Prevention of post-thrombotic syndrome with rosuvastatin: A multicenter randomized controlled pilot trial (SAVER).

BACKGROUND: Post-thrombotic syndrome (PTS) is one of the most frequent complications of venous thromboembolism (VTE) leading to considerable morbidity and cost. Apart from appropriate anticoagulation, there is no drug or medical intervention that helps to prevent PTS. We conducted a multicenter randomized controlled trial to determine whether rosuvastatin can prevent PTS. METHODS: 312 patients receiving standard anticoagulation for a newly diagnosed VTE were randomly allocated to adjuvant rosuvastatin 20 mg once daily for 180 days (n = 155) or no rosuvastatin (n = 157). At the last study visit (Day 180 ± 21), an independent observer who was blinded to study treatment performed a PTS assessment using the Villalta scale. The primary clinical outcome of the trial was mean Villalta score at Day 180. We also explored the presence of PTS as defined by Villalta score > 4 at Day 180. Patients mean age was 46.7 ± 10.8 years, 55.8% were female. RESULTS: At Day 180, the Villalta score was 3.5 ± 0.3 in the rosuvastatin arm vs. 3.3 ± 0.3 in the control arm (p = 0.59), and presence of PTS (Villalta >4) was 29.7% in the rosuvastatin arm vs. 25.5% in the control arm (p = 0.41). Secondary analyses showed no difference between trial arms for presence of severe PTS at Day 180 (2.0% vs. 2.7%, p = 1) and for changes in Villalta score between baseline and Day 180 (-3.7 ± 4.4 vs. -4.0 ± 5.0, p = 0.59). CONCLUSION: This randomized controlled pilot trial did not demonstrate efficacy of rosuvastatin to reduce Villalta score. Further studies with longer duration of exposure to rosuvastatin are needed. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02679664.

Folic Acid Supplementation in Early Pregnancy, Homocysteine Concentration, and Risk of Gestational Diabetes Mellitus.

We used a prospective cohort of pregnant women at 12 to 20 weeks gestation between 2002 and 2008 in Ottawa and Kingston to evaluate the impact of early pregnancy folic acid supplementation on the risk of gestational diabetes mellitus. Among 7552 eligible women, 84 (1.11%) were diagnosed of gestational diabetes mellitus. Non-significant associations were observed between gestational diabetes mellitus and folate supplementation, homocysteine levels, and methylenetetrahydrofolate reductase 677 TT genotype. Although we found no significant associations between folic acid supplementation and the risk of gestational diabetes mellitus, genetic associations were not confounded by lifestyle or socioeconomic factors, which may have biased previous studies.

Statins for venous event reduction in patients with venous thromboembolism: A multicenter randomized controlled pilot trial assessing feasibility.

BACKGROUND: Statins may reduce the risk for recurrent venous thromboembolism (VTE); however, no randomized trials have explored this hypothesis. We performed a pilot randomized trial to determine feasibility of recruitment for a larger trial of secondary VTE prevention with rosuvastatin. METHODS: Patients with a newly diagnosed symptomatic proximal deep vein thrombosis and/or pulmonary embolism, receiving standard anticoagulation, were randomly allocated to adjuvant rosuvastatin 20 mg once daily for 180 days or no rosuvastatin for 6 months. RESULTS: Between November 2016 and December 2019, 3391 patients were assessed for eligibility in six centers. Of these patients, 1347 (39.7%) were eligible and approached for participation in the trial and 312 (23.1%) were randomized. The mean rate of randomization was 8.2 ± 4.3 patients per month. During follow-up, five recurrent VTE events were observed, three (1.9%) in the rosuvastatin group (two pulmonary embolism, one deep vein thrombosis), and two (1.3%) in the control group (two pulmonary embolism; P = 0.68). One major arterial event occurred in the rosuvastatin arm and none in the control arm (0.6% vs. 0%, P = 0.50). CONCLUSION: This pilot trial supports the feasibility of a larger scale randomized controlled trial to determine the efficacy of adjuvant rosuvastatin for the secondary prevention of VTE.

The determinants of maternal homocysteine in pregnancy: findings from the Ottawa and Kingston Birth Cohort.

OBJECTIVE: Observational studies have linked elevated homocysteine to vascular conditions. Folate intake has been associated with lower homocysteine concentration, although randomised controlled trials of folic acid supplementation to decrease the incidence of vascular conditions have been inconclusive. We investigated determinants of maternal homocysteine during pregnancy, particularly in a folic acid-fortified population. DESIGN: Data were from the Ottawa and Kingston Birth Cohort of 8085 participants. We used multivariable regression analyses to identify factors associated with maternal homocysteine, adjusted for gestational age at bloodwork. Continuous factors were modelled using restricted cubic splines. A subgroup analysis examined the modifying effect of MTHFR 677C>T genotype on folate, in determining homocysteine concentration. SETTING: Participants were recruited in Ottawa and Kingston, Canada, from 2002 to 2009. PARTICIPANTS: Women were recruited when presenting for prenatal care in the early second trimester. RESULTS: In 7587 participants, factors significantly associated with higher homocysteine concentration were nulliparous, smoking and chronic hypertension, while factors significantly associated with lower homocysteine concentration were non-Caucasian race, history of a placenta-mediated complication and folic acid supplementation. Maternal age and BMI demonstrated U-shaped associations. Folic acid supplementation of >1 mg/d during pregnancy did not substantially increase folate concentration. In the subgroup analysis, MTHFR 677C>T modified the effect of folate status on homocysteine concentration. CONCLUSIONS: We identified determinants of maternal homocysteine relevant to the lowering of homocysteine in the post-folic acid fortification era, characterised by folate-replete populations. A focus on periconceptional folic acid supplementation and improving health status may form an effective approach to lower homocysteine.

Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty.

BACKGROUND: Clinical trials and meta-analyses have suggested that aspirin may be effective for the prevention of venous thromboembolism (proximal deep-vein thrombosis or pulmonary embolism) after total hip or total knee arthroplasty, but comparisons with direct oral anticoagulants are lacking for prophylaxis beyond hospital discharge. METHODS: We performed a multicenter, double-blind, randomized, controlled trial involving patients who were undergoing total hip or knee arthroplasty. All the patients received once-daily oral rivaroxaban (10 mg) until postoperative day 5 and then were randomly assigned to continue rivaroxaban or switch to aspirin (81 mg daily) for an additional 9 days after total knee arthroplasty or for 30 days after total hip arthroplasty. Patients were followed for 90 days for symptomatic venous thromboembolism (the primary effectiveness outcome) and bleeding complications, including major or clinically relevant nonmajor bleeding (the primary safety outcome). RESULTS: A total of 3424 patients (1804 undergoing total hip arthroplasty and 1620 undergoing total knee arthroplasty) were enrolled in the trial. Venous thromboembolism occurred in 11 of 1707 patients (0.64%) in the aspirin group and in 12 of 1717 patients (0.70%) in the rivaroxaban group (difference, 0.06 percentage points; 95% confidence interval [CI], -0.55 to 0.66; P<0.001 for noninferiority and P=0.84 for superiority). Major bleeding complications occurred in 8 patients (0.47%) in the aspirin group and in 5 (0.29%) in the rivaroxaban group (difference, 0.18 percentage points; 95% CI, -0.65 to 0.29; P=0.42). Clinically important bleeding occurred in 22 patients (1.29%) in the aspirin group and in 17 (0.99%) in the rivaroxaban group (difference, 0.30 percentage points; 95% CI, -1.07 to 0.47; P=0.43). CONCLUSIONS: Among patients who received 5 days of rivaroxaban prophylaxis after total hip or total knee arthroplasty, extended prophylaxis with aspirin was not significantly different from rivaroxaban in the prevention of symptomatic venous thromboembolism. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT01720108 .).

Comparison of risk factors and outcomes of gestational hypertension and pre-eclampsia.

BACKGROUND: It remains an enigma whether gestational hypertension (GH) and pre-eclampsia (PE) are distinct entities or different spectrum of the same disease. We aimed to compare the risk factors and outcomes between GH and PE. METHOD: A total of 7,633 pregnant women recruited between 12 and 20 weeks of gestation in the Ottawa and Kingston Birth Cohort from 2002 to 2009 were included in the analysis. Cox proportional hazards model was used to identify and compare the risk factors for GH and PE by treating gestational age at delivery as the survival time. Logistic regression model was used to compare outcome. Subgroup analysis was performed for early- and late-onset PE. RESULTS: GH and PE shared most risk factors including overweight and obesity, nulliparity, PE history, type 1 and 2 diabetes, and twin birth. Effect size of PE history (RR = 14.1 for GH vs. RR = 6.4 for PE) and twin birth (RR = 4.8 for GH vs. RR = 10.3 for PE) showed substantial difference. Risk factors modified gestational age at delivery in patients with GH and PE in similar pattern. Subgroup analysis showed that early- and late-onset PE shared some risk factors with different effect sizes, whereas folic acid supplementation showed protective effect for early-onset PE only. PE was strongly associated with several adverse outcomes including cesarean section, placental abruption, small for gestational age, preterm birth, and 5 min Apgar score < 7, whereas GH was associated with increased risk of preterm birth only. CONCLUSIONS: GH and PE shared common risk factors. Differences in effect sizes of risk factors and outcomes indicate that the conditions may have different pathophysiology and mechanism.

Serum and red-blood-cell folate demonstrate differential associations with BMI in pregnant women.

OBJECTIVE: To examine the association between BMI and folate concentrations in serum and red blood cells (RBC) in pregnant women. DESIGN: A cross-sectional comparison of folate concentrations in serum and RBC sampled simultaneously from the same individual. SETTING: The Ottawa Hospital and Kingston General Hospital, Ontario, Canada. SUBJECTS: Pregnant women recruited between 12 and 20 weeks of gestation. RESULTS: A total of 869 pregnant women recruited from April 2008 to April 2009 were included in the final analysis. Serum folate was inversely associated and RBC folate positively associated with BMI, after adjusting for folic acid supplementation, age, gestational age at blood sample collection, race, maternal education, annual income, smoking and MTHFR 677C→T genotype. In stratified analyses, this differential association was significant in women with the MTHFR CC variant. In women with the CT and TT variants, the differential associations were in the same direction but not significant. Folic acid supplementation during pregnancy did not alter the differential association of BMI with serum and RBC folate concentration. This indicates that the current RBC folate cut-off approach for assessing risk of neural tube defects in obese women may be limited. CONCLUSIONS: BMI is inversely associated with serum folate and positively associated with RBC folate in pregnant women, especially for those with the MTHFR CC variant.

Folic Acid Supplementation in Pregnancy and the Risk of Pre-Eclampsia-A Cohort Study.

This prospective cohort study designed to assess the effect of folic acid supplementation in pregnancy on the risk of preeclampsia (PE) took place in Ottawa, ON and Kingston, ON, Canada, from September 1, 2002 to August 31, 2008. Pregnant women, less than 20 weeks gestational age were recruited and delivered in the Ottawa region and the Kingston General Hospital. Demographic characteristics of the study participants and the patterns of supplementation of folic acid were described and occurrence of PE between women with folic acid supplementation during pregnancy and women without were compared. Multiple logistic regression was used in the estimation of the independent effect of supplementation of folic acid. Additional analyses assessing the effect of low RBC and serum folate and dose-response relationship were performed. Analyses were performed in all study participants, and then in high risk and low risk sub-groups, respectively. A total of 7,669 participants were included in the final analysis. Ninety five percent of the study participants were taking folic acid supplementation in early second trimester. The rate of PE was lower in the supplementation group than in the no supplementation group, and the difference was statistically significant in high risk women. Similar patterns of associations were observed in analysis by RBC and serum folate levels and in dose-response analysis. Folic acid supplementation in pregnancy may reduce PE risk in pregnant women, especially in those women with increased risk of developing PE.

Treatment of venous thromboembolism.

IMPORTANCE: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common, potentially lethal condition with acute morbidity. OBJECTIVE: To review the etiology of VTE and the 3 phases of VTE treatment: acute (first 5-10 days), long-term (from end of acute treatment to 3-6 months), and extended (beyond 3-6 months). EVIDENCE REVIEW: Cochrane reviews, meta-analyses, and randomized controlled trials, as well as other clinical trials for topics not covered by the former, were reviewed. Literature searches using broad terms were used to find meta-analyses published in the last 15 years. The ninth edition of the American College of Chest Physicians Antithrombotic Therapy Guidelines was used to supplement the literature search. Guidelines from specialty organizations were consulted when relevant. The Canadian Agency for Drugs and Technologies in Health was searched for relevant cost-effectiveness studies. We also searched our own literature database of 8386 articles for relevant research. FINDINGS: Low-molecular-weight heparin (LMWH) along with with vitamin K antagonists and the benefits and proven safety of ambulation have allowed for outpatient management of most cases of DVT in the acute phase. Development of new oral anticoagulants further simplifies acute-phase treatment and 2 oral agents can be used as monotherapy, avoiding the need for LMWH. Patients with PE can also be treated in the acute phase as outpatients, a decision dependent on prognosis and severity of PE. Thrombolysis is best reserved for severe VTE; inferior vena cava filters, ideally the retrievable variety, should be used when anticoagulation is contraindicated. In general, DVT and PE patients require 3 months of treatment with anticoagulants, with options including LMWH, vitamin K antagonists, or direct factor Xa or direct factor IIa inhibitors. After this time, decisions for further treatment are based on balancing the risk of VTE recurrence, determined by etiology of the VTE (transient risk factors, unprovoked or malignancy associated), against the risk of major hemorrhage from treatment. Better prediction tools for major hemorrhage are needed. Experience with new oral anticoagulants as acute, long-term, and extended therapy options is limited as yet, but as a class they appear to be safe and effective for all phases of treatment. CONCLUSIONS AND RELEVANCE: The mainstay of VTE treatment is anticoagulation, while interventions such as thrombolysis and inferior vena cava filters are reserved for limited circumstances. Multiple therapeutic modes and options exist for VTE treatment with small but nonetheless important differential effects to consider. Anticoagulants will probably always increase bleeding risk, necessitating tailored treatment strategies that must incorporate etiology, risk, benefit, cost, and patient preference. Although great progress has been made, further study to understand individual patient risks is needed to make ideal treatment decisions.

Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis.

OBJECTIVE: To summarise and compare the efficacy and safety of various oral anticoagulants (dabigatran, rivaroxaban, apixaban, and vitamin K antagonists) and antiplatelet agents (acetylsalicylic acid) for the secondary prevention of venous thromboembolism. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Literature search using Medline (1950 to present), Embase (1980 to present), and the Cochrane Register of Controlled Trials using the OVID interface. Publications from potentially relevant journals were also searched by hand. REVIEW METHODS: Randomised controlled trials of patients receiving anticoagulants, antiplatelet drugs, or placebo or observation for secondary prevention of venous thromboembolism. Selected outcomes were rates of recurrent venous thromboembolism and major bleeding. Two reviewers independently extracted data onto standardised forms. RESULTS: 12 articles met our inclusion criteria, with 11,999 patients evaluated for efficacy and 12,167 for safety. All treatments reduced the risk of recurrent venous thromboembolism. Compared with placebo or observation, vitamin K antagonists at a standard adjusted dose (target international normalised ratio 2.0-3.0) showed the highest risk difference (odds ratio 0.07; 95% credible interval 0.03 to 0.15) and acetylsalicylic acid showed the lowest risk difference (0.65; 0.39 to 1.03). Risk of major bleeding was higher with a standard adjusted dose of vitamin K antagonists (5.24; 1.78 to 18.25) than with placebo or observation. Fatal recurrent venous thromboembolism and fatal bleeding were rare. Detailed subgroup and individual patient level data were not available. CONCLUSIONS: All oral anticoagulants and antiplatelet agents investigated in this analysis were associated with a reduced recurrence of venous thromboembolism compared with placebo or observation, although acetylsalicylic acid was associated with the lowest risk reduction. Vitamin K antagonists given at a standard adjusted dose was associated with the greatest risk reduction in recurrent venous thromboembolism, but also the greatest risk of major bleeding.

Effect of 200µG/day of vitamin K1 on the variability of anticoagulation control in patients on warfarin: a randomized controlled trial.

BACKGROUND: Controversy exists whether low-dose vitamin K supplementation can improve anticoagulation control in patients with unstable anticoagulation under warfarin. In a single- centre randomized, double-blind, placebo-controlled study, we evaluated the effectiveness of 200 µg/day of vitamin K1 in patients with unstable control under warfarin. METHODS: Effectiveness of Vitamin K1 supplementation was primarily assessed by the percentage (%) of Time-in-Therapeutic-Range (TTR) and secondarily by the standard deviation (SD) of the patient's INR values; the proportion of out-of-range INRs; and the number of dose changes on warfarin. Their change scores were obtained by subtracting the mean value in the 6 months pre-randomization from the mean value in the 6 months post-randomization. Multivariable linear-regressions identified factors associated with anticoagulation instability. RESULTS: Fifty out of 54 patients were analyzed (intervention: n=26; placebo: n=24). Most indications (87%) for anticoagulation were venous thromboembolism (VTE). The intervention was associated with a greater reduction in the change scores for the SD of INRs between the pre and post-randomization periods compared with placebo. The mean change score was -0.259±0.307 with the intervention and -0.046±0.345 with placebo (p=0.026). There was no effect on the change scores of the (%) TTR (p=0.98), the number of INRs out-of-range (p=0.58) and the number of dose changes (p=0.604). Factors independently associated with increased variability in the SD of INRs were increased alcoholic drinks/week (p=0.017), dosing errors (p=0.0009) and missed INR appointments (p=0.035). CONCLUSION: Vitamin K1 supplementation reduces the SD of INRs as an indicator of the variability in anticoagulation control in patients treated with warfarin for VTE.

The Ottawa and Kingston (OaK) Birth Cohort: development and achievements.

OBJECTIVE: The Ottawa and Kingston (OaK) Birth Cohort collected data on maternal and infant genetic and epidemiologic variables in order to (1) explore the association between folate supplementation or thrombophilias and adverse, placenta-mediated pregnancy outcomes; (2) create a biobank of maternal and infant biological and genetic samples; and (3) stimulate future research using this cohort data. METHODS: A prospective cohort design was used to collect mother and infant data. Women were recruited at 12 to 20 weeks' gestation, during prenatal care visits at The Ottawa Hospital and Kingston General Hospital from October 2002 to April 2009. Data on maternal and infant demographics, maternal health, obstetrical history, and pregnancy outcomes were collected. Testing was done for biological/serological markers associated with adverse pregnancy outcomes. Maternal and cord blood samples were biobanked. RESULTS: A total of 8085 mothers were recruited to the OaK Birth Cohort. Analysis of the cohort data showed that taking multivitamin supplements containing folic acid was associated with a reduced risk of preeclampsia (aOR 0.37; 95% CI 0.18 to 0.75). The majority of participants agreed to have their genetic/biological samples biobanked (samples collected for n = 7241 mothers, n = 2175 infants) and to be re-contacted regarding future research opportunities. CONCLUSION: Birth cohorts are a useful tool in determining associations between risk factors and adverse maternal and fetal outcomes, and can serve as a repository of data for future research. Creating strong research partnerships helped enhance financial resources and increase participant recruitment potential. Epidemiological and biobanked data and samples from the OaK Birth Cohort are available for use by other investigators.

Folic acid supplementation in early second trimester and the risk of preeclampsia.

OBJECTIVE: The objective of the study was to evaluate the association between folic acid supplementation in early second trimester and the risk of developing preeclampsia. STUDY DESIGN: We carried out a prospective cohort study between October 2002-December 2005. We recruited women who had their prenatal care visit (12-20 weeks' gestation) at the Ottawa Hospital and Kingston General Hospital. All charts for participants with a diagnosis of preeclampsia were audited and blindly adjudicated by 4 study investigators to validate the diagnosis. RESULTS: A total of 2951 pregnant women were included in the final analysis. Supplementation of multivitamins containing folic acid was associated with increased serum folate (on average 10.51 micromol/L), decreased plasma homocysteine (on average 0.39 micromol/L), and reduced risk of preeclampsia (adjusted odds ratio, 0.37; 95% confidence interval, 0.18-0.75). CONCLUSION: Supplementation of multivitamins containing folic acid in the second trimester is associated with reduced risk of preeclampsia.