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Leukocytes contribute to the pathogenesis of thrombosis in essential thrombocythemia (ET) through recently discovered mechanisms of activation and interaction with platelets and endothelial cells. To evaluate whether an increased leukocyte count was associated with thrombosis and whether this effect can be modulated by therapy, we analyzed the clinical course of 439 patients with ET followed at the Ospedali Riuniti di Bergamo. The strength of the association was measured at diagnosis or before thrombotic events by multivariable analyses carried out using data at baseline as well as time-varying covariates. The results showed that (1) an increased leukocyte count at diagnosis was associated with thrombosis during follow-up ("baseline analysis," relative risk [RR] 2.3, 95% confidence interval [CI] 1.4-3.9, P = .001); (2) hydroxyurea (HU) lowered leukocytosis and reduced the strength of the association between leukocytosis and thrombosis ("time-dependent analysis," RR 1.6, 95% CI 0.9-2.0, not significant [NS]); (3) the association of leukocytosis and thrombosis was more evident in untreated low-risk patients (RR 2.7, 95% CI 1.2-6.4, P = .01) compared with HU-treated high-risk patients (RR 1.6, 95% CI 0.8-3.2, NS); and (4) the presence of JAK2 V617F was not identified as a risk factor for thrombosis during follow-up despite a significant association between the mutation and leukocytosis. We suggest validation of these findings in prospective clinical studies.

In polycythemia vera, vascular risk assessment is based on age and thrombotic history, while the role of other potential predictors of this risk is still uncertain. Thus, we exploited the large database collected by the observational study of the European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) to investigate the association of hematologic variables and cardiovascular risk factors with the thrombotic risk. Among 1638 polycythemic patients followed for 2.7 +/- 1.3 years, there were 205 thromboses. Subjects with hypertension had a mild nonsignificant increase in the risk of arterial thrombosis, while this risk was significantly increased by smoking (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.15-3.14; P = .012). The time-dependent analysis adjusted for potential confounders showed that patients with a white blood cell count above 15 x 10(9)/L, compared with those with a white blood cell count below 10 x 10(9)/L, had a significant increase in the risk of thrombosis (HR, 1.71; 95% CI, 1.10-2.65; P = .017), mainly deriving from an increased risk of myocardial infarction (HR, 2.84; 95% CI, 1.25-6.46; P = .013). Thus, leukocyte count may help in defining the vascular risk of polycythemic subjects.

Polycythemia vera (PV) is a chronic myeloproliferative disorder whose major morbidity and mortality are thrombohaemorragic events and progression to acute leukaemia or myelofibrosis. Whether the haematocrit and platelet count predict such complications remains unclear. The European Collaboration on Low-dose Aspirin in Polycythemia Vera prospective study included 1638 PV patients. A total of 164 deaths (10%), 145 (8.85%) major thrombosis and 226 (13.8%) total thrombosis were encountered during 4393 person-years follow-up (median 2.8 years). In time-dependent multivariable analysis, a haematocrit in the evaluable range of 40-55% was neither associated with the occurrence of thrombotic events, mortality nor with haematological progression in the studied population. The haematocrit of patients in the highest and lowest deciles at baseline was maintained within a narrow interval of haematocrit values ranging from 40% to 47% throughout follow-up. High platelet count was associated with a lower progression rate to acute leukaemia/myelofibrosis, whereas it had no significant relationship with thrombotic events or mortality. Our findings do not suggest that the range of haematocrit (<55%) and platelet counts (<600 x 10(9)/l) we encountered in our population had an impact on the outcome of PV patients treated by current therapeutic strategies.

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.

Background: Metabolic syndrome (MS) is associated with late-onset diabetes. However, diagnostic criteria for individual components of MS are based on categorical/arbitrary cut points and, therefore, do not exploit the information yield of each factor. We aimed to generate a diagnostic score for MS (MS-Score), aimed at predicting diabetes by giving appropriate weight to the individual components of MS., Methods: Of 11,323 patients with prior myocardial infarction and followed up for 3.5 years in the GISSI-Prevenzione study, 3855 subjects with diabetes at baseline or missing information for relevant variables were excluded. A Cox proportional hazards model including age, sex, glycemia, high-density lipoprotein cholesterol, triglycerides, hypertension, and body mass index was fitted to create a diagnostic score. A cutoff point of 28 of the score was the best compromise between sensitivity and specificity for MS diagnosis (MS-Score). The prognostic performance of the MS-Score was compared with that of the diagnostic criteria of MS, as defined by National Cholesterol Education Program Adult Treatment Panel III (MS-ATP)., Results: Of 7468 patients, 940 developed diabetes. The risk of getting diabetes significantly and progressively increased in the quintiles of the score reaching > 6-fold higher risk in the last one. The predictive capability of MS-Score was significantly higher than that of the MS-ATP (AUC = 0.650 vs 0.587, sensitivity 67% vs 52%, specificity 63% vs 66%, P = .0002). The MS-Score, but not the MS-ATP, was significantly associated with mortality., Conclusion: MS-Score improves the prediction of diabetes development by using the full informative content of individual components for diagnosis of MS.

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.

Objectives: To assess the pharmacological treatment and the control of major modifiable cardiovascular risk factors in everyday practice according to the patients' cardiovascular risk level., Methods: In a cross-sectional study general practitioners (GPs) had to identify a random sample of their patients with cardiovascular risk factors or diseases and collect essential data on the pharmacological treatment and control of hypertension, hyperlipidemia, and diabetes according to the patients' cardiovascular risk level and history of cardiovascular disease. Participants were subjects of both sexes, aged 40-80 years, with at least one known cardiovascular risk factor or a history of cardiovascular diseases., Results: From June to December 2000, 162 Italian GPs enrolled 3120 of their patients (2470 hypertensives, 1373 hyperlipidemics, and 604 diabetics). Despite the positive association between the perceived level of global cardiovascular risk and lipid-lowering drug prescriptions in hyperlipidemic subjects (from 26% for lowest risk to 56% for highest risk p < 0.0001) or the prescription of combination therapy in hypertensives (from 41% to 70%, p < 0.0001) and diabetics (from 24% to 43%, p = 0.057), control was still inadequate in 48% of diabetics, 77% of hypertensives, and 85% of hyperlipidemics, with no increase in patients at highest risk. Trends for treatment and control were similar in patients with cardiovascular diseases., Conclusions: Even in high-risk patients, despite a tendency towards more intensive treatment, pharmacological therapy is still under used and the degree of control of blood pressure, cholesterol level and diabetes is largely unsatisfactory.

Introduction and Objectives: Improvement in the early phase of myocardial infarction (MI) is associated with a higher rate of late complications, including late-onset heart failure (LHF). The factors predicting LHF are not well understood. Our aims were to identify the factors predicting LHF and to determine the survival rate in these patients., Patients and Method: The GISSI-Prevenzione trial involved 11,323 low-risk patients (NYHA class < or = II) who had had a recent MI (< 3 months). It was a multicenter, open-label, clinical trial of the efficacy of treatment with polyunsaturated fatty acids, vitamin E, both, or neither. Patients with heart failure at baseline and those whose ejection fraction was unknown (n = 2908) were excluded from the present analysis. Late-onset heart failure was defined prospectively as hospital admission due to heart failure. A Cox regression model adjusted for major covariates was used for risk analysis., Results: The study included 8415 patients. During 3.5 years of follow-up, 192 (2.3%) developed LHF. The risk of LHF could be predicted from readily available parameters: age (per year; RR=1.07; 95% CI, 1.05-1.09), ejection fraction (per 1% increment; RR=0.96; 95% CI, 0.94-0.97), heart rate (> or = 74 beats/min; RR=1.62; 95% CI, 1.21-2.16), white blood cell count (> or = 8900 per ml; RR=1.42; 95% CI, 1.05-1.94), diabetes (RR=1.62; 95% CI, 1.17-2.24), hypertension (RR=1.76; 95% CI, 1.33-2.34), peripheral artery disease (RR=2.11; 95% CI, 1.32-3.37), and reinfarction (RR=2.09; 95% CI, 1.28-3.39). LHF was associated with poor survival: (RR=2.34; 95% CI, 1.63-3.36)., Conclusions: The risk of LHF in post-MI patients can be predicted from readily available parameters. LHF was associated with a poor prognosis.

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.

Background: Sudden death (SD) has a major impact on mortality (M) in patients with left ventricular systolic dysfunction (SyD). In GISSI-Prevenzione, treatment with n-3 polyunsaturated fatty acids (PUFA) reduced M and SD in post-MI patients, but their effect in patients with SyD is unknown., Methods: 11,323 patients with prior MI and NYHA class < or = II were recruited. After excluding patients with no ejection fraction (EF) measurement (1684), and those with missing data (n=9), 9630 patients were available for analysis. Multivariate Cox regression adjusted models were fitted., Results: Compared to patients with EF > 50%, SyD patients had higher M (12.3% vs. 6.0%) and SD (3.4% vs. 1.4%) rates. PUFA reduced M similarly in patients with (RR 0.76 (0.60-0.96) P=0.02) and without SyD (RR 0.81 (0.59-1.10) P=0.17) (heterogeneity tests P=0.55). In contrast, the effect on SD was markedly asymmetrical: PUFA produced a marked reduction (RR 0.42 (0.26-0.67) P=0.0003) of risk in SyD patients whereas the effect was less evident (RR 0.89 (0.41-1.69) P=0.71) in patients with EF > 50% (heterogeneity tests P=0.07). There was a significant increase in SD with worsening EF (P test for trend=0.02), the benefit on SD in patients with EF < or = 40% being 4-fold higher than in those with EF > 50%., Conclusions: Increasing SyD is associated with elevated risk of SD and with increasing benefit from PUFA. The effect of PUFA on SD reduction was greater in patients with SyD. Prospective trials testing the effect of PUFA in populations with SyD are required.

Objectives: We aimed to assess the prevalence and prognostic role of metabolic syndrome (METS) and diabetes in post-myocardial infarction (MI) patients., Background: Diabetes is a well known risk factor for patients with previous MI, but glycemic dysmetabolism develops over a protracted period of time. Scanty data are available on the role of METS in patients with previous MI., Methods: Adjusted Cox's regression models, having diabetes, death, major cardiovascular events (CVE), and hospitalization for congestive heart failure (CHF) during follow-up as outcome events, were fitted on 11,323 patients with prior MI enrolled in the GISSI-Prevenzione Trial., Results: At baseline, 21% and 29% of patients had diabetes mellitus and METS, respectively. The METS patients had a significant (93%) increased risk of diabetes during follow-up. As compared with control subjects, the probability of death and CVE were higher in both METS (+29%, p = 0.002; +23%, p = 0.005) and diabetic patients (+68%, p <0.0001; +47%, p <0.0001), although diabetic but not METS patients were more likely to be hospitalized for CHF (+89%, p <0.0003 and +24%, p = 0.241). Moderate (-6% to -10%) and substantial (>-10%) weight reduction were associated with a significant (18% and 41%, respectively) decreased risk of diabetes. Weight gain was significantly associated with increased risk of diabetes. The risk conferred by METS and diabetes tended to be higher among women., Conclusions: In patients with MI, METS and diabetes were highly prevalent and are associated with increased risk of death and CVE. Diabetes is also associated with increased risk of hospitalization for CHF. Weight reduction significantly decreased the risk of becoming diabetic in patients with METS.

Purpose: The clinical course of polycythemia vera is often complicated by thrombosis as well as by the possible transition to myeloid metaplasia with myelofibrosis or acute myeloid leukemia. The aim of this study was to assess the rate of these complications in subjects receiving currently recommended treatments., Patients and Methods: Overall, 1,638 patients from 12 countries were enrolled onto a large, prospective multicenter project aimed at describing the clinical history of polycythemia vera for the following outcomes: survival, the cumulative rate of cardiovascular death and thrombosis, the cumulative rate of leukemia, myelodysplasia, and myelofibrosis. The mean duration of the disease at entry and the duration of the follow-up were 4.9 and 2.7 years, respectively., Results: The overall mortality rate of 3.7 deaths per 100 persons per year resulted from a moderate risk of cardiovascular death and a high risk of death from noncardiovascular causes (mainly hematologic transformations). Age older than 65 years and a positive history of thrombosis were the most important predictors of cardiovascular events. Antiplatelet therapy, but not cytoreductive treatment, was significantly associated with a lower risk of cardiovascular events. We found a consistent association between age and risk of leukemia, and between duration of the disease with risk of myelofibrosis., Conclusion: The European Collaboration on Low-Dose Aspirin in Polycythemia Vera study documents that large international collaborative studies are feasible in this field, in which few epidemiologic data are available. The persistently high mortality rate from hematologic malignancies characterizes the unmet therapeutic need of polycythemic patients and suggests a priority for future studies in this disease.

Progression to acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) is a possible evolution of polycythemia vera (PV), but whether some patients are at increased natural risk for this complication and how much the contribution of pharmacologic cytoreduction can affect the natural course of the disease remain uncertain. The European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) prospective project included 1638 patients with PV. AML/MDS was diagnosed in 22 patients after a median of 2.5 years from recruitment in the study and a median of 8.4 years from the diagnosis of PV. Variables associated with progression to AML/MDS were assessed using different models of multivariate analysis. Older age was confirmed as the main independent risk factor (hazard ratio [HR], 4.30; 95% confidence interval [95% CI], 1.16-15.94; P = .0294), whereas overall disease duration failed to reach statistical significance (more than 10 years: HR, 1.91; 95% CI, 0.64-5.69; P = .2466). Exposure to P32, busulphan, and pipobroman (HR, 5.46; 95% CI, 1.84-16.25; P = .0023), but not to hydroxyurea (HU) alone (HR, 0.86; 95% CI, 0.26-2.88; P = .8021), had an independent role in producing an excess risk for progression to AML/MDS compared with treatment with phlebotomy or interferon.

Background: The GISSI Heart Failure project is a large-scale, randomized, double-blind study designed to investigate the effects of n-3 polyunsaturated fatty acids and rosuvastatin on mortality and morbidity in patients with symptomatic heart failure., Methods and Results: Patients with New York Heart Association classes II to IV heart failure, already receiving optimized recommended therapy, will be recruited in a nation-wide network of more than 300 cardiology and internal medicine services to be randomly allocated to treatment with n-3 polyunsaturated fatty acids (1 g daily) or the corresponding placebo. Patients with no clear indication or contraindication to cholesterol-lowering therapy will be further randomized to receive low-dose rosuvastatin (10 mg daily) or placebo. According to data available in heart failure registries, it is expected that 70% of the patients will be suitable to enter both components of the trial, which assume the same co-primary endpoints: (a) 15% reduction of all-cause mortality and (b) 20% reduction of all-cause mortality or cardiovascular hospitalizations. The trial is event-driven and will continue either until at least 1252 deaths have been recorded or a reduction of all-cause mortality will satisfy the significance boundaries, which have been established to stop the study. The recruitment of the planned sample size of approximately 7000 patients randomized in the n-3 PUFA trial is expected to be completed within 18 months from the trial start. As of February 29, 2004, 4624 heart failure patients have been included in the trial., Conclusion: The GISSI-HF project, with its protocol articulated into two independent randomization schemes, has the aim and the power to verify the hypothesis that n-3 polyunsaturated fatty acids and rosuvastatin can favorably modify the prognosis of patients with symptomatic heart failure.

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.

Population studies indicate omega-3 that a high fish intake, such as reported in the early Eskimo and Japanese studies, is associated with a low mortality from coronary heart disease (CHD). These effects have been associated with measurable effects on a series of established and possible risk factors. In most of the later population studies much lower daily intake of fish has been observed, such intake having only small or not even measurable effects on established risk factors. Still, their association with reduced CHD mortality, particularly sudden cardiac death seem to be reasonably well established. Beneficial effects are found at a level of consumption of about 30 g per day or 1 fish meal per week compared with populations rarely or never consuming fish. Such findings are also reflected in studies including analysis of fatty acid composition in adipose tissue and cell membranes. Fish consumption may be a marker for a healthier lifestyle or, alternatively, fish consumers may be at higher self-perceived risk for CHD and are therefore eating fish to reduce their high baseline risk. Despite all these limitations, the population studies seem to indicate that a high fish intake is associated with a low mortality from CHD. GISSI-Prevenzione was conceived as a population, pragmatic trial on patients with recent myocardial infarction and it was conducted in the framework of the Italian public health system. In GISSI-Prevenzione, 11,323 patients were enrolled in a clinical trial aimed at testing the effectiveness of omega-3 PUFA and vitamin E. Patients were invited to follow Mediterranean dietary habits, and were treated with up-to-date preventive pharmacological interventions. Long-term omega-3 PUFA 1 g daily, but not vitamin E 300 mg daily, was beneficial for death and for combined death, non-fatal myocardial infarction, and stroke. All the benefit, however, was attributable to the decrease in risk for overall, cardiovascular, cardiac, coronary, and sudden death. In GISSI-Prevenzione, long-term administration of omega-3 PUFA (1 g daily) significantly decreased the risk of overall (-20%), cardiovascular (-30%), and sudden death (-45%). At variance from the orientation of a scientific scenario largely dominated by the "cholesterol-heart hypothesis", GISSI-Prevenzione results indicate omega-3 PUFA (virtually devoid of any cholesterol-lowering effect) as a relevant pharmacological treatment for secondary prevention after myocardial infarction.

The Philadelphia chromosome-negative chronic myeloproliferative disorders (CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF), have overlapping clinical features but exhibit different natural histories and different therapeutic requirements. Phenotypic mimicry amongst these disorders and between them and nonclonal hematopoietic disorders, lack of clonal diagnostic markers, lack of understanding of their molecular basis and paucity of controlled, prospective therapeutic trials have made the diagnosis and management of PV, ET and IMF difficult. In Section I, Dr. Jerry Spivak introduces current clinical controversies involving the CMPD, in particular the diagnostic challenges. Two new molecular assays may prove useful in the diagnosis and classification of CMPD. In 2000, the overexpression in PV granulocytes of the mRNA for the neutrophil antigen NBI/CD177, a member of the uPAR/Ly6/CD59 family of plasma membrane proteins, was documented. Overexpression of PRV-1 mRNA appeared to be specific for PV since it was not observed in secondary erythrocytosis. At this time, it appears that overexpression of granulocyte PRV-1 in the presence of an elevated red cell mass supports a diagnosis of PV; absence of PRV-1 expression, however, should not be grounds for excluding PV as a diagnostic possibility. Impaired expression of Mpl, the receptor for thrombopoietin, in platelets and megakaryocytes has been first described in PV, but it has also been observed in some patients with ET and IMF. The biologic basis appears to be either alternative splicing of Mpl mRNA or a single nucleotide polymorphism, both of which involve Mpl exon 2 and both of which lead to impaired posttranslational glycosylation and a dominant negative effect on normal Mpl expression. To date, no Mpl DNA structural abnormality or mutation has been identified in PV, ET or IMF. In Section II, Dr. Tiziano Barbui reviews the best clinical evidence for treatment strategy design in PV and ET. Current recommendations for cytoreductive therapy in PV are still largely similar to those at the end of the PVSG era. Phlebotomy to reduce the red cell mass and keep it at a safe level (hematocrit < 45%) remains the cornerstone of treatment. Venesection is an effective and safe therapy and previous concerns about potential side effects, including severe iron deficiency and an increased tendency to thrombosis or myelofibrosis, were erroneous. Many patients require no other therapy for many years. For others, however, poor compliance to phlebotomy or progressive myeloproliferation, as indicated by increasing splenomegaly or very high leukocyte or platelet counts, may call for the introduction of cytoreductive drugs. In ET, the therapeutic trade-off between reducing thrombotic events and increasing the risk of leukemia with the use of cytoreductive drugs should be approached by patient risk stratification. Thrombotic deaths seem very rare in low-risk ET subjects and there are no data indicating that fatalities can be prevented by starting cytoreductive drugs early. Therefore, withholding chemotherapy might be justifiable in young, asymptomatic ET patients with a platelet count below 1500000/mm(3) and with no additional risk factors for thrombosis. If cardiovascular risk factors together with ET are identified (smoking, obesity, hypertension, hyperlipidemia) it is wise to consider platelet-lowering agents on an individual basis. In Section III, Dr. Gianni Tognoni discusses the role of aspirin therapy in PV based on the recently completed European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Study, a multi-country, multicenter project aimed at describing the natural history of PV as well as the efficacy of low-dose aspirin. Aspirin treatment lowered the risk of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (relative risk 0.41 [95% CI 0.15-1.15], P =.0912). Total and cardiovascular mortality were also reduced by 46% and 59%, respectively. Major bleedings were slightly increased nonsignificnsignificantly by aspirin (relative risk 1.62, 95% CI 0.27-9.71). In Section IV, Dr. Giovanni Barosi reviews our current understanding of the pathophysiology of IMF and, in particular, the contributions of anomalous megakaryocyte proliferation, neoangiogenesis and abnormal CD34(+) stem cell trafficking to disease pathogenesis. The role of newer therapies, such as low-conditioning stem cell transplantation and thalidomide, is discussed in the context of a general treatment strategy for IMF. The results of a Phase II trial of low-dose thalidomide as a single agent in 63 patients with myelofibrosis with meloid metaplasia (MMM) using a dose-escalation design and an overall low dose of the drug (The European Collaboration on MMM) will be presented. Considering only patients who completed 4 weeks of treatment, 31% had a response: this was mostly due to a beneficial effect of thalidomide on patients with transfusion dependent anemia, 39% of whom abolished transfusions, patients with moderate to severe thrombocytopenia, 28% of whom increased their platelet count by more than 50 x 10(9)/L, and patients with the largest splenomegalies, 42% of whom reduced spleen size of more than 2 cm.

The aim of the present study was to investigate whether the overall oxidation state of plasma proteins is associated with changes of circulating pro- and anticoagulant markers in healthy subjects (n = 99, 49 males, 50 females, aged from 6 to 91 yrs.). The carbonyl content of plasma proteins was measured and validated as an ex vivo index of the overall protein oxidation state due to its correlation with the plasma level of o-tyrosine (r = 0.87, P <0.0001), which is a well known oxidized product of L-phenylalanine. Using a multivariate analysis the carbonyl content of plasma protein was positively associated with procoagulant markers such as prothrombin F1 + 2 (r = 0.28, P = 0.0019) and fibrinopeptide A, (FpA) (r = 0.278, P = 0.003), as well as with the soluble derivative of the endothelial protein thrombomodulin (TM) (r = 0.469, P <0.0001). The procoagulant marker of thrombin activity, FpA, was significantly and positively correlated with the anticoagulant product of thrombin, namely the Protein C activation peptide (PCP), only in the tertile with low protein carbonyl content. At higher tertiles this correlation was no longer observed, thus suggesting a detrimental effect of oxidative stress on the TM/Protein C anticoagulant pathway. In 15 subjects with high carbonyl content of plasma protein, treatment for 18 days with 600 mg/d of vitamin E did not substantially modify the protein carbonyl content, the anticoagulant markers APC/PCP, and all procoagulant markers except F1+2, whose value significantly decreased by 25%. In conclusion, the present study shows that a high plasma protein oxidation ex vivo is associated with an overall hemostatic imbalance, which favors procoagulant markers. Vitamin E treatment in vivo restores only in part the equilibrium between pro- and anticoagulant pathways. This may open the way to further studies aimed at elucidating the mechanisms by which the oxidative stress is linked to activation of the coagulation system in atherothrombotic disorders.

An expert round table discussion on the relationship between intake of n-3 polyunsaturated fatty acids (PUFA) mainly of marine sources and coronary heart disease at the 34th Annual Scientific Meeting of European Society for Clinical Investigation came to the following conclusions: 1. Consumption of 1-2 fish meals/wk is associated with reduced coronary heart disease (CHD) mortality. 2. Patients who have experienced myocardial infarction have decreased risk of total, cardiovascular, coronary, and sudden death by drug treatment with 1 g/d of ethylesters of n-3 PUFA, mainly as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The effect is present irrespective of high or low traditional fish intake or simultaneous intake of other drugs for secondary CHD prevention. n-3 PUFA may also be given as fatty fish or triglyceride concentrates. 3. Patients who have experienced coronary artery bypass surgery with venous grafts may reduce graft occlusion rates by administration of 4 g/d of n-3 PUFA. 4. Patients with moderate hypertension may reduce blood pressure by administration of 4 g/d of n-3 PUFA. 5. After heart transplantation, 4 g/d of n-3 PUFA may protect against development of hypertension. 6. Patients with dyslipidemia and or postprandial hyperlipemia may reduce their coronary risk profile by administration of 1-4 g/d of marine n-3 PUFA. The combination with statins seems to be a potent alternative in these patients. 7. There is growing evidence that daily intake of up to 1 energy% of nutrients from plant n-3 PUFA (alpha-linolenic acid) may decrease the risk for myocardial infarction and death in patients with CHD. This paper summarizes the conclusions of an expert panel on the relationship between n-3 PUFA and CHD. The objectives for the experts were to formulate scientifically sound conclusions on the effects of fish in the diet and the administration of marine n-3 PUFA, mainly eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), and eventually of plant n-3 PUFA, alpha-linolenic acid (ALA, 18:3n-3), on primary and secondary prevention of CHD. Fish in the diet should be considered as part of a healthy diet low in saturated fats for everybody, whereas additional administration of n-3 PUFA concentrates could be given to specific groups of patients. This workshop was organized on the basis of questions sent to the participants beforehand, on brief introductions by the participants, and finally on discussion and analysis by a group of approximately 40 international scientists in the fields of nutrition, cardiology, epidemiology, lipidology, and thrombosis.

Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardio (GISSI)-Prevenzione was conceived as a population, pragmatic trial on patients with recent myocardial infarctions conducted in the framework of the Italian public health system. In GISSI-Prevenzione, patients were invited to follow Mediterranean dietary habits, and were treated with up-to-date preventive pharmacological interventions. Long-term n-3 PUFA (1 g daily) but not vitamin E (300 mg daily) was beneficial for death and for combined death, nonfatal myocardial infarction, and stroke. All the benefit, however, was attributable to the decrease in risk for overall, cardiovascular, cardiac, coronary, and sudden death. At variance with the orientation of a scientific scenario largely dominated by the "cholesterol-heart hypothesis," GISSI-Prevenzione results indicate n-3 PUFA (virtually devoid of any cholesterol-lowering effect) as a relevant pharmacological treatment for secondary prevention after myocardial infarction. As to the relevance and comparability of GISSI-Prevenzione results, up to 5.7 lives could be saved every 1000 patients with previous myocardial infarction treated with n-3 PUFA (1 g daily) per year. Such a result is comparable to that observed in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial, where 5.2 lives could be saved per 1000 hypercholesterolemic, coronary heart disease patients treated with pravastatin for 1 yr. The choice of a relatively low-dose regimen (1-g capsule daily) more acceptable for long-term treatment in a population of patients following Mediterranean dietary habits, and the pattern of effects seen in GISSI-Prevenzione (namely, reduction of overall mortality with no decrease in the rate of nonfatal myocardial infarction) all strongly suggest that n-3 PUFA treatment should be considered a recommended new component of secondary prevention. The importance of this combined/additive effect is further suggested by the analyses of the interplay between diet and n-3 PUFA: There is an interesting direct correlation between size of the effect and "correctness" of background diets. It can be anticipated that a conceptual barrier must be overcome: A "dietary drug" should be added to "dietary advice," which remains fundamental to allow this statement to become true in clinical practice.

Naturally occurring antioxidants such as vitamin E, beta-carotene, and vitamin C can inhibit the oxidative modification of low density lipoproteins. This action could positively influence the atherosclerotic process and, as a consequence, the progression of coronary heart disease. A wealth of experimental studies provide a sound biological rationale for the mechanisms of action of antioxidants, whereas epidemiologic studies strongly sustain the "antioxidant hypothesis." To date, however, clinical trials with beta-carotene supplements have been disappointing, and their use as a preventive intervention for cancer and coronary heart disease should be discouraged. Only scanty data from clinical trials are available for vitamin C. As to vitamin E, discrepant results have been obtained by the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study with a low-dose vitamin E supplementation (50 mg/d) and the Cambridge Heart Antioxidant Study (400-800 mg/d). The results of the GISSI-Prevenzione (300 mg/d) and HOPE (400 mg/d) trials suggest the absence of relevant clinical effects of vitamin E on the risk of cardiovascular events. Currently ongoing are several large-scale clinical trials that will help in clarifying the role of vitamin E in association with other antioxidants in the prevention of atherosclerotic coronary disease.

Observational studies have shown an inverse relationship between consumption of fruits and vegetables high in beta-carotene, vitamins C and E, and ischemic heart disease (IHD) and stroke. In large observational studies, beta- carotene reduced the risk of IHD events in men, particularly in smokers. In contrast, four large randomized trials did not reveal a reduction in cardiovascular events with beta-carotene use, and may, in fact, increase IHD and total mortality in male smokers. There have been only a few large observational studies and one randomized trial with vitamin C, which have shown no beneficial or deleterious impact of this vitamin on cardiovascular events. Most large observational studies have shown an inverse relationship between vitamin E and IHD. However, a meta-analysis of the four randomized trials done in Europe and America involving a total of 51,000 participants allocated to vitamin E or placebo for 1.4 to 6 years, did not demonstrate a reduction in cardiovascular and IHD mortality and nonfatal myocardial infarction. Currently, there are no data to support the use of these vitamins to reduce the risk of cardiovascular events. Trials are in progress to determine whether a longer duration of administration of vitamin E or the association of vitamin E with cofactors may reduce cardiovascular events.

We performed a meta-analysis of randomized clinical trials of more than 6 months duration to describe how fatal and nonfatal strokes are related to cholesterol lowering and to the type of intervention. A total of 41 individual trials including approximately 80,000 subjects and followed for an average of about 4 years were included in the overview. There was a 16% (95% CI, 7-25%) reduction in risk of stroke among treated patients compared to control patients (test for heterogeneity, p = 0.76). When trials that used different interventions were separately examined, a significant reduction in stroke occurrence was observed only for those using statins as active treatment (risk reduction 23%; 95% CI 13-33%). A variance-weighted regression analysis of the logarithmic odds ratios for stroke incidence against the percentage of cholesterol reduction indicated that a reduction of fatal and nonfatal stroke can be obtained for a cholesterol reduction of 9% (95% CI 6.8-13.6%). The combined data of primary and secondary prevention trials indicate that a large reduction of blood cholesterol, achievable with statin drugs, can reduce the incidence of stroke., (Copyright 2000 S. Karger AG, Basel.)

Plasma fibrinogen is a major determinant of platelet aggregation and blood viscosity. The decrease in plasma fibrinogen by bezafibrate is associated with a decrease in the risk of reinfarctions. To strengthen the predictive value of plasma fibrinogen with respect to cardiovascular risk, we performed a meta-analysis of studies conducted between 1984 and 1998. Emphasis has been put on the relationship between high levels of plasma fibrinogen and fatal and/or nonfatal cardiovascular events in both the general population and in patients with previous cardiovascular events. Twenty-two studies (13 prospective, 5 cross-sectional, and 4 case-control) addressing the association between fibrinogen plasma concentrations and cardiovascular disease were analyzed. The overall estimate of risk of cardiovascular event in subjects with plasma fibrinogen levels in the higher tertile, was twice as high as that of subjects in the lower one (odds ratio, 1.99; 95% confidence interval, 1.85 to 2.13). High plasma fibrinogen levels were associated with an increased risk of cardiovascular disease in healthy as much as in high-risk individuals. A metaregression showed no confounding effects attributable to selected characteristics of retrieved studies. A subgroup analysis (study design, follow up, mean fibrinogen levels, percentage of smokers, and mean age) allowed us to conclude that fibrinogen is an independent risk factor for cardiovascular disease; that it interacts with major determinants of myocardial and cerebrovascular ischemia; and that, in secondary prevention studies, it enhances by 8% the prediction of future events by established risk factors. Thus, fibrinogen measurements should be encouraged to refine the overall risk profiles of individuals and to better tailor preventive interventions.

Lupus anticoagulants belong to the family of antiphospholipid antibodies. They include two phospholipid-dependent inhibitors of coagulation that may be distinguished on the basis of specific coagulation profiles generated from the comparison of the ratios of the Kaolin Clotting Time (KCT) and the dilute Russell's Viper Venom Time (dRVVT): when the ratio of the KCT exceeds that of the dRVVT, the plasma is allocated to the "KCT" coagulation profile, when the opposite occurs, the plasma is defined to belong to the "dRVVT" coagulation profile group. We prospectively followed-up a historical cohort of 100 consecutive patients with lupus anticoagulants referred to our Institution between January 1988 and October 1997 to investigate the relationship between their coagulation profile at diagnosis and the development of thrombosis during a median follow-up time of 37.5 months (range 1-115 months). Fifty-six patients were allocated to the "dRVVT" coagulation profile, whereas the other 44 displayed the "KCT" profile. Lupus anticoagulants were transient in 17 patients, without differences between the two groups. None of these patients developed clinical events before disappearance of the phospholipid-dependent inhibitors of coagulation. The 83 cases with persistent lupus anticoagulants consistently displayed the same coagulation profile they had been allocated to at entry. Fourteen patients developed 18 thromboembolic events during the follow-up, with an overall rate of thrombosis of 4.2% patients-year. Twelve of them belonged to the "dRVVT" coagulation profile, whereas the other 2 to the "KCT" profile (p = 0.03). The "dRVVT" coagulation profile gave an odds ratio of thrombosis of 5.25 (95% confidence interval [C.I]: 1.17-23.50). Ten of the 14 patients who developed thrombosis during follow-up had already experienced thrombosis: a previous thrombotic event caused an odds ratio of recurrency of 2.72 (95% C.I.: 0.85-8.73) (p = 0.09). By multivariate analysis, the "dRVVT" coagulation profile was still associated with a trend to a higher risk of thrombosis, but the difference did not reach statistical significance. Increased levels of anticardiolipin antibodies (> 40 GPL and/or MPL units) were found in all the 14 patients (p = 0.0064). The "KCT" coagulation profile was significantly associated (p = 0.005) with moderate thrombocytopenia (platelets 50-150 X 10(9)/l). Neither profile was found to represent a risk factor for the development of recurrent miscarriages, neoplastic diseases and death. In conclusion, the "dRVVT" profile appears to have predictive value with respect to the thrombotic complications suffered by patients with antiphospholipid antibodies.

Fifteen thousand nine hundred ten men and 13,674 women (age, 30-69 years) were enrolled in an epidemiological survey of the general population, between December 1984 and April 1987. Each participant was submitted to ultrasonography (US) of the gallbladder and completed a food-frequency questionnaire, covering 38 food items. A common portion size was identified and subjects were asked how often each item was consumed. Nutrient intake was computed by multiplying the intake frequency and nutrient content per portion for each item, and then by summing the product over all foods. Each nutrient intake was adjusted for energy intake. Alcohol intake was calculated by summing the consumption of wine, beer, and liquor. Having excluded subjects aware of having gallstones (GS) or previously submitted to cholecystectomy (to avoid prothopatic bias), 787 males and 1,014 females with GS and 14,272 males and 10,836 females without GS were available for analysis. Relative risks (RR) of GS were computed by quintiles of nutrient intake. The overnight fasting period was calculated as the difference between the specified time of dinner and the time of the next meal (breakfast or lunch). A significant negative association was found between RR of GS and total energy intake for males (chi2 for trend = 8.37; P = .004), fiber intake for females (chi2 = 5.45; P = .02), and daily alcohol consumption for males (chi2 = 10.86; P = .001). A positive association was observed between RR of GS and carbohydrate (chi2 = 5.95; P = .01 for males; chi2 = 9.39; P = .002 for females) and protein intake only for males (chi2 = 10.92; P = .01). Prevalence of GS was higher among subjects who had an overnight fasting period of over 12 hours than subjects with that of less than 12 hours. (RR: 1.35; 95% CI: 1.01-1.80 for males; RR: 1.28; 95% CI: 1.03-1.60 for females). These data do not confirm that high energy intake is associated with an increased risk of GS. Factors protecting against GS comprise: low carbohydrate (males and females) and protein (males) intakes, high fiber (females) and moderate alcohol intake (males) consumption, and a shorter overnight fasting period for both sexes.

In two consecutive and unselected cohorts of diffuse large cell lymphoma (DLCL) patients with advanced stage disease (IIB or bulk or more) and aged < 60 years, we compared a standard (MACOP-B for 12 weeks, 60 patients) versus a high-dose chemotherapy programme (8 weeks of MACOP-B plus one or two cycles of intensification with mitoxanthrone, dexamethasone, high-dose Ara-C, and finally BEAM chemotherapy with autologous haemopoietic progenitor cell transplantation, 61 patients). 41 patients (68%) in the standard group and 51 (84%) in the high-dose chemotherapy group, achieved a complete remission (CR) or an uncertain complete remission (CRu) (P = 0.0491). With a median follow-up time of 28 months for the high-dose group and 63.5 months for the standard group, the actuarial estimate of event-free survival (EFS) at 2 years demonstrates a significant benefit (70% v 50%, P = 0.03) for patients treated with the intensive regimen. The analysis of subgroups of patients showed that only high-risk patients (two or three risk factors) benefitted from the high-dose chemotherapy programme. Nevertheless, the overall survival does not show a significant difference between the two treatment modalities. The treatment-related morbidity was similar and the mortality rate was 8% in the standard (MACOP-B) group and 3% in the high-dose chemotherapy programme. In conclusion, our results show that high-dose chemotherapy and autologous stem cell transplantation is a safe procedure which should be considered for the front-line treatment of non-Hodgkin lymphoma patients with poor prognostic features.

Arterial and venous thromboses and microcirculatory disturbances such as erythromelalgia and neurologic and visual symptoms are the thrombotic manifestations occurring in Polycythaemia Vera and Essential Thrombocythaemia. The increased in vivo thromboxane A2 generation existing in these patients and the selective sensitivity of erythromelalgia to aspirin suggest that platelet PGG/H synthase products may be involved in transducing the increased thrombotic risk. The relationship between Thromboxane A2 production and thrombotic accidents will be investigated by the European Collaboration on Low-Dose Aspirin in Polycythaemia Vera (ECLAP) which will test the efficacy of low-dose aspirin by a randomised clinical trial. The haemorrhagic diathesis of polycythaemic and thrombocythaemic subjects is generally mild and spontaneous bleeding usually manifests in patients with very high platelet count. Its mechanism may be related to quantitative as well as to qualitative platelet changes. Possible mechanisms linking the high grade thrombocytosis to bleeding are consumption of von Willebrand factor and clot fragility due to a mechanical effect of the high platelet count or to inhibition of fibrin polymerization by platelet Glycoprotein Ib.

We report on long-term haematological recovery and clinical outcome after high-dose chemotherapy supported by circulating progenitor cells (CPC) transplantation in non-Hodgkin's lymphoma (NHL) patients, and analyse the role of variables which might influence engraftment. 63 consecutive NHL patients were enrolled in this study. Two groups of patients were considered for analysis: the first 34 patients had untreated diffuse large cell lymphoma with unfavourable prognostic factors. A second group of 29 patients underwent transplantation for resistant or relapsing NHL with low, intermediate and high grade histology. All patients received the BEAM conditioning regimen. As already reported in many studies, all patients showed a rapid haematological reconstitution. 43 patients (68%) achieved long-term complete trilineage engraftment within a median of 107 d from CPC transplantation. The neutrophil count was the first parameter reaching complete normalization, and haemoglobin was the last. Failure to meet the trilineage levels was due to lack of platelet recovery and was more frequent in patients transplanted in the setting of salvage protocols. By Kaplan-Meier analysis, the probability of a full reconstitution was 80% in patients to whom transplant was offered as part of a front-line therapy and 50% when transplant was given in the salvage programmes. Multivariate analysis showed that sustained long-term haematological reconstitution was significantly related to younger age, the time taken to achieve short-term reconstitution, and bone marrow involvement.

Thrombotic complications characterize the clinical course of polycythemia vera (PV) and represent the main cause of morbidity and mortality. However, uncertainty still exists as to the benefit/risk ratio of aspirin prophylaxis in this setting. In vivo platelet biosynthesis of thromboxane A2 is enhanced and can be suppressed by low-dose aspirin in PV, thus providing a rationale for assessing the efficacy and safety of a low-dose aspirin regimen in these patients. The Gruppo Italiano Studio Policitemia Vera has recently performed a pilot study on 112 patients randomized to receive aspirin, 40 mg daily, or placebo and followed for 16 +/- 6 months (mean +/- SD). This study showed that low-dose aspirin is well tolerated in PV patients, and that a large-scale efficacy trial is feasible in this setting. In this article we report the protocol of the European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study, which is a randomized trial designed to assess the risk/benefit ratio of low-dose aspirin in PV. To estimate the size and the follow-up duration required for the ECLAP trial, a retrospective analysis of the clinical epidemiology of a large PV population has recently been completed by the Gruppo Italiano Studio Policitemia Vera. On this basis, approximately 3500 patients will be enrolled in the ECLAP study with a follow-up of 3 to 4 years. The uncertainty principle will be used as the main eligibility criterion: Polycythemic patients of any age, having no clear indication for or contraindication to aspirin treatment, will be randomized in a double-blind fashion to receive oral aspirin (100 mg daily) or placebo. According to current therapeutic recommendations, the basic treatment of randomized patients should be aimed at maintaining the hematocrit value < or = 45% in subjects aged < or = 50, and hematocrit < 45% as well as platelet count < 400 x 10(9)/L in patients aged > 50. Randomization will be stratified by participating center. The study is funded by the European Union BIOMED 2 program.

Acute cerebrovascular disease is a major cause of morbility, disability and mortality. Despite its enormous importance in term of public health, considerable uncertainty still exists regarding the efficacy and cost-effectiveness of many routine clinical practices currently used in the management of stroke. A multicenter study was conducted on 204 patients (100 males and 104 females; mean age 71.5 years; range 21-94) consecutively admitted in 12 hospitals in Abruzzo (Southern Italy) from September 1, 1990 to December 31, 1990, because of sudden onset of neurological deficit which was presumed to be of a vascular origin. One hundred and ninety-six patients were hospitalized less than 24 hours after stroke onset. Cerebral computerized tomography was performed in 135 patients, but only 43 had the examination within 24 hours of symptoms onset. Other instrumental investigations (carotid doppler, transcranial doppler, echocardiography, etc.) were rarely performed. Ischemic stroke was diagnosed in 69 patients, intraparenchimal hemorrhagic stroke in 33, sub-arachnoid hemorrhage in 10, undefined stroke in 40 and transient ischemic attack in 49. Antioedema were largely used in the first 48 hours after admission, and osmotic diuretics (glycerol and mannitol) were preferred to steroid treatment. Antiplatelet drugs (25.8%), calcium antagonists (20.1%) and barbiturates (19.1%) were also frequently prescribed. In conclusion, our study had shown an absolute lackness of standard criteria for management of patients with acute cerebrovascular disease.

Although it has long been recognised as the only reliable instrument for producing scientific evidence on the benefit/risk profile of therapeutic interventions, the technology of randomised clinical trials (RCT) is far from being the backbone of medical knowledge. Randomised clinical trials in polycythemia vera have been carried out when their methodology was being built up and, therefore, was rather unsatisfactory. Now we have aggressive cytoreductive treatments with chemotherapeutic agents loaded with doubts on long-term safety, while phlebotomy and preventive antiplatelet therapy are left to personal preferences because of debatable results of old, low-power clinical trials. A complex profile of uncertainties requires a simple, but articulated strategy of care and research to allow at the same time a reasonable transfer of the best available validated knowledge and a timely investigation of the most relevant questions. Without doubts, multi-country, collaborative RCTs is the key (not isolated or abstract) element of the current scenario. The declared background hypothesis is the willingness of a medical caring community of being, at the same time and with the same patients, a research community. The trial design comes in as the simplest technical way to deal with uncertainty. Data to be collected, criteria, contents, intensity of follow-up, and documentation of the events are exactly the same as those which are planned and adopted in routine 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 assistance to the majority of patients. The purpose of this paper is therefore twofold: a) to provide a brief methodological review of the controlled evidence available for the direction of therapeutic practice for PV: b) to outline and discuss the opportunity, general design, and feasibility of research strategies where a comparative large-scale trial between therapeutic alternatives could play a central role.

A comprehensive case-control study was conducted in an Italian region in order to compare the influence of family history of cardiovascular events, socioeconomic factors, social networks, and their joint associations with major risk factors, on the risk, of myocardial infarction (MI), unstable angina (UA) and ischemic stroke (IS). A total of 513 patients with MI, 178 with UA, 237 with IS, and 928 hospitalised controls were recruited. The odds ratio (OR) of MI for two or more relatives with a positive history of MI was 3.6 (95% CI: 1.8-7.3). Family history of MI was predictive for UA (OR = 5.8; 95% CI: 1.2-28.7), but not for IS. A family history of stroke was more associated with the risk of MI than of IS. After adjustment for known risk factors, the OR of MI for more educated people was 2.1 (1.3-3.6) compared with less-educated people. Large family size seemed to be protective for MI. The effect of major risk factors on MI ranged from additive (diabetes) to multiplicative jointly with high education and family history of MI. A family history of stroke increased IS risk threefold jointly with smoking and hyperlipidemia, and eightfold with diabetes. Besides a family history of MI and IS, in this community a higher educational status seems to better identify groups at increased risk of MI. The joint associations have important preventive implications since by identifying high-risk individuals (for MI and IS) a more careful assessment and control of risk factors amenable to intervention may be performed.

Circulating progenitor cells (CPCs) mobilized from bone marrow will replace the use of bone marrow transplantation because hematopoietic reconstitution is more rapid using the former technique. We report on early and late recovery of hematopoiesis after CPC transplantation in patients with non-Hodgkin's lymphoma (NHL) and analyze the role of variables possibly influencing engraftment. From December 1992 through September 1995, 57 consecutive NHL patients were enrolled in this study. Patients could be divided into 2 groups: the first comprised 32 patients with untreated diffuse large-cell lymphoma and unfavorable prognostic factors; the second comprised 25 patients with resistant or relapsing NHL of low-and high-grade histology. All patients received high-dose chemotherapy (carmustine, cytarabine, etoposide, and melphalan; BEAM) followed by CPC transplantation. In all, 25 patients were treated with granulocyte colony-stimulating factor (G-CSF) after CPC administration. The time to short-and long-term hematologic engraftment and variables correlating with multilineage long-term reconstitution were examined. The time to bilineage (neutrophils and platelets) hematopoietic reconstitution did not differ in G-CSF-treated and-untreated patients. In contrast, the time taken to reach a neutrophil count of 0.5 x 10(9)/1 and a WBC of 1 x 10(9)/1 was significantly shorter in G-CSF-treated patients. Overall, 33 patients achieved long-term, complete trilineage engraftment after a median of 117 days from CPC transplantation. The leukocyte count was the first parameter to reach full engraftment and hemoglobin was the last. According to Kaplan-Meier analysis, 80% of the patients are projected to reconstitute fully at 12 months after transplantation. Univariate and multivariate analyses showed that sustained, long-term hematopoiesis was significantly related to a younger age, an early bilineage reconstitution, and the quantity of CD34+ cells infused.

We examined the relationship between the hemoglobin concentration and the risk of ischemic stroke using data from a hospital-based case-control study. A total of 143 patients (age 30-69 years) with a diagnosis of cerebral infarction confirmed by computerized tomography scan and 143 age- and sex-matched controls entered the study. Hemoglobin was higher in the patients with stroke (14.2 +/- 1.6 g/l, mean +/- SD) than in controls (13.7 +/- 1.6 g/l; p < 0.05). Compared with subjects with hemoglobin levels of less than 13 g/l (reference category), the relative risk of ischemic stroke, after allowance for potential risk factors, was 2.0 (95% CI 0.8-4.9) for the 13-13.9 g/l quartile, 2.8 (95% CI 1.2-6.5) for the 14-14.9 g/l quartile, and 3.2 (95% CI 1.4-7.4) for the 14 + g/l quartile (chi 2 for linear trend 7.27, p < 0.01). We conclude that the hemoglobin concentration may be an indicator of risk for ischemic stroke.

Background: While a positive relation between serum cholesterol and the risk of myocardial infarction has been consistently reported, the association between serum cholesterol and the risk of ischemic stroke lacks consistency. To further investigate the strength of cholesterol as a risk factor for myocardial infarction and stroke we conducted a comparative study., Methods: A case-control study was conducted from 1990 to 1992. A network of 21 hospitals in Abruzzo, southern Italy, was created. First, computerized tomography scans confirmed ischemic stroke patients (230 with median age: 64; range: 31-69 years) and 230 sex- and age-matched controls with acute disorders unrelated to known cardiovascular risk factors. Acute myocardial infarction patients (513) and 513 matched controls were simultaneously recruited for a parallel study comparison. Total serum cholesterol concentration was measured within the first 48 hr following admission and the response to a structured questionnaire was evaluated., Results: The mean (standard deviation) serum cholesterol level was 220.7 mg/dl (50.9) among stroke patients and 201.5 mg/dl (41.6) among controls (P < 0.0001). Compared with the lowest quintile (< 160 mg/dl), the odds ratio of ischemic stroke for patients in the highest quintile (> 240 mg/dl), after simultaneous adjustment for other potentially confounding covariates, was 2.6 (95% confidence interval: 1.4-4.8). A significant linear trend in risk was found (chi 2 1 df = 7.27, P < 0.01). Within each total serum cholesterol quintile, adjusted odds ratios for myocardial infarction were higher than that for ischemic stroke, and a stronger linear trend in risk was found (chi 2 1 df = 21.3, P < 0.0001)., Conclusions: Our data confirm the strong linear relationship between total serum cholesterol and the risk of myocardial infarction and suggest that, at least in our population, cholesterol seems to be an indicator of ischemic stroke risk.

The experimental progression-regression human model offers an excellent opportunity for testing the pathophysiological hypotheses that have arisen in the study of atherosclerosis. Nevertheless, it is still necessary to demonstrate that the modifications of angiographic patterns are strictly related to changes in coronary events, and this evidence is not yet supported to date by performed trials. Ten randomized controlled trials designed with the aim of angiographically evaluating the evolution of coronary lesions in patients with coronary heart disease made over the past 13 years were reviewed to perform a meta-analysis. Quality of design and execution of the trials, and the analysis of the primary and secondary end-points chosen for each trial, as well as the methods used to measure the changes in atherosclerotic plaques were also assessed. The phenomenon of plaque regression in human beings seems to occur, but clinical, methodological and physiopathologic heterogeneity between examined trials made it unfeasible to perform a meta-analysis. Coronary events are the consequence of the interaction of known and unknown factors, and coronary arterial narrowing from a mild to moderate degree is only one of these factors. The choice of the regression of atherosclerotic plaques as the primary end-point of a trial should probably be confined to phase 2 studies, while proof of clinical efficacy should be based on harder end-points that are representative of the very objective of medical interventions: amelioration and/or prolongation of a patient's life.

On the basis of their promising experimental evidence, calcium channel blockers are today largely used in clinical practice for treatment of patients with cerebrovascular disorders. We propose a meta-analytical evaluation of published clinical trials on nimodipine, a dihydropiridin calcium antagonist, in subarachnoid hemorrhage and in ischemic stroke. In seven trials of subarachnoid hemorrhage, 112 deaths occurred among 682 patients randomized to active treatment compared with 154 deaths among 689 control patients (odds ratio of 0.68, 95% confidence interval of 0.52 to 0.90). Poor outcome due to delayed cerebral ischemia following subarachnoid hemorrhage was also lower in the group allocated to receive nimodipine (odds ratio of 0.47, 95% confidence interval of 0.36 to 0.62). In 12 trials of ischemic stroke, 382 deaths occurred among 2056 patients allocated to receive nimodipine compared to 288 deaths among 1462 control patients (odds ratio of 0.98, 95% confidence interval of 0.82 to 1.18). Pooled results strongly suggest a protective effect of nimodipine in delayed cerebral ischemia following subarachnoid hemorrhage and no effect in ischemic stroke, but the direction and the significance of these results are due to the contribution of a single large trial on subarachnoid hemorrhage and of two trials on ischemic stroke, which account respectively for 40% and 65% of randomized patients. The dissociated effect of nimodipine on these similar conditions could be related to its preventive role in ischemic damage, resembling animal models of ischemic stroke where a beneficial effect of calcium antagonists was clearly shown only when treatment was started before experimental cerebral artery occlusion. In this view, the negative results obtained from the clinical setting of ischemic stroke seem to indicate nimodipine as an aspecific neuroprotective agent without a curative effect.