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Response We thank Mark Crowther and his colleagues for the comments that they have made on our paper.[1][1] While we welcome their opinions, it is worth noting that systematic reviews and meta-analyses are areas where opinions differ, controversy remains, and comments on published work are common

Introduction : Knowing the prevalence of ITP is important to determine the burden of this rare disease. Multiple new thrombopoietin agonists are being developed for the treatment of ITP, despite the paucity of reliable and generalizable estimates of ITP prevalence. Only two studies have previously reported the prevalence of ITP in the United States (US) (the only other prevalence estimate focused on children with chronic ITP in the United Kingdom). Segal et al (J Thromb Haemost2006; 4:2377–2383) report a one-year age adjusted prevalence of 9.5 per 100,000 persons aged 1–64 years; Feudjo-Tepie et al (J Thromb Haemost2008; 6:711–712) report a one-year prevalence of adult chronic ITP of 23.6 per 100,000 adults 318 years of age. Both studies based their estimates on private insurance claims data. The goal of this study was to determine the prevalence of ITP in all patients in the State of Oklahoma, regardless of insurance status and age. Methods : Similar to the previous 2 studies, the ICD-9-CM code of 287.3 was used to identify ITP. Unlike the previous 2 studies, we obtained data directly and entirely from hematologists. In November 2007, there were 93 hematologists in Oklahoma who cared for ITP patients. Our preliminary data documented that hematologists saw 3 92% of all patients with ITP and that primary care physicians in Oklahoma reported they were ‘likely’ to refer 85% of patients with platelet counts 16 years), and the overall population. The denominator was the Oklahoma population (US Census 2000). Results : The 2003 prevalence estimates were: 8.8 per 100,000 children, 11.6 per 100,000 adults, and 11.0 overall per 100,000 persons. The 2004 prevalence estimates were: 7.4 per 100,000 children, 12.6 per 100,000 adults, and 11.4 overall per 100,000 persons. The average annual prevalence estimates were: 8.1 per 100,000 children (95% CI 6.7, 9.5), 12.1 per 100,000 adults (95%CI 11.1, 13.0), and overall 11.2 per 100,000 persons (95% CI 10.4, 12.0). The children were 51% female, 49% male, and the average age was six years. Adults were 57% female, 43% male, and the average age was 55 years. Conclusion : This is the first population based study to determine the prevalence of ITP for an entire defined geographic region, regardless of insurance status and age. These results represent the most generalizable estimates of prevalence currently available on which to determine the burden of ITP. Results from this study should be generalizable because the demographics of Oklahoma closely resemble the demographics of the US. Additionally, these results confirm and extend the previously published prevalence estimate of Segal et al, 2006. This information is important not only for pharmaceutical companies, regulatory agencies, and heath care authorities, but also for patients with ITP.

Background: Since the introduction of plasmapheresis, TTP-associated mortality has declined from 90% to 10–20%. However, 20–50% of patients experience recurrent disease. The goal of this study was to describe the clinical spectrum of TTP, determine the clinical outcome of patients with TTP and identify risk factors for disease relapse or recurrence. Methods: We retrospectively reviewed consecutive TTP patients treated between January 1992 and April 2008 at the Johns Hopkins Hospital. Complete demographic, clinical, laboratory, treatment, and response data were collected. A standard treatment protocol of corticosteroids (Methylprednisolone 100 mg IV q12h) and daily plasmapheresis (1.5 plasma volumes) was used during the study period. Rituximab, azathioprine and vincristine were employed in refractory or relapsing patients at physician’s discretion. Logistic regression was used to examine the association of clinical and laboratory parameters with four ordered outcome categories in TTP survivors: relapse ( Results: A total of 75 patients and 138 episodes of TTP were treated during the study period. Microangiopathic hemolytic anemia was noted in all cases. The median follow-up was 31.5 months (IQR 6 – 76 months). The median age was 42 years (range 13–82). Of the 75 patients, 73% were females and 56% were African American. 68% of the TTP episodes presented acutely (< 1 week), while 25% were subacute (1–4 weeks) and 7% had a chronic presentation (≥ 1 month). Neurologic abnormalities were present in 67% episodes while 35% had abnormal renal function on admission; 95% and 90% resolved on discharge or during follow-up, respectively. The median platelet count on admission was 15×103/μL (range 1 – 144) and the median lactate dehydrogenase (LDH) value was 927U/L (range 152 – 5950). The mean time for platelet recovery was 10 days (range 2 – 48) while the mean time for LDH recovery was 20 days (range 2 – 100) (p < 0.0001). The mean length of hospital stay for each episode was 21 days (range 1 – 84). ADAMTS13 results were available in 45 episodes (39 patients) — 69% had severe ADAMTS13 deficiency (25%). Inhibitors were present in 74% of episodes with severe ADAMTS13 deficiency and 60% of episodes with moderate deficiency. All patients received plasmapheresis and most (95%) received corticosteroid treatment. The mean time from admission to plasmapheresis initiation was 1.9 days (range 1– 14). The mean number of pheresis sessions required to achieve a complete remission was 17 (range 3 – 66) over a total of 22 days (range 3 – 89). The mortality rate was 4% in both first-episode patients and all TTP episodes. The relapse/recurrence rate was 44% in first-episode patients and 50% in all TTP episodes. The average time-to-relapse/recurrence was 14 months (range 0.07–93 months) and 83% of relapses or recurrences occurred during the first two years. When categorized into four different outcome groups (i.e. relapse vs. early recurrence vs. late recurrence vs. remission), patients who relapsed were more likely to be African American (p = 0.002), had a higher platelet count (p = 0.02) and white blood cell count (p = 0.009) on admission and a higher LDH value on discharge (p = 0.031). There was no significant difference in ADAMTS13 results among the four groups. In a secondary analysis when we pooled all suboptimal outcomes, we found that African American patients had an odds of remission that was just 0.42 (p=0.042) that of Caucasians. Episodes with an admission platelet count in the upper quartile (mean of 82 x103/μL) were 2.9 times (95% confidence interval 1.2 to 6.8) more likely to have a suboptimal outcome than episodes with platelet count in the lowest quartile (mean of 8 x103/μL). Analysis restricted to the first-episode patients yielded similar outcomes. Conclusion: Using a standardized protocol of daily plasmapheresis and high-dose corticosteroids we have achieved a low mortality rate (4%) in patients with TTP. Risk factors for recurrence include African American ethnicity and high platelet counts on admission. If these risk factors remain valid in prospective studies, they may prove useful in identifying TTP patient in whom more aggressive initial treatment (e.g., Rituximab, etc.) may be warranted.

Introduction: Venous thromboembolism (VTE) is increasingly diagnosed among individuals with hematologic malignancies. It is unclear whether patients undergoing hematopoietic stem cell transplantation (HSCT) are at risk for VTE. We aimed to describe the incidence of VTE and risk factors among patients undergoing HSCT. Methods: Using ICD-9 procedure codes in a discharge database, we identified all patients undergoing inpatient HSCT at Johns Hopkins between July 1, 1993, and June 30, 2005. We reviewed electronic medical records for each patient to identify VTE and bleeding. The associations between VTE and clinical characteristics were tested using parametric and non-parametric statistical tests and survival analysis methods. Results: 1,570 patients had 3,425 person-years of follow-up. Median age was 46 years and 51% of patients were male. All patients had indwelling central venous catheters; pharmacological VTE prophylaxis was not used for any patient but ambulation was encouraged. Between admission and 180 days after HSCT, 75 VTE occurred in 70 patients (4.5%; 95% CI, 3.5–5.6%). VTE included 55 (73%) catheter-associated and 11 (15%) non-catheter-associated deep venous thromboses (DVT), and 9 (12%) pulmonary emboli (PE). Median platelet count at time of VTE was 77 K/mm3 (interquartile range [IQR] 42–159 K/mm3), and platelet count was < 50 K/mm3 at the time of VTE in 31% of cases. In multivariate analyses, VTE was associated with a history of prior VTE (OR 2.86; 95% CI, 1.25–6.55) and with graft-versus-host-disease (GVHD) (OR 2.36; 95% CI, 1.38–4.04). 86% of patients received anticoagulation for treatment. Clinically significant bleeding occurred in 238 patients after HSCT (15%), of whom 56 patients had fatal bleeding. Bleeding was associated with GVHD (OR 2.32; 95% CI, 1.71–3.16) and with initiation of anticoagulation for VTE diagnosed after HSCT (OR=3.00; 95% CI, 1.73–5.21). Bleeding was not associated with the continuation of anticoagulation initiated prior to admission (OR=1.13; 95% CI, 0.54–2.35). Conclusions: VTE occurs relatively infrequently among patients undergoing HSCT and primarily in association with central venous catheter use. In contrast, clinically significant bleeding is a relatively common complication of HSCT, even in the absence of pharmacologic VTE prophylaxis. The unique hemostatic milieu associated with HSCT should be carefully considered when contemplating routine VTE prophylaxis in this patient population. The low risk of VTE associated with the high risk of bleeding makes pharmacologic VTE prophylaxis in this population both unnecessary and hazardous.

New treatments are available for venous thromboembolism. This background paper to the guidelines on treatment of venous thromboembolism from the American College of Physicians and the American Acad...

ContextRecent randomized trials suggest that women may not accrue the same cardioprotective benefits as men do from low-dose aspirin therapy used in primary prevention. Failure of aspirin to suppress platelet aggregation in women is one hypothesized mechanism.ObjectiveTo examine differential platelet reactivity to low-dose aspirin therapy by sex.Design, Setting, and ParticipantsA clinical trial of aspirin at 81 mg/d for 14 days was conducted in 571 men and 711 women. Baseline and post–aspirin therapy measures included platelet aggregation to arachidonic acid, adenosine diphosphate, epinephrine, and platelet function analyzer closure time.Main Outcome MeasureSex differences in cyclooxygenase 1 (COX-1) direct and indirect platelet activation pathways before and after administration of aspirin.ResultsIn 10 of the 12 platelet agonist exposures, women's platelets were significantly more reactive at baseline. However, after aspirin therapy, the percent aggregation to arachidonic acid (the direct COX-1 pathway) decreased more in women than in men (P

Background: Patients with immune thrombocytopenic purpura (ITP) infected with Helicobacter pylori (H. pylori) are often treated with antibiotics to eradicate infection and raise platelet counts. We aimed to systematically review the evidence regarding this practice to better quantify response rate. Study Design and Methods: We searched MEDLINE through April 2005, without language restriction; reviewed reference lists and queried experts for articles describing treatment of ITP with antibiotics targeting H. pylori. We included studies of any design involving more than 5 patients. Response rates were tabulated using the authors’ definitions, and pooled using a random effects model. Techniques of meta-regression were used to assess whether patient or study characteristics influenced response rates. Results: We retrieved 52 potentially eligible studies. Of these, 16 studies met our inclusion criteria. From 10 studies, we had individual level patient data. None of the studies was a controlled trial. The pooled response rate (both partial and complete responses) was 45% [95% confidence interval (C.I.) 32% to 58%]. The number of previous treatments (0–1, 2, 3 or more) influenced the response rate with an 18% (p=0.001) decline in response rate with each higher category; duration of disease did not independently predict response. In analyses of individual patient data, quartile of platelet count upon entry also influenced response rate; 58% of patients in the highest quartile responded compared to 34% in the lowest quartile (p=0.018). Conclusions: No randomized controlled trial has tested H. pylori eradication with antibiotics as a treatment for ITP. The sixteen observational studies we reviewed were fairly consistent with approximately half of treated patients having a platelet response to therapy. Without control groups, these studies do not provide strong evidence to support practice recommendations. However, given the low toxicity of antibiotic therapy, this treatment may be appropriate for patients who have not demonstrated refractoriness to multiple therapies. Response Rates by Number of Previous Treatments Response Rates by Number of Previous Treatments

Introduction: Heparin-induced thrombocytopenia (HIT) is a syndrome in which anti-platelet factor 4/heparin antibodies (HITab) and thrombocytopenia develop after heparin exposure. While HIT is an established risk factor for arterial and venous thromboses, HITab, in the absence of thrombocytopenia, may also be a prothrombotic risk factor. As patients with chronic kidney disease on hemodialysis are chronically exposed to heparin, we hypothesized that the presence of HITab may contribute to the high rates of thrombotic disease and mortality in these patients. Patients and methods: We analyzed data from the CHOICE study, a prospective cohort study of incident dialysis patients. Clinical data were available from medical record review. Arterial cardiovascular events and events of vascular access occlusion were validated by chart review and adjudication. Venous thromboembolic events were defined by ICD-9 codes. Thrombocytopenia was defined as a platelet count 50% decline from a previous platelet count. Median duration of follow-up is 2.7 years. We measured HITab using a commercial ELISA assay in stored serum obtained 6 months after cohort enrollment of 740 participants (596 on hemodialysis, 144 on peritoneal dialysis). ELISA results were corrected for inter-plate variability. A positive HITab test associated with thrombocytopenia in the subsequent three months was considered compatible with HIT. We used techniques of logistic regression and of survival analysis with adjustment for potential confounders in our analyses. Results: 10.3% of all patients were positive for HITab at six months. HITab positivity was not associated with thrombocytopenia. HITab did not predict subsequent outcomes including cardiovascular (hazard ratio (HR) 0.96, 95% confidence interval (CI) 0.65–1.41), vascular access occlusive (HR 0.82, CI 0.40–1.71), or venous thromboembolic events (HR 1.39, CI 0.17–11.5) and did not predict mortality (HR 1.00, CI 0.66–1.53). 9 patients (1.2%) had results compatible with HIT (thrombocytopenia + HITab). 1 patient with HIT (0.13%) had venous thrombosis yielding a hazard ratio of 13.7 (CI 1.63–115.5) for HIT and thrombosis. Conclusions: HITab seropositivity after six months of dialysis is frequent, but is not associated with thrombocytopenia. In end-stage renal disease patients treated by dialysis HITab seropositivity in the absence of thrombocytopenia is not an independent risk factor for cardiovascular morbidity or mortality. However, HIT may occur in this patient population and is associated with thrombosis.

Background: The possibility of variation in platelet count by age and genetic background has not been examined. Identification of subpopulations with elevated platelet counts, within what is traditionally considered a normal range, may identify a group with excessive morbidity or mortality. Furthermore, platelet count differences may suggest populations in which genetic polymorphisms in regulatory proteins such as the thrombopoietin receptor influence platelet production. We hypothesized that there were differences in platelet count by ethnicity, sex and age not explained by environmental factors. Objective: To demonstrate differences in mean platelet counts by ethnicity, sex, and age while controlling for variables known to influence platelet count. Methods and Design: We used data from the National Health, Nutrition and Examination Survey III (NHANES III), which is a multistage probability sample of the United States population with data collected between 1988 and 1994. Using appropriate weighting for the complex sampling design, the geometric mean platelet count was calculated for the total population and the population stratified by ethnicity, sex, and age, while controlling for C-reactive protein, white blood cell count, iron-deficiency, serum folate, markers of alcohol intake, presence of hepatitis B or C antibodies, and diabetes mellitus. Other potential influences, such as medications, were found not to affect the predicted counts and not included in the models. Results: The lowest mean platelet counts were among whites (259 K/ml [95% C.I. 255–264 K/ml]) and the highest were in non-Hispanic blacks (275 K/ml [95% C.I. 270–280 K/ml]) with Mexican-Americans having intermediate values (266 K/ml [95% C.I. 261–272 K/ml]), when controlled for age and sex. Older men and women of each ethnicity consistently had lower mean platelet counts, with 60–69 years olds having mean counts approximately 7 K/ml lower than young adults (p=0.015) and 70–90 year olds having mean counts 19 K/ml lower than young adults (p Conclusion: Mean platelet counts differ by ethnicity, sex, and age and these differences are not explained by covariates known to influence platelet count. This suggests that genetic influences on the platelet count are operative. These data also suggest that there may be a hormonal regulation of platelet count. The decline with age may reflect decreased stem cell function with age; alternatively, there may be a survival advantage to having a lower platelet count. Longitudinal studies of platelet count with aging are indicated.

This review, which supports the recommendations of the American Academy of Family Physicians and the American College of Physicians, summarizes the available evidence about the efficacy of medicati...

Post-marketing drug surveillance for adverse drug events (ADEs) has typically relied on spontaneous reporting. Recently, regulatory agencies have turned their attention to more preemptive approaches that use existing data for surveillance. We conducted an environmental scan to identify active surveillance systems worldwide that use existing data for the detection of ADEs. We extracted data about the systems’ structures, data, and functions. We synthesized the information across systems to identify common features of these systems. We identified nine active surveillance systems. Two systems are US based—the FDA Sentinel Initiative (including both the Mini-Sentinel Initiative and the Federal Partner Collaboration) and the Vaccine Safety Datalink (VSD); two are Canadian–the Canadian Network for Observational Drug Effect Studies (CNODES) and the Vaccine and Immunization Surveillance in Ontario (VISION); and two are European–the Exploring and Understanding Adverse Drug Reactions by Integrative Mining of Clinical Records and Biomedical Knowledge (EU-ADR) Alliance and the Vaccine Adverse Event Surveillance and Communication (VAESCO). Additionally, there is the Asian Pharmacoepidemiology Network (AsPEN) and the Shanghai Drug Monitoring and Evaluative System (SDMES). We identified two systems in the UK—the Vigilance and Risk Management of Medicines (VRMM) Division and the Drug Safety Research Unit (DSRU), an independent academic unit. These surveillance systems mostly use administrative claims or electronic medical records; most conduct pharmacovigilance on behalf of a regulatory agency. Either a common data model or a centralized model is used to access existing data. The systems have been built using national data alone or via partnership with other countries. However, active surveillance systems using existing data remain rare. North America and Europe have the most population coverage; with Asian countries making good advances. Electronic supplementary material The online version of this article (doi:10.1007/s40264-014-0194-3) contains supplementary material, which is available to authorized users.

In this chapter of the Evidence-based Practice Centers Methods Guide for Medical Tests, we describe how the decision to use a medical test generates a broad range of outcomes and that each of these outcomes should be considered for inclusion in a systematic review. Awareness of these varied outcomes affects how a decision maker balances the benefits and risks of the test; therefore, a systematic review should present the evidence on these diverse outcomes. The key outcome categories include clinical management outcomes and direct health effects; emotional, social, cognitive, and behavioral responses to testing; legal and ethical outcomes, and costs. We describe the challenges of incorporating these outcomes in a systematic review, suggest a framework for generating potential outcomes for inclusion, and describe the role of stakeholders in choosing the outcomes for study. Finally, we give examples of systematic reviews that either included a range of outcomes or that might have done so. The following are the key messages in this chapter: Consider both the outcomes that are relevant to the process of testing and those that are relevant to the results of the test. Consider inclusion of outcomes in all five domains: clinical management effects, direct test effects; emotional, social, cognitive and behavioral effects; legal and ethical effects, and costs. Consider to which group the outcomes of testing are most relevant. Given resource limitations, prioritize which outcomes to include. This decision depends on the needs of the stakeholder(s), who should be assisted in prioritizing the outcomes for inclusion.

ObjectivesThe purpose of this study was to determine if an incomplete response to or inadequate antiplatelet effect of aspirin, or both, contribute to saphenous vein graft (SVG) occlusion after coronary artery bypass graft (CABG) surgery.BackgroundThrombosis is the predominant cause of early SVG occlusion. Aspirin, which inhibits cyclooxygenase-1 activity and thromboxane generation in platelets, reduces early SVG occlusion by one-half.MethodsAspirin responsiveness and platelet reactivity were characterized 3 days and 6 months after coronary artery bypass graft surgery in 229 subjects receiving aspirin monotherapy by platelet aggregation to arachidonic acid, adenosine diphosphate, collagen and epinephrine, Platelet Function Analyzer-100 (Siemens Healthcare Diagnostics, Newark, Delaware) closure time (CT) using collagen/epinephrine agonist cartridge and collagen/adenosine diphosphate (CADP) agonist cartridge, VerifyNow Aspirin assay (Accumetrics, Inc., San Diego, California), and urine levels of 11-dehydro-thromboxane B2 (UTXB2). SVG patency was determined 6 months after surgery by computed tomography coronary angiography.ResultsInhibited arachidonic acid-induced platelet aggregation, indicative of aspirin-mediated cyclooxygenase-1 suppression, occurred in 95% and >99% of subjects 3 days and 6 months after surgery, respectively. Despite this, 73% and 31% of subjects at these times had elevated UTXB2. Among tested parameters, only UTXB2 and CADP CT measured 6 months after surgery correlated with outcome. By multivariate analysis, CADP CT of ≤88 s (odds ratio: 2.85, p = 0.006), target vessel diameter of ≤1.5 mm (odds ratio: 2.38, p = 0.01), and UTXB2 of ≥450 pg/mg creatinine (odds ratio: 2.59, p = 0.015) correlated with SVG occlusion. CADP CT and UTXB2 in combination further identified subjects at particularly high and low risk for SVG occlusion.ConclusionsAspirin-insensitive thromboxane generation measured by UTXB2 and shear-dependent platelet hyper-reactivity measured by Platelet Function Analyzer-100 CADP CT are novel independent risk factors for early SVG thrombosis after coronary artery bypass graft surgery.

This guideline summarizes the current approaches for the diagnosis of venous thromboembolism. The importance of early diagnosis to prevent mortality and morbidity associated with venous thromboembolism cannot be overstressed. This field is highly dynamic, however, and new evidence is emerging periodically that may change the recommendations. The purpose of this guideline is to present recommendations based on current evidence to clinicians to aid in the diagnosis of lower extremity deep venous thrombosis and pulmonary embolism.

Background Obesity affects cancer risk and treatment outcomes. Preventing weight gain may prevent some cancers, improve cancer outcomes, reduce cancer recurrence and increase cancer-related survival. We performed a systematic review to identify strategies to prevent weight gain in individuals with or at risk for breast cancer. Findings We included 2 studies from 27,879 citations. In premenopausal women at risk for breast cancer, a low fat diet prevented weight gain at 12 months. Among women with breast cancer, effective strategies to prevent weight gain included low-fat dietary counseling with self-management techniques. One trial reported on cancer outcomes, mortality and adverse events. Low-fat dietary counseling wilth self-management techniques lowers the risk breast cancer relapse by 24% compared with less intensive counseling with maintenance of nutritional status goal. There was no difference in overall mortality and no adverse events were observed. Conclusion Limited evidence suggests that women with or at risk for breast cancer may successfully employ dietary and exercise strategies to prevent weight gain for at least one year. Low fat dietary counseling may improve cancer outcomes in women with breast cancer. Future studies should confirm these findings and evaluate the impact of weight gain prevention on cancer incidence, recurrence and survival. Electronic supplementary material The online version of this article (doi:10.1186/2193-1801-2-277) contains supplementary material, which is available to authorized users.

Background The United States (U.S.) Food and Drug Administration, as protectors of public health, encourages generic drug development and use so that patients can access affordable medications. The FDA, however, has limited mechanisms to encourage generic drug manufacturing. Main results Generic drug manufacturers make decisions regarding development of products based on expected profitability, influenced by market forces, features of the reference listed drug, and manufacturing capabilities, as well as regulatory restrictions. Barriers to the development of generic drugs include the challenge of demonstrating bioequivalence of some products, particularly those that are considered to be complex generics. Conclusions We present here a focused review describing the influences on generic manufacturers who are prioritizing drugs for generic development. We also review proposed strategies that regulators may use to incentivize generic drug development.