Thromboembolism In Users Research Articles

Association of Antipsychotic Drugs with the Risk of Recurrent Venous Thromboembolism: A Retrospective Study of Data from a Japanese Inpatient Database.

Approximately a decade has passed since the addition of venous thromboembolism to the list of significant adverse reactions of antipsychotic drugs. However, only a few studies have investigated the relationship between antipsychotic use and venous thromboembolism in the Japanese population. We aimed to evaluate the risk of recurrent venous thromboembolism in users of antipsychotic drugs and update the evidence on venous thromboembolism in the Japanese population. A cross-sectional retrospective analysis of data from a large Japanese claims database, managed by Medical Data Vision Co. Ltd., was conducted. Adult patients who experienced venous thromboembolism between October 2014 and September 2018 in acute care hospitals were identified. The risk of recurrent venous thromboembolism was evaluated with logistic regression using demographic variables. The data of patients using antipsychotic drugs within specific therapeutic classes were also evaluated. We included 8960 patients (mean age, 69years; 59.2% female). Recurrent venous thromboembolism was observed in 686 patients (7.7%). The risk of recurrent venous thromboembolism was significantly higher in younger patients [<65years: reference; 65-74years: odds ratio (OR) 0.81, 95% confidence interval (CI) 0.66-0.99, p = 0.04; ≥75years: OR 0.77, 95% CI 0.64-0.94, p = 0.01], those with history of surgery (OR 1.39, 95% CI 1.18-1.65, p = 0.01), and anticoagulant users (OR 2.25, 95% CI 1.46-3.48, p = 0.01) and was significantly lower in the presence of comorbidities (OR 0.68, 95% CI 0.58-0.81, p< 0.01) and fractures (OR 0.49, 95% CI 0.26-0.94, p = 0.03). Long-term antipsychotic drug prescriptions (>14days) were associated with a higher risk of venous thromboembolism than short-term prescriptions (≤14days) (OR 1.56, 95% CI 1.04-2.34, p = 0.03). In patients with a history of venous thromboembolism, particular attention should be paid to recurrence in younger patients. If antipsychotic drugs are prescribed for >14days to patients with a history of venous thromboembolism, they should be administered carefully, guided by reported findings. Further evaluations using different databases or populations are required to generalize the findings of this study.

Venous thromboembolism in users of hormonal contraception and non-steroidal anti-inflammatory drugs: a nationwide cohort study

Abstract Objective To study the influence of concomitant use of hormonal contraception and non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of venous thromboembolism. Design: Nationwide cohort study. Setting: Denmark through national registries. Participants: All 15-49-year-old women living in Denmark between the years 1996-2017 with no medical history of any venous or arterial thrombotic event, cancer, thrombophilia, hysterectomy, bilateral oophorectomy, sterilisation, or infertility treatment. Main outcome measure: A first-time discharge diagnosis of lower-limb deep venous thrombosis or pulmonary embolism. Results Among 2.0 million women followed for 21.0 million person-years, 8710 venous thromboembolic events occurred. Compared to non-use of NSAIDs, use of NSAIDs was associated with an adjusted incidence rate ratio of venous thromboembolism of 8.1 (95% confidence interval (CI) 6.9 to 9.6) in women not using hormonal contraception, 12.1 (10.6 to 13.9) in women using high-risk hormonal contraception, 8.7 (6.5 to 11.6) in users of medium-risk hormonal contraception, and 5.1 (2.9 to 9.1) with low/no-risk hormonal contraception. Compared to non-use of NSAIDs, the number of extra venous thromboembolic events per 100,000 one-week NSAID treatments was 4 in women not using hormonal contraception, 18 in women using high-risk hormonal contraception, 9 in users of medium-risk hormonal contraception, and 2 in women using low/no-risk hormonal contraception. Conclusions NSAID use was positively associated with the development of venous thromboembolism. The association was stronger in women concomitantly using high-risk hormonal contraceptives and weaker in women using low/no-risk hormonal contraception. Women requiring both hormonal contraception and regular use of NSAIDs should be advised accordingly.

ESTRADIOL IS ASSOCIATED WITH DECREASED CARDIOVASCULAR RISK COMPARED TO ETHINYLESTRADIOL WHEN CONTAINED IN COMBINED HORMONAL PREPARATIONS: IMPLICATIONS FOR THE DEVELOPMENT OF NEW ENDOMETRIOSIS THERAPIES

Combined estrogen-progestin preparations have a long history in women’s health and are currently used for multiple indications, including the treatment of endometriosis-related symptoms. Empirically, estradiol (E2) and its ester, estradiol valerate (E2Val) carry a reduced cardiovascular risk due to their reduced impact on the hepatic system compared to the most-widely used estrogen ethinylestradiol (EE). However, robust comparative studies in pre-menopausal women are limited. A new hormonal product containing E2 in combination with the progestin norethindrone acetate (NETA) and the gonadotropin-releasing hormone receptor antagonist, relugolix, has been developed for the treatment of uterine fibroids and endometriosis. This analysis tries to quantify the cardiovascular risk of E2/E2Val-NETA in pre-menopausal women. A pooled analysis of four large cohort studies assessing the risk of cardiovascular events in users of combined oral contraceptives (COCs). Data regarding users of COCs containing either E2/E2Val or EE≤30μg were retrieved from four large prospective, controlled, observational, cohort studies in 14 European countries, US and Canada. Baseline characteristics, including reproductive, contraceptive and medical history, were summarized using descriptive statistics. Propensity score sub-classification was applied to balance baseline parameters between cohorts and time-to-event analysis of venous and arterial thromboembolic events was carried out based on the extended Cox model to calculate crude and adjusted hazard ratios (HR) including 95%-confidence intervals (CI). The analysis was based on 210,000 women, who contributed 470,000 women years of exposure. The observed prevalence of prognostic factors at baseline showed typical features of US and European COC users. However, the mean age in the E2/E2Val cohort was higher compared to the EE≤30μg cohort (31.7 years ±9.76 and 26.1 years ±7.89, respectively). A time-to-event analysis of the VTE data was carried out based on the extended Cox model. Validity of the model was demonstrated by the standardized differences summarized over strata as weighted average yielded upon PS sub-classification, which were consistently <0.25 and mostly <0.1. A comparison between cohorts showed a decreased risk of venous thromboembolism in users of COCs containing E2/E2Val vs users of COCs containing EE≤30μg; adjusted hazard ratio: 0.49 (95% CI, 0.28-0.84). A risk reduction in the E2/E2Val cohort was also observed with regards to arterial thromboembolic events; adjusted hazard ratio: 0.26 (95% CI, 0.08-0.83). Data presents a solid safety assessment of combined hormonal preparations in over 200,000 pre-menopausal women and shows a decreased cardiovascular risk of E2/E2Val when compared to low-dose EE. This provides reassurance for current users of E2/E2Val-containing COCs and opens new perspectives for the development of safe and effective endometriosis treatments, such as the recently developed product containing E2/NETA, in combination with relugolix.

Risk of venous thromboembolism in users of contraception and menopausal hormone therapy during the COVID-19 pandemic.

The outbreak of coronavirus disease (COVID-19) is a public health emergency of international concern. Inflammatory changes are part of COVID-19 pathophysiology and this might generate a higher thromboembolic risk in patients using combined hormonal contraception and menopausal hormone therapy. We aimed to discuss the main aspects related to this issue and propose management strategies for women affected by COVID-19. This narrative review collected information from several articles published since the beginning of the outbreak of the new coronavirus disease about the pathophysiology, stage of the disease, the occurrence of thrombotic events, and the risk of thromboembolism in users of contraception and hormonal therapy. This article consolidates clinical parameters about the risk of venous thromboembolism in users of contraception and menopausal hormone therapy emphasizing the probable increase of that risk in women with suspected or confirmed COVID-19 and bringing safer recommendations. In this scenario, apart from the fundamental orientations of preventive measures, like social isolation and hygiene, it is important that all female health professionals have knowledge of the new rules and adopt safety measures, especially on the prescription of hormonal therapy and contraception.

Changes in haemostatic parameters during the menstrual cycle and subsequent use of drospirenone-containing oral contraceptives

IntroductionOral contraceptives (OC) increase the risk of venous thromboembolism that depends on the OC formulation and could at least partially be explained by impaired function of the protein C-system (APC resistance) and the tissue factor pathway inhibitor (TFPI)-system. There is limited information available on the effects of OC, containing a newer progestogen- drospirenone (DRSP-OC) on these two major anticoagulant pathways, thrombin generation, reflecting the overall state of coagulation, and other coagulation parameters. MethodsIn a study population consisting of 14 healthy women (age 21–33years) we investigated the effect of the menstrual cycle and subsequent use of DRSP-OC on APC resistance, the function of the TFPI-system, thrombin generation and on their major determinants, i.e. prothrombin, antithrombin, FV, FX, FVIII, protein C, protein S(total and free) and TFPI(full-length and free). ResultsAll studied parameters remained unchanged during the menstrual cycle. During DRSP-OC use we observed a significant increase in APC resistance (~2.4-fold), thrombin generation measured at low (~2.2-fold) and high tissue factor concentrations (~1.4-fold), plasma concentrations of prothrombin (19%), FX (31%), FVIII (17%) and protein C (43%). DRSP-OC use impaired the function of the TFPI-system and decreased plasma levels of antithrombin (−6%), FV (−22%), protein Stotal (−21%), protein Sfree (−20%), TFPIfull-length (−36%) and TFPIfree (−46%). ConclusionsDRSP-OC caused procoagulant changes in all studied haemostatic parameters. The impairment of the protein C- and TFPI-systems was more pronounced than the impairment of the coagulation pathways and can at least partially account for the increased risk of venous thromboembolism in users of DRSP-OC.

Association of venous thromboembolism with hormonal contraception and thrombophilic genotypes.

To investigate associations between combined hormonal contraception and progestogen-only contraception and risks of venous thromboembolism by progestogen and carriership of genetic hemostatic variations. This was a case-control study in Sweden carried out between 2003 and 2009, which included 948 patients with venous thromboembolism and 902 individuals in a control group, all aged 18-54 years. Information was obtained by telephone interviews and DNA analyses of blood samples. Radiologic referrals were used for case ascertainment. For comparisons, odds ratios were estimated by unconditional logistic regression analysis adjusting for smoking, body mass index (BMI), and immobilization. The odds ratio (OR) for current use of combined hormonal contraception was 5.3 (95% confidence interval [CI] 4.0-7.0). Desogestrel combinations had the highest OR (11.4, 95% CI 6.0-22.0). The OR for injection of medroxyprogesterone acetate was 2.2 (95% CI 1.3-4.0). In users of combined hormonal contraception with the factor V Leiden mutation, the OR was 20.6 (95% CI 8.9-58). In women who used progestogen-only contraception and carried the factor V Leiden mutation, the OR was 5.4 (95% CI 2.5-13). Risks of venous thromboembolism in association with combined hormonal contraception vary by type of progestogen and independently of BMI and smoking. Thrombophilic genotypes such as factor V Leiden increase risks of venous thromboembolism in users of combined hormonal contraception. Except for injection of medroxyprogesterone acetate, progestin-only contraception seems to be the least thrombogenic hormonal contraception for women carrying genetic hemostatic variations. II.

Estimate of venous thromboembolism and related-deaths attributable to the use of combined oral contraceptives in France.

PurposeTo estimate the number of venous thromboembolic events and related-premature mortality (including immediate in-hospital lethality) attributable to the use of combined oral contraceptives in women aged 15 to 49 years-old between 2000 and 2011 in France.MethodsFrench data on sales of combined oral contraceptives and on contraception behaviours from two national surveys conducted in 2000 and 2010 were combined to estimate the number of exposed women according to contraceptives generation and age. Absolute risk of first time venous thromboembolism in non-users of hormonal contraception and increased risk of thromboembolism in users vs. non-users of hormonal contraception were estimated on the basis of literature data. Finally, immediate in-hospital lethality due to pulmonary embolism and premature mortality due to recurrent venous thromboembolism were estimated from the French national database of hospitalisation and literature data.ResultsIn France, more than four million women are daily exposed to combined oral contraceptives. The mean annual number of venous thromboembolic events attributable to their use was 2,529 (778 associated to the use of first- and second-generation contraceptives and 1,751 to the use of third- and fourth-generation contraceptives), corresponding to 20 premature deaths (six with first- and second-generation contraceptives and fourteen with third- and fourth-generation contraceptives), of which there were eight to nine immediate in-hospital deaths. As compared to the use of first- and second-generation contraceptives, exposure to third- and fourth-generation contraceptives led to a mean annual excess of 1,167 venous thromboembolic events and nine premature deaths (including three immediate in-hospital deaths).ConclusionsCorrective actions should be considered to limit exposure to third- and fourth-generation contraceptives, and thus optimise the benefit-risk ratio of combined oral contraception.

Combined hormonal contraception and risk of venous thromboembolism within the first year following pregnancy

Estimating the risk of venous thromboembolism (VTE) associated with combined hormonal contraceptives following early terminated pregnancies or birth, a Danish nationwide retrospective cohort observing a one-year follow-up was defined using three unique registries. All Danish women with confirmed pregnancies aged 15-49 during the period of 1995-2009 were included. The main outcomes were relative and absolute risks of first time venous thromboembolism in users as well as non-users of combined hormonal contraceptives. In 985,569 person-years, 598 venous thromboembolisms were recorded. After early terminated pregnancies and births, respectively, 113 and 485 events occurred in 212,552 and 773,017 person-years. After early terminated pregnancies, the crude VTE incidence ratios were similar, and the numbers needed to harm were equal between groups that did or did not use combined hormonal contraceptives throughout the follow-up year. After childbirth, individuals that used combined hormonal contraceptives were more likely than non-users to experience VTE depicted by crude incidence ratios; however, the difference was only significant after 14 weeks. This implied that the numbers needed to harm were lower for those that used compared to those that did not use combined oral contraceptives in the initial 14 weeks postpartum. In conclusion, the use of combined hormonal contraceptives after early terminated pregnancies was not detrimental, but during the puerperal period, they should be used with caution.

Can a meta-analysis that included articles with high heterogeneity appropriately evaluate the risk of venous thromboembolism in users of combined hormonal contraceptives containing drospirenone or desogestrel? A reply to Rosa et al.

Concerns about the appropriateness of high heterogeneity in the meta-analysis evaluating the risk of venous thromboembolism in users of combined hormonal contraceptives are discussed in this reply to a critical response of the original study. The response claimed that some of the study’s meta-analyses were compromised by the high heterogeneity which affected two studies one pertaining to drospirenone and the other one to desogestrel. The authors acknowledge previously pointed out methodological flaws in the cohort studies. Finally taking into account the discussed limitations the authors consider that observational studies will not add relevant information and only well-designed prospective studies will help to better understand the real risks of hormonal contraception.

Can a meta-analysis that included articles with high heterogeneity appropriately evaluate the risk of venous thromboembolism in users of combined hormonal contraceptives containing drospirenone or desogestrel?

The authors suggest that the authors of the systematic review reassess the meta-analyses which demonstrated high diversities. The reanalysis of the cohort studies comparing venous thromboembolism (VTE) risk in users of combined oral contraceptives (COCs) containing desogestrel with that of women taking a COC containing levonorgestrel brought no substantial change to light with regard to the aforementioned author’s findings. On the contrary when reassessing the cohort studies comparing users of COCs containing drospirenone with women taking a COC containing levonorgestrel unlike the review authors they found no significant difference in VTE risk between these two groups. The authors’ meta-analysis of nested case control studies did show a higher VTE risk associated with the use of drosperinone-containing pills. Future studies of higher quality and longer duration are needed to determine whether the risk of VTE associated with the use of COCs containing drosperinone is greater than with those containing levonorgestrel.

Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: Nested case-control study based on UK General Practice Research Database

Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: Nested case-control study based on UK General Practice Research Database

Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9

Objective To assess the risk of venous thromboembolism from use of combined oral contraceptives according to progestogen type and oestrogen dose.Design National historical registry based cohort study.Setting Four registries in...

The risk of venous thromboembolism in users of an etonogestrel/ethinylestradiol containing vaginal ring – interim results from the tasc study

To assess the risks of short and long-term use of an etonogestrel/ethinylestradiol containing vaginal ring (VR) and to compare it to the risks of established combined oral contraceptives (COCs) in a study population that is representative of the actual users of the individual preparations.

Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database

Objective To examine the risk of non-fatal idiopathic venous thromboembolism in current users of a combined oral contraceptive containing drospirenone, relative to current users of preparations containing levonorgestrel.Design Nested case-control...

Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data

Objective To compare the risk of non-fatal venous thromboembolism in women receiving oral contraceptives containing drospirenone with that in women receiving oral contraceptives containing levonorgestrel.Design Nested case-control and cohort study.Setting...

The risk of venous thromboembolism in users of a drospirenone-containing oral contraceptive with a 24-day regimen – results from the INAS-OC Study

OBJECTIVE: To assess the risks of short and long-term use of a recently launched OC with a 24-day drospirenone regimen (DRSP24d) and to compare it to the risks of established OCs in a study population that is representative of the actual users of the individual preparations.

Incidence of Venous Thromboembolism in Users of Strontium Ranelate

Strontium ranelate is indicated for the treatment of postmenopausal osteoporosis. An association between strontium ranelate and venous thromboembolism (VTE) was identified in an analysis of phase III clinical trials. To estimate the incidence of VTE in patients within the strontium ranelate (Protelos(R)) Prescription-Event Monitoring (PEM) study cohort during the first 12 months after starting treatment. Patients in this analysis were identified from dispensed prescriptions that had been issued by general practitioners (GPs) in England for strontium ranelate between October 2004 and January 2008. For each individual patient, a Green Form questionnaire was sent to their GP 12 months after the date of the first prescription issued for strontium ranelate, requesting information about the patient including start and stop dates of treatment (if stopped), age, sex, indication, any history of VTE events, reasons for stopping and whether the patient had any events since starting the drug. VTE was defined as reports of deep vein thrombosis (DVT) or pulmonary embolism (PE). The crude incidence of VTE was calculated for events that occurred during the first 12 months after starting treatment (plus 30 days after stopping), with 95% Poisson exact CIs for the whole cohort, and subsets defined by age and past history of VTE. The final analysis cohort consisted of 10 782 patients. Where specified, mean age was 73.3 years (SD 11.45) [n = 10 696]; 9833 (91.3%) were female and 934 (8.7%) were male. Where the history of VTE was specified, 233 patients (2.6%) had a history of VTE prior to starting. In the first 12-month period, there were 48 incident reports of VTE (DVT or PE) during treatment (or within 30 days of stopping) in the cohort, with 7696.89 years of exposure, giving a crude incidence rate of VTE of 6.24 cases (95% CI 4.60, 8.27) per 1000 patient-years exposed. This analysis has provided an estimate of the incidence of VTE in patients treated with strontium ranelate in the general practice setting. The rate is similar to estimates in populations of similar age and corresponds to the incidence found in patients from phase III clinical studies and observational cohort studies of strontium ranelate on this topic. The crude annual incidence rate of VTE in the PEM cohort is higher than the background annual incidence rate found in the UK population, but is similar to estimates in populations of similar age and populations receiving treatment for postmenopausal osteoporosis. Also, we acknowledge the potential for underestimating the incidence in this population. Nevertheless, this analysis contributes to the ongoing postmarketing safety assessment of this product.

Hormonal contraception and risk of venous thromboembolism: national follow-up study

Objective To assess the risk of venous thrombosis in current users of different types of hormonal contraception, focusing on regimen, oestrogen dose, type of progestogen, and route of administration.Design National...

Revisiting the combined oral contraceptive's use

Vicky Padbury highlights new research findings on the risks of venous thromboembolism in users of the oral contraceptive pill and considers revised advice on missed pills

Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 μg of ethinyl estradiol

Context In 2006, we published a study that indicated that the new transdermal contraceptive patch containing ethinyl estradiol (EE) and the progestin norelgestromin did not increase the risk for venous thromboembolism (VTE) compared to oral contraceptive containing norgestimate and 35 μg of EE. Objective This report updates information on the risk of nonfatal VTE in women using the contraceptive patch in comparison to women using oral contraceptives containing norgestimate (either monophasic or triphasic) and 35 μg of EE (norgestimate-35) using an additional 17months of data. Design, Setting and Participants Nested case-control design based on information from PharMetrics, a US-based company that collects and organizes information on claims paid by managed care plans. The study was nested among all women, aged 15 to 44 years, who started either the contraceptive patch or norgestimate-35 after April 1, 2002. Cases were women with current use of one of these two study drugs and a documented diagnosis of VTE in the absence of identifiable clinical risk factors (idiopathic VTE) who were not in the earlier study. Up to four controls were matched to each case by age and calendar time. Main Outcome Measures Odds ratios (ORs) comparing the risk of nonfatal VTE in new users of the two contraceptives. Results We identified 56 new cases of newly diagnosed, idiopathic VTE in the updated study population. The OR comparing the contraceptive patch to norgestimate-35 was 1.1 (95% CI 0.6–2.1). Conclusions After evaluating an additional 17 months of data, the results indicate that the risk of nonfatal VTE for the contraceptive patch is closely similar to the risk for oral contraceptives containing 35 μg of EE and norgestimate.