Prognostic value of D-dimer in elderly patients with Pulmonary Embolism.

In a general population with acute Pulmonary Embolism (PE) elevated D-dimer concentrations associate with increased mortality. The aim of the study was to assess the ability of D-dimer to predict 30 and 90-days mortality in elderly patients with acute PE. Hemodynamically stable patients aged ≥65 years old with confirmed PE were included in this retrospective cohort study. A pulmonary computerized tomography angiography scan, D-dimer concentrations, simplified Pulmonary Embolism Severity Index (sPESI) variables and vital status were available for all patients. The study included 154 confirmed cases of PE (23.5 % of suspected), median age 79.1 years. D-dimer was higher in patients dead than in those alive at 30 (median 14,547 vs. 8340 ng/mL, p = 0.05) and 90 days (13,604 vs. 7973 ng/mL, p = 0.013). When adding D-dimer to sPESI, the discriminant capacity to predict mortality within 30 and 90 days was increased by 0.080 and 0.089, respectively. The contribution of D-dimer to the discriminating ability was NRI = 0.286 (95 % CI -0.198 to 0.770, p value: 0.247) at 30 days and NRI = 0.605 (95 % CI 0.223-0.988, p-value: 0.002) at 90 days.D-dimer concentration was associated with 30 and 90-days mortality and showed a higher discriminant capacity than sPESI alone to predict 90-days mortality. Adding D-dimer concentrations to sPESI score seems to improve its prognostic ability, supporting multivariable risk models as the best approach to estimate prognosis in elderly patients with PE.

Thromboprophylaxis with low-molecular-weight heparins: an assessment of the methodological quality of studies.

Low-molecular-weight heparin (LMWH) represents the standard of care for prophylaxis of venous thromboembolism (VTE). We conducted a review of the evidence supporting the use of the different LMWHs employed in VTE prophylaxis, in different clinical settings, and analyzed its progression over time. To evaluate the standards of methodological quality of studies, we elaborated a quality assessment tool. By electronic databases, PubMed, MEDLINE, and Scopus databases, 249 articles deemed eligible for the analysis were selected. Several LMWHs did not have publications in all clinical settings. Extended duration of prophylaxis was documented only for a few LMWH. The quality score yielded statistically significant differences between the medians of the four settings (p = 0.0021) with a higher score in major orthopedic surgery (median, 16; 95% confidence interval [CI], 15-16) when compared with general surgery (median, 14; 95% CI, 13-14; p < 0.001). Median score for studies published after the year 1990 was higher than for those published earlier (p < 0.001). We conclude that the quality of the studies supporting LMWH for VTE prophylaxis in the different clinical settings is not homogeneous and inferior for studies performed before the year 1990. Clinical interchangeability of LMWHs in clinical practice remains a critical issue, and the selection of a product should be based on evidence available for each agent, and for each clinical indication derived from clinical trials.

The dogma of aspirin: a critical review of evidence on the best monotherapy after dual antiplatelet therapy.

Dual antiplatelet therapy based on the combination of an adenosine diphosphate (ADP)-receptor antagonist plus aspirin has demonstrated to be more effective in reducing the rate of major ischemic vascular events compared to aspirin monotherapy in some clinical settings. The current controversy on the duration of dual antiplatelet therapy should not conceal another major issue: the choice of the more appropriate antiplatelet monotherapy after the dual treatment phase. The aim of this article is to critically analyze the available evidence in this topic. Data from studies like CAPRIE, MATCH, PROFESS, CHANCE, DAPT and others, raise questions as why antiplatelet monotherapy after the dual phase should only be based on aspirin, in spite of a lack of evidence surprisingly not highlighted by key opinion leaders and experts. We conclude that, whether ADP-receptor antagonist rather than aspirin may be proposed as monotherapy seems not only have no answer but also not place in the current specialists' analysis, as if a dogmatic approach were prevalent. Perhaps the time for an open debate on these topics is ripe.

The definition of valvular and non-valvular atrial fibrillation: results of a physicians' survey.

AIMS: To assess different aspects of the definition of valvular/non-valvular atrial fibrillation (AF) used in clinical practice by physicians who usually treat this condition. METHODS AND RESULTS: We prospectively conducted a web-based survey including cardiologists and internists who attended continuing medical education courses on cardiovascular medicine. A questionnaire was drawn up, containing 17 questions clustered into five main topics: (A) known rheumatic aetiology; (B) site/type of valve involvement; (C) prosthetic heart valve; (D) haemodynamic relevance; (E) miscellaneous. The overall response rate was 22.4% (21.1% for cardiologists and 24% for internists). Coexistence of both medical history of rheumatic disease and clinical signs of valvular involvement were considered as essential prerequisites for the diagnosis of rheumatic AF by half of the respondents, and one-third assumed that lone aortic valve disease was sufficient for AF to be defined as valvular. A similar proportion of respondents considered that in the presence of mitral regurgitation, AF had to be defined as valvular. The majority of responding physicians considered the degree of valvular defect of lesser importance for the definition of valvular or non-valvular origin of AF. CONCLUSION: We found important heterogeneity and uncertainties in the answers given by physicians who usually treat patients with AF, as evidence of the lack of precise and unique definitions of the origin of AF (valvular/non-valvular). It is urgent to issue clear widely accepted definitions of the origin of AF, which should improve clinical practice and research.

Warfarin and atrial fibrillation: from ideal to real the warfarin affaire.

Vitamin K Antagonists (VKAs) are widely used in clinical practice and nearly 1% of the entire population receives oral anticoagulation at least once in life. However, the rate of prescription of anticoagulation is low, compared to what it should be. No more than 50-60% of patients affected by atrial fibrillation (AF) receive anticoagulation. In the setting of AF, VKAs are safe and effective when properly managed, reducing stroke and systemic embolism by more than 60%. VKAs safety and effectiveness are closely related to the quality of anticoagulation (e.g. time in therapeutic range), and anticoagulation clinics offer the best management of anticoagulant therapy. However, a sizeable proportion of patients are managed elsewhere. In clinical practice, in the setting of AF, a low prescription rate of VKAs is frequently observed and this is due also to difficulties in managing laboratory monitoring and drug dose adjustment. The suboptimal management of therapy with VKAs leads to a lesser efficacy than that reported in clinical trials, and to an increase in adverse reactions. VKAs still remain the first and only available therapy for a number of diseases (e.g. valvular atrial fibrillation and mechanical prosthetic heart valves). Now, since approval of the new oral anticoagulants (NOAs), the choice of anticoagulant therapy in definite settings, such as stroke prevention in non-valvular atrial fibrillation (SPAF) or treatment of venous thromboembolism, has surely become more intriguing but also more problematic. In light of these new therapeutic options, we reviewed VKAs therapy, in the setting of atrial fibrillation, focusing on VKAs impact in real life. We analyzed the data about efficacy and safety of warfarin at three levels: clinical trial and real life, outside and inside anticoagulation clinics.

Investigation on Dabigatran Etexilate and Worsening of Renal Function in Patients with Atrial fibrillation: The IDEA Study.

BACKGROUND AND OBJECTIVES: Warfarin-related nephropathy is an unexplained acute kidney injury, and may occur in patients with supratherapeutic INR, in the absence of overt bleeding. Similar findings have been observed in rats treated with dabigatran etexilate. We conducted a prospective study in dabigatran etexilate-treated patients to assess the incidence of dabigatran-related nephropathy and to investigate the possible correlation between dabigatran plasma concentration (DPC) and worsening renal function. METHOD: One hundred and seven patients treated long term with dabigatran etexilate for non-valvular atrial fibrillation (NVAF) were followed up for 90 days. DPC, serum creatinine (SCr) and serum cystatin C were prospectively measured. Ninety five patients had complete follow-up data and were evaluable for primary endpoint. RESULTS: Eleven patients had supratherapeutic DPC, defined as DPC higher than 200 ng/ml at study enrolment, but at the end of follow-up no patient showed a persistent increase in SCr. No patients experienced acute kidney injury. CONCLUSIONS: Our study shows that no persistent renal detrimental effect is associated with dabigatran treatment. An increase in SCr during dabigatran treatment is reversible and it seems to be unrelated to dabigatran itself.

Non-vitamin K oral anticoagulant use in the elderly: a prospective real-world study - data from the REGIstry of patients on Non-vitamin K oral Anticoagulants (REGINA).

PURPOSE: Numerous studies on thromboembolic prevention for non-valvular atrial fibrillation (NVAF) have shown either equal or better efficacy and safety of non-vitamin K oral anticoagulants (NOACs) compared to warfarin, even for patients aged ≥75 years. Data on elderly patients, in particular, octogenarians, are lacking. Paradoxically, this population is the one with the highest risk of bleeding and stroke with a worse prognosis. This study aims to describe safety and effectiveness of NOACs in an elderly comorbid population. PATIENTS AND METHODS: REGIstry of patients on Non-vitamin K oral Anticoagulants (REGINA) is a prospective observational study enrolling consecutive NVAF patients started on NOACs and followed up to 1 year (at 1, 6, 12 months). The primary endpoint was the incidence rate of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB). The secondary endpoints were the incidence of 1) stroke or systemic embolism, 2) hospitalization, 3) death, and 4) drug-related adverse events. RESULTS: We enrolled 227 patients aged 81.6±6.1 years (range 67-95 years; ≥80 years in 59.4%). The median CHA2DS2-VASc was 5 (IQR 4-5) and HAS-BLED was 4 (IQR 3-5). The estimated glomerular filtration rate was 59.27±24.12 mL/min. During follow-up, only 10 MB and 23 CRNMB occurred, with a total incidence of 4.4% (95% CI: 1.7%-7.17%) and 5.7% (95% CI: 2.68%-8.72%), respectively. There were 2 cerebral ischemic events, with a total incidence of 0.88% (95% CI: 0.84%-0.92%), 23 NOAC-related hospitalizations, no NOAC-related deaths, and 4 minor drug-related adverse effects. CONCLUSION: In a population of aged and clinically complex patients, mainly octogenarians, NOACs were safe and effective.

Dabigatran etexilate: appropriate use in patients with chronic kidney disease and in the elderly patients.

Dabigatran etexilate (DE) is a direct thrombin inhibitor, which has been approved for the treatment of non-valvular atrial fibrillation (AF), and for the prevention and treatment of venous thromboembolism (VTE). Despite large randomized clinical trials and independent observational studies providing robust data concerning DE safety and efficacy, some physicians still perceive mild-to-moderate renal impairment and old age as a relative contraindication to its use. In this article, we review the available scientific evidence supporting the use of DE in these clinical situations. Patients with AF and chronic kidney disease (CKD) are per se at high risk of stroke, bleeding and mortality. Although there is evidence of clinical benefit of anticoagulation in these patients, anticoagulant therapy requires caution and demands careful clinical monitoring, regardless of the drug used. In patients with no contraindication to its use, the clinical benefit of DE versus warfarin is independent of renal function. The elderly with AF are frequently undertreated because of the perception of high bleeding risk and limited clinical benefit. However, the clinical benefit of anticoagulation is independent of patient age, and age per se should not represent a contraindication to anticoagulation. DE has been extensively studied in the elderly, both in randomized clinical trials and in observational studies: DE 150 mg BID should not be used in patients 80 years of age or older, while DE 110 mg BID is as safe as warfarin. Intracranial haemorrhages reduction by DE compared with warfarin is preserved in the elderly. Therefore, mild and moderate CKD and being elderly should not deter physicians from prescribing DE. Furthermore, the availability of a specific antidote is expected to improve the safety of the use of DE in clinical practice.

Mortality at 30 and 90 days in elderly patients with pulmonary embolism: a retrospective cohort study.

Pulmonary Embolism (PE) incidence increases with age. Data on mortality and prognosis in elderly patients with suspected PE are lacking. (1) To assess 30- and 90-day mortality in subjects with PE from an elderly population seen in the emergency department (ED); (2) to test the prognostic accuracy of a simplified Pulmonary Embolism Severity Index (sPESI) coupled to a highly sensitive cardiac Troponin T (hs-cTnT) level. A retrospective cohort study was performed, including patients evaluated in the ED of Vimercate Hospital for clinically suspected PE from 2010 to 2012. Study population: n = 470, 63.4% women, mean age ± SD 73.06 ± 16.0 years, 40% aged ≥80 and 77.7% ≥65 years old, confirmed PE: 22.6% (106 cases). Within 30 and 90 days, mortality among patients with confirmed PE was 14.2% (8.8-22.0) and 20.8% (16.5-41.7). In subjects aged ≥80 years, 30-day mortality was 18.9% among patients with confirmed PE, and 12.6% among those with PE excluded (p = 0.317). Ninety-day mortality rates were 29.7 and 19.9%, respectively (p = 0.193). In patients with confirmed PE, Negative Predictive Value of sPESI was 94.1% (80.3-99.3) for 30 days and 88.2% (72.3-96.7) for 90-day mortality. Adding the hs-cTnT level to sPESI did not improve its performance. (1) In an elderly population referring to the ED with clinically suspected PE, mortality was high both in subjects with and without confirmed PE; (2) the ability of sPESI and hs-cTnT to predict PE mortality seems to be lower than reported in studies based on data from younger populations. Better risk stratification tools will be necessary to improve clinical management in this setting.

Hematopoietic stem cell transplantation in adult acute lymphoblastic leukemia: a single-centre analysis.

The role of autologous or allogeneic hematopoietic stem cell transplantation (HSCT) in ALL is controversial because of its adverse risk/benefit ratio, and the main policy is to reserve it for high-risk patients. In our Institution, between 1984 and 2002, 40 patients received an allogeneic HSCT and 39 underwent autografting. The conditioning regimen included HD-Ara-C, HD-CTX and 10 Gy fractionated TBI. After allogeneic SCT in first CR, four patients relapsed, leading to a 10-year EFS chance of 78.3%; of the other patients, 5 are still in CR. After autografting in first CR, there was an early death, one secondary AML, one death in CR and six relapses, leading to a 10-year EFS chance of 44.4%; of the other patients, 6 are still in CR. Even considering the limited number of patients and the slow accrual rate, selection bias cannot be considered a sufficient explanation for the favorable outcome of allografting in first CR as the majority of the patients had adverse prognostic factors. It cannot be claimed that allogeneic SCT was performed in patients already cured, as the autografted patients had a notably worse outcome, and a 10-year EFS chance of about 80% is an uncommon finding even in standard-risk ALL patients. It might be inferred that the timing of SCT as late intensification, in addition to a rather aggressive conditioning regimen, helped to minimize the leukemic burden, thus favoring the expression of a GVL effect. Conversely, the results in more advanced disease phases are discouraging, due to poor quality CRs and inefficacy of GVL in managing large residual disease.

A higher d-dimer threshold safely rules-out pulmonary embolism in very elderly emergency department patients.

INTRODUCTION: D-dimer is commonly used in the workup of suspected Pulmonary Embolism (PE), but its specificity decreases with age. We evaluated whether using a higher cutoff value for D-dimer could increase the test specificity without reducing its sensitivity for ruling-out PE in elderly and very elderly patients presenting to the Emergency Department (ED). MATERIAL AND METHODS: All patients with D-dimer and pulmonary Computed Tomography Angiography (CTA) performed in the ED of Vimercate Hospital, from 2010 through 2012 for clinical suspicion of PE were included in this retrospective cohort study. RESULTS: Study population 481 patients (63.4% women, mean age 73.0 ± 16.1 years, confirmed PE 22.5%). In very elderly patients (aged 80 or more years, n=191), compared with standard 490 ng/mL D-dimer threshold, both higher fixed (1000 ng/mL) and age-adjusted cutoffs increase the specificity of D-dimer for the exclusion of PE maintaining a Negative Predictive Value of 100%. Potentially avoided CTAs were 12(6.3%) using 1000 ng/mL cutoff and 10(5.2%) age-adjusted. In very elderly patients the Number Needed to Test was incalculable for the standard cutoff (0 cases), 16 for 1000 ng/mL and 19 for age-adjusted. In patients with PE, index episode mortality was 6.5%, and death occurred only in subjects with D-dimer values above 1000ng/mL and age-adjusted thresholds. CONCLUSION: For very elderly patients with suspected PE in ED, both higher fixed D-dimer (1000 ng/mL) and age-adjusted thresholds increase test specificity for excluding PE without reducing its sensitivity, leading to a safe reduction in the number of CTAs.

RAS mutations contribute to evolution of chronic myelomonocytic leukemia to the proliferative variant.

PURPOSE: The biological and clinical heterogeneity of chronic myelomonocytic leukemia features renders its classification difficult. Moreover, because of the limited knowledge of the mechanisms involved in malignant evolution, chronic myelomonocytic leukemia remains a diagnostic and therapeutic challenge and a poor prognosis disease. We aimed to verify the biological and clinical significance of the discrimination, based on the leukocyte count, between myelodysplastic chronic myelomonocytic leukemia (MD-CMML) and myeloproliferative chronic myelomonocytic leukemia (MP-CMML). EXPERIMENTAL DESIGN: Peripheral blood samples from 22 patients classified as MD-CMML and 18 as MP-CMML were collected at different time points during disease course, and patients' clinical characteristics were examined. RAS mutational screening was done by sequencing and, for each substitution identified, a highly selective allele-specific PCR was set up to screen all specimens. RESULTS: MP-CMML patients showed a significantly poorer survival (P = 0.003) and a higher frequency of RAS mutations (P = 0.033) by sequencing compared with MD-CMML. Overall, five MD-CMML patients progressed to myeloproliferative disease: in two, allele-specific PCR unveiled low levels of the RAS mutations predominating in the myeloproliferative phase at the time of myelodysplastic disease, documenting for the first time the expansion of a RAS mutated clone in concomitance with chronic myelomonocytic leukemia evolution. Moreover, one of the progressed patients harbored the FLT3-ITD and two MP-CMML patients presented with the JAK2 V617F substitution. All these lesions were mutually exclusive. CONCLUSIONS: Our results strongly suggest RAS mutations to function as a secondary event that contributes to development of the chronic myelomonocytic leukemia variant with the poorer prognosis (MP-CMML) and therefore advise their detection to be implemented in chronic myelomonocytic leukemia diagnostics and monitoring.