Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial

BACKGROUND: Oral anticoagulants, such as dabigatran etexilate, an oral, direct thrombin inhibitor, that do not require monitoring or dose adjustment offer potential for prophylaxis against venous thromboembolism (VTE) after total knee replacement surgery. METHODS: In this randomized, double-blind study, 2076 patients undergoing total knee replacement received dabigatran etexilate, 150 mg or 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery, for 6-10 days. Patients were followed-up for 3 months. The primary efficacy outcome was a composite of total VTE (venographic or symptomatic) and mortality during treatment, and the primary safety outcome was the incidence of bleeding events. RESULTS: The primary efficacy outcome occurred in 37.7% (193 of 512) of the enoxaparin group versus 36.4% (183 of 503) of the dabigatran etexilate 220 mg group (absolute difference, -1.3%; 95% CI, -7.3 to 4.6) and 40.5% (213 of 526) of the 150 mg group (2.8%; 95% CI, -3.1 to 8.7). Both doses were noninferior to enoxaparin based on the pre-specified noninferiority criterion. The incidence of major bleeding did not differ significantly between the three groups (1.3% versus 1.5% and 1.3% respectively). No significant differences in the incidences of liver enzyme elevation and acute coronary events were observed during treatment or follow-up. CONCLUSIONS: Dabigatran etexilate (220 mg or 150 mg) was at least as effective and with a similar safety profile as enoxaparin for prevention of VTE after total knee-replacement surgery.     

Indicators of lifetime endogenous estrogen exposure and risk of venous thromboembolism

BACKGROUND: Lifetime estrogen exposure has been related to breast cancer risk, osteoporosis, and cardiovascular disease but data on venous thromboembolism (VTE) risk are limited. METHODS: Data from a hospital-based case-control study among 608 postmenopausal women (191 with a first episode of idiopathic VTE and 417 age-matched controls) were used to determine whether estrogen exposure, as assessed by age at menopause [classified as early (< or = 45 years), normal (46-54 years) and late menopause (> or = 55 years)] and parity, was associated with the risk of VTE. RESULTS: After adjustment for potential confounding variables, the risk of VTE was increased with each year's delay in the menopause [odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.02-1.10, P < 0.0075]. When compared with women with normal menopause used as a reference, the adjusted OR for VTE was 0.59 (95% CI = 0.36-0.97) and 2.53 (95% CI = 1.28-4.99) for women with early menopause and late menopause, respectively (P = 0.001). Adjusted OR for VTE was also higher for women with more than two children when compared with those with less than or equal to two children (1.56, 95% CI = 1.03-2.34, P = 0.03). The lowest risk of VTE was observed in women with early menopause and lower parity (adjusted OR = 0.60, 95% CI = 0.30-1.24), the highest risk was among women with late menopause who have had more than two children (adjusted OR = 3.41, 95% CI = 1.46-9.25). CONCLUSION: These results show that the longer exposure to endogenous estrogen is associated with an increased VTE risk.     

Hyperhomocysteinemia and low B vitamin levels are independently associated with venous thromboembolism: results from the EDITH study: a hospital-based case–control study

BACKGROUND: Moderate hyperhomocysteinemia and B vitamins deficiency are thought to be risk factors for venous thromboembolism (VTE). The causality and independence of those associations are still questioned. METHODS: We measured fasting serum total homocysteine, folates, and vitamin B12 levels as well as 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T genotypes in 467 patients hospitalized with a first well-documented deep vein thrombosis and/or pulmonary embolism not related to a major acquired risk factor and 467 controls matched for gender and age. RESULTS: Mild hyperhomocysteinemia, low serum folates, and vitamin B12 were associated with VTE independently of each other. In multivariate analysis, odds ratios (OR) (95% CI) for VTE associated with mild hyperhomocysteinemia (>15 micromol L(-1)), low serum folates (< or = 4.9 nmol L(-1)), and vitamin B12 (< or = 253 pmol L(-1)) were 1.48 (1.05-2.08), 3.14 (1.35-7.32) and 1.42 (1.03-1.98), respectively. An MTHFRC677T genotype was not significantly associated with VTE; OR (95% CI): 1.13 (0.70-1.81) CONCLUSIONS: The current data provides further knowledge in the complex relationship between hyperhomocysteinemia, low vitamin levels, and VTE.     

The prognostic significance of post-infarction angina pectoris and the effect of verapamil on the incidence of angina pectoris and prognosis

The prognostic sign of angina pectoris and the effect of interventionwith verapamil on the incidence of angina pectoris were studiedin patients recovering from myocardial infarction and includedin the Danish Verapamil Infarction Trial II. During the secondweek after admission patients were double-blindly randomizedto treatment with verapamil 360 mg. day^–1 or placebo.Treatment was continued for up to 18 months. At discharge anginapectoris was reported in 11% of 869 patients randomized to verapamiland in 12% of 888 randomized to placebo (ns). One month afterdischarge a significantly increase in the prevalance of anginapectoris was reported in both the verapamil (33%) (P<0·001)and the placebo groups (39%) (P <0·001). The one monthprevalence of angina pectoris (P=0·03) and the 18 monthsoverall incidence of angina pectoris (P= 0·002) wereboth .sigificant lower in the verapamil group compared withplacebo. Stable angina pectoris during the first month of follow-upwas a significant predictor of major events (i.e. death or reinfarction)(hazard ratio = 1·45; 95% confidence limits: 1·101·89). As verapamil significantly reduced the incidenceof angina pectoris during daily activities, and thereby thenumber of patients at high risk, the beneficial effect of verapamilin reducing major events in patients recovering from myocardialinfarction is likely to be due to abolishing myocardial ischaemia.     

Three-year follow-up of the Oxford Cholesterol Study: assessment of the efficacy and safety of simvastatin in preparation for a large mortality study

We report the results of a randomized single-centre study designedto assess the effects of simvastatin on blood lipids, bloodbiochemistry, haematology and other measures of safety and tolerabilityin preparation for a large-scale multicentre mortality study.Six hundred and twenty-one individuals considered to be at increasedrisk of coronary heart disease were randomized, following a2-month placebo ‘run-in’ period, to receive 40 mgdaily simvastatin, 20 mg daily simvastatin or matching placebo.Their mean age was 63 years, 85% were male, 62% had a historyof prior myocardial infarction (MI), and the mean baseline totalcholesterol was 7·0 mmol. 1^–1. Median follow-upin the present report is 3·4 years. Eight weeks after randomization, 40 mg daily simvastatin hadreduced non-fasting total cholesterol by 29·2% ±1·1 (2·03 ± 0·08 mmol. 1^–1)and20 mg daily simvastatin had reduced it by 26·8% ±1·0 (1·87 ± 0·07 mmol. 1^–1).Almost all of tile difference in total cholesterol at 8 weekswas due to the reduction in LDL cholesterol (40·8±1·6and 38·2%±1·4 among patients allocated40mg and 20mg of simvastatin daily respectively), but simvastatinalso reduced triglycerides substantially (19·0% and 17·3%)and produced a small increase in HDL cholesterol (6·4%and 4·8%). These effects were largely sustained overthe next 3 years, with 40 mg daily simvastatin producing a slightlygreater reduction in total cholesterol at 3 years (25·7%±1·9reduction) than did 20 mg daily simvastatin (22·2%±1·8). There were no differences between the treatment groups in thenumbers of reports of ‘possible adverse effects’of treatment or of a range of different symptoms or conditions(including those related to sleep or mood) recorded at regularclinic follow-up. Mean levels of alanine aminotransferase, aspartateaminotransferase and creatine kinase were slightly increasedby treatment, but there were no significant difference betweenthe treatment groups in the numbers of patients with significantlyelevated levels. A slightly lower platelet count in the simvasatingroup was the only haematological difference from placebo, withno difference in the numbers of patients with low platelet counts. In summary, the simvastatin regimens studied produced largesustained reductions in total cholesterol, LDL cholesterol andtriglyceride and small increases in HDL cholesterol. They werewell tolerated, with no evidence of serious side-effects duringthe first 3 years of this study. Consequently, simvastatin providesan opportunity to conduct large randomized studies that assessthe effects of cholesterol lowering on total mortality and oncause-spec mortality. Even with such an effective cholesterollowering treatment, however such mortality studies will stillneed to be prolonged and to involve some tens of thousands ofpatients at substantial risk of coronary heart disease if clearevidence is to emerge.     

Immune tolerance treatment in haemophilia patients with inhibitors: the Spanish Registry

We present a retrospective study of immune tolerance treatment (ITT) carried out in 42 Spanish haemophiliac patients. Most of the patients were high responders (39/42), with a median maximum titre of 67 Bethesda units (BU) (range 6-2984). The median inhibitor titre at the start the ITT was 11 BU (range 1-256 BU) and the median age of the patients was 7 years (range 0-57). The mean factor dosage was 140 IU kg bodyweight(-1) day(-1) (range 25-500). In most of the ITTs, plasma-derived factor concentrate of intermediate and high purity was used. The inhibitor was eradicated in 26/38 (68%) of the patients who completed the treatment and two patients changed their status from high to low responders. Multivariate logistic regression analysis showed that three significant variables were associated with the highest probability of success: (i) the use of low factor doses for ITT (< or = 100 IU kg(-1) day(-1); P = 0.0106; 95% CI 0.000289-0.342); (ii) a titre of < 10 BU at start of ITT (P = 0.0286; 95% CI 0.00253-0.7189) and (iii) a lower maximum titre (P = 0.0214; 95% CI 0.98-0.9994).     

Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene

Inherited factor X deficiency (FXD) is a rare (1:1,000,000) recessive bleeding disorder. The clinical and laboratory phenotypes of FXD are poorly correlated and few regional studies on the genotype and the clinical manifestations of FXD are known. To understand the association between clinical manifestations and causative genotype, detailed evaluation of bleeding pattern in a high number of patients is needed. This international study analysed the phenotype and genotype of 102 subjects from Central Europe (Germany, Poland and Slovakia) and Latin America (Costa Rica and Venezuela) with causative mutations in the F10 gene, via sequencing. Twenty-eight homozygous, seven compound-heterozygous and 67 heterozygous FXD subjects were characterized. Twenty-nine different causative mutations, including 15 novel mutations, were analysed. Spontaneous bleeding symptoms in 42 symptomatic individuals (26 homozygous, seven compound heterozygous and nine heterozygous) comprised easy bruising (55%), haematoma (43%), epistaxis (36%), haemarthrosis (33%), intracranial haemorrhage (ICH; 21%), and gastrointestinal (GI) haemorrhage (12%). The manifestation of bleeding symptoms in 9 of 67 (13%) symptomatic heterozygous subjects is described. The bleeding patterns of the enrolled patients showed differences that are associated with the types of F10 mutation, and the corresponding genotypes. The homozygous patients were evaluated for genotype-phenotype correlation. The results suggested that ICH seems to be associated with the F10 mutation Gly380Arg, and possibly with the mutations IVS7-1G>A and Tyr163delAT. A tentative association of other mutations to severe symptoms such as haemarthrosis and GI haemorrhage is reported. The severity of FXD, the genotype-phenotype association, and the results of regional studies are discussed.     

The revised CONSORT statement for reporting randomized trials: explanation and elaboration

Overwhelming evidence now indicates that the quality of reporting of randomized, controlled trials (RCTs) is less than optimal. Recent methodologic analyses indicate that inadequate reporting and design are associated with biased estimates of treatment effects. Such systematic error is seriously damaging to RCTs, which boast the elimination of systematic error as their primary hallmark. Systematic error in RCTs reflects poor science, and poor science threatens proper ethical standards. A group of scientists and editors developed the CONSORT (Con solidated S tandards o f R eporting T rials) statement to improve the quality of reporting of RCTs. The statement consists of a checklist and flow diagram that authors can use for reporting an RCT. Many leading medical journals and major international editorial groups have adopted the CONSORT statement. The CONSORT statement facilitates critical appraisal and interpretation of RCTs by providing guidance to authors about how to improve the reporting of their trials. This explanatory and elaboration document is intended to enhance the use, understanding, and dissemination of the CONSORT statement. The meaning and rationale for each checklist item are presented. For most items, at least one published example of good reporting and, where possible, references to relevant empirical studies are provided. Several examples of flow diagrams are included. The CONSORT statement, this explanatory and elaboration document, and the associated Web site ( http://www.consort-statement.org ) should be helpful resources to improve reporting of randomized trials. Throughout the text, terms marked with an asterisk are defined at end of text.     

Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks

Background  Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, but are not without risks.
Aim  To provide evidence-based management recommendations to help clinicians determine optimal long-term NSAID therapy and the need for gastroprotective strategies based on an assessment of both gastrointestinal (GI) and cardiovascular (CV) risks.
Methods  A multidisciplinary group of 21 voting participants revised and voted on the statements and the strength of evidence (assessed according to GRADE) at a consensus meeting.
Results  An algorithmic approach was developed to help manage patients who require long-term NSAID therapy. The use of low-dose acetylsalicylic acid in patients with high CV risk was assumed. For patients at low GI and CV risk, a traditional NSAID alone may be acceptable. For patients with low GI risk and high CV risk, full-dose naproxen may have a lower potential for CV risk than other NSAIDs. In patients with high GI and low CV risk, a COX-2 inhibitor plus a proton pump inhibitor (PPI) may offer the best GI safety profile. When both GI and CV risks are high and NSAID therapy is absolutely necessary, risk should be prioritized. If the primary concern is GI risk, a COX-2 inhibitor plus a PPI is recommended; if CV risk, naproxen 500 mg b.d. plus a PPI would be preferred. NSAIDs should be used at the lowest effective dose for the shortest possible duration.
Conclusion  More large, long-term trials that examine clinical outcomes of complicated and symptomatic upper and lower GI ulcers are needed.