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.).

MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis.

From 2007 to 2011, 66 patients with primary myelofibrosis or myelofibrosis (MF) preceded by essential thrombocythemia or polycythemia vera were enrolled into a prospective phase 2 clinical trial of reduced-intensity allogeneic hematopoietic stem cell transplantation (AHSCT), Myeloproliferative Disorder Research Consortium 101 trial. The study included patients with sibling donors (n = 32) receiving fludarabine/melphalan (FluMel) as a preparative regimen and patients with unrelated donors (n = 34) receiving conditioning with FluMel plus anti-thymocyte globulin (ATG). Patient characteristics in the 2 cohorts were similar. Engraftment occurred in 97% of siblings and 76% of unrelated transplants, whereas secondary graft failure occurred in 3% and 12%, respectively. With a median follow-up of 25 months for patients alive, the overall survival (OS) was 75% in the sibling group (median not reached) and 32% in the unrelated group (median OS: 6 months, 95% confidence interval [CI]: 3, 25) (hazard ratio 3.9, 95% CI: 1.8,8.9) (P < .001). Nonrelapse mortality was 22% in sibling and 59% in unrelated AHSCT. Survival correlated with type of donor, but not with the degree of histocompatibility match, age, or JAK2(V617F) status. In patients with MF with sibling donors, AHSCT is an effective therapy, whereas AHSCT from unrelated donors with FluMel/ATG conditioning led to a high rate of graft failure and limited survival. This trial was registered at www.clinicaltrials.gov as #NCT00572897.

Systematic review of trials using vasodilators in pulmonary arterial hypertension: why a new approach is needed.

BACKGROUND: In a previous meta-analysis on the approved treatments for pulmonary hypertension, we reported that all therapies caused small changes in 6-minute walk distance over a short period, with minimal effects on hemodynamics and no effect on survival. Since that last review, 10 new clinical trials with about 1,500 patients have been published, which has increased the statistical power of our observations. METHODS: A systematic review of all clinical trials in pulmonary arterial hypertension was done. RESULTS: The pooled effect of all treatments strategies (relative risk [95% CI], P) now shows a significant reduction of 39% (2%-62%, P = .041) in all-cause mortality. The benefits were confined only to patients with advanced disease for 16 weeks, regardless of which class of drug is used. When considering the effects within each drug family, no class of drug produced a statistically significant reduction in all-cause mortality. The improved survival bore no relationship with the change in 6-minute walk, the primary end point in most of the trials. CONCLUSIONS: The impact of vasodilators on long-term survival in pulmonary arterial hypertension remains uncertain. Future trials need to (a) adopt new trial designs that can better address clinical benefits, (b) use new end points that incorporate our best understanding of the disease rather than the ones that are easy to administer, and (c) include longer durations of study and other strategies to clarify if survival is affected.

A meta-analysis of trials of pulmonary hypertension: a clinical condition looking for drugs and research methodology.

BACKGROUND: Various innovative pharmacologic strategies for the treatment of patients with pulmonary hypertension have been tested in recent years. Neither their comparative efficacy on surrogate end points nor the overall impact on mortality have been formally reviewed. METHODS: We did a systematic overview of all randomized trials on the therapeutic yield of prostacyclin and analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors in patients with pulmonary hypertension searched in EMBASE, MEDLINE, and CINAHL databases from January 1985 to December 2005. RESULTS: Sixteen trials involving 1962 patients met the inclusion criteria. Up to 80% of the patients were in functional class III/IV with a median walking distance of 330 m at baseline. Overall, experimental treatments were associated with (1) a nonsignificant reduction in all-cause mortality (relative risk 0.70, 95% CI 0.41-1.22), (2) a minor but statistically significant improvement in exercise capacity of 42.8 m (95% CI 27.8-57.8), and (3) an improved dyspnea status by at least one functional class (relative risk 1.83, 95% CI 1.26-2.66). Changes in exercise capacity were not found to be predictive of a survival benefit. CONCLUSIONS: Although confirming the limited benefits in clinical end points documented by each trial, the overview fails to support a significant survival advantage and does not support the predictive power of surrogate end points.

Meta-analysis of effect of statin treatment on risk of sudden death.

Despite significant progress in the prevention and treatment of cardiovascular disease, sudden cardiac death (SCD) is a major public health problem. Statins showed consistent benefits on cardiovascular events, but scant data were available about their effects on SCD. This meta-analysis aimed to assess the effect of statins on SCD. Additional analyses were carried out to evaluate lipid reduction as a possible mediator of the effect. Randomized controlled trials from January 1966 to July 2006 were retrieved by searching the MEDLINE database. Inclusion criteria were outcome focusing on the incidence of SCD, statin treatment compared with placebo or no treatment, randomized design, >or=100 patients enrolled, and follow-up>or=6 months. Data were independently abstracted by 2 investigators using a standardized protocol. Ten randomized controlled trials enrolling a total of 22,275 patients were included in the meta-analysis. Risks of SCD were 3% in patients receiving statins and 3.8% in control patients. Statin treatment was associated with a significant 19% risk reduction for SCD (odds ratio 0.81, 95% confidence interval 0.71 to 0.93, p=0.003). In subgroup analysis, the benefit of statins was independent from the main characteristics of the studies and changes in patient lipid levels during the study. In conclusion, our results suggest that statins decrease the risk of SCD.

The potential role of hematocrit control on symptom burden among polycythemia vera patients: Insights from the CYTO-PV and MPN-SAF patient cohorts.

Current guidelines suggest that polycythemia vera (PV) patients maintain a strict hematocrit less than 45%. However, to date, little is known about the relationship between HCT control and PV- related symptom burden. In this study, PV patient data was analyzed from the CYTO PV trial (n = 224) and the MPN-SAF study cohort (n = 645). No significant differences in symptom burden were seen at the 6 and 12 month follow-up when evaluating prospective hematocrit control in the CYTO PV cohort. Patients in the MPN-SAF cohort with a worst item score of greater than 5/10 on the Myeloproliferative Neoplasm Symptom Total Symptom Score had a significantly lower mean hematocrit (p = .0376). These findings suggest a relationship between traditional aggressive therapy for PV and increased symptom burden with prolonged therapy. Thus, symptom burden should be considered when contemplating the choice of therapy in the second-line setting for PV.

A clinically practicable diagnostic score for metabolic syndrome improves its predictivity of diabetes mellitus: the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI)-Prevenzione scoring.

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.

Prognostic impact of metabolic syndrome in patients with chronic heart failure: data from GISSI-HF trial.

OBJECTIVES: The adverse prognostic impact of metabolic syndrome (METS) in unselected populations and in patients with coronary heart disease has been previously shown. The aim of the current analysis was to evaluate the impact of METS on prognosis in chronic heart failure (HF). METHODS: International Diabetes Federation criteria were used for the diagnosis of METS. Adjusted Cox regression models with all-cause and HF death as outcomes were fitted in 6648 patients enrolled in GISSI-HF trial with no missing values for the variables of interest. RESULTS: Risk of all-cause and HF death was significantly reduced in patients with METS compared to patients without METS (HR: 0.83, 95% CI: 0.72 to 0.95, p=0.005; HR: 0.76, 95% CI: 0.59 to 0.98, p=0.031; respectively). As compared with patients with no METS and no type 2 diabetes mellitus (DM), the risk of all-cause and HF death was significantly lower in patients with METS and no DM (HR: 0.76, 95% CI: 0.62 to 0.95, p=0.015; HR: 0.65, 95% CI: 0.42 to 0.99, p=0.046; respectively), whereas it was significantly increased in patients with DM and no METS (HR: 1.34, 95% CI: 1.21 to 1.48, p<0.001; HR: 1.44, 95% CI: 1.21 to 1.72, p<0.001; respectively). Patients with METS and DM showed no difference for risk of total and HF death compared with patients with no METS and no DM (HR: 1.03, 95% CI: 0.87 to 1.21, p=0.762; HR: 0.99; 95% CI: 0.73 to 1.35; p=0.963; respectively). CONCLUSIONS: METS is associated with reduced all-cause and HF mortality in patients with HF. HF patients with DM without METS are at the highest risk of mortality, whereas METS attenuates mortality risk in HF patients with DM.

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.

[Lifestyle, health and cardiovascular risk: the results of the study "Rischio & Prevenzione"]. / Stili di vita, salute e rischi cardiovascolari: i risultati dello studio "Rischio & Prevenzione"

Lifestyle, health and cardiovascular risk: the results of the study "Rischio & Prevenzione". The substantial agreement of the recommendations aimed to promote the so called "healthy lifestyle habits" dose not coincide to a rebut body of evidences on the transferability of the guidelines into daily conditions of care. The large cohort of ~12.000 patients included in a prospective-observational and experimental study conducted by a country-wide network of 860 Italian General Practitioners, provided the opportunity of testing the yield of the broad spectrum of life habits found across ages (>55 years, sex, regions, on the prognosis for fatal and not fatal events). While documenting and quantifying over the relative short period of time of the study (~ 4 years) the highly significant advantage of each of the components (diet and physical exercise) of the habits, as well as their combination, the study could be the sum as specifically important for two more general reasons: a) it is the general practice based documentation of the public health importance of recommendations in an adult old population; b) the instruments developed and tested to qualify-quantify the risk profiles are specifically praticable in the busy setting of daily care.

Cholesterol-lowering interventions and stroke: insights from a meta-analysis of randomized controlled trials.

OBJECTIVES: This meta-analysis was performed to determine the effects of various cholesterol-lowering treatments on the risk of stroke and its relationship with the extent of cholesterol lowering. BACKGROUND: Statins reduce the incidence of stroke, and it has been proposed that such effect is independent of cholesterol lowering and is explained by alternative mechanisms. METHODS: We performed a meta-analysis of randomized trials of cholesterol-lowering treatments in cardiovascular disease reporting on stroke, involving 266,973 patients investigated and a cumulative 946,582 person-years of exposure, and a meta-regression analysis of the extent of stroke reduction as a function of changes in total cholesterol. RESULTS: The odds ratio (OR) for the incidence of stroke in actively treated groups versus controls was 0.88 (95% confidence interval: 0.83 to 0.94, p < 0.001). No treatment affected fatal strokes. Whereas statins decreased the risk of total stroke significantly (OR: 0.85, 95% confidence interval: 0.78 to 0.92; p < 0.001), the benefit of nonstatin interventions was smaller and not statistically significant (diet OR: 0.92, fibrates OR: 0.98, other treatments OR: 0.81). We found a significant relationship between percent reduction of total (and low-density lipoprotein) cholesterol and percent reduction of total strokes (p = 0.0017), with each 1% reduction of total cholesterol predicting a 0.8% relative risk reduction of stroke. We found no significant association between stroke reduction and changes of high-density lipoprotein cholesterol levels, and inconsistent associations with reduction of triglycerides. CONCLUSIONS: Among cholesterol-lowering treatments, statins are the most effective at decreasing the risk of total stroke, but their benefit is proportional to the percent reduction of total cholesterol and low-density lipoprotein cholesterol. No lipid-lowering intervention was associated with a reduction of fatal stroke.

Modulation of sensitized C-fibers by adrenergic stimulation in human neuropathic pain.

UNLABELLED: The chronic constriction injury model is widely used in studying mechanisms of neuropathic pain. In this model neuropathic pain can be influenced by sympathetic interventions. It is assumed that similar mechanisms as in animals are responsible for pain arising from nerve entrapment syndromes in humans. The aim of the present study was to investigate if in patients with nerve entrapment nociceptive afferents can be modulated by adrenergic stimulation. METHODS: Twenty patients with pain due to a unilateral entrapment of the median nerve and 10 controls were included in the study. Spontaneous pain, mechanical and thermal evoked pain were assessed within the innervation territory of the lesioned nerve and the corresponding contralateral segment in patients and on the right hand side in healthy volunteers. The examinations were performed at baseline, during whole body cooling (sympathetic activation) and whole body warming (sympathetic inhibition), and after norepinephrine iontophoresis. RESULTS: All patients reported spontaneous pain. Mechanical allodynia, punctate hyperalgesia and cold allodynia was not found. According to side-to-side differences in heat pain thresholds, patients were separated in patients with (n=10) and without (n=10) heat hyperalgesia. Adrenergic stimulation did not induce or enhance spontaneous or mechanical evoked pain in any patient or control subject. However in patients with pre-existing heat hyperalgesia sympathetic stimulation aggravated heat hyperalgesia significantly. Further in these patients the decrease in heat pain thresholds observed after norepinephrine iontophoresis was significantly higher compared to patients without pre-existing heat hyperalgesia. CONCLUSION: Sympathetic-afferent interaction does not play a major role in pain generation due to nerve entrapment. Nevertheless in a subgroup of patients nociceptive afferents show sensitivity to physiological and pharmacological sympathetic stimulation. This finding is important because it emphasises that despite there is no clinical detectable effect on pain sympathetic afferent interaction can be found.

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.