Cardiovascular events and intensity of treatment in polycythemia vera.

BACKGROUND: Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been tested in a randomized clinical trial. METHODS: We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed. RESULTS: After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events. CONCLUSIONS: In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT01645124, and EudraCT number, 2007-006694-91.).

Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: The standard busulfan-cyclophosphamide myeloablative conditioning regimen is associated with substantial non-relapse mortality in patients older than 40 years with acute myeloid leukaemia who are undergoing allogeneic stem-cell transplantation. Because the combination of busulfan plus fludarabine has been proposed to reduce non-relapse mortality, we aimed to compare this treatment with busulfan plus cyclophosphamide as a preparative regimen in these patients. METHODS: We did an open-label, multicentre, randomised, phase 3 trial for patients with acute myeloid leukaemia at 25 hospital transplant centres in Italy and one in Israel. Eligible patients were aged 40-65 years, had an Eastern Cooperative Oncology Group performance status less than 3, and were in complete remission. Patients were randomly assigned 1:1 to receive intravenous busulfan plus cyclophosphamide or busulfan plus fludarabine. Treatment allocations were not masked to investigators or patients. Randomisation was done centrally via a dedicated web-based system using remote data entry, with patients stratified by donor type and complete remission status. Patients allocated to busulfan plus cyclophosphamide received intravenous busulfan 0·8 mg/kg four times per day during 2 h infusions for four consecutive days (16 doses from days -9 through -6; total dose 12·8 mg/kg) and cyclophosphamide at 60 mg/kg per day for two consecutive days (on days -4 and -3; total dose 120 mg/kg). Patients allocated to busulfan plus fludarabine received the same dose of intravenous busulfan (from days -6 through -3) and fludarabine at 40 mg/m(2) per day for four consecutive days (from days -6 through -3; total dose 160 mg/m(2)). The primary endpoint was 1-year non-relapse mortality, which was assessed on an intention-to-treat basis; safety outcomes were assessed in the per-protocol population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT01191957. FINDINGS: Between Jan 3, 2008, and Dec 20, 2012, we enrolled and randomly assigned 252 patients to receive busulfan plus cyclophosphamide (n=125) or busulfan plus fludarabine (n=127). Median follow-up was 27·5 months (IQR 9·8-44·3). 1-year non-relapse mortality was 17·2% (95% CI 11·6-25·4) in the busulfan plus cyclophosphamide group and 7·9% (4·3-14·3) in the busulfan plus fludarabine group (Gray's test p=0·026). The most frequently reported grade 3 or higher adverse events were gastrointestinal events (28 [23%] of 121 patients in the busulfan plus cyclophosphamide group and 26 [21%] of 124 patients in the busulfan plus fludarabine group) and infections (21 [17%] patients in the busulfan plus cyclophosphamide group and 13 [10%] patients in the busulfan plus fludarabine group had at least one such event). INTERPRETATION: In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients. FUNDING: Agenzia Italiana del Farmaco.

Randomized trial of radiation-free central nervous system prophylaxis comparing intrathecal triple therapy with liposomal cytarabine in acute lymphoblastic leukemia.

Developing optimal radiation-free central nervous system prophylaxis is a desirable goal in acute lymphoblastic leukemia, to avoid the long-term toxicity associated with cranial irradiation. In a randomized, phase II trial enrolling 145 adult patients, we compared intrathecal liposomal cytarabine (50 mg: 6/8 injections in B-/T-cell subsets, respectively) with intrathecal triple therapy (methotrexate/cytarabine/prednisone: 12 injections). Systemic therapy included methotrexate plus cytarabine or L-asparaginase courses, with methotrexate augmented to 2.5 and 5 g/m(2) in Philadelphia-negative B- and T-cell disease, respectively. The primary study objective was the comparative assessment of the risk/benefit ratio, combining the analysis of feasibility, toxicity and efficacy. In the liposomal cytarabine arm 17/71 patients (24%) developed grade 3-4 neurotoxicity compared to 2/74 (3%) in the triple therapy arm (P=0.0002), the median number of episodes of neurotoxicity of any grade was one per patient compared to zero, respectively (P=0.0001), and even though no permanent disabilities or deaths were registered, four patients (6%) discontinued intrathecal prophylaxis on account of these toxic side effects (P=0.06). Neurotoxicity worsened with liposomal cytarabine every 14 days (T-cell disease), and was improved by the adjunct of intrathecal dexamethasone. Two patients in the liposomal cytarabine arm suffered from a meningeal relapse (none with T-cell disease, only one after high-dose chemotherapy) compared to four in the triple therapy arm (1 with T-cell disease). While intrathecal liposomal cytarabine could contribute to improved, radiation-free central nervous system prophylaxis, the toxicity reported in this trial does not support its use at 50 mg and prompts the investigation of a lower dosage. (clinicaltrials.gov identifier: NCT-00795756).

Plasma n-3 polyunsaturated fatty acids in chronic heart failure in the GISSI-Heart Failure Trial: relation with fish intake, circulating biomarkers, and mortality.

UNLABELLED: Treatment with long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) can improve clinical outcomes in patients with heart failure (HF). Circulating levels of n-3 PUFA, an objective estimation of exposure, have never been measured in a large cohort of patients with HF. METHODS: We measured n-3 PUFA in plasma phospholipids at baseline and after 3 months in 1,203 patients with chronic HF enrolled in the GISSI-Heart Failure trial and randomized to n-3 PUFA 1 g/daily or placebo. N-3 PUFA levels were related to clinical characteristics, pharmacologic treatments, dietary habits, circulating biomarkers, and mortality. RESULTS: Baseline n-3 PUFA (5.1 ± 1.8 mol%) was associated with dietary fish intake, with an average difference of 43% between patients with the lowest and highest consumptions (P < .0001). Baseline eicosapentaenoic acid (EPA) but not docosahexaenoic acid (DHA) was inversely related to C-reactive protein, pentraxin-3, adiponectin, natriuretic peptide, and troponin levels. Three-month treatment with n-3 PUFA raised their levels by 43%, independently of dietary fish consumption; increases in EPA levels were associated with decreased pentraxin-3. Low baseline levels of EPA but not DHA were no longer related to higher mortality after the addition of circulating biomarkers to multivariable models. CONCLUSION: Before supplementation, circulating n-3 PUFA levels in patients with chronic HF mainly depend on dietary fish consumption and are inversely related to inflammatory markers and disease severity. Three-month treatment with n-3 PUFA markedly enriched circulating EPA and DHA, independently of fish intake, and lowered pentraxin-3. Low EPA levels are inversely related to total mortality in patients with chronic HF.

Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.

BACKGROUND: Trials of statin therapy have had conflicting findings on the risk of development of diabetes mellitus in patients given statins. We aimed to establish by a meta-analysis of published and unpublished data whether any relation exists between statin use and development of diabetes. METHODS: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1994 to 2009, for randomised controlled endpoint trials of statins. We included only trials with more than 1000 patients, with identical follow-up in both groups and duration of more than 1 year. We excluded trials of patients with organ transplants or who needed haemodialysis. We used the I(2) statistic to measure heterogeneity between trials and calculated risk estimates for incident diabetes with random-effect meta-analysis. FINDINGS: We identified 13 statin trials with 91 140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95% CI 1.02-1.17), with little heterogeneity (I(2)=11%) between trials. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255 (95% CI 150-852) patients with statins for 4 years resulted in one extra case of diabetes. INTERPRETATION: Statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low both in absolute terms and when compared with the reduction in coronary events. Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change. FUNDING: None.

Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione.

BACKGROUND: Our purpose was to assess the time course of the benefit of n-3 polyunsaturated fatty acids (PUFAs) on mortality documented by the GISSI-Prevenzione trial in patients surviving a recent (<3 months) myocardial infarction. METHODS AND RESULTS: In this study, 11 323 patients were randomly assigned to supplements of n-3 PUFAs, vitamin E (300 mg/d), both, or no treatment (control) on top of optimal pharmacological treatment and lifestyle advice. Intention-to-treat analysis adjusted for interaction between treatments was carried out. Early efficacy of n-3 PUFA treatment for total, cardiovascular, cardiac, coronary, and sudden death; nonfatal myocardial infarction; total coronary heart disease; and cerebrovascular events was assessed by right-censoring follow-up data 12 times from the first month after randomization up to 12 months. Survival curves for n-3 PUFA treatment diverged early after randomization, and total mortality was significantly lowered after 3 months of treatment (relative risk [RR] 0.59; 95% CI 0.36 to 0.97; P=0.037). The reduction in risk of sudden death was specifically relevant and statistically significant already at 4 months (RR 0.47; 95% CI 0.219 to 0.995; P=0.048). A similarly significant, although delayed, pattern after 6 to 8 months of treatment was observed for cardiovascular, cardiac, and coronary deaths. CONCLUSIONS: The early effect of low-dose (1 g/d) n-3 PUFAs on total mortality and sudden death supports the hypothesis of an antiarrhythmic effect of this drug. Such a result is consistent with the wealth of evidence coming from laboratory experiments on isolated myocytes, animal models, and epidemiological and clinical studies.

Clinical trials in myeloproliferative disorders: looking forward.

Although far from perfect, randomized clinical trials (RCTs) are the best mechanism available for evaluating the risk/benefit profile of a particular therapy. Given this, it is particularly unfortunate that there have been few clinical trials of therapy for myeloproliferative diseases (MPDs) as these therapies are often based on agents with unclear long-term safety. A complex profile of MPD uncertainties requires a simple, but articulated strategy of care and research to allow a reasonable transfer of the best available validated knowledge and a timely investigation of the most relevant questions. The multi-country, collaborative RCTs are key to generating valid data. The prerequisite for success is the close interaction of the clinical community and the research community studying the same patients. Data to be collected, criteria, contents, frequency of follow-up, and documentation of the events should be as similar as possible to those used in routine clinical care. One of the greatest achievements of the multicenter trials with this orientation has been to produce a "core" of data and practices, on which the main analyses will be made, but which at the same time reflect an optimal level of patient care for the majority of patients.

Regular wine consumption in chronic heart failure: impact on outcomes, quality of life, and circulating biomarkers.

BACKGROUND: Moderate, regular alcohol consumption is generally associated with a lower risk of cardiovascular events but data in patients with chronic heart failure are scarce. We evaluated the relations between wine consumption, health status, circulating biomarkers, and clinical outcomes in a large Italian population of patients with chronic heart failure enrolled in a multicenter clinical trial. METHODS AND RESULTS: A brief questionnaire on dietary habits was administered at baseline to 6973 patients enrolled in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI-HF) trial. The relations between wine consumption, fatal and nonfatal clinical end points, quality of life, symptoms of depression, and circulating biomarkers of cardiac function and inflammation (in subsets of patients) were evaluated with simple and multivariable-adjusted statistical models. Almost 56% of the patients reported drinking at least 1 glass of wine per day. After adjustment, clinical outcomes were not significantly different in the predefined 4 groups of wine consumption. However, patients with more frequent wine consumption had a significantly better perception of health status (Kansas City Cardiomyopathy Questionnaire score, adjusted P<0.0001), less frequent symptoms of depression (Geriatric Depression Scale, adjusted P=0.01), and lower plasma levels of biomarkers of vascular inflammation (osteoprotegerin and C-terminal proendothelin-1, adjusted P<0.0001, and pentraxin-3, P=0.01) after adjusting for possible confounders. CONCLUSIONS: We show for the first time in a large cohort of patients with chronic heart failure that moderate wine consumption is associated with a better perceived and objective health status, lower prevalence of depression, and less vascular inflammation, but does not translate into more favorable clinical 4-year outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT0033633.

Uric acid: a cardiovascular risk factor in patients with recent myocardial infarction.

BACKGROUND: To date uric acid (UA) is not considered a cardiovascular risk factor, although evidence about a relationship between UA and cardiovascular diseases has been reported. METHODS: Information from 10,840 patients enrolled in the GISSI-Prevenzione trial was used to evaluate the relationship between UA and risk for total mortality and cardiovascular events (CVE). UA levels were categorized in quintiles, as ≤ 4.5 (Q1), 4.6 to 5.3 (Q2), 5.4 to 6.0 (Q3), 6.1 to 6.8 (Q4) and >6.8 (Q5) mg/dL. Multivariable analysis was used to estimate the relative risks (HR) of outcome measures across categories of UA. The analysis of the area under the receiver operating characteristic curve (AUC), the net reclassification improvement (NRI), and the integrated discrimination improvement (IDI) tests were used to evaluate the incremental prognostic information of UA. RESULTS: During 36,802 person-years of follow-up, 974 deaths and 1120 cardiovascular events occurred. We found a statistically significant association between high UA and total mortality [HR, P value]: Q1 [reference category, 1.00]; Q2 [1.13, 0.267]; Q3 [1.06, 0.619]; Q4 [1.23, 0.063]; Q5 [1.63, <0.0001], test for trend P<0.0001. Similar results were obtained for cardiovascular events [HR, P value]: Q1 [reference category, 1.00]; Q2 [1.12, 0.271]; Q3 [1.19, 0.094]; Q4 [1.25, 0.031]; Q5 [1.38, 0.002], test for trend P=0.0009. The prognostic accuracy of prediction models for CVE was significantly increased by adding UA to classical cardiovascular risk factors (AUC P=0.0041; NRI P=0.0004; IDI P<0.0001). CONCLUSION: High UA may be considered a risk factor for death and CVE.

Clinical significance of different antiphospholipid antibodies in the WAPS (warfarin in the antiphospholipid syndrome) study.

To assess the clinical significance of lupus anticoagulants (LAs) and antiphospholipid antibodies (aPLs) toward thrombosis and abortions, we measured them in 112 patients whose samples were available at enrollment in the warfarin in the antiphospholipid syndrome (WAPS) study. Enzyme-linked immunosorbent assay (ELISA) and coagulation test values in the highest and lowest tertiles were compared. When considered separately, IgG antibodies to beta2-glycoprotein I (abeta2GPI) and prothrombin (aPT) were associated with anamnestic arterial and venous thrombosis, respectively, and those to annexin AV (aAnAV) with abortions. IgM antibodies to protein S and the lupus ratio of the dilute prothrombin time were associated with prospective thrombosis. No other association for IgM antibodies was seen. LA-positive patients who carried abeta2GPI antibodies were at risk of anamnestic arterial and total thrombosis and aPT antibodies to that of anamnestic venous and total thrombosis. LA-positive patients who carried IgG abeta2GPI and aAnAV antibodies were at risk for both anamnestic abortion and prospective thrombosis. Overall, these data support the inclusion of abeta2GPI antibodies in and suggest the removal of anticardiolipin antibodies from the laboratory criteria of the antiphospholipid syndrome. They also suggest that the measurement of aPT and aAnAV antibodies is useful in some selected situations and that there is little role for IgM antibody detection.

Efficacy of n-3 polyunsaturated fatty acids according to clinical characteristics of patients with recent myocardial infarction: insights from the GISSI-Prevenzione trial.

The GISSI-Prevenzione trial established the efficacy of n-3 polyunsaturated fatty acids (PUFAs) for reducing mortality in patients after recent myocardial infarction. The generalisability of such results to clinical practice could vary according to other individual patient characteristics. We analysed the GISSI-Prevenzione database to assess whether other major risk factors, comorbidities, dietary habits, or medications could interact with the efficacy of n-3 PUFA treatment to reduce total mortality. We found no evidence that concomitant disease states, habits, or interventions altered the therapeutic benefit of n-3 PUFA consumption in survivors of recent myocardial infarction.

Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia.

JAK2 617V>F mutation occurs in a homozygous state in 25% to 30% of patients with polycythemia vera (PV) and 2% to 4% with essential thrombocythemia (ET). Whether homozygosity associates with distinct clinical phenotypes is still under debate. This retrospective multicenter study considered 118 JAK2 617V>F homozygous patients (104 PV, 14 ET) whose clinical characteristics were compared with those of 587 heterozygous and 257 wild-type patients. Irrespective of their clinical diagnosis, homozygous patients were older, displayed a higher leukocyte count and hematocrit value at diagnosis, and presented larger spleen volume. Aquagenic pruritus was significantly more common among homozygous PV patients. JAK2 617V>F homozygosity associated with more frequent evolution into secondary myelofibrosis in both PV and ET. After adjustment for sex, age, leukocyte count, and previous thrombosis in a multivariate analysis, homozygous ET patients displayed a significantly higher risk of cardiovascular events (hazard ratio [HR] 3.97, 95% confidence interval [CI] 1.34-11.7; P = .013) than wild-type (HR = 1.0) or heterozygous patients (HR = 1.49). No significant association of JAK2 617V>F homozygosity with thrombosis risk was observed in PV. Finally, JAK2 617V>F homozygous patients were more likely to receive chemotherapy for control of disease. We conclude that JAK2 617V>F homozygosity identifies PV or ET patients with a more symptomatic myeloproliferative disorder and is associated with a higher risk of major cardiovascular events in patients with ET.

Analysis of the benefits of a Mediterranean diet in the GISSI-Prevenzione study: a case study in imputation of missing values from repeated measurements.

The problem of missing values has increasingly being recognized in epidemiology. New methods allow for the analysis of missing data that can provide valid estimates of epidemiological quantities of interest. The GISSI-Prevenzione study was aimed to reliably assess the long-term relationship between the consumption of foods typical of the Mediterranean diet and the risk of mortality amongst 11,323 Italians with prior myocardial infarction. Food intake frequencies were recorded repeatedly over the 4.5 years of follow-up and missing values affected each food variable at increasing rates over the course of the study. Comparisons were made between the results obtained from the analysis of the complete data and those obtained after imputing the missing data with simple imputation methods and with various implementations of the multiple imputation (MI) method. MI appeared to best address the issue of missing data on the food intake frequencies, preserving the observed distributions and relationships between variables whilst producing plausible estimates of variability. Given its theoretical properties and flexibility to different types of data, MI is more likely to provide valid estimates, compared to complete data analysis and imputation by simple methods, and is thus worthy of wider consideration amongst epidemiological researchers.

Vitamin E increases the risk of developing heart failure after myocardial infarction: Results from the GISSI-Prevenzione trial.

OBJECTIVE: Although results from basic science suggested a protective role of vitamin E treatment in the prevention of cardiovascular disease, recent evidence indicates increased cardiovascular mortality due to vitamin E treatment. Recently, the HOPE trial showed an increment of the incidence of congestive heart failure (CHF) in patients treated with vitamin E. METHODS: We explored the effect of vitamin E on development of CHF in 8415 postinfarction patients without CHF at baseline, with an echocardiographic measure of left ventricular ejection fraction, who have been followed up for 3.5 years in the GISSI-Prevenzione trial. CHF during follow-up was defined as hospitalization or death for CHF. Cox regression models adjusted for relevant prognostic indicators were fitted. RESULTS: Main clinical characteristics were balanced in the 4202 and 4213 patients allocated vitamin E and control group, respectively. During follow-up, 220 patients (2.6%) developed CHF. Patients allocated vitamin E had a nonsignificant 20% (95% confidence intervals 0.92-1.56, P = 0.18) increased risk of developing CHF. Vitamin E treatment, however, was associated with a significant 50% increase (95% confidence intervals 1.03-2.20, P = 0.034) of CHF in patients with left ventricular dysfunction (ejection fraction < 50%). CONCLUSIONS: Our results confirm and extend previous evidence on the possible harmful effect of vitamin E on ventricular function in patients with cardiovascular disease. Available evidence should discourage the use of vitamin E in patients with left ventricular dysfunction.

Early modifications of fatty acid composition in plasma phospholipids, platelets and mononucleates of healthy volunteers after low doses of n-3 polyunsaturated fatty acids.

OBJECTIVES: Although previous data suggested that only doses of 4 g/day or higher of n-3 polyunsaturated fatty acids (PUFA) have had a beneficial effect in the prevention of atherosclerosis and cardiovascular diseases, the GISSI-Prevenzione Study in a 3-year trial showed that 1 g/day reduced total and cardiovascular mortality in over 11,000 post-infarction patients. The aim of this study was to investigate the time course and the extent of incorporation of n-3 fatty acids in plasma and blood cells after 1 g/day of n-3 PUFA, the dose effective in the GISSI-Prevenzione in comparison with higher doses. METHODS: Thirty-six healthy volunteers were given 1, 2 and 4 g/day of n-3 PUFA ethyl esters for 12 weeks, followed by a 4-week washout. Blood was collected at weeks 0, 1, 2, 4, 8, 12 and 16 and used for lipid profile analysis and measurement of fatty acid composition in plasma phospholipids, platelets and mononucleates. RESULTS: Total n-3 PUFA increased by 2.0-, 2.2- and 2.9-fold versus baseline after 12-week treatment with 1, 2 and 4 g respectively. A statistically significant raise of total n-3 PUFA was seen in platelets and mononucleates. Among individual n-3 PUFA, 22:5 n-3 was enriched early and dose dependently in plasma phospholipids, platelets and mononucleates; the raise of 22:6 n-3 was less marked especially in platelets and mononucleates. CONCLUSIONS: One gram per day of n-3 PUFA induces fast (within 1 week) and striking changes in blood composition of PUFA that may well explain their beneficial effects against cardiovascular diseases.