoid “Spice” during intake assessment for treatment of alcohol dependence. He reported using Spice about 4 times over a 2-month period. He purchased a small jar of the substance from a party store for $15 per gram and understood its contents to be synthetic marijuana, which he appreciated for its low cost and assumed legality. He denied having any understanding of the package’s contents beyond “synthetic marijuana.”

The patient ingested the drug by smoking and inhaling from a pipe. For the first 3 times that he used the substance, Mr. W reported feeling a pleasant sensation that started quickly and lasted about 30 minutes. The fourth time that he used synthetic cannabis he felt nauseated and vomited several times, had auditory hallucinations, and increased anxiety; he also reported a hangover effect after this use. He identified that the effects may have been different the fourth time “because the brands were changing.”

Mr. W also reported that his neighbor—a daily user of synthetic cannabinoids for several months—became paranoid, suspicious, and developed incomprehensible speech. His neighbor’s symptoms and his own unpleasant experiences prompted a discontinuation of use.

Synthetic cannabinoids are a diverse group of agents numbering in excess of 100 artificial compounds that act as agonists at cannabinoid receptors, mimicking the effects of tetrahydrocannabinol (THC), an active ingredient in marijuana.^28,54 The availability of these drugs online and in specialty shops has been documented since the mid-2000s.^27,28,32 Their packaging often describes the contents as incense or herbal blends, using various names. Spice is a common name, but these products are also known by a myriad of other designations (Table 1).²⁸ A single packet usually contains several grams of the drug and costs about $30.⁵⁵

To the user, who may already be familiar with marijuana, the contents intentionally appear similar to the dried buds of cannabis.^30,56 In reality, the drug has just been sprayed onto inert plant material.⁵⁷ The drug is smoked, and the psychoactive dose can be as little as 1 mg.³⁰ Users describe potent drug effects (Table 2). There is a rapid onset of action, and duration of effects last 1 to 2 hours.⁵⁸

The compounds’ mechanism of action and appeal are derived from their high affinity for the cannabinoid receptors. The CB1 receptor is located primarily in the central nervous system and is responsible for the psychoactive component of the drugs’ actions.^27,30,58,59 Two particular synthetic cannabinoids, cannibicyclohexanol and JWH-018, are potent cannabinoid CB1 agonists with affinity exceeding their natural counterparts.^{27,30, 32,56,58,59}

Chemically, these drugs are varied. The largest structural family of these compounds is the JWH group, which includes JWH-018.⁶⁰ Also common are CP 47,497 and other CP compounds.⁵⁸ HU compounds, such as HU-210, have also been identified and have been shown to be 100 to 800 times more potent at the CB1 and CB2 receptors than is THC.^60,61 A final group includes the benzoylindoles, such as AM-964 and RCS-4, which also bind strongly to CB1 and CB2.^60,62

Constitutional symptoms of synthetic cannabinoid intoxication include disorientation, anxiety, tremulousness, palpitations, tachycardia, agitation, injected conjunctivae, hyperreflexia, nausea, vomiting, lateral gaze nystagmus, and myoclonic jerks, which have been mistaken for seizure activity.^27,30,55 Pupils are often normal sized.⁵⁵ Withdrawal phenomena are similar to those of cannabis withdrawal: irritability, anxiety, tremor, palpitations, diaphoresis, insomnia, headache, diarrhea, nausea, and vomiting.⁵⁹

Given the established link between cannabis use and psychosis, synthetic cannabinoids may stand as a precipitant of psychotic symptoms, which may include visual hallucinations, auditory hallucinations, disorganized speech, paranoia, grandiose delusions, disorganization, or bizarre behavior.^58,63-66 These symptoms may represent a relapse of a primary thought disorder or, for some unfortunate individuals, a de novo psychotic illness.^58,65,66 Symptoms can linger for months after drug use.⁶⁵

A key risk in the use of synthetic cannabinoid moieties may involve the absence of cannabidiol. Cannabidiol naturally occurs in many strains of cannabis and is thought to have antipsychotic, neuroprotective properties.⁶⁷ The absence of this molecule in synthetic cannabinoids may at least partially explain their severe psychoactive effects. Treatment for synthetic cannabinoid intoxication and related psychosis is largely supportive and may include the use of antipsychotic medication.⁶⁶

Detection of synthetic cannabinoids in urine is difficult, yet many compounds can be detected via GC-MS or LC-MS. Molecules of significance include JWH-018, JWH-073, JWH-015, JWH-250, CP-47 497, HU-210, cannabicyclohexanol, and oleamide; however, these compounds are rarely excreted in urine in their pure form. The many hydroxylated or dealkylated metabolites of these compounds, mostly unnamed, are more consistently detected in urine.^68,69 One author has noted that the pentanoic acid metabolite of JWH-018 seems to appear most reliably in urine specimens.⁶⁸

Many synthetic cannabinoid herbal mixes also contain a detectable compound called tocopherol, seemingly added as an antioxidant.^69,70 Synthetic cannabinoids are an evolving drug class, and reliable detection will require that laboratories stay up-to-date in their detection methods. As stated earlier, a commercial laboratory in the region accepted the civilian and veteran patient samples for these case studies. The synthetic cannabinoid panels offered evaluation of the drug itself (GC-MS), an oral fluid screen (LC-MS), and isolation of metabolites in urine (enzyme-linked immunosorbent assay).

Conclusion

Designer drugs will remain a challenge for providers caring for veterans for several key reasons: (1) Veterans are a vulnerable population who abuse substances at higher rates than do their civilian counterparts; (2) Chemists are able to manufacture variations of known habit-forming substances; (3) Modern technology facilitates the purchase and wide distribution of addictive substances; (4) Many designer drugs are deceptively packaged and marketed; (5) The effects of the drugs are often severe; (6) No standardized treatment guidelines exist; and (7) Detection of the drugs is difficult, and new versions of the molecules may evade even cutting-edge techniques.

Due to the high cost of detecting synthetic cathinones and synthetic cannabinoids in body fluids, screening should be considered only in settings where severe symptoms are accompanied by reasonable clinical suspicion of use and an otherwise negative toxicologic workup. As more designer drugs inevitably emerge, research will be needed on their pharmacology, toxidromes, and detection. Military and civilian practitioners must remain abreast of the dynamic trends in designer drugs to ensure that their patients receive the highest level of medical care.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.  

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Although the elevated risks and rates of veterans’ substance abuse patterns are well documented, little has been written about veterans’ use of designer drugs.^1-6 In recent months throughout Europe and the U.S., there has been a flurry of media attention for 2 classes of designer drugs: synthetic cathinones and synthetic cannabinoids.^7,8 In the U.S., the popularity of these drugs has surged, and a disproportionate amount of use of these 2 drug classes is coming from locations near military instillations.^9,10

The purpose of this article is to raise awareness regarding these 2 burgeoning designer drug classes and their impact on veterans. Designer drugs affecting vulnerable populations are not a new phenomenon, yet many providers are unfamiliar with the effects of these unique drugs of abuse on their veteran populations.^11-13

Many designer drugs begin their existence as variations of other addictive or psychoactive drugs. Others begin in laboratories as investigative research compounds that end up on the street, often promising a novel mind-altering experience as a “legal high.”^14-18 The Designer Drug Enforcement Act of 1986 was an initial attempt in the U.S. to define and control the early rise of copycat drugs that appeared on the streets and mimicked the effects of other illicit substances. More recent legislation enacted in the U.S. has imposed Schedule I controls on the manufacture, distribution, possession, importation, and exportation of these types of drugs, including both synthetic cathinones and synthetic cannabinoids. State laws are perennially in flux trying to keep up with the latest drug trends.^19-21

Similar efforts have been made by the European Union to control mephedrone, a synthetic cathinone, citing multiple fatalities, seizures, related crime, lack of medical use, and risk of dependence.²² Although uniform levels of control do not exist in Europe for synthetic cannabinoids, many countries have independently acted to limit their use.²³

In its recent World Drug Report 2013, the United Nations Office on Drugs and Crime documents its growing concern about the “new psychoactive substances” category of illicit recreational substances (in which synthetic cannabinoids and cathinones are included) that has increased by 50% since 2009.²⁴ Alone, this category now outnumbers the total number of substances controlled by international drug conventions.

The novelty and variability of designer drugs causes difficulties with detection and regulation. Innovative chemists can legally manufacture new versions of known molecules intended for illicit use with a rapidity that outpaces bureaucratic control. Local law enforcement officials may be unaware of the latest designer drug trends, stifling efforts at public education or restriction. Designer drugs are often deceptively packaged and are available in convenience stores, tobacco outlets, gas stations, pawnshops, tattoo parlors, and truck stops.^25-28 The Internet may be the singular reason, however, that designer drugs continue to be widely available to veterans.^11,18

Innumerable websites discuss, promote, and sell designer drugs or deceitfully market them as safe, legitimate household products (“not for human consumption”), which can be ordered online and shipped by commercial carriers.¹² Little accurate information is known about their effects or about the specific compounds they contain. When the recreational nature of the drugs is actually acknowledged, information on how the buyer can evade prosecution is often provided in tandem. The suppliers’ inventory of the drugs has been shown to be variable and inconsistent, and the product ingredients can be similarly unpredictable despite comparatively more stable naming and labeling.^14,29

In the clinical setting, a reliable patient drug history may not be available. This ensures that the diagnosis of designer drug use will be an exclusionary process involving routine laboratory work, physical examination, and at times electroencephalogram and/or neuroimaging. Psychiatric consultation is often useful in this setting. Routine immunoassay tests do not detect either synthetic cathinones or synthetic cannabinoids.³⁰

Both cannabinoids and cathinones can be identified using gas chromatography-mass spectroscopy (GC-MS) or liquid chromatography-mass spectroscopy (LC-MS). However, this technology is limited to specialized laboratories.^31,32 The laboratory results often are not immediately available, potentially limiting the tests’ use in emergency or inpatient settings, as the patient may have left the hospital by the time the results are available. Additionally, these drugs’ prevalence of use, while increasing, often does not justify the cost of these tests.

The inability to routinely detect metabolites in urine may increase the enticement of these drugs given the likelihood that active-duty personnel could use them surreptitiously. Further, these compounds are evolving and seemingly limitless in their variability, and there is often a paucity of pure reference materials. As such, it is impossible to guarantee reliable test results.

The following profiles of each of these drug classes will be accompanied by clinical cases depicting the drugs’ effects and how an affected veteran might present clinically. The severe effects of these novel agents illustrate the value in maintaining a functional knowledge base about emerging drug trends. The accuracy of diagnosis as well as the outcome of a veteran’s treatment may depend on the provider’s ability to identify the presence of a drug and manage its effects.

Synthetic Cathinones

Mr. H is a 28-year-old Iraq War veteran with a history of posttraumatic stress disorder (PTSD), alcohol abuse, and opioid dependence who presented for inpatient psychiatric admission after making suicidal statements to his wife in the context of 2 weeks of “bath salts” use. A family member initially introduced him to the drug. His first drug purchase had been 1 gram ($30) at a local movie rental store.

After discharge from the hospital, Mr. H began purchasing increasing amounts online with a credit card. Although he initially had been insufflating and inhaling the substance, he later began injecting it (dissolving it in tap water and loading it through a cotton filter in a syringe). The patient admitted to finding the drug significantly more addictive than any others he had used, and his use resulted in leaving his job and abandoning his family.

Severe cravings and depression were present between episodes of use. He spent $40,000 over 6 months of use. Insomnia lasted for several days, his appearance changed dramatically (including persistent skin infections), and he became paranoid, believing that everyone around him was an undercover police officer. He remained on medications for persistent anxiety. His daily drug cravings continued,
although he remained uncertain about the actual ingredients of bath salts.

Cathinone is a naturally occurring stimulant from the khat plant (Catha edulis), which grows indigenously in Egypt and on the Arabian Peninsula. The recreational and religious use of this plant has occurred for thousands of years, though it is not without risk: The chewing of the leaves containing natural cathinones has been associated with esophagitis, gastritis, oral keratosis, myocardial infarction, dilated cardiomyopathy, hypertension, cerebral ischemia, thromboembolism, diabetes, sexual dysfunction, duodenal ulcer, and hepatitis.^33,34

The stimulants known colloquially as bath salts are synthetic cathinones, which have become more widely available within the past 10 years: first in the Middle East, then Europe, and now in the U.S.^{5,9,10,14,19,25,35-41,44} Although the current rise in use has occurred in the past few years, the first documented abuse of synthetic cathinones in the U.S. dates to the early 1990s in Michigan.⁴²

Bath salts is the most common of the many names used to denote synthetic cathinones. The compounds have no utility when used as such but often are marketed as research chemicals, plant fertilizer, or shoe polish. It is this deliberate counterfeit of household product names that allows many distributors to avoid classifying the compounds according to the true, intended use. More appealing brand names may also be used to entice the user (Table 1).²⁵

Synthetic cathinones owe their popularity to similarities with cocaine and methamphetamine. They are sympathomimetic with synaptic increases of monoamines after use: Surges in norepinephrine and dopamine account for the stimulant qualities, and serotonergic changes mediate distinct psychoactive effects (Table 2).⁴⁰ Users are interested in the drugs for many of the same reasons that other recreational stimulants have appeal: euphoria, energy, empathy, heightened sexuality, sociability, and an overall intensification of senses. Synthetic cathinones have become preferred to cocaine for some users.⁴³

The drugs can be used via oral and anal routes. Using methods known as “bombing” or “keystering,” users deliver boluses of the powder wrapped in cigarette paper, which they swallow or insert into the rectum. Insufflation and IV injection are also common methods of administration with a quicker onset of action expected.⁴⁰ The prices of the drugs range from $25 to $50 per 500-mg packet (though the cost is increasing with more regulation). Users typically use 500 mg to 2 g in one session.

The 2 most commonly abused synthetic cathinones are mephedrone and MDPV (methylenedioxypyrovalerone). There is some regional variability about which ingredient is present; mephedrone tends to be more prevalent in Europe, whereas MDPV is noted to be more common in the U.S.^10,44

When ordering a laboratory test to evaluate for the presence of these drugs, a specific request should be given to the technicians to look for signals of MDPV (most common metabolite is dimethylenyl-methyl-MDPV), mephedrone (4-methylmethcathinone), 3-bromomethcathinone (3-BMC), or 3-fluoromethcathinone (fluphedrone).^45-48 The study testing (both in VA and civilian settings) for Mr. H was done by a commercial laboratory several states away where patented techniques can screen for more than 30 compounds via LC-MS. The laboratory offered bath salts panels for urine, serum/plasma, and blood samples.

Synthetic cathinones are dangerous, and as the body of medical literature continues to expand, reports of significant morbidity and death related to their use are appearing. The harmful effects of recreational synthetic cathinone use has been documented across the globe in the form of serotonin syndrome, intoxication delirium, hyperthermia and multi-organ failure, myocarditis, hypo-osmotic hyponatremia with encephalopathy, agitation, psychosis, and death after cardiac arrest.^{5,12,38,39,49-53} Published treatment methods are largely supportive with the available literature, suggesting that benzodiazepines, antipsychotics (both typical and atypical), restraints to maintain safety, and IV fluids may be indicated.^5,9,50

Synthetic Cannabinoids

Mr. W is a 58-year-old veteran with a history of alcohol dependence and PTSD who reported use of the synthetic cannabinoid “Spice” during intake assessment for treatment of alcohol dependence. He reported using Spice about 4 times over a 2-month period. He purchased a small jar of the substance from a party store for $15 per gram and understood its contents to be synthetic marijuana, which he appreciated for its low cost and assumed legality. He denied having any understanding of the package’s contents beyond “synthetic marijuana.”

The patient ingested the drug by smoking and inhaling from a pipe. For the first 3 times that he used the substance, Mr. W reported feeling a pleasant sensation that started quickly and lasted about 30 minutes. The fourth time that he used synthetic cannabis he felt nauseated and vomited several times, had auditory hallucinations, and increased anxiety; he also reported a hangover effect after this use. He identified that the effects may have been different the fourth time “because the brands were changing.”

Mr. W also reported that his neighbor—a daily user of synthetic cannabinoids for several months—became paranoid, suspicious, and developed incomprehensible speech. His neighbor’s symptoms and his own unpleasant experiences prompted a discontinuation of use.

Synthetic cannabinoids are a diverse group of agents numbering in excess of 100 artificial compounds that act as agonists at cannabinoid receptors, mimicking the effects of tetrahydrocannabinol (THC), an active ingredient in marijuana.^28,54 The availability of these drugs online and in specialty shops has been documented since the mid-2000s.^27,28,32 Their packaging often describes the contents as incense or herbal blends, using various names. Spice is a common name, but these products are also known by a myriad of other designations (Table 1).²⁸ A single packet usually contains several grams of the drug and costs about $30.⁵⁵

To the user, who may already be familiar with marijuana, the contents intentionally appear similar to the dried buds of cannabis.^30,56 In reality, the drug has just been sprayed onto inert plant material.⁵⁷ The drug is smoked, and the psychoactive dose can be as little as 1 mg.³⁰ Users describe potent drug effects (Table 2). There is a rapid onset of action, and duration of effects last 1 to 2 hours.⁵⁸

The compounds’ mechanism of action and appeal are derived from their high affinity for the cannabinoid receptors. The CB1 receptor is located primarily in the central nervous system and is responsible for the psychoactive component of the drugs’ actions.^27,30,58,59 Two particular synthetic cannabinoids, cannibicyclohexanol and JWH-018, are potent cannabinoid CB1 agonists with affinity exceeding their natural counterparts.^{27,30, 32,56,58,59}

Chemically, these drugs are varied. The largest structural family of these compounds is the JWH group, which includes JWH-018.⁶⁰ Also common are CP 47,497 and other CP compounds.⁵⁸ HU compounds, such as HU-210, have also been identified and have been shown to be 100 to 800 times more potent at the CB1 and CB2 receptors than is THC.^60,61 A final group includes the benzoylindoles, such as AM-964 and RCS-4, which also bind strongly to CB1 and CB2.^60,62

Constitutional symptoms of synthetic cannabinoid intoxication include disorientation, anxiety, tremulousness, palpitations, tachycardia, agitation, injected conjunctivae, hyperreflexia, nausea, vomiting, lateral gaze nystagmus, and myoclonic jerks, which have been mistaken for seizure activity.^27,30,55 Pupils are often normal sized.⁵⁵ Withdrawal phenomena are similar to those of cannabis withdrawal: irritability, anxiety, tremor, palpitations, diaphoresis, insomnia, headache, diarrhea, nausea, and vomiting.⁵⁹

Given the established link between cannabis use and psychosis, synthetic cannabinoids may stand as a precipitant of psychotic symptoms, which may include visual hallucinations, auditory hallucinations, disorganized speech, paranoia, grandiose delusions, disorganization, or bizarre behavior.^58,63-66 These symptoms may represent a relapse of a primary thought disorder or, for some unfortunate individuals, a de novo psychotic illness.^58,65,66 Symptoms can linger for months after drug use.⁶⁵

A key risk in the use of synthetic cannabinoid moieties may involve the absence of cannabidiol. Cannabidiol naturally occurs in many strains of cannabis and is thought to have antipsychotic, neuroprotective properties.⁶⁷ The absence of this molecule in synthetic cannabinoids may at least partially explain their severe psychoactive effects. Treatment for synthetic cannabinoid intoxication and related psychosis is largely supportive and may include the use of antipsychotic medication.⁶⁶

Detection of synthetic cannabinoids in urine is difficult, yet many compounds can be detected via GC-MS or LC-MS. Molecules of significance include JWH-018, JWH-073, JWH-015, JWH-250, CP-47 497, HU-210, cannabicyclohexanol, and oleamide; however, these compounds are rarely excreted in urine in their pure form. The many hydroxylated or dealkylated metabolites of these compounds, mostly unnamed, are more consistently detected in urine.^68,69 One author has noted that the pentanoic acid metabolite of JWH-018 seems to appear most reliably in urine specimens.⁶⁸

Many synthetic cannabinoid herbal mixes also contain a detectable compound called tocopherol, seemingly added as an antioxidant.^69,70 Synthetic cannabinoids are an evolving drug class, and reliable detection will require that laboratories stay up-to-date in their detection methods. As stated earlier, a commercial laboratory in the region accepted the civilian and veteran patient samples for these case studies. The synthetic cannabinoid panels offered evaluation of the drug itself (GC-MS), an oral fluid screen (LC-MS), and isolation of metabolites in urine (enzyme-linked immunosorbent assay).

Conclusion

Designer drugs will remain a challenge for providers caring for veterans for several key reasons: (1) Veterans are a vulnerable population who abuse substances at higher rates than do their civilian counterparts; (2) Chemists are able to manufacture variations of known habit-forming substances; (3) Modern technology facilitates the purchase and wide distribution of addictive substances; (4) Many designer drugs are deceptively packaged and marketed; (5) The effects of the drugs are often severe; (6) No standardized treatment guidelines exist; and (7) Detection of the drugs is difficult, and new versions of the molecules may evade even cutting-edge techniques.

Due to the high cost of detecting synthetic cathinones and synthetic cannabinoids in body fluids, screening should be considered only in settings where severe symptoms are accompanied by reasonable clinical suspicion of use and an otherwise negative toxicologic workup. As more designer drugs inevitably emerge, research will be needed on their pharmacology, toxidromes, and detection. Military and civilian practitioners must remain abreast of the dynamic trends in designer drugs to ensure that their patients receive the highest level of medical care.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.  

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Although the elevated risks and rates of veterans’ substance abuse patterns are well documented, little has been written about veterans’ use of designer drugs.^1-6 In recent months throughout Europe and the U.S., there has been a flurry of media attention for 2 classes of designer drugs: synthetic cathinones and synthetic cannabinoids.^7,8 In the U.S., the popularity of these drugs has surged, and a disproportionate amount of use of these 2 drug classes is coming from locations near military instillations.^9,10

The purpose of this article is to raise awareness regarding these 2 burgeoning designer drug classes and their impact on veterans. Designer drugs affecting vulnerable populations are not a new phenomenon, yet many providers are unfamiliar with the effects of these unique drugs of abuse on their veteran populations.^11-13

Many designer drugs begin their existence as variations of other addictive or psychoactive drugs. Others begin in laboratories as investigative research compounds that end up on the street, often promising a novel mind-altering experience as a “legal high.”^14-18 The Designer Drug Enforcement Act of 1986 was an initial attempt in the U.S. to define and control the early rise of copycat drugs that appeared on the streets and mimicked the effects of other illicit substances. More recent legislation enacted in the U.S. has imposed Schedule I controls on the manufacture, distribution, possession, importation, and exportation of these types of drugs, including both synthetic cathinones and synthetic cannabinoids. State laws are perennially in flux trying to keep up with the latest drug trends.^19-21

Similar efforts have been made by the European Union to control mephedrone, a synthetic cathinone, citing multiple fatalities, seizures, related crime, lack of medical use, and risk of dependence.²² Although uniform levels of control do not exist in Europe for synthetic cannabinoids, many countries have independently acted to limit their use.²³

In its recent World Drug Report 2013, the United Nations Office on Drugs and Crime documents its growing concern about the “new psychoactive substances” category of illicit recreational substances (in which synthetic cannabinoids and cathinones are included) that has increased by 50% since 2009.²⁴ Alone, this category now outnumbers the total number of substances controlled by international drug conventions.

The novelty and variability of designer drugs causes difficulties with detection and regulation. Innovative chemists can legally manufacture new versions of known molecules intended for illicit use with a rapidity that outpaces bureaucratic control. Local law enforcement officials may be unaware of the latest designer drug trends, stifling efforts at public education or restriction. Designer drugs are often deceptively packaged and are available in convenience stores, tobacco outlets, gas stations, pawnshops, tattoo parlors, and truck stops.^25-28 The Internet may be the singular reason, however, that designer drugs continue to be widely available to veterans.^11,18

Innumerable websites discuss, promote, and sell designer drugs or deceitfully market them as safe, legitimate household products (“not for human consumption”), which can be ordered online and shipped by commercial carriers.¹² Little accurate information is known about their effects or about the specific compounds they contain. When the recreational nature of the drugs is actually acknowledged, information on how the buyer can evade prosecution is often provided in tandem. The suppliers’ inventory of the drugs has been shown to be variable and inconsistent, and the product ingredients can be similarly unpredictable despite comparatively more stable naming and labeling.^14,29

In the clinical setting, a reliable patient drug history may not be available. This ensures that the diagnosis of designer drug use will be an exclusionary process involving routine laboratory work, physical examination, and at times electroencephalogram and/or neuroimaging. Psychiatric consultation is often useful in this setting. Routine immunoassay tests do not detect either synthetic cathinones or synthetic cannabinoids.³⁰

Both cannabinoids and cathinones can be identified using gas chromatography-mass spectroscopy (GC-MS) or liquid chromatography-mass spectroscopy (LC-MS). However, this technology is limited to specialized laboratories.^31,32 The laboratory results often are not immediately available, potentially limiting the tests’ use in emergency or inpatient settings, as the patient may have left the hospital by the time the results are available. Additionally, these drugs’ prevalence of use, while increasing, often does not justify the cost of these tests.

The inability to routinely detect metabolites in urine may increase the enticement of these drugs given the likelihood that active-duty personnel could use them surreptitiously. Further, these compounds are evolving and seemingly limitless in their variability, and there is often a paucity of pure reference materials. As such, it is impossible to guarantee reliable test results.

The following profiles of each of these drug classes will be accompanied by clinical cases depicting the drugs’ effects and how an affected veteran might present clinically. The severe effects of these novel agents illustrate the value in maintaining a functional knowledge base about emerging drug trends. The accuracy of diagnosis as well as the outcome of a veteran’s treatment may depend on the provider’s ability to identify the presence of a drug and manage its effects.

Synthetic Cathinones

Mr. H is a 28-year-old Iraq War veteran with a history of posttraumatic stress disorder (PTSD), alcohol abuse, and opioid dependence who presented for inpatient psychiatric admission after making suicidal statements to his wife in the context of 2 weeks of “bath salts” use. A family member initially introduced him to the drug. His first drug purchase had been 1 gram ($30) at a local movie rental store.

After discharge from the hospital, Mr. H began purchasing increasing amounts online with a credit card. Although he initially had been insufflating and inhaling the substance, he later began injecting it (dissolving it in tap water and loading it through a cotton filter in a syringe). The patient admitted to finding the drug significantly more addictive than any others he had used, and his use resulted in leaving his job and abandoning his family.

Severe cravings and depression were present between episodes of use. He spent $40,000 over 6 months of use. Insomnia lasted for several days, his appearance changed dramatically (including persistent skin infections), and he became paranoid, believing that everyone around him was an undercover police officer. He remained on medications for persistent anxiety. His daily drug cravings continued,
although he remained uncertain about the actual ingredients of bath salts.

Cathinone is a naturally occurring stimulant from the khat plant (Catha edulis), which grows indigenously in Egypt and on the Arabian Peninsula. The recreational and religious use of this plant has occurred for thousands of years, though it is not without risk: The chewing of the leaves containing natural cathinones has been associated with esophagitis, gastritis, oral keratosis, myocardial infarction, dilated cardiomyopathy, hypertension, cerebral ischemia, thromboembolism, diabetes, sexual dysfunction, duodenal ulcer, and hepatitis.^33,34

The stimulants known colloquially as bath salts are synthetic cathinones, which have become more widely available within the past 10 years: first in the Middle East, then Europe, and now in the U.S.^{5,9,10,14,19,25,35-41,44} Although the current rise in use has occurred in the past few years, the first documented abuse of synthetic cathinones in the U.S. dates to the early 1990s in Michigan.⁴²

Bath salts is the most common of the many names used to denote synthetic cathinones. The compounds have no utility when used as such but often are marketed as research chemicals, plant fertilizer, or shoe polish. It is this deliberate counterfeit of household product names that allows many distributors to avoid classifying the compounds according to the true, intended use. More appealing brand names may also be used to entice the user (Table 1).²⁵

Synthetic cathinones owe their popularity to similarities with cocaine and methamphetamine. They are sympathomimetic with synaptic increases of monoamines after use: Surges in norepinephrine and dopamine account for the stimulant qualities, and serotonergic changes mediate distinct psychoactive effects (Table 2).⁴⁰ Users are interested in the drugs for many of the same reasons that other recreational stimulants have appeal: euphoria, energy, empathy, heightened sexuality, sociability, and an overall intensification of senses. Synthetic cathinones have become preferred to cocaine for some users.⁴³

The drugs can be used via oral and anal routes. Using methods known as “bombing” or “keystering,” users deliver boluses of the powder wrapped in cigarette paper, which they swallow or insert into the rectum. Insufflation and IV injection are also common methods of administration with a quicker onset of action expected.⁴⁰ The prices of the drugs range from $25 to $50 per 500-mg packet (though the cost is increasing with more regulation). Users typically use 500 mg to 2 g in one session.

The 2 most commonly abused synthetic cathinones are mephedrone and MDPV (methylenedioxypyrovalerone). There is some regional variability about which ingredient is present; mephedrone tends to be more prevalent in Europe, whereas MDPV is noted to be more common in the U.S.^10,44

When ordering a laboratory test to evaluate for the presence of these drugs, a specific request should be given to the technicians to look for signals of MDPV (most common metabolite is dimethylenyl-methyl-MDPV), mephedrone (4-methylmethcathinone), 3-bromomethcathinone (3-BMC), or 3-fluoromethcathinone (fluphedrone).^45-48 The study testing (both in VA and civilian settings) for Mr. H was done by a commercial laboratory several states away where patented techniques can screen for more than 30 compounds via LC-MS. The laboratory offered bath salts panels for urine, serum/plasma, and blood samples.

Synthetic cathinones are dangerous, and as the body of medical literature continues to expand, reports of significant morbidity and death related to their use are appearing. The harmful effects of recreational synthetic cathinone use has been documented across the globe in the form of serotonin syndrome, intoxication delirium, hyperthermia and multi-organ failure, myocarditis, hypo-osmotic hyponatremia with encephalopathy, agitation, psychosis, and death after cardiac arrest.^{5,12,38,39,49-53} Published treatment methods are largely supportive with the available literature, suggesting that benzodiazepines, antipsychotics (both typical and atypical), restraints to maintain safety, and IV fluids may be indicated.^5,9,50

Synthetic Cannabinoids

Mr. W is a 58-year-old veteran with a history of alcohol dependence and PTSD who reported use of the synthetic cannabinoid “Spice” during intake assessment for treatment of alcohol dependence. He reported using Spice about 4 times over a 2-month period. He purchased a small jar of the substance from a party store for $15 per gram and understood its contents to be synthetic marijuana, which he appreciated for its low cost and assumed legality. He denied having any understanding of the package’s contents beyond “synthetic marijuana.”

The patient ingested the drug by smoking and inhaling from a pipe. For the first 3 times that he used the substance, Mr. W reported feeling a pleasant sensation that started quickly and lasted about 30 minutes. The fourth time that he used synthetic cannabis he felt nauseated and vomited several times, had auditory hallucinations, and increased anxiety; he also reported a hangover effect after this use. He identified that the effects may have been different the fourth time “because the brands were changing.”

Mr. W also reported that his neighbor—a daily user of synthetic cannabinoids for several months—became paranoid, suspicious, and developed incomprehensible speech. His neighbor’s symptoms and his own unpleasant experiences prompted a discontinuation of use.

Synthetic cannabinoids are a diverse group of agents numbering in excess of 100 artificial compounds that act as agonists at cannabinoid receptors, mimicking the effects of tetrahydrocannabinol (THC), an active ingredient in marijuana.^28,54 The availability of these drugs online and in specialty shops has been documented since the mid-2000s.^27,28,32 Their packaging often describes the contents as incense or herbal blends, using various names. Spice is a common name, but these products are also known by a myriad of other designations (Table 1).²⁸ A single packet usually contains several grams of the drug and costs about $30.⁵⁵

To the user, who may already be familiar with marijuana, the contents intentionally appear similar to the dried buds of cannabis.^30,56 In reality, the drug has just been sprayed onto inert plant material.⁵⁷ The drug is smoked, and the psychoactive dose can be as little as 1 mg.³⁰ Users describe potent drug effects (Table 2). There is a rapid onset of action, and duration of effects last 1 to 2 hours.⁵⁸

The compounds’ mechanism of action and appeal are derived from their high affinity for the cannabinoid receptors. The CB1 receptor is located primarily in the central nervous system and is responsible for the psychoactive component of the drugs’ actions.^27,30,58,59 Two particular synthetic cannabinoids, cannibicyclohexanol and JWH-018, are potent cannabinoid CB1 agonists with affinity exceeding their natural counterparts.^{27,30, 32,56,58,59}

Chemically, these drugs are varied. The largest structural family of these compounds is the JWH group, which includes JWH-018.⁶⁰ Also common are CP 47,497 and other CP compounds.⁵⁸ HU compounds, such as HU-210, have also been identified and have been shown to be 100 to 800 times more potent at the CB1 and CB2 receptors than is THC.^60,61 A final group includes the benzoylindoles, such as AM-964 and RCS-4, which also bind strongly to CB1 and CB2.^60,62

Constitutional symptoms of synthetic cannabinoid intoxication include disorientation, anxiety, tremulousness, palpitations, tachycardia, agitation, injected conjunctivae, hyperreflexia, nausea, vomiting, lateral gaze nystagmus, and myoclonic jerks, which have been mistaken for seizure activity.^27,30,55 Pupils are often normal sized.⁵⁵ Withdrawal phenomena are similar to those of cannabis withdrawal: irritability, anxiety, tremor, palpitations, diaphoresis, insomnia, headache, diarrhea, nausea, and vomiting.⁵⁹

Given the established link between cannabis use and psychosis, synthetic cannabinoids may stand as a precipitant of psychotic symptoms, which may include visual hallucinations, auditory hallucinations, disorganized speech, paranoia, grandiose delusions, disorganization, or bizarre behavior.^58,63-66 These symptoms may represent a relapse of a primary thought disorder or, for some unfortunate individuals, a de novo psychotic illness.^58,65,66 Symptoms can linger for months after drug use.⁶⁵

A key risk in the use of synthetic cannabinoid moieties may involve the absence of cannabidiol. Cannabidiol naturally occurs in many strains of cannabis and is thought to have antipsychotic, neuroprotective properties.⁶⁷ The absence of this molecule in synthetic cannabinoids may at least partially explain their severe psychoactive effects. Treatment for synthetic cannabinoid intoxication and related psychosis is largely supportive and may include the use of antipsychotic medication.⁶⁶

Detection of synthetic cannabinoids in urine is difficult, yet many compounds can be detected via GC-MS or LC-MS. Molecules of significance include JWH-018, JWH-073, JWH-015, JWH-250, CP-47 497, HU-210, cannabicyclohexanol, and oleamide; however, these compounds are rarely excreted in urine in their pure form. The many hydroxylated or dealkylated metabolites of these compounds, mostly unnamed, are more consistently detected in urine.^68,69 One author has noted that the pentanoic acid metabolite of JWH-018 seems to appear most reliably in urine specimens.⁶⁸

Many synthetic cannabinoid herbal mixes also contain a detectable compound called tocopherol, seemingly added as an antioxidant.^69,70 Synthetic cannabinoids are an evolving drug class, and reliable detection will require that laboratories stay up-to-date in their detection methods. As stated earlier, a commercial laboratory in the region accepted the civilian and veteran patient samples for these case studies. The synthetic cannabinoid panels offered evaluation of the drug itself (GC-MS), an oral fluid screen (LC-MS), and isolation of metabolites in urine (enzyme-linked immunosorbent assay).

Conclusion

Designer drugs will remain a challenge for providers caring for veterans for several key reasons: (1) Veterans are a vulnerable population who abuse substances at higher rates than do their civilian counterparts; (2) Chemists are able to manufacture variations of known habit-forming substances; (3) Modern technology facilitates the purchase and wide distribution of addictive substances; (4) Many designer drugs are deceptively packaged and marketed; (5) The effects of the drugs are often severe; (6) No standardized treatment guidelines exist; and (7) Detection of the drugs is difficult, and new versions of the molecules may evade even cutting-edge techniques.

Due to the high cost of detecting synthetic cathinones and synthetic cannabinoids in body fluids, screening should be considered only in settings where severe symptoms are accompanied by reasonable clinical suspicion of use and an otherwise negative toxicologic workup. As more designer drugs inevitably emerge, research will be needed on their pharmacology, toxidromes, and detection. Military and civilian practitioners must remain abreast of the dynamic trends in designer drugs to ensure that their patients receive the highest level of medical care.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.  

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.