Hematologic Complications,Healthcare Utilization,and Costs in Commercially Insured Patients with Myelodysplastic Syndrome Receiving Supportive Care

Background

Myelodysplastic syndrome (MDS) is rare in people aged <50 years. Most patients with this disorder experience progressive worsening of blood cytopenias, with an increasing need for transfusion. The more advanced and severe the disorder, the greater the risk that it will progress to acute myeloid leukemia. Therapy is typically based on the patient''s risk category, age, and performance status. Supportive care alone is a major option for lower-risk, older patients with MDS or those with comorbidities. The only potentially curative treatment option is hematopoietic stem-cell transplantation, which is typically used to treat high-risk, younger patients.

Objective

To describe and compare the hematologic complications, healthcare utilization, and costs of supportive care in patients with MDS aged <50 years and in older patients aged ≥50 years.

Methods

Using the i3/Ingenix LabRx claims database, this retrospective study included patients who were continuously enrolled (ie, 6 months preindex through 1 year postindex) in the study and who had an initial claim of MDS (index date) between February 1, 2007, and July 31, 2008. Patients treated with hypomethylating agents or thalidomide analogues were excluded. Claims included information on office visits, medical procedures, hospitalizations, drug use, and tests performed. The hematologic complications, costs, and utilization analyses were stratified by age into 2 age-groups—patients aged <50 years and those aged ≥50 years. The MDS-related diagnoses, utilization, and costs were analyzed postindex. The data used in this study spanned the period from August 1, 2006, to July 31, 2009.

Results

We identified 1133 newly diagnosed patients with MDS who received supportive care only during the study period; of these, 19.5% were younger than age 50 years. These younger patients included more females (62.0% vs 52.5%; P = .011) and had fewer comorbidities (mean Charlson comorbidy index, 1.2 vs 2.4; P <.001) and physician office visits than those aged ≥50 years. Postindex, compared with the older patients, the younger patients had less use of erythropoietin therapy and fewer transfusions, anemia diagnoses, and potential complications of neutropenia and pneumonia diagnoses; however, more diagnoses of neutropenia and of decreased white blood cell counts were seen in the younger patients than in the older patients (P ≤.034 for all comparisons). Furthermore, younger patients had fewer mean office visits in the postindex period than older patients (17.5 vs 24.2, respectively; P <.001) and fewer hospitalizations (32.1% vs 44.6%, respectively; P = .004), but they had a longer (although not statistically significant) mean length of hospital stay (21 vs 14 days, respectively; P = .131). Mean total healthcare charges were $96,277 (median, $21,287) in younger patients compared with $84,102 (median, $39,402) in older patients, although this difference, too, was not significant.

Conclusions

MDS is associated with frequent and prolonged hospitalizations, frequent outpatient visits, and high costs in younger and in older patients who are receiving supportive care. Although this study shows that younger patients aged <50 years do not have significantly higher costs overall, a small proportion may have a higher healthcare utilization and cost-related burden of MDS than patients aged ≥50 years.Myelodysplastic syndrome (MDS) encompasses a heterogeneous group of clonal disorders of hematopoiesis and is characterized by dysplastic morphology of marrow and blood cells, ineffective hematopoiesis, and peripheral blood cytopenias.1,2 Most patients with MDS experience progressive worsening of blood cytopenias, with an increasing need for transfusion.2 These patients also have an increasing number of potentially fatal infections and hemorrhagic complications.2 The more advanced and severe the MDS is, the greater the risk that the disease will progress to acute myeloid leukemia (AML).3 The disease may be classified into 1 of 5 subtypes—refractory anemia, refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess of blasts (RAEB), RAEB in transformation (RAEB-T), or chronic myelomonocytic leukemia.3 Approximately 5% to 15% of the relatively lower-risk patients with refractory anemia/RARS transform to AML; by contrast, 40% to 50% of the high-risk patients with RAEB/RAEB-T transform to AML.3The therapeutic options that are tailored for specific MDS subgroups are typically based on factors such as the patient''s risk category, age, and performance status.3,4 The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology recommend that all patients with MDS receive supportive care,3 which includes blood transfusions, erythropoietin with or without granulocyte colony-stimulating factor, iron chelation therapy, and prophylactic antibiotics.4,5 Other therapies indicated for the treatment of patients with MDS include the thalidomide analogue lenalidomide and the hypomethylating agents decitabine and 5-azacytidine.3,4 The only potentially curative treatment option is hematopoietic stem-cell transplantation, which is typically used to treat younger, high-risk patients.3,4 Supportive care alone remains a leading option for the treatment of lower-risk, older patients with MDS or those with comorbidities.3,4Data on the distribution of MDS in the general population are inconsistent, possibly because of misdiagnoses and/or underreporting of the disease.6,7 The most recent estimates of the annual incidence of MDS in the United States range from 3.3 to 5.0 per 100,000 persons.3,7,8 Some studies indicate that the median age of patients with MDS is approximately 65 years, whereas others note that more than 70% of cases occur in patients aged ≥70 years in the United States.3,6,9 The incidence of MDS in individuals aged ≥70 years is between 22 and 45 per 100,000 persons and increases with age.3,6,9–11Less than 10% of patients with MDS are aged <50 years; therefore, little is known about this disease in this younger age-group, particularly among patients who receive supportive care only.6,11,12 Some data suggest that younger patients with MDS have less aggressive disease.12,13 We compared hematologic complications, healthcare utilization, and costs in patients aged <50 years and in those aged ≥50 years who were newly diagnosed with MDS and received supportive care only.

KEY POINTS

• ▸ The more advanced and severe the myelodysplastic syndrome (MDS) is, the greater the risk of progression to acute myeloid leukemia. Therapy is currently based on risk category, age, and performance status.
• ▸ In the United States, the majority of newly diagnosed patients with MDS receive only supportive care, although for younger patients at high-risk, hematopoietic stem-cell transplantation is potentially the only curative option.
• ▸ This analysis compares the hematologic complications, healthcare utilization, and cost of care between patients with MDS aged <50 years and those aged ≥50 years who receive supportive care only.
• ▸ Although the younger patients had fewer office visits, they had longer mean length of hospital stay than the older group (21 vs 14 days, respectively).
• ▸ Mean total healthcare charges were $96,277 in younger patients compared with $84,102 in older patients.
• ▸ Based on this study, approximately 20% of patients with MDS are under age 50 years.
• ▸ The results of this study suggest that a small proportion of younger patients with MDS who receive supportive care only may have a higher healthcare utilization and cost-related burden of MDS than older patients with this condition.

     

Minimal Diversity of Drug-Resistant Mycobacterium tuberculosis Strains,South Africa

Multidrug- (MDR) and extensively drug-resistant tuberculosis (XDR TB) are commonly associated with Beijing strains. However, in KwaZulu-Natal, South Africa, which has among the highest incidence and mortality for MDR and XDR TB, data suggest that non-Beijing strains are driving the epidemic. We conducted a retrospective study to characterize the strain prevalence among drug-susceptible, MDR, and XDR TB cases and determine associations between strain type and survival. Among 297 isolates from 2005–2006, 49 spoligotype patterns were found. Predominant strains were Beijing (ST1) among drug-susceptible isolates (27%), S/Quebec (ST34) in MDR TB (34%) and LAM4/KZN (ST60) in XDR TB (89%). More than 90% of patients were HIV co-infected. MDR TB and XDR TB were independently associated with mortality, but TB strain type was not. We conclude that, although Beijing strain was common among drug-susceptible TB, other strains predominated among MDR TB and XDR TB cases. Drug-resistance was a stronger predictor of survival than strain type. Key words: Mycobacterium tuberculosis, drug resistance, transmission, genotype, South Africa, HIV, bacteria, tuberculosis, tuberculosis and other mycobacteria, antimicrobial resistanceDrug-resistant tuberculosis (TB) has emerged as a substantial threat to advances in global TB control over the past several decades (1). Worldwide, an estimated 630,000 cases of multidrug-resistant (MDR) TB occurred in 2011, and extensively drug-resistant (XDR) TB has now been reported in 84 countries (2). MDR TB and XDR TB are each associated with very high mortality rates (3), and their transmission—both in community and health care settings—remains an ongoing challenge in resource-limited settings and in countries with high rates of HIV co-infection.In South Africa, the incidence of MDR TB has increased 5-fold since 2002 (2,4). MDR TB treatment is now estimated to consume more than half of the budget allocated for TB control in South Africa (5). The emergence of XDR TB, and its associated high mortality rates, have further underscored the need for clarifying the factors driving the drug-resistant TB epidemic to better focus control efforts (3,6,7).Drug-resistant TB is generally considered a human-made phenomenon that occurs when inadequate TB treatment creates selection pressure for the emergence of drug-resistant Mycobacterium tuberculosis subpopulations (acquired resistance) (1). Researchers initially believed that the mutations causing drug resistance would exert a “fitness cost,” rendering those strains too weak to be transmitted (8,9). Nonetheless, transmission of drug-resistant TB strains has now been well-documented (10–13), and laboratory studies have shown that clinical strains may have minimal fitness costs or even none (14). Emerging data suggest that most MDR TB and XDR TB cases in South Africa and worldwide are likely caused by primary transmission of drug-resistant strains (2,15–19).Although the M. tuberculosis W/Beijing strain family has been described among cases of drug-susceptible, MDR TB, and XDR TB in South Africa, numerous other strain types have also been identified (20,21). Little is known about the transmissibility and virulence of M. tuberculosis strains aside from the W/Beijing strain family (22,23). In the Eastern Cape and Western Cape Provinces of South Africa, strains from the W/Beijing family have most often been associated with transmission of drug-resistant TB (24–27). At our study site in KwaZulu-Natal Province, however, the LAM4/KZN strain type has predominated among MDR TB and XDR TB cases and has been linked to nosocomial transmission and high mortality rates (3,16,17,28,29). This strain is a member of the Euro-American strain family and was first described in this region in 1994, evolving into an increasingly resistant phenotype over time (29).The reasons for why the LAM4/KZN strain is prominent in KwaZulu-Natal Province, rather than the Beijing strain, which is seen globally and in other parts of South Africa, is unclear. Moreover, it is unknown whether the higher mortality among patients with MDR TB and XDR TB in KwaZulu-Natal can be explained, in part, by a difference in genotypic prevalence and associated differences in strain virulence (3,6,7,28). In this study, we sought to characterize the genotypic diversity of M. tuberculosis strains among isolates causing drug-susceptible TB, MDR TB, and XDR TB in KwaZulu-Natal Province, South Africa. We also examined the relationship between M. tuberculosis strain, drug resistance, and patient survival.     

Modeling the Frequency and Costs Associated with Postsurgical Gastrointestinal Adverse Events for Tapentadol IR versus Oxycodone IR

Background

Few studies have estimated the economic effect of using an opioid that is associated with lower rates of gastrointestinal (GI) adverse events (AEs) than another opioid for postsurgical pain.

Objective

To estimate the number of postsurgical GI events and incremental hospital costs, including potential savings, associated with lower GI AE rates, for tapentadol immediate release (IR) versus oxycodone IR, using a literature-based calculator.

Methods

An electronic spreadsheet–based cost calculator was developed to estimate the total number of GI AEs (ie, nausea, vomiting, or constipation) and incremental costs to a hospital when using tapentadol IR 100 mg versus oxycodone IR 15 mg, in a hypothetical cohort of 1500 hospitalized patients requiring short-acting opioids for postsurgical pain. Data inputs were chosen from recently published, well-designed studies, including GI AE rates from a previously published phase 3 clinical trial of postsurgical patients who received these 2 opioids; GI event–related incremental length of stay from a large US hospital database; drug costs using wholesale acquisition costs in 2011 US dollars; and average hospitalization cost from the 2009 Healthcare Cost and Utilization Project database. The base case assumed that 5% (chosen as a conservative estimate) of patients admitted to the hospital would shift from oxycodone IR to tapentadol IR.

Results

In this hypothetical cohort of 1500 hospitalized patients, replacing 5% of oxycodone IR 15-mg use with tapentadol IR 100-mg use predicted reductions in the total number of GI events from 1095 to 1085, and in the total cost of GI AEs from $2,978,400 to $2,949,840. This cost reduction translates to a net savings of $22,922 after factoring in drug cost. For individual GI events, the net savings were $26,491 for nausea; $12,212 for vomiting; and $7187 for constipation.

Conclusion

Using tapentadol IR in place of a traditional μ-opioid shows the potential for reduced GI events and subsequent cost-savings in the postsurgical hospital setting. In the absence of sufficient real-world data, this literature-based cost calculator may assist hospital Pharmacy & Therapeutics committees in their evaluation of the costs of opioid-related GI events.Pain is a global health problem that affects 1 of 5 adults in the community1 and occurs in 43% to 77%2–4 of the approximate 35.1 million patients who are hospitalized annually in the United States.5 Pain is ubiquitous among the nearly 30.2 million people who undergo inpatient surgery annually in the United States.5 Opioid analgesics are a mainstay of postsurgical pain management,6 but are often associated with treatment-limiting gastrointestinal (GI), central nervous system, and respiratory adverse events (AEs).7 Of these, opioid-related GI AEs are the most common,8–10 with an incidence rate of 10% to 32% for nausea and/or vomiting and 15% to 41% for constipation.7,11–14 These GI AEs are particularly troublesome after surgery, because they can exacerbate anesthesia-induced nausea and decreased GI motility, sometimes resulting in ileus.7 Furthermore, GI AEs are associated with increased healthcare resource utilization because of additional medications used to manage the GI AEs and an increase in hospital length of stay (LOS).7,10,15–17

KEY POINTS

• ▸ Opioid analgesics, a key to postsurgical pain management, are associated with lower gastrointestinal (GI) and other adverse event rates.
• ▸ Unlike traditional opioids, such as oxycodone IR, that exert analgesic activity by binding to μ-opioid receptors, tapentadol IR has a second mechanism involving norepinephrine reuptake inhibition, which may help to minimize GI events.
• ▸ Previous studies have shown that tapentadol IR causes fewer GI events than oxycodone IR in the postsurgical setting.
• ▸ This new study compared the total GI events and associated incremental costs for tapentadol IR versus oxycodone IR in the postsurgical setting from a hospital perspective, using a cost calculator and a hypothetical cohort of 1500 hospitalized patients requiring short-acting opioids.
• ▸ Replacing 5% of oxycodone IR 15-mg use with tapentadol IR 100 mg reduced the total number of postsurgical GI events from 1095 to 1085, which was associated with a cost reduction from $2,978,400 to $2,949,840.
• ▸ Individual GI event net savings for the 5% use of tapentadol IR instead of oxycodone IR were $26,491 for nausea, $12,212 for vomiting, and $7187 for constipation.
• ▸ The potential cost-savings associated with reduced GI events seen with tapentadol IR versus oxycodone IR in the postsurgical setting may suggest the need to look beyond drug-acquisition cost to consider the effect on net costs of care when making formulary decisions.

The guidelines for managing surgery-related pain advocate a multimodal, opioid-sparing approach to improve analgesic activity and to minimize the risk for opioid-related AEs.6,18 Most traditional opioids exert analgesic activity by binding to μ-opioid receptors in the brain; these receptors are also present in the GI tract. Tapentadol is a centrally acting analgesic with 2 mechanisms of action—μ-opioid receptor agonism and norepinephrine reuptake inhibition.19,20 These 2 mechanisms of action may account for the significant analgesia, along with the lower incidence and intensity of AEs that are normally associated with traditional μ-opioid receptor agonists, such as oxycodone.21In 2 phase 3 studies of patients with acute pain, including postoperative pain, the incidence of GI AEs was lower with tapentadol immediate release (IR) than with oxycodone IR at equianalgesic doses, including dose strengths other than tapentadol IR 100 mg.22,23We chose oxycodone IR as the traditional opioid because of its inclusion in guidelines for surgery-related pain,6 the availability of pivotal clinical studies comparing oxycodone IR with tapentadol IR,23,24 and its spectrum of AEs that is similar to that of tapentadol IR.23,24Although the clinical benefits of using opioids with different mechanisms of action are well documented, few studies have examined the potential economic effect of this strategy in postsurgical populations.The objective of this study was to estimate the number of potential reductions in postsurgical GI AEs and incremental hospital costs for GI event rates associated with tapentadol IR versus oxycodone IR, using a literature-based calculator. The analysis focused on data related to postsurgical GI AE rates, because of their availability in the published literature.     

West Nile virus encephalitis and myocarditis in wolf and dog

In the third season (2002) of the West Nile virus epidemic in the United States, two canids (wolf and dog) were diagnosed with West Nile virus encephalitis and myocarditis with similarities to known affected species (humans, horses, and birds). The West Nile virus infections were confirmed by immunohistochemistry and polymerase chain reaction.Since its 1999 introduction in New York, West Nile virus (WNV) has spread to >40 states, causing seasonal mosquito-borne disease in humans, horses, and birds (1–7). We recently identified two Illinois canids (a captive wolf and a domestic dog) with severe disease associated with WNV infection.Outside the Western Hemisphere, WNV has been endemic for decades (4,8–11). Canids have not been thought to be important in the epidemiology of this virus. However, a dog with neurologic disease that died in Africa in 1977 is now thought to have been infected with WNV (9,12). In a recent study in which four dogs were experimentally infected, no clinical disease was observed, and a low viremia developed in one dog (11). Natural infections occur in dogs, as indicated by serum antibodies; seropositivity in surveys was 37% in the 1980s in South Africa, 24% in the 1990s in India, and 5% in 1999 in New York City (10,11,13). In addition, a few individuals of some mammalian species have been listed as infected (not diseased): 14 bats, four rodents, three rabbits, two cats, two raccoons, and a skunk (6).     

Fixed-Dose Combination Gel of Adapalene and Benzoyl Peroxide plus Doxycycline 100 mg versus Oral Isotretinoin for the Treatment of Severe Acne: Efficacy and Cost Analysis

Background

Acne vulgaris is a chronic skin disease with a high prevalence. Left untreated or inadequately treated, acne vulgaris can lead to psychological and physical scarring, as well as to unnecessary medical expenses. Oral isotretinoin is an effective treatment for severe resistant nodular and conglobate acne vulgaris. A regimen consisting of a fixed-dose combination of adapalene and benzoyl peroxide gel, 0.1%/2.5% (A-BPO) with oral doxycycline 100 mg (A-BPO/D) has been demonstrated to be efficacious and well tolerated in patients with severe acne and may be an alternative to oral isotretinoin for some patients with severe acne.

Objective

The objective of this analysis was to compare the relative efficacy and associated costs of A-BPO/D versus oral isotretinoin.

Methods

In this analysis, comparisons of relative efficacy were made using previously published studies involving similar patient populations with severe acne that warrant the use of oral isotretinoin. The pricing for oral doxycycline and oral isotretinoin was estimated based on the maximum allowable cost from 9 states, and the pricing for A-BPO was calculated as the range between the average wholesale price and the wholesale acquisition cost. For this analysis, 2 treatment models were generated to compare costs: (1) a basic treatment model that examined the costs of an initial regimen of either A-BPO/D or oral isotretinoin without considering probable outcomes, and (2) a long-term model that factored in likely treatment outcomes and subsequent treatments into associated costs. The basic treatment model assumed that patients would be prescribed a single regimen of A-BPO/D for 12 weeks or oral isotretinoin for 20 weeks. The long-term model considered the probability of each treatment successfully managing patients'' acne, as well as likely additional regimens of A-BPO monotherapy or an additional regimen of oral isotretinoin. As a result of different treatment durations, the costs for each treatment were normalized to weekly cost of treatment.

Results

Based on evidence from the published literature, patients treated with A-BPO/D would be expected to have an initial 72% reduction in inflammatory lesions, and patients treated with oral isotretinoin would have an 80% to 90% reduction of these lesions. The median weekly cost for the basic treatment model was $44 for A-BPO/D and $62 for oral isotretinoin. The weekly median costs for the long-term model were $44 for patients initially receiving a regimen of A-BPO/D followed by a maintenance regimen of A-BPO monotherapy and $50 for patients receiving an initial regimen of A-BPO/D who required a subsequent regimen of oral isotretinoin. The weekly cost for oral isotretinoin in the long-term model was $62.

Conclusions

The comparison of these 2 treatments demonstrated that they are both effective in treating severe acne, and that A-BPO/D was less expensive weekly than oral isotretinoin. These models show that A-BPO/D is safer than and is a more cost-effective alternative to oral isotretinoin for treating patients with severe acne vulgaris.Acne vulgaris is a chronic skin disease predominantly affecting the face, trunk, and back.1 The prevalence of acne vulgaris is high in many countries: acne afflicts up to 87% of adolescents and up to 54% of adults.2,3 Skin diseases, including acne, are often dismissed as being trivial or not as important as diseases of other organ systems.4 However, acne can negatively affect the patient''s quality of life (QOL).4 Responses to the 36-Item Short Form Survey, a generic QOL questionnaire, demonstrate that patients with acne report social, psychological, and emotional problems at levels as great as patients with epilepsy, diabetes, back pain, disabling asthma, or arthritis.4 Patients with acne also have fewer feelings of pride, lower self-esteem, lower body image satisfaction, more depressive symptoms, and more feelings of uselessness than people without acne.5 Adolescents with severe acne have suicidal thoughts more frequently than those with less severe acne.6 If left untreated, acne can result in significant psychosocial morbidity.7 Treatment improves the QOL of patients with acne and can prevent scarring.8–10

KEY POINTS

• ▸ Acne vulgaris is a chronic, prevalent skin disease that can affect a patient''s quality of life and lead to unnecessary medical expenses.
• ▸ Oral isotretinoin is indicated for the treatment of severe resistant nodular and conglobate acne vulgaris and is the only therapy that targets all 4 causitive factors.
• ▸ However, oral isotretinoin is a teratogenic drug that is associated with significant side effects and carries a REMS program; and although it is indicated for severe recalcitrant acne, it is often prescribed for mild or moderate acne.
• ▸ A fixed-dose combination of adapalene and benzoyl peroxide gel, 0.1%/2.5% (A-BPO) is efficacious and well tolerated in patients with severe acne.
• ▸ This new analysis of previously published data shows that although oral isotretinoin and A-BPO plus oral doxycycline 100 mg (A-BPO/D) are both effective for treating severe acne, A-BPO/D is less expensive per patient per week.
• ▸ Because the 2 treatment regimens are different in nature, a weekly cost analysis was used for comparison, showing that the median weekly cost for A-BPO/D is $44 compared with $62 for oral isotretinoin.
• ▸ In addition to being safer than oral isotretinoin for the management of patients with severe acne vulgaris, A-BPO/D is a cost-effective alternative to oral isotretinoin, which is associated with potential serious side effects that may further increase the indirect costs of treatment.

The pathophysiology of acne is multifactorial, involving 4 causative factors, including inflammation, hyperkeratinization, Propionibacterium acnes proliferation, and excess sebum production.11 Several topical and oral treatment options target the various causative mechanisms. The Global Alliance to Improve Outcomes in Acne has published recommended guidelines for the treatment of acne.12 Topical treatment is recommended for milder forms of acne. Oral isotretinoin is indicated for the most severe forms of nodular and conglobate acne and is the only available therapy that targets all 4 causative factors.Although indicated for severe recalcitrant acne, oral isotretinoin is frequently prescribed for the treatment of mild or moderate acne.13 However, oral isotretinoin is a pregnancy category × teratogen and is associated with significant side effects.14 The reported side effects associated with the use of oral isotretinoin include depression, attempted suicide, cheilitis, dermatitis, myalgia, dry eyes, nonspecific gastrointestinal symptoms, and arthralgia, among others.14 Patients who are prescribed oral isotretinoin must enroll in the Risk Evaluation and Mitigation Strategy (REMS) program iPLEDGE.15 Patients also require laboratory tests to monitor liver function and serum lipid levels.14For patients with severe acne with less nodular involvement, an oral antibiotic with a topical retinoid and benzoyl peroxide is recommended.12 Doxycycline 100 mg once daily is efficacious against acne and is relatively well tolerated.16 Adapalene, a third-generation retinoid with an established safety profile, has anticomedogenic and anti-inflammatory properties that are effective against acne.17–21 Benzoyl peroxide is an antimicrobial agent with demonstrated efficacy in treating acne.22 Benzoyl peroxide is more advantageous than other topical antibiotics, because it does not induce bacterial resistance and because it is effective against resistant P acnes strains.23A fixed-dose combination of adapalene and benzoyl peroxide gel, 0.1%/2.5% (A-BPO; Epiduo Gel) was approved by the US Food and Drug Administration in 2008. This is the only fixed-dose drug combination that is formulated with a topical retinoid and benzoyl peroxide. The safety and efficacy of A-BPO for the treatment of acne have been established in clinical trials.24,25Two related clinical trials investigated the use of A-BPO with oral doxycycline 100 mg once daily (A-BPO/D) for 12 weeks,26 followed by a maintenance therapy of A-BPO in patients with severe acne for an additional 24 weeks.27 Severe acne vulgaris in these studies was defined as up to 3 nodules or cysts, 30 to 120 noninflammatory lesions, and at least 20 inflammatory lesions.26,27 In the study by Gold and colleagues, patients who were treated with A-BPO/D had significantly better improvement in acne symptoms and in the acne symptom portion of the Acne-QOL questionnaire than patients given vehicle gel and doxycycline 100 mg.9,26 Patients with at least a “good” improvement in the first study, whether they were in the A-BPO/D group or in the vehicle gel plus doxycycline group, were eligible for the second study and were randomized to a maintenance regimen of A-BPO or to vehicle gel. Symptoms of acne and the QOL of patients using A-BPO continued to improve, whereas in patients using vehicle gel, QOL and acne symptoms worsened during the 24-week period.9,27 The majority of adverse events were mild and included erythema, scaling, dryness, and stinging and burning.26,27In addition to treating severe acne, A-BPO is also recommended for the treatment of mild and moderate acne, making it a versatile topical medication that can treat a spectrum of disease severity.12A model was developed to compare the efficacy and related costs of A-BPO/D versus oral isotretinoin in treating severe acne vulgaris.     

Characterization of waterborne outbreak-associated Campylobacter jejuni, Walkerton, Ontario

The Walkerton, Canada, waterborne outbreak of 2000 resulted from entry of Escherichia coli O157:H7 and Campylobacter spp. from neighboring farms into the town water supply. Isolates of Campylobacter jejuni and Campylobacter coli obtained from outbreak investigations were characterized by phenotypic and genotypic methods, including heat-stable and heat-labile serotyping, phage typing, biotyping, fla–restriction fragment length polymorphism (RFLP) typing, and pulsed-field gel electrophoresis. Two main outbreak strains were identified on the basis of heat-stable serotyping and fla-RFLP typing. These strains produced a limited number of types when tested by other methods. Isolates with types indistinguishable from, or similar to, the outbreak types were found only on one farm near the town of Walkerton, whereas cattle from other farms carried a variety of Campylobacter strains with different type characteristics. Results of these analyses confirmed results from epidemiologic studies and the utility of using several different typing and subtyping methods for completely characterizing bacterial populations.An outbreak of Campylobacter jejuni in a farming community in southern Ontario, Canada, in 1985 resulted from contamination of well water caused by spring run-off and heavy rains (1). In May 2000, a second waterborne outbreak of Escherichia coli O157:H7 and Campylobacter occurred in Bruce County, Ontario. Well water serving the town of Walkerton was contaminated by surface water carrying livestock waste immediately after heavy rains (2,3). A detailed microbiologic and epidemiologic analysis of the most recent outbreak may provide insights that could help make this type of outbreak less frequent.Most sporadic cases of campylobacteriosis are associated with preparation or consumption of poultry products (4). Outbreaks have been associated with consumption of unpasteurized milk or unchlorinated water (5). An estimated 20% of cases of illness caused by C. jejuni are due to vehicles of infection other than food, including water (6). Waterborne outbreaks of Campylobacter tend to occur in spring or early fall, an association attributed to seasonality of surface water contamination and infection in cattle herds (5). Contaminated water sources have been implicated in outbreaks involving E. coli O157:H7 and Campylobacter together in Scotland (7) and in New York State (8,9). The former outbreak resulted from sewage contamination of the water supply of a small village in Fife, Scotland. The latter outbreak was associated with contamination of wells at a state fair (10). Excrement from birds and animals, including cattle, has been shown to contaminate surface water supplies used by humans infected with Campylobacter (9).Campylobacter spp. have been found to cause water-borne outbreaks worldwide; such outbreaks are a particular problem in Scandinavian countries where many people drink untreated water from streams and other sources (11). Untreated surface water has also been implicated in Campylobacter outbreaks in New Zealand (12,13), Finland (14), England, Wales (15,16), Australia (17), and the United States (18). In Canada, outbreaks have been rarely detected and have been associated with contamination of surface water (19,20) and consumption of unpasteurized milk (21).In the United States, disease caused by C. jejuni or C. coli has been estimated to affect 7 million people annually, causing 110–511 deaths and costing $1.2–$6 billion (22). These organisms are responsible for 17% of all hospitalizations related to foodborne illness in the United States, and although associated with a much lower case-fatality rate than Salmonella spp. and E. coli O157:H7, they account for 5% of food-related deaths (6). Although the incidence of Campylobacter infections generally appears to be higher in industrialized than in developing nations, some evidence exists that campylobacteriosis may be important from a social and economic point of view (23).Epidemiologic and microbiologic analyses were undertaken to better understand the circumstances leading to the Walkerton outbreak. C. jejuni was isolated from patients associated with the outbreak, and C. jejuni and C. coli were isolated from animals and animal manure on farms located near the town wells. This work summarizes the phenotypic and genotypic typing results for isolates associated with the outbreak.     

Multidrug-Resistant Salmonella enterica Serotype Typhi,Gulf of Guinea Region,Africa

We identified 3 lineages among multidrug-resistant (MDR) Salmonella enterica serotype Typhi isolates in the Gulf of Guinea region in Africa during the 2000s. However, the MDR H58 haplotype, which predominates in southern Asia and Kenya, was not identified. MDR quinolone-susceptible isolates contained a 190-kb incHI1 pST2 plasmid or a 50-kb incN pST3 plasmid.Typhoid fever, which is caused by Salmonella enterica serotype Typhi, is endemic to the developing world; there were an estimated 26.7 million cases in 2010 (1). The incidence of typhoid fever in sub-Saharan Africa was an estimated 725 cases/100,000 persons in 2010, despite a lack of incidence studies conducted in West and central Africa (1). Antimicrobial susceptibility data are also scarce for this part of Africa. This issue is problematic because treatment with appropriate antimicrobial drugs is essential for recovery in the context of the global emergence of multidrug resistance.In the Indian subcontinent and Southeast Asia, the multidrug-resistant (MDR) Salmonella Typhi H58 clone, which was named after its haplotype (a combination of defined chromosomal single-nucleotide polymorphisms [SNPs]) (2,3), has spread rapidly and become endemic and predominant. During the 1990s, this clone acquired a large conjugative incHI1 pST6 plasmid encoding resistance to ampicillin, chloramphenicol, and co-trimoxazole (4,5); also in the 1990s, this MDR clone became resistant to quinolones and showed decreased susceptibility to ciprofloxacin because of point mutations in the chromosomal gyrA gene (2). The H58 clone has also spread to eastern Africa, where it has been the most prevalent haplotype (87%) in Kenya since the early 2000s (6).During 1997–2011, high incidence of MDR Salmonella Typhi was reported in some countries near the Gulf of Guinea in Africa, including Nigeria (7), Ghana (8,9), Togo (10), and the Democratic Republic of the Congo (11). During 1999–2003, a British surveillance system reported a prevalence of 19% (49/421) for MDR Salmonella Typhi isolates among imported cases of typhoid fever acquired in Africa, particularly in Ghana (12). However, nothing is known about the genotypes of these isolates, including whether they belong to the spreading MDR H58 clone.We report data for the occurrence, genotypes, and characterization of the resistance mechanisms of MDR Salmonella Typhi isolates. These isolates were obtained from the French National Reference Center for Salmonella (FNRC-Salm), Institut Pasteur (Paris, France), and Centre Pasteur du Cameroun (Yaoundé, Cameroon).     

Burkholderia pseudomallei Isolates in 2 Pet Iguanas,California, USA

Burkholderia pseudomallei, the causative agent of melioidosis, was isolated from abscesses of 2 pet green iguanas in California, USA. The international trade in iguanas may contribute to importation of this pathogen into countries where it is not endemic and put persons exposed to these animals at risk for infection.Key words: Burkholderia pseudomallei, iguana, zoonoses, abscess, melioidosis, bacteriaBurkholderia pseudomallei, a gram-negative bacterium, is the causative agent of melioidosis. Melioidosis is endemic in countries in Southeast Asia and in northern Australia, and has been sporadically reported from Central and South America (1). In the United States, most case-patients have traveled to disease-endemic areas (2).B. pseudomallei infection occurs through direct cutaneous inoculation with soil or water containing B. pseudomallei and through ingestion or inhalation of aerosolized bacteria. In humans, the incubation period is typically 1–21 days, but some patients demonstrate clinical signs years after exposure (1). Acute melioidosis can manifest as a severe pneumonia and septicemia, with death rates >40% in countries where access to medical care is limited. In chronic melioidosis, abscesses occur in various organs, including the lungs, liver, spleen, and cutaneous sites (1,3). In animals, abscesses and acute illness are common (4).B. pseudomallei is classified by US federal agencies as a tier 1 select agent. Tier 1 agents are believed to pose the greatest threat for deliberate misuse and potential harm to public health. Multiple regulations restrict access to these agents and reduce the risk of their release from secure settings (5). Infection is generally diagnosed by culture. Commercially available bacterial identification systems may provide initial identification; however, B. pseudomallei may be misidentified by some systems (6). Other identification tests are available, including PCR and antigen detection; these are not commonly used outside disease-endemic regions (3,7,8).     

Hypertension Management: An Update

Hypertension is a significant and costly public health problem. It is a major, but modifiable contributor for the development of cardiovascular disease. Randomized controlled trials have shown that controlling hypertension reduces the risk of stroke, coronary artery disease, congestive heart failure, end-stage renal disease, peripheral vascular disease, as well as overall mortality. The risk of developing these hypertension-related complications is continuous, starting at a blood pressure level as low as 115/75 mm Hg. Despite the inherent health risks associated with uncontrolled hypertension, elevated blood pressure remains inadequately treated in the majority of patients. This article reviews guidelines for optimal evaluation of hypertension and current therapeutic options available to combat this common yet pervasive disease.Hypertension affects approximately 1 of 3 adults in the United States, and about 2 million new cases are diagnosed each year.1,2 An additional 28% of the US population is afflicted with prehypertension, and approximately 7% of Americans are not aware that they even have hypertension.3 Globally, hypertension affects more than 1 billion people and is projected to reach 1.56 billion by 2025.4 It is the leading cause of death and the second leading cause of lost disability-adjusted life-years worldwide.4 Randomized controlled clinical trials have shown that control of hypertension reduces the risk of stroke, coronary artery disease, congestive heart failure, end-stage renal disease, peripheral vascular disease, and mortality.1,5 The risk of developing these complications is continuous, starting at a blood pressure (BP) level as low as 115/75 mm Hg.6The total direct and indirect cost for hypertension in the United States in 2009 is estimated at $73.4 billion.3 Approximately 10% ($15 billion) of the US total annual drug expenditure is on antihypertensive medications.7 Despite these staggering costs, only 34% of Americans with hypertension are at their BP goal (<140/90 mm Hg).1 The reason for this failure is multi-factorial and only speculative, and not because of the lack of awareness or lack of effective pharmacologic agents or lack of understanding of the role of lifestyle modification. Since hypertension will develop in most Americans in their lifetime,8 early preventive measures and prompt management, including lifestyle and pharmacologic options, are essential to minimize complications associated with this condition.     

Increased Patient Cost-Sharing,Weak US Economy,and Poor Health Habits: Implications for Employers and Insurers

Many healthcare stakeholders, including insurers and employers, agree that growth in healthcare costs is inevitable. But the current trend toward further cost-shifting to employees and other health plan members is unsustainable. In 2008, the Zitter Group conducted a large national study on the relationship between insurers and employers, to understand how these 2 healthcare stakeholders interact in the creation of health benefit design. The survey results were previously summarized and discussed in the February/March 2009 issue of this journal. The present article aims to assess the implications of those results in the context of the growing tendency to increase patient cost-sharing, a weak US economy, and poor health habits. Increasing cost-sharing is a blunt instrument: although it may reduce utilization of frivolous services, it may also result in individuals forgoing medically necessary care. Increases in deductibles will lead to an overall decrease in optimal care-seeking behavior as families juggle healthcare costs with a weak economy and stagnating wages.In the spring of 2008, the Zitter Group conducted a large national study of the insurer—employer relationship to understand how these 2 stakeholders interact in the creation of healthcare benefit design. The 2-arm study consisted of concurrent web-based quantitative surveys with commercial managed care executives, large employers, and major employer benefits consultants.1 It was designed to provide a richly detailed snapshot of trends in employer-sponsored healthcare coverage. Despite having varying ideas on specific healthcare benefit design strategies, employers and insurers assign similar weights to the importance of cost, quality, and access when making benefit design decisions.1,2 For both groups, the importance assigned to cost is 1.5 times higher in value than healthcare access or healthcare quality.1 Throughout the survey, both groups cited access and quality concerns, but in the current environment of steadily rising cost growth, the importance assigned to cost takes on an even greater significance. The survey results were summarized in the February/March issue of this journal.1 The present article is a follow-up to that article, and its goal is to place those survey results in the context of increased patient cost-sharing, a weak US economy, and the poor health habits that are characteristic of many segments of the American population.According to the data from the Benefit Design Index, in the absence of clear alternatives to traditional benefit designs, cost-shifting to patients through increases in copayments, deductibles, and premiums remains the primary cost-containment strategy used by employers and insurers. More than half of employers and three quarters of insurers have increased their premiums and deductibles between June 2007 and June 2008.1 Furthermore, two thirds of insurers and half of employers do not believe that the recent slowing growth rate of premiums is sustainable and, as a result, expect to increase all forms of patient cost-sharing.1 However, employers remain aware of the dangers of passing too many costs to employees; high out-of-pocket costs can translate into reduced adherence to medical treatments and, ultimately, deteriorating employee health and productivity.1,2In 2003, 30% of employees reported having a chronic health condition.3 That rate was likely to be even higher in 2008.4 The American Hospital Association reported that approximately 69 million workers took 1 or more sick days in 2003, totaling 407 million lost work days.3 In addition, 50% of employees reported being distracted at work by health concerns, reducing their productivity.3 Although absenteeism and lost productivity cost estimates vary widely, it is likely that they cost US businesses several million dollars a year.5,6 Combine the burdens of high employer healthcare costs, deteriorating employee health, and a weak US economy, and you have the ingredients for a “perfect storm”—one that is likely to lead to an insurance “death spiral,” from which we may not be able to recover.     

The Impact of 5-HT3RA Use on Cost and Utilization in Patients with Chemotherapy-Induced Nausea and Vomiting: Systematic Review of the Literature

Background

Individual studies have assessed the impact of standard prophylactic therapy with 5-hydroxytryptamine receptor antagonists (5-HT₃RAs) for chemotherapy-induced nausea and vomiting (CINV) on cost and utilization, but no synthesis of the findings exists.

Objective

To systematically review published literature on costs and utilization associated with CINV prophylaxis with palonosetron and other 5-HT₃RAs.

Methods

PubMed and the National Institute for Health Research Centre for Reviews and Dissemination databases, conferences of 4 organizations (ie, Academy of Managed Care Pharmacy, American Society of Clinical Oncology, International Society for Pharmacoeconomics and Outcomes Research, and Multinational Association of Supportive Care in Cancer), and the bibliographies of relevant articles were queried for the medical subject headings and key terms of “ondansetron,” “granisetron,” “palonosetron,” “dolasetron mesylate,” “costs,” “cost analysis,” and “economics.” We included records published (full-length articles after 1997 and conference presentations after 2010) in English and with human patients, reporting data on cost and utilization (rescue medication, outpatient and inpatient services) associated with the use of 5-HT₃RAs for the treatment or prevention of CINV.

Results

Of the 434 identified studies, 32 are included in the current analysis: 7 studies report costs, 18 report utilization, and 7 studies report both. The costs are reported in US dollars (7 studies), in Euros (5 studies), and in Canadian dollars (2 studies). The studies vary in designs, patients, 5-HT₃RA regimens, and the definition of outcomes. The US studies report higher drug costs for CINV prophylaxis with palonosetron compared with ondansetron, lower medical outpatient and inpatient costs for palonosetron versus other 5-HT₃RAs, and higher acquisition costs for palonosetron versus ondansetron or other 5-HT₃RAs. Fewer patients receiving palonosetron versus with ondansetron or other 5-HT₃RAs required rescue medication or used outpatient or inpatient care. In Europe and in Canada, the total pharmacy costs and use of rescue medications reported are lower for patients receiving prophylaxis with palonosetron.

Conclusions

This analysis shows that prophylaxis with palonosetron for the treatment of CINV is associated with higher acquisition treatment costs, but also with lower use of rescue medications and outpatient and inpatient services compared with ondansetron or other 5-HT₃RAs in the United States. Therefore, the use of palonosetron as a standard treatment may lead to reduced service utilization for CINV.Chemotherapy-induced nausea and vomiting (CINV) is an adverse effect of cancer treatment. It may occur within a few minutes of or up to 24 hours after the administration of chemotherapy (ie, acute CINV), or it may occur more than 24 hours after treatment (ie, delayed CINV). CINV may last up to 7 days.1–7Although there are several patient-specific factors that place patients at an increased risk for developing CINV (eg, female sex, low consumption of alcohol, history of motion or morning sickness, age under 50 years, previous CINV), the most contributory risk factor is the emetogenic potential of the chemotherapy regimen itself.8

KEY POINTS

• ▸ Poorly controlled CINV may lead to nutrient depletion, reduced functional ability, diminished quality of life, or the premature discontinuation of chemotherapy.
• ▸ Previous studies have examined the impact of CINV prophylaxis with palonosetron and other 5-HT₃RAs on cost and utilization, but this is the first systematic review of the published literature on this topic.
• ▸ A total of 32 studies were included in this systematic literature review, of which 14 studies report costs and 25 reported utilization.
• ▸ This review indicates that palonosetron is associated with higher treatment costs but also with lower rescue medication use and outpatient and inpatient services use compared with other 5-HT₃RAs.
• ▸ Based on this analysis, the use of palonosetron as a standard treatment may lead to reduced service utilization for CINV.

More than 90% of patients undergoing highly emetogenic chemotherapy (HEC) will experience emesis without antiemetic prophylaxis, and 30% to 90% of those undergoing moderately emetogenic chemotherapy (MEC) will vomit without the prophylactic administration of antiemetics.8 From 10% to 30% of the patients receiving low emetogenic risk chemotherapy (LEC), and <10% of patients receiving minimal emetogenic risk chemotherapy (MinEC), will experience emesis without the administration of antiemetics.3,6,7,9 The dose, frequency, and length of administration, as well as the combination of agents may impact the emetogenicity of the chemotherapy.7Poorly controlled CINV may lead to nutrient depletion, reduced functional ability, diminished quality of life, or the premature discontinuation of chemotherapy.1-4,6,7,9 The use of prophylactic antiemetic medications in patients undergoing HEC may reduce the incidence of CINV to as low as 30%.7 A multidrug regimen containing a 5-hydroxytryptamine receptor antagonist (5-HT₃RA) is the standard approach for CINV prophylaxis.7 Drugs in this category include dolasetron mesylate, granisetron, ondansetron, palonosetron, and tropisetron, with palonosetron recommended as the preferred 5-HT₃RA for CINV prophylaxis with MEC by the guidelines of the National Comprehensive Cancer Network (NCCN), the Multinational Association of Supportive Care in Cancer/Economic Society for Medical Oncology (MASCC/ESMO), and the American Society of Clinical Oncology (ASCO).5,7,10Secondary rescue medications are used to treat breakthrough CINV among patients who have received prophylaxis.7 These medications may include metoclopramide, lorazepam, diphenhydramine, olanzapine, prochlorperazine, or dexamethasone.CINV increases direct costs (eg, medication, office visits, or hospitalizations) and indirect costs (eg, missed work).3,4,9 The effective prevention of CINV may reduce these costs. The clinical and economic impact of CINV underscore the importance of achieving CINV prophylaxis.3,4,9 Palonosetron—which has greater binding affinity and a longer half-life than the other 5-HT₃RAs, binds allosterically, stimulates receptor internalization, demonstrates positive cooperativity, and cross talks with the neurokinin (NK)-1 signaling pathway—prevents both acute and delayed CINV more effectively than the other 5-HT₃RAs.7,11-14The extent to which the clinical benefit of 5-HT₃RAs translates into reduced costs or utilization of healthcare services among patients with CINV has been shown in individual studies for subsets of outcomes,3,15 but no summary of the literature exists. We conducted a systematic literature review of published research on the healthcare costs and utilization associated with the use of 5-HT₃RAs for the prevention of CINV in patients receiving chemotherapy, with the goal of comparing palonosetron with the other 5-HT₃RAs.     

The Economic Burden of Ischemic Stroke and Major Hemorrhage in Medicare Beneficiaries with Nonvalvular Atrial Fibrillation: A Retrospective Claims Analysis

Background

Understanding the economic implications of oral anticoagulation therapy requires careful consideration of the risks and costs of stroke and major hemorrhage. The majority of patients with atrial fibrillation (AF) are aged ≥65 years, so focusing on the Medicare population is reasonable when discussing the risk for stroke.

Objective

To examine the relative economic burden associated with stroke and major hemorrhage among Medicare beneficiaries who are newly diagnosed with nonvalvular atrial fibrillation (NVAF).

Methods

This study was a retrospective analysis of a 5% sample of Medicare claims data for patients with NVAF from 2006 to 2008. Patients with NVAF without any claims of AF during the 12 months before the first (index) claim for AF in 2007 (baseline period) were identified and were classified into 4 cohorts during a 12-month follow-up period after the index date. These cohorts included (1) no claims for ischemic stroke or major hemorrhage (without stroke or hemorrhage); (2) no claims for ischemic stroke and ≥1 claims for major hemorrhage (hemorrhage only); (3) ≥1 claims for ischemic stroke and no major hemorrhage claims (stroke only); and (4) ≥1 claims each for ischemic stroke and for major hemorrhage (stroke and hemorrhage). The 1-year mean postindex total all-cause healthcare costs adjusted by the Centers for Medicare & Medicaid Services Hierarchical Condition Categories (HCC) score were compared among the study cohorts. Results: Of the 9455 eligible patients included in this study, 3% (N = 261) of the patients had ischemic stroke claims only, 3% (N = 276) had hemorrhage claims only, and <1% (N = 13) had both during the follow-up period. The unadjusted follow-up healthcare costs were $63,781 and $64,596 per patient for the ischemic stroke only and the hemorrhage only cohorts, respectively, compared with $35,474 per patient for those without hemorrhage or stroke claims. After adjustment for HCC risk score, the mean incremental costs for patients with stroke claims only and hemorrhage claims only, relative to those without stroke or hemorrhage claims, were $26,776 (95% confidence interval [CI], $20,785-$32,767; P <.001) and $26,168 (95% CI, $20,375-$31,961; P <.001), respectively.

Conclusion

The economic burden of managing patients with NVAF who experience ischemic stroke and hemorrhage were similarly significant during the first year after a diagnosis of NVAF. The burden of major bleeding complications on patients, clinicians, and payers should not be overlooked, and these complications should be considered in conjunction with the cost-savings associated with ischemic stroke risk reduction in future cost-benefit evaluations of oral anticoagulation therapy.Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia.1,2 The most recent estimates (published in 2013) of the prevalence of AF in the United States are for 2010 and range from 2.7 million to 6.1 million.3,4 The prevalence of AF doubles with each decade of life after the age of 60 years and occurs in approximately 10% of the US population aged ≥80 years.5–7 A recent study estimates that the number of patients with AF in the United States could potentially reach 12.1 million by 20303; other estimates range from 5.6 million to 12 million patients with AF by 2050.4Patients with AF have an approximate 5-fold increased risk for stroke compared with patients in normal sinus rhythm.4 Furthermore, the percentage of strokes that can be attributed to AF increases steeply with age, with rates of 1.5% in patients aged 50 to 59 years and 23.5% in those aged 80 to 89 years.4 The term “nonvalvular atrial fibrillation” (NVAF) is used to describe cases of AF that occur in the absence of rheumatic mitral valve disease, mitral valve repair, or a prosthetic heart valve.8 NVAF affects approximately 85% of the overall population with AF and is a substantial medical burden for Medicare beneficiaries (aged ≥65 years) in the United States.9,10The current evidence-based clinical guidelines recommend the use of oral anticoagulation in patients with NVAF who are at an intermediate to high risk for stroke.8,11 Although the efficacy of oral anticoagulation therapy to prevent stroke in patients with NVAF is well-established, it is also associated with a risk of bleeding.12–15 Understanding the relative economic burdens of stroke and major hemorrhage is important when considering the costs and benefits of anticoagulation therapy.Several studies have reported the incremental costs associated with stroke alone or with hemorrhage alone using different NVAF payer populations (ie, commercial or Medicare), and a few recent studies have provided incremental cost data for stroke and hemorrhage for the Medicare population, reporting significant incremental costs in the year after the stroke or hemorrhage index dates.7,16–20 Other studies have analyzed the incremental costs associated with stroke alone or with hemorrhage alone, or have analyzed these costs for a commercial population with NVAF.21–24 Most of these studies were done in separate patient populations and different time periods, making assessment of the relative economic burden of stroke versus bleeding difficult. By contrast, our study provides the cost estimates for these 2 conditions simultaneously based on the same patient population, which allows a more appropriate comparison of the economic implication of these 2 major consequences of oral anticoagulation therapy for the prevention of stroke among patients with NVAF.The prespecified objective in our study was to assess the relative economic burden (including Medicare Part D costs) associated with ischemic stroke and with major hemorrhagic events (ie, intracranial and gastrointestinal [GI] bleeding) among Medicare beneficiaries with newly diagnosed NVAF in the 12 months after the NVAF index diagnosis.     

Whole-Genome Characterization of Epidemic Neisseria meningitidis Serogroup C and Resurgence of Serogroup W,Niger, 2015

In 2015, Niger reported the largest epidemic of Neisseria meningitidis serogroup C (NmC) meningitis in sub-Saharan Africa. The NmC epidemic coincided with serogroup W (NmW) cases during the epidemic season, resulting in a total of 9,367 meningococcal cases through June 2015. To clarify the phylogenetic association, genetic evolution, and antibiotic determinants of the meningococcal strains in Niger, we sequenced the genomes of 102 isolates from this epidemic, comprising 81 NmC and 21 NmW isolates. The genomes of 82 isolates were completed, and all 102 were included in the analysis. All NmC isolates had sequence type 10217, which caused the outbreaks in Nigeria during 2013–2014 and for which a clonal complex has not yet been defined. The NmC isolates from Niger were substantially different from other NmC isolates collected globally. All NmW isolates belonged to clonal complex 11 and were closely related to the isolates causing recent outbreaks in Africa.Key words: Meningococcal meningitis, Neisseria meningitidis serogroup C, whole-genome sequencing, Niger, meningitis belt, bacteriaNeisseria meningitidis commonly causes meningitis in the African meningitis belt, where periodic meningococcal epidemics have contributed to the highest reported incidence of meningococcal meningitis in the world (1). Most meningococcal disease historically has been caused by N. meningitidis serogroup A (NmA); however, NmA disease dramatically decreased after the preventative MenAfriVac vaccination campaign was initiated in 2010 (2). Serogroup W (NmW) has been the major cause of meningococcal disease in the region since then (2).N. meningitidis serogroup C (NmC) disease has rarely been reported in the meningitis belt; it has not been detected in many molecular studies of invasive isolates (3,4) and is rarely found in carriage studies (5,6). The last large NmC epidemic in Africa occurred in Burkina Faso (then Upper Volta) in 1979 (7). During 2013 and 2014, NmC outbreaks were reported in Nigeria (8). The Nigerian outbreaks were caused by a novel NmC strain with a previously undescribed sequence type, 10217 (ST-10217), which does not belong to a defined clonal complex. In 2015, an epidemic of 9,367 meningococcal meningitis cases occurred in Niger, with NmC disease comprising most laboratory-confirmed cases (9).NmW disease has been reported in the meningitis belt since the 1980s (10,11), and NmW from clonal complex 11 (CC11) has been a major concern in the region since 2001 (12). The first large epidemic of disease caused by CC11 NmW occurred during 2002 in Burkina Faso (13). Subsequently, NmW disease outbreaks were reported in Niger during 2010 and 2011, both involving CC11 (14). These outbreaks were followed by another large epidemic caused by CC11 NmW in Burkina Faso during 2012 (15). Whole-genome sequencing (WGS) analysis of diverse NmW isolates from around the world has demonstrated that a clone within CC11, commonly associated with NmC, became globally dispersed after it switched to serogroup W (16,17). WGS analyses also provided sufficient resolution to assign isolates from the meningitis belt to a long-standing regional population and to a clone that became globally dispersed after an outbreak during the 2000 Hajj pilgrimage (16,17; A. Retchless, unpub. data).In addition to distinguishing among closely related strains, WGS provides information about allelic variation in genes that may affect antibiotic susceptibility and the coverage of protein-based vaccines. Two vaccines designed for serogroup B meningococcus have been approved for use in the United States and Europe: Trumenba and Bexsero. Trumenba targets the factor H–binding protein (FHbp), and includes components belonging to FHbp subfamilies A and B (18). Bexsero includes 4 different components: an FHbp of variant 1 (subfamily B); a Neisseria adhesion A protein (NadA); a neisserial heparin-binding antigen (NhbA); and outer membrane vesicles from a serogroup B strain containing PorA P1.4 (19). Recognizing the diversity of these genes among strains can aid in evaluating whether these vaccines may provide protection. Likewise, whole-genome sequences can be rapidly screened for indications of antibiotic resistance when the genetic determinants are well characterized, as with genes penA, gyrA, and rpoB, which are involved in reduced susceptibility to penicillin, ciprofloxacin, and rifampin, respectively. To clarify the meningococcal population in Niger during the 2015 epidemic season, we completed genomic analysis on the 102 NmC and NmW invasive isolates collected during this period.