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Haematologica Aug 2007Factor V Leiden (FVL) and prothrombin G20210A mutation (PTM) are the two most common genetic polymorphisms known to predispose to a first episode of venous... (Review)
Review
Factor V Leiden (FVL) and prothrombin G20210A mutation (PTM) are the two most common genetic polymorphisms known to predispose to a first episode of venous thromboembolism (VTE). However, whether these thrombophilic abnormalities are also risk factors for recurrent VTE is unclear. We conducted a systematic review of prospective studies to assess the risk of recurrent VTE associated with heterozygous carriage of each of these mutations. All randomized controlled trials and prospective cohort studies that reported the incidence of recurrent VTE in patients with and without FVL and PTM after discontinuation of anticoagulant treatment were collected and analyzed. The risk ratios (RR) and their 95% confidence intervals (CI) for recurrent VTE were calculated in heterozygous carriers of FVL or PTM and compared to those of non-carriers. Eleven studies fulfilled the inclusion criteria. Recurrent VTE occurred in 114 out of 557 heterozygous carriers of FVL (20.5%) as compared to 382 out of 2,646 non-carriers (14.4%); and in 38 out of 212 heterozygous carriers of PTM (17.9%) compared to 428 of 2,996 non-carriers (14.3%). The RR of VTE recurrence conferred by the heterozygous carriage of FVL and PTM was 1.39 (95% CI, range 1.15 to 1.67) and 1.20 (range 0.89 to 1.61), respectively, using the Mantel-Haenszel fixed-effects model; 1.45 (1.13 to 1.85) and 1.36 (1.02 to 1.82), respectively, using the Der Simonian and Laird random effects method. In symptomatic patients with VTE, heterozygous carriage of FVL is clearly associated with a definitely increased risk of recurrent thromboembolism. The risk is lower with PTM and is difficult to interpret since it varies according to the assessment method used.
Topics: 3' Untranslated Regions; Activated Protein C Resistance; Adolescent; Adult; Aged; Aged, 80 and over; Cohort Studies; Factor V; Female; Heterozygote; Humans; Incidence; Male; Middle Aged; Prevalence; Prospective Studies; Prothrombin; Randomized Controlled Trials as Topic; Recurrence; Risk; Thromboembolism; Thrombophilia; Venous Thrombosis
PubMed: 17650440
DOI: 10.3324/haematol.10234 -
Frontiers in Nutrition 2022Physical training can improve several health variables in patients with type 2 diabetes mellitus (T2DM). A growing body of studies also finds a positive influence of...
INTRODUCTION
Physical training can improve several health variables in patients with type 2 diabetes mellitus (T2DM). A growing body of studies also finds a positive influence of dietary supplement (DS) intake. The aim of this review is to shed light on the possible effects of training interventions combined with DS intake in T2DM patients.
METHODS
A systematic search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the PubMed and BISp Surf databases. Inclusion criteria were defined using the Patient-Intervention-Comparison-Outcome (PICO) scheme. The Physiotherapy Evidence Database (PEDro) scale was used for quality assessment and risk of bias analysis.
RESULTS
Ten controlled interventional studies with a total number of 643 subjects met the inclusion criteria. These studies investigated the effects of (a) vitamin D (VD), (b) VD + whey protein, (c) polyphenol containing antioxidant capsules, (d) creatine, (e) L-arginine, (f) leucine-rich amino acids, and (g) broccoli sprouts powder. Eight studies investigated effects on one or more of the following health outcomes: body mass index, fat mass, insulin resistance, glycemic control, lipid profile, oxidative stress/antioxidative capacity and/or inflammatory markers/molecules. Five of the studies show clear superior effects of physical training combined with DS intake (supplements a, b, c, e) on some of these variables compared with training only. However, one study indicates that VD intake might attenuate the training effects on triglyceride levels. Another study found that training + VD + whey protein intake increased tumor necrosis factor-α levels in T2DM patients. The effects of training combined with DS intake on renal function (supplement d) or incretin metabolism (supplement a) were investigated in two further studies. These studies do not show any additional effects of DS intake. The quality of the majority of the studies was high.
CONCLUSION
DS intake can potentially increase the benefits of physical training for specific health outcomes in T2DM patients. However, negative effects can also be observed. Possible cellular and molecular mechanisms behind potential synergistic or divergent effects of exercise training and DS use in T2DM should be explored in detail in future studies for the development of safe recommendations.
PubMed: 35356737
DOI: 10.3389/fnut.2022.817724 -
Journal of the National Comprehensive... Jan 2019Exercise can ameliorate cancer- and treatment-related toxicities, but poor adherence to exercise regimens is a barrier. Exercise interventions using digital activity...
Exercise can ameliorate cancer- and treatment-related toxicities, but poor adherence to exercise regimens is a barrier. Exercise interventions using digital activity trackers (E-DATs) may improve exercise adherence, but data are limited for patients with cancer. We conducted a systematic review examining the feasibility of E-DATs in cancer survivors and effects on activity level, body composition, objective fitness outcomes, health-related quality of life (HRQoL), self-reported symptoms, and biomarkers. We identified randomized controlled trials (RCTs) of E-DATs in adult cancer survivors published in English between January 1, 2008, and July 27, 2017. Two authors independently reviewed article titles (n=160), removed duplicates (n=50), and reviewed the remaining 110 articles for eligibility. A total of 12 RCTs met eligibility criteria, including 1,450 patients (mean age, 50-70 years) with the following cancers: breast (n=5), colon or breast (n=2), prostate (n=1), acute leukemia (n=1), or others (n=3). Duration of E-DATs ranged from 4 to 24 weeks, and the follow-up period ranged from 4 to 52 weeks, with retention rates of 54% to 95%. The technology component of E-DATs included pedometers (n=8); pedometers with smartphone application (n=1), Wii Fit (n=1), heart rate monitor (n=1); and a wireless sensor with accelerometer, gyroscope, and magnetometer (n=1). Adherence by at least one measure to E-DATs was >70% in 8 of 8 RCTs. Compared with controls, E-DATs significantly improved patients' step count in 3 of 5 RCTs, activity level in 6 of 9 RCTs, and HRQoL in 7 of 9 RCTs (all 05), with no significant changes in biomarkers (eg, interleukin 6, tumor necrosis factor α, C-reactive protein, c-peptide, lipid panel) in 3 RCTs. Duration of E-DAT was not significantly correlated with adherence or study retention. This systematic review shows that E-DATs are feasible to implement in cancer survivors. Future research should examine the optimal type, dose, and schedule of E-DATs for cancer survivors.
Topics: Cancer Survivors; Exercise Therapy; Fitness Trackers; Humans; Neoplasms; Patient Compliance; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 30659130
DOI: 10.6004/jnccn.2018.7082 -
Health Technology Assessment... Mar 2005To assess the clinical and cost-effectiveness of drotrecogin alfa (activated) for the treatment of adults with severe sepsis in a UK context.
Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris) for the treatment of severe sepsis in adults: a systematic review and economic evaluation.
OBJECTIVES
To assess the clinical and cost-effectiveness of drotrecogin alfa (activated) for the treatment of adults with severe sepsis in a UK context.
DATA SOURCES
Electronic databases. Data from the commercial use of the drug up to April 2002. Data from the manufacturer submission to the National Institute for Clinical Excellence (NICE).
REVIEW METHODS
A systematic review of the literature and an economic evaluation were undertaken. Data were synthesised through a narrative review with full tabulation of results from included studies.
RESULTS
The evidence on the effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis came primarily from one large pivotal randomised controlled trial, the PROWESS study. This study demonstrated a statistically significant absolute reduction in 28-day mortality of 6.5%. Longer term survival benefit was maintained to 90 days. By 9 months, the trend towards increased median survival was non-significant, although the survival curves did not cross. Results presented by the number of organ dysfunctions were not statistically significant, but when mortality rates for those with two or more organ failures were combined, the relative risk of death was significantly lower in those treated with drotrecogin alfa (activated) compared with placebo. However, this report highlights a number of considerations relevant to the subgroup analyses reported for the PROWESS study. Published cost-effectiveness studies of treatment with drotrecogin alfa (activated) have applied a range of methods to the estimation of benefits, estimating an incremental gain per treated patient of between 0.38 and 0.68 life-years (for patients with severe sepsis). For patients with severe sepsis and multiple organ dysfunction, the manufacturer (Eli Lilly) estimated an incremental gain of 1.115 life-years per treated patient, compared to 1.351 life-years per treated patient estimated by the Southampton Health Technology Assessments Centre (SHTAC). These latter UK analyses are based on a patient group that is more severely affected by disease, where effectiveness is greater and the baseline risk of all-cause mortality is much higher (SHTAC analysis), these factors are associated with the noted difference in effect. The three published cost-effectiveness studies report cost for US and Canadian patient groups; for those patients with severe sepsis they report the additional cost per patient treated in a range around 10,000-16,000 dollars. The manufacturer's submission reports analysis for the UK, based on 28-day survival data in patients with severe sepsis and multiple organ dysfunction (the European licence indication), with the additional mean cost per treated patient estimated to be 5106 pounds. The analysis undertaken by SHTAC, for a UK group of patients with severe sepsis and multiple organ dysfunction, estimates an additional mean cost per patient treated of 6661 pounds. The manufacturer's submission to NICE presents cost-effectiveness estimates for drotrecogin alfa (activated) in the UK, in patients with severe sepsis and multiple organ dysfunction, at 6637 pounds per quality-adjusted life-year (QALY) based on 28-day effectiveness data, and 10,937 pounds per QALY based on longer term follow-up data. SHTAC developed an independent cost-effectiveness model and estimated a base-case cost per QALY of 8228 pounds in patients with severe sepsis and multiple organ failure (based on 28-day survival data). Simulation results indicate that where the NHS is willing to pay 20,000 pounds per QALY, drotrecogin alfa (activated) is a cost-effective use of resources in 98.7% of cases. Published economic evaluations report various sensitivity analyses, with results sensitive to changes in the measure of treatment effect, but otherwise studies reported that results were robust to variations in most assumptions used in the cost-effectiveness analysis.
CONCLUSIONS
Drotrecogin alfa (activated) plus best supportive care appears clinically and cost-effective compared with best supportive care alone, in a UK cohort of severe sepsis patients, and in the subgroup of more severely affected patients with severe sepsis and multiple organ failure. The introduction of drotrecogin alfa (activated) will involve a substantial additional cost to the NHS. The treatment-eligible population in England and Wales may comprise up to 16,570 patients, with an estimated annual drug acquisition cost of over 80 million pounds, excluding VAT. Further research is required on the longer term impact of drotrecogin alfa (activated) on both mortality and morbidity in UK patients with severe sepsis, on the clinical and cost-effectiveness of drotrecogin alfa (activated) in children (under 18 years) with severe sepsis, and on the effect of the timing of dosage and duration of treatment on outcomes in severe sepsis.
Topics: Adolescent; Adult; Female; Humans; Male; Acute Disease; Cost-Benefit Analysis; Evidence-Based Medicine; Placebos; Protein C; Randomized Controlled Trials as Topic; Recombinant Proteins; Sepsis; Treatment Outcome; United Kingdom
PubMed: 15774234
DOI: 10.3310/hta9110 -
Critical Care (London, England) 2005The design of clinical trials of interventions aimed at reducing mortality in patients with severe sepsis assumes that the relative treatment effect of the intervention... (Review)
Review
INTRODUCTION
The design of clinical trials of interventions aimed at reducing mortality in patients with severe sepsis assumes that the relative treatment effect of the intervention is independent of the patients' risk for death. We reviewed published data from phase III clinical studies of severe sepsis to determine whether a relationship exists between risk for death and the relative benefit of the investigational agent. Such an interaction might warrant a change in the assumptions that underlie current trial designs.
METHODS
We conducted a systematic review of published phase III, randomized, placebo-controlled trials in adult patients with sepsis, severe sepsis, or septic shock up to November 2004. All studies enrolled patients with known or suspected infection, evidence of a systemic response to the infection, and one or more organ dysfunctions resulting from the systemic response.
RESULTS
Twenty-two publications, investigating 17 molecular entities, fulfilled criteria for phase III or equivalent studies aimed at reducing mortality in adult patients with severe sepsis or septic shock. Three studies achieved the prospectively defined primary end-point of a statistically significant reduction in 28-day all-cause mortality. The control group mortality rates for these studies were 31%, 43% and 61%, indicating that the beneficial effects of adjunct therapies could be demonstrated over a wide range of illness severity. Analysis of subgroup data from failed studies provided no evidence that the efficacy of the therapeutics being investigated varied by baseline placebo mortality rates. Among all studies, interventions with anticoagulant activity or anti-inflammatory activity did not appear to be harmful in patients with evidence of less coagulopathy or less inflammation.
CONCLUSION
Our review of published clinical data does not support the hypothesis that mortality risk of the population studied alters the relative treatment effect associated with anti-inflammatory or other agents used to treat severe sepsis. Clinical studies in severe sepsis should continue to enroll patients over a wide range of disease severity, as long as patients enrolled have evidence of sepsis-induced organ dysfunction(s), patients are at an appreciable risk for death (e.g. as evidenced by admission to an intensive care unit), and the potential for benefit outweighs the potential for harm.
Topics: APACHE; Adult; Anti-Infective Agents; Anti-Inflammatory Agents; Anticoagulants; Clinical Trials, Phase III as Topic; Critical Care; Critical Illness; Humans; Immunologic Factors; Protein C; Receptors, Interleukin-1; Recombinant Proteins; Sepsis; Shock, Septic; Survival Analysis; Treatment Outcome
PubMed: 16280057
DOI: 10.1186/cc3795 -
BMC Anesthesiology Jun 2007Activated drotrecogin alfa (human activated protein C, rhAPC), is produced by recombinant DNA technology, and purports to improve clinical outcomes by counteracting the...
BACKGROUND
Activated drotrecogin alfa (human activated protein C, rhAPC), is produced by recombinant DNA technology, and purports to improve clinical outcomes by counteracting the inflammatory and thrombotic consequences of severe sepsis. Controversy exists around the clinical benefits of this drug and an updated economic study that considers this variability is needed.
METHODS
A systematic literature review was performed using Medline, Embase and the International Network of Agencies for Health Technology Assessment (INAHTA) databases to determine efficacy, safety and previous economic studies. Our economic model was populated with systematic estimates of these parameters and with population life tables for longer term survival information. Monte Carlo simulations were used to estimate the incremental cost-effectiveness ratios (ICERs) and variance for the decision analytic models.
RESULTS
Two randomized clinical trials (RCTS) of drotrecogin alfa in adults with severe sepsis and 8 previous economic studies were identified. Although associated with statistical heterogeneity, a pooled analysis of the RCTs did not show a statistically significant 28-day mortality benefit for drotrecogin alfa compared to placebo either for all patients (RR: 0.93, 95% CI: 0.69, 1.26) or those at highest risk as measured by APACHE II >or= 25 (RR: 0.90, 95% CI: 0.54, 1.49). Our economic analysis based on the totality of the available clinical evidence suggests that the cost-effectiveness of drotrecogin alfa is uncertain (< 59% probability that incremental cost-effectiveness ratio (ICER) life year gained (LYG)
or= 25 (93% probability ICER CONCLUSION
The evidence supporting the clinical and economic attractiveness of drotrecogin alfa is not conclusive and further research appears to be indicated.
PubMed: 17592639
DOI: 10.1186/1471-2253-7-5