Venous 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.

Does administration of vaginal estrogens increase the risk of venous thromboembolism: A case-control study.

Does administration of vaginal estrogens increase the risk of venous thromboembolism: A case-control study.

The Risk of Venous Thromboembolism (VTE) in Men with Benign Prostatic Hyperplasia Treated with 5-Alpha Reductase Inhibitors (5ARIs).

BackgroundMany men receive 5-alpha reductase inhibitors (5ARIs) for ongoing treatment of benign prostatic hyperplasia (BPH). The increased risk of cardiovascular complications with 5ARIs has been documented in BPH studies and the occurrence of cerebral venous thrombosis, presumably due to increased estrogen level following 5ARI use, was described in multiple case reports. The objective of this study was to determine if 5ARIs with or without alpha blockers (AB) were associated with an increased risk of venous thromboembolism (VTE) in males with BPH.MethodsWe conducted a nested case–control study among a population of men ages 40–79 who received at least one 5ARI or AB prescription for treatment of BPH between 1995 and 2015 in the UK-based Clinical Practice Research Datalink GOLD. Cases of incident VTE (pulmonary embolism [PE] or deep venous thrombosis [DVT]) and matched controls were identified from this population. We used descriptive analyses and conditional logistic regression to evaluate the risk of VTE in users of 5ARIs compared to users of ABs.ResultsFor 5ARI only users, the adjusted odds ratios (aORs), (95% CI) for VTE were 1.51 (0.98–2.32) in current 5ARI users and 1.23 (0.70–2.17) in recent/distant past, compared to AB only users. However, the aOR (95% CI) in men who had 50 or more current 5ARI prescriptions compared to users of ABs only was higher: 2.29 (1.14–4.63). For 5ARI with AB use, the aORs, (95% CI) for VTE were 1.16 (0.64–2.10) in current 5ARI+AB users and 1.93 (0.71–5.25) in recent/distant past, compared to AB only users. The aOR (95% CI) in men who had 50 or more current 5ARI+AB prescriptions compared to users of ABs only was 1.65 (0.64–4.26).ConclusionCurrent use of 5ARI, particularly long-term use, is associated with an increased risk of incident idiopathic VTE compared to patients treated with AB use only.

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.

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

Venous Thrombosis in Users of Non-Oral Hormonal Contraception: Follow-Up Study, Denmark 2001-10

Conclusion: Women who use transdermal patches or vaginal rings for contraception have approximately a six to seven times increased risk of venous thromboembolism (VTE) compared to women who do not use hormonal contraception. Summary: It is well known oral contraceptive agents increase the risk of VTE. There are, however, little to no data regarding the effects of methods other than pills to deliver hormonal contraceptive agents. Such methods include transdermal patches, subcutaneous implants, and vaginal rings. The authors used a historic national registry in a cohort study design to assess absolute and relative risk of VTE in Danish women using nonoral hormonal contraception. This national registry-based cohort study used four national registries from Denmark. All Danish nonpregnant women aged 15 to 49 years (n = 1,626,158), who were free of previous VTE or cancer, were followed up from 2001 to 2010. The main outcome measures were incidence rates of VTE in users of transdermal, vaginal, intrauterine, or subcutaneous hormonal contraception. Relative risk of venous thrombosis was compared with nonusers of hormonal contraception, and rate ratios of venous thrombosis in current users of nonoral products were compared with the standard reference of an oral contraceptive with levonorgestrel and estrogen (30-40 μg). A diagnosis of VTE was considered confirmed if there was at least 4 weeks of anticoagulation therapy after the initial VTE diagnosis. There were 5,287 first ever VTE events recorded within 9,429,128 women-years of observation. Of these VTE events, 3,434 were confirmed. The rate of confirmed VTE events was 2.1/10,000 years in nonusers of hormonal contraception. After adjustment for age, calendar year, and education, the relative risks and 95% confidence interval (95% CI) of confirmed VTE in users of transdermal combined contraceptive patches and vaginal ring compared with nonusers of hormonal contraception were 7.9 (3.5-17.7) and 6.5 (7.4-8.9), respectively. Corresponding incidence events per 10,000 exposure-years were 9.7 and 7.8 events. The relative risk (95% CI) was increased in women who used subcutaneous implants (1.4 [0.6-3.4]) but not in those who use the levonorgestrel intrauterine system (0.6 [0.4-0.8]). Compared with users of combined oral contraceptives containing levonorgestrel, the adjusted relative risk (95% CI) of VTE was 2.3 (1.0-5.2) in users of transdermal patches and 1.9 (1.3-2.7) in users of the vaginal ring. Comment: In the last paragraph of the discussion portion of this article the authors succinctly point out the implications of their study, “if the incidence rate of venous thrombosis in women using combined oral contraceptives containing levonorgestrel is 6 per 10,000 exposure years, that of the vaginal ring is 11 per 10,000 exposure years, and that of the transdermal patch is 14 per 10,000 exposure years, then 2000 women using the vaginal ring, and 1250 using the transdermal patch should shift to combined oral contraceptives with levonorgestrel to prevent 1 event of VTE in one year. A risk of 10 per 10,000 years implies a risk of VTE more than 1% over a 10 year user period. Therefore, women are generally advised to use combined oral contraceptives with levonorgestrel or norgestimate, rather than to use transdermal patches or vaginal rings.”

Venous Thromboembolism in Recipients of Antipsychotics

Since chlorpromazine was introduced to the market in the early 1950s, the use of antipsychotic drugs has been associated with venous thromboembolism (VTE) in a number of reports. During the last decade the evidence has been strengthened with large epidemiological studies. Whether all antipsychotics increase the risk for VTE or the risk is confined to certain drugs is still unclear. The aim of this article is to present an updated critical review focusing on the incidence, mechanisms and management of VTE in users of antipsychotics. After searching the databases PubMed and Scopus for relevant articles we identified 12 observational studies, all of which were published after the year 2000. In most of these studies an elevated risk of VTE was observed for antipsychotic drugs, with the highest risk for clozapine, olanzapine and low-potency first-generation antipsychotics. The risk seems to be correlated with dose. The elderly, who mainly use lower doses, do not show an increased risk of VTE to the same extent as younger subjects. The underlying biological mechanisms explaining the association between antipsychotic medication and VTE are to a large extent unknown. Several hypotheses have been proposed, such as body weight gain, sedation, enhanced platelet aggregation, increased levels of antiphospholipid antibodies, hyperprolactinaemia and hyperhomocysteinaemia. The risk of VTE in schizophrenia and other psychotic disorders may also be related to the underlying disease rather than the medication. Very limited evidence exists to guide how cases of VTE in subjects using antipsychotics should be handled. An attempt to compile an algorithm where the patients' individual risk of VTE is assessed and preventive clinical measures are suggested has been published recently. Strong consideration should be given to discontinuation of the offending antipsychotic drug in patients experiencing a VTE, and another antipsychotic drug with a presumably lower risk should be chosen if antipsychotic drug treatment is still indicated. It is essential that physicians and patients are aware that VTE may be an adverse drug reaction to the antipsychotic treatment so the condition is identified early and treated appropriately.

Hormonal contraception and venous thromboembolism

New studies about the influence of hormonal contraception on the risk of venous thromboembolism (VTE) have been published. To evaluate new epidemiological data and to propose clinical consequences. A literature survey. Studies assessing the risk of specific types of hormonal contraception were evaluated, compared and set into a clinical perspective. The majority of newer studies have demonstrated a threefold increased risk of VTE in current users of medium- and low-dose combined oral contraceptives (COCs) with norethisterone, levonorgestrel (LNG) or norgestimate compared with non-users. The same studies have demonstrated a sixfold increased risk of VTE in users of combined pills with desogestrel, gestodene, drospirenone or cyproteroneacetate, and in users of the contraceptive vaginal ring, compared with non-users. The rate ratio of VTE between users of COCs with newer progestogens compared with users of COCs with LNG was 1.5-2.8 in seven studies and 1.0 in two studies. Progestogen-only contraception did not confer an increased risk of VTE in any study. The incidence rate of VTE in non-pregnant women aged 15-49 years using non-hormonal contraception is three per 10 000 years. For women starting on hormonal contraception, we recommend medium- or low-dose combined pills with norethisterone, LNG or norgestimate as first-choice preparations. For the many women who are users of COCs with newer progestogens, although the absolute risk of VTE is low, a change to combined pills with norethisterone, LNG or norgestimate may halve their risk of VTE. Finally, we recommend COCs with 20 μg estrogen combined with the older progestogens to be launched in the Scandinavian countries. Women at an increased risk of VTE should consider progestogen-only contraception or non-hormonal contraception.

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.