Maura Marcucci

Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH).

Summary.  Background:  In patients with unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulation is anchored on estimating the risk of disease recurrence.

Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review

Summary.  Background: Different rates of inhibitor development after either plasma‐derived (pdFVIII) or recombinant (rFVIII) FVIII have been suggested. However, conflicting results are reported in the literature. Objectives: To systematically review the incidence rates of inhibitor development in previously untreated patients (PUPs) with hemophilia A treated with either pdFVIII or rFVIII and to explore the influence of both study and patient characteristics. Methods: Summary incidence rates (95% confidence interval) from all included studies for both pdFVIII and rFVIII results were recalculated and pooled. Sensitivity analysis was used to investigate the effect of study design, severity of disease and inhibitor characteristics. Meta‐regression and analysis‐of‐variance were used to investigate the effect of covariates (testing frequency, follow‐up duration and intensity of treatment). Results: Two thousand and ninety‐four patients (1167 treated with pdFVIII, 927 with rFVIII; median age, 9.6 months) from 24 studies were investigated and 420 patients were observed to develop inhibitors. Pooled incidence rate was 14.3% (10.4–19.4) for pdFVIII and 27.4% (23.6–31.5) for rFVIII; high responding inhibitor incidence rate was 9.3% (6.2–13.7) for pdFVIII and 17.4% (14.2–21.2) for rFVIII. In the multi‐way anova study design, study period, testing frequency and median follow‐up explained most of the variability, while the source of concentrate lost statistical significance. It was not possible to analyse the effect of intensity of treatment or trigger events such as surgery, and to completely exclude multiple reports of the same patient or changes of concentrate. Conclusions: These findings underscore the need for randomized controlled trials to address whether or not the risk of inhibitor in PUPs with hemophilia A differs between rFVIII and pdFVIII.

Risk of Recurrence After a First Episode of Symptomatic Venous Thromboembolism Provoked by a Transient Risk Factor: A Systematic Review

BACKGROUND We aimed to determine the risk of recurrence for symptomatic venous thromboembolism (VTE) provoked by different transient risk factors. DATA SOURCES MEDLINE, EMBASE, and Cochrane Collaboration Registry of Randomized Trials databases were searched. STUDY SELECTION Prospective cohort studies and randomized trials of patients with a first episode of symptomatic VTE provoked by a transient risk factor and treated for at least 3 months were identified. DATA EXTRACTION Number of patients and recurrent VTE during the 0- to 12-month and 0- to 24-month intervals after stopping therapy, study design, and provoking risk factor characteristics were extracted. DATA SYNTHESIS Annualized recurrence rates were calculated and pooled across studies. At 24 months, the rate of recurrence was 3.3% per patient-year (11 studies, 2268 patients) for all patients with a transient risk factor, 0.7% per patient-year (3 studies, 248 patients) in the subgroup with a surgical factor, and 4.2% per patient-year (3 studies, 509 patients) in the subgroup with a nonsurgical factor. In the same studies, the rate of recurrence after unprovoked VTE was 7.4% per patient-year. The rate ratio for a nonsurgical compared with a surgical factor was 3.0 and for unprovoked thrombosis compared with a nonsurgical factor was 1.8 at 24 months. CONCLUSIONS The risk of recurrence is low if VTE is provoked by surgery, intermediate if provoked by a nonsurgical risk factor, and high if unprovoked. These risks affect whether patients with VTE should undergo short-term vs indefinite treatment.

Risk of recurrence after venous thromboembolism in men and women: patient level meta-analysis

Objective To determine the effect of sex on the risk of recurrent venous thromboembolism in all patients and in patients with venous thromboembolism that was unprovoked or provoked (by non-hormonal factors). Data source Comprehensive search of electronic databases (Medline, Embase, CINAHL, Cochrane Central Register of Controlled Trials) until July 2010, supplemented by review of conference abstracts and contact with content experts. Study selection Seven prospective studies investigating an association between D-dimer, measured after anticoagulation was stopped, and disease recurrence in patients with venous thromboembolism. Data extraction Patient level databases were obtained, transferred to a central database, checked, and completed with further information provided by authors. Data synthesis 2554 patients with a first venous thromboembolism had follow-up for a mean of 27.1 (SD 19.6) months. The one year incidence of recurrent venous thromboembolism was 5.3% (95% confidence interval 4.1% to 6.7%) in women and 9.5% (7.9% to 11.4%) in men, and the three year incidence of recurrence was 9.1% (7.3% to 11.3%) in women and 19.7% (16.5% to 23.4%) in men. Among patients with unprovoked venous thromboembolism, men had a higher risk of recurrence than did women (hazard ratio 2.2, 95% confidence interval 1.7 to 2.8). After adjustment for women with hormone associated initial venous thromboembolism, the risk of recurrence remained higher in men (hazard ratio 1.8, 1.4 to 2.5). In patients with provoked venous thromboembolism, occurring after exposure to a major risk factor, recurrence of disease did not differ between men and women (hazard ratio 1.2, 0.6 to 2.4). In women with hormone associated venous thromboembolism and no other risk factors, recurrence was lower than that in women with unprovoked venous thromboembolism and no previous hormone use (hazard ratio 0.5, 0.3 to 0.8). Conclusion In patients with a first unprovoked venous thromboembolism, men have a 2.2-fold higher risk of recurrent venous thromboembolism than do women, which remained 1.8-fold higher in men after adjustment for previous hormone associated venous thromboembolism in women. In patients with a first provoked venous thromboembolism, risk of recurrence does not differ between men and women with or without hormone associated venous thromboembolism. Indefinite anticoagulation may be given greater consideration in men than in women after a first venous thromboembolism.

A tutorial on sensitivity analyses in clinical trials: the what, why, when and how

BackgroundSensitivity analyses play a crucial role in assessing the robustness of the findings or conclusions based on primary analyses of data in clinical trials. They are a critical way to assess the impact, effect or influence of key assumptions or variations—such as different methods of analysis, definitions of outcomes, protocol deviations, missing data, and outliers—on the overall conclusions of a study.The current paper is the second in a series of tutorial-type manuscripts intended to discuss and clarify aspects related to key methodological issues in the design and analysis of clinical trials.DiscussionIn this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sensitivity analyses; and 4) some suggestions on how to report the results of sensitivity analyses in clinical trials.SummaryWhen reporting on a clinical trial, we recommend including planned or posthoc sensitivity analyses, the corresponding rationale and results along with the discussion of the consequences of these analyses on the overall findings of the study.

Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient-level meta-analysis

Summary.  Aim: To determine if the mode of presentation of venous thromboembolism (VTE), as deep vein thrombosis (DVT) or pulmonary embolism (PE), predicts the likelihood and type of recurrence. Methods: We carried out a patient‐level meta‐analysis of seven prospective studies in patients with a first VTE who were followed after anticoagulation was stopped. We used Kaplan‐Meier analysis to determine the cumulative incidence of recurrent VTE according to mode of presentation, and multivariable Cox regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for mode of and extent of DVT as potential risk factors for recurrence. Results: The 5‐year cumulative rate of recurrent VTE in 2554 patients was 22.6%. In 869 (36.1%) patients with PE, the 5‐year rate of any recurrence (DVT or PE) was 22.0%, and recurrence as PE was 10.6%. In 1365 patients with proximal DVT, the 5‐year recurrence rate was 26.4%, and recurrence with PE was 3.6%. The risk of recurrence as PE was 3.1‐fold greater in patients presenting with symptomatic PE than in patients with proximal DVT (HR, 3.1; 95% CI, 1.9–5.1). Patients with proximal DVT had a 4.8‐fold higher cumulative recurrence rate than those with distal DVT (HR, 4.8; 95% CI, 2.1–11.0). Conclusion: Whilst DVT and PE are manifestations of the same disease, the phenotypic expression is predetermined. Patients presenting with PE are three times more likely to suffer recurrence as PE than patients presenting with DVT. Patients presenting with calf DVT are at low risk of recurrence and at low risk of recurrence as PE.

Patient-Level Meta-analysis: Effect of Measurement Timing, Threshold, and Patient Age on Ability of d-Dimer Testing to Assess Recurrence Risk After Unprovoked Venous Thromboembolism

BACKGROUND In patients with a first unprovoked venous thromboembolism (VTE), an elevated d-dimer level after anticoagulation is stopped is a risk factor for recurrent VTE. However, questions remain about the utility of measuring d-dimer in clinical practice. PURPOSE To determine whether the timing of testing, patient age, and the cut point used to define a positive or negative result affect the ability of d-dimer testing to distinguish risk for recurrent disease. DATA SOURCES Comprehensive search of electronic databases (MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials) until July 2010, supplemented by reviewing conference abstracts and contacting content experts. STUDY SELECTION 7 prospective studies that investigated an association between d-dimer, measured after stopping anticoagulation, and disease recurrence in patients with a first unprovoked VTE (proximal deep venous thrombosis, pulmonary embolism, or both). DATA EXTRACTION Patient-level databases were obtained, transferred to a central database, checked, completed with further information provided by study investigators, and pooled into a single database. DATA SYNTHESIS 1818 patients with a first unprovoked VTE were followed for a mean of 26.9 months (SD, 19.1). A study-stratified multivariate Cox regression model, which included patient age, sex, hormone therapy use at the time of the index event, body mass index, timing of postanticoagulation d-dimer testing, and inherited thrombophilia as possible confounders, indicated that the hazard ratio for d-dimer status (positive vs. negative) was 2.59 (95% CI, 1.90 to 3.52). Only male sex had a significant effect on risk for recurrent VTE independent of d-dimer status. The Cox regression model and the log-rank test confirmed that the risk for recurrent VTE was higher in patients with a positive d-dimer result than in those with a negative result, regardless of the timing of postanticoagulation d-dimer testing or patient age. No study- or assay-specific d-dimer effect was found, and reassessing the analysis after recoding data according to specific quantitative d-dimer cut points (500 µg/L and 250 µg/L) did not change the results. LIMITATIONS Unmeasured variables could have affected the risk for recurrent VTE. The study population was predominantly white. CONCLUSION In patients with a first unprovoked VTE who have their d-dimer level measured after stopping anticoagulation, the timing of d-dimer testing, patient age, and the assay cut point used do not affect the ability of d-dimer to distinguish patients with a higher or lower risk for recurrent VTE.

Prevalence and appropriateness of drug prescriptions for peptic ulcer and gastro-esophageal reflux disease in a cohort of hospitalized elderly.

BACKGROUND Proton pump inhibitors (PPI) are among the most commonly prescribed medicines and their overuse is widespread in both primary and secondary care. Inappropriate prescription is of particular concern among elderly patients, who have often multiple comorbidities and need many drugs. METHODS We evaluate the appropriateness of drugs for peptic ulcer or gastro-esophageal reflux disease (GERD) in a sample of elderly patients (65 years old or older) at admission and discharge in 38 internal medicine wards between January 2008 and December 2008, according to the presence of specific conditions or gastro-toxic drug combinations. RESULTS Among 1155 patients eligible for the analysis, 466 (40.3%) were treated with drugs for GERD or peptic ulcer were at hospital admission and 647 (56.0%) at discharge; 62.4% of patients receiving a drug for peptic ulcer or GERD at admission and 63.2% at discharge were inappropriately treated. Among these, the number of other drugs prescribed was associated with greater use of drugs for peptic ulcer or GERD, even after adjustment for age, sex and number of diagnoses at admission (OR 95% CI=1.26 (1.18-1.34), p=.0001) or discharge (OR 95% CI=1.11 (1.05-1.18), p=0.0003). CONCLUSIONS Prevalence of inappropriate prescription of drugs for peptic ulcer or GERD remained almost the same at admission and discharge. Inappropriate use of these drugs is related to the concomitant use of other drugs. Careful assessment of clinical conditions and stricter adherence to evidence-based guidelines are essential for a rational and cost-effective use of drugs for peptic ulcer or GERD.

Association between clusters of diseases and polypharmacy in hospitalized elderly patients: Results from the REPOSI study

BACKGROUND Although the association between multimorbidity and polypharmacy has been clearly documented, no study has analyzed whether or not specific combinations of diseases influence the prescription of polypharmacy in older persons. We assessed which clusters of diseases are associated with polypharmacy in acute-care elderly in-patients. METHODS This cross-sectional study was held in 38 Italian internal medicine and geriatric wards participating in the Registro Politerapie SIMI (REPOSI) study during 2008. The study sample included 1155 in-patients aged 65 years or older. Clusters of diseases, defined as two or more co-occurring specific chronic diseases, were identified using the odds ratio (OR) for the associations between pairs of diseases followed by cluster analysis. Polypharmacy was defined as the prescription of five or more different medications at hospital discharge. Logistic regression models were run to analyze the association between clusters of diseases and polypharmacy. RESULTS Among clusters of diseases, the highest mean number of drugs (>8) was found in patients affected by heart failure (HF) plus chronic obstructive pulmonary disease (COPD), HF plus chronic renal failure (CRF), COPD plus coronary heart disease (CHD), diabetes mellitus plus CRF, and diabetes mellitus plus CHD plus cerebrovascular disease (CVD). The strongest association between clusters of diseases and polypharmacy was found for diabetes mellitus plus CHD plus CVD, diabetes plus CHD, and HF plus atrial fibrillation (AF). CONCLUSIONS The observed knowledge of the relationship among co-occurring diseases and polypharmacy should help to identify and monitor older in-patients at risk of polypharmacy.

Factors affecting adherence to guidelines for antithrombotic therapy in elderly patients with atrial fibrillation admitted to internal medicine wards

INTRODUCTION Current guidelines for ischemic stroke prevention in atrial fibrillation or flutter (AFF) recommend Vitamin K antagonists (VKAs) for patients at high-intermediate risk and aspirin for those at intermediate-low risk. The cost-effectiveness of these treatments was demonstrated also in elderly patients. However, there are several reports that emphasize the underuse of pharmacological prophylaxis of cardio-embolism in patients with AFF in different health care settings. AIMS To evaluate the adherence to current guidelines on cardio-embolic prophylaxis in elderly (> 65 years old) patients admitted with an established diagnosis of AFF to the Italian internal medicine wards participating in REPOSI registry, a project on polypathologies/polytherapies stemming from the collaboration between the Italian Society of Internal Medicine and the Mario Negri Institute of Pharmacological Research; to investigate whether or not hospitalization had an impact on guidelines adherence; to test the role of possible modifiers of VKAs prescription. METHODS We retrospectively analyzed registry data collected from January to December 2008 and assessed the prevalence of patients with AFF at admission and the prevalence of risk factors for cardio-embolism. After stratifying the patients according to their CHADS(2) score the percentage of appropriateness of antithrombotic therapy prescription was evaluated both at admission and at discharge. Univariable and multivariable logistic regression models were employed to verify whether or not socio-demographic (age >80years, living alone) and clinical features (previous or recent bleeding, cranio-facial trauma, cancer, dementia) modified the frequency and modalities of antithrombotic drugs prescription at admission and discharge. RESULTS Among the 1332 REPOSI patients, 247 were admitted with AFF. At admission, CHADS(2) score was ≥ 2 in 68.4% of patients, at discharge in 75.9%. Among patients with AFF 26.5% at admission and 32.8% at discharge were not on any antithrombotic therapy, and 43.7% at admission and 40.9% at discharge were not taking an appropriate therapy according to the CHADS(2) score. The higher the level of cardio-embolic risk the higher was the percentage of antiplatelet- but not of VKAs-treated patients. At admission or at discharge, both at univariable and at multivariable logistic regression, only an age >80 years and a diagnosis of cancer, previous or active, had a statistically significant negative effect on VKAs prescription. Moreover, only a positive history of bleeding events (past or present) was independently associated to no VKA prescription at discharge in patients who were on VKA therapy at admission. If heparin was considered as an appropriate therapy for patients with indication for VKAs, the percentage of patients admitted or discharged on appropriate therapy became respectively 43.7% and 53.4%. CONCLUSION Among elderly patients admitted with a diagnosis of AFF to internal medicine wards, an appropriate antithrombotic prophylaxis was taken by less than 50%, with an underuse of VKAs prescription independently of the level of cardio-embolic risk. Hospitalization did not improve the adherence to guidelines.