Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study


  1. Amani Meaidi, doctor, postdoctoral researcher1 2,
  2. Annamaria Mascolo, pharmacovigilance officer3 4,
  3. Maurizio Sessa, affiliate professor5,
  4. Anne Pernille Toft-Petersen, doctor6,
  5. Regitze Skals, statistician7,
  6. Thomas Alexander Gerds, professor8,
  7. Charlotte Wessel Skovlund, postdoctoral researcher9,
  8. Lina Steinrud Morch, senior researcher9,
  9. Francesco Rossi, professor3 4,
  10. Annalisa Capuano, professor3 4,
  11. Oejvind Lidegaard, professor1 2,
  12. Christian Torp-Pedersen, professor8 10 11
  1. 1Division of Gynecology, Rigshospitalet, College of Copenhagen, Copenhagen, Denmark
  2. 2Division of Scientific Drugs, College of Copenhagen, Copenhagen, Denmark
  3. 3Division of Experimental Drugs, Part of Pharmacology “L. Donatelli,” College of Campania ‘L. Vanvitelli’, Naples, Italy
  4. 4Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Naples, Italy
  5. 5Division of Drug Design and Pharmacology, College of Copenhagen, Copenhagen, Denmark
  6. 6Division of Scientific Drugs, Aalborg College, Aalborg, Denmark
  7. 7Unit of Scientific Biostatistics, Aalborg College Hospital, Aalborg, Denmark
  8. 8Division of Public Well being, Part of Biostatistics, College of Copenhagen, Copenhagen, Denmark
  9. 9Most cancers Surveillance and Pharmacoepidemiology, The Danish Most cancers Society Analysis Middle, Copenhagen, Denmark
  10. 10Division of Cardiology, Nordsjaellands Hospital, Hilleroed, Denmark
  11. 11Division of Scientific Epidemiology and Cardiology, Aalborg College Hospital, Aalborg, Denmark
  1. Correspondence to: A Meaid amani-meaidi{at}dwell.dk

Summary

Goal To review the affect of concomitant use of hormonal contraception and non-steroidal anti-inflammatory medicine (NSAIDs) on the danger of venous thromboembolism.

Design Nationwide cohort examine.

Setting Denmark by way of nationwide registries.

Members All 15-49 yr previous ladies residing in Denmark between 1996 and 2017 with no medical historical past of any venous or arterial thrombotic occasion, most cancers, thrombophilia, hysterectomy, bilateral oophorectomy, sterilisation, or infertility remedy (n=2 029 065).

Principal final result measure A primary time discharge prognosis of decrease limb deep venous thrombosis or pulmonary embolism.

Outcomes Amongst 2.0 million ladies adopted for 21.0 million individual years, 8710 venous thromboembolic occasions occurred. In contrast with non-use of NSAIDs, use of NSAIDs was related to an adjusted incidence price ratio of venous thromboembolism of seven.2 (95% confidence interval 6.0 to eight.5) in ladies not utilizing hormonal contraception, 11.0 (9.6 to 12.6) in ladies utilizing excessive threat hormonal contraception, 7.9 (5.9 to 10.6) in these utilizing medium threat hormonal contraception, and 4.5 (2.6 to eight.1) in customers of low/no threat hormonal contraception. The corresponding numbers of additional venous thromboembolic occasions per 100 000 ladies over the primary week of NSAID remedy in contrast with non-use of NSAIDs had been 4 (3 to five) in ladies not utilizing hormonal contraception, 23 (19 to 27) in ladies utilizing excessive threat hormonal contraception, 11 (7 to fifteen) in these utilizing medium threat hormonal contraception, and three (0 to five) in customers of low/no threat hormonal contraception.

Conclusions NSAID use was positively related to the event of venous thromboembolism in ladies of reproductive age. The variety of further venous thromboembolic occasions with NSAID use in contrast with non-use was considerably bigger with concomitant use of excessive/medium threat hormonal contraception in contrast with concomitant use of low/no threat hormonal contraception. Ladies needing each hormonal contraception and common use of NSAIDs needs to be suggested accordingly.

Introduction

Use of hormonal contraception and use of non-steroidal anti-inflammatory medicine (NSAIDs) have individually been related to an elevated threat of venous thromboembolism.123 Proof on the magnitude of the danger of venous thromboembolism in ladies utilizing hormonal contraception and NSAIDs concomitantly is missing.

Use of mixed hormonal contraception, containing oestrogen and progestin, is an acknowledged threat issue for decrease limb deep venous thrombosis and pulmonary embolism.124 Research have proven that the magnitude of the elevated threat relies on the dose of oestrogen and kind of progestin.124 Oestrogen is thought to trigger hypercoagulability by selling transcription of genes for a number of coagulation components.5 The affect of progestin on the coagulation system is extra advanced. Use of the progestin-only contraception injection, which delivers a excessive dose and efficiency of progestin, has been related to an elevated threat of venous thromboembolism67; nevertheless, research have reported a detectable hypocoagulability and decreased threat of venous thromboembolism with use of the levonorgestrel releasing intrauterine machine, which delivers solely a small dose of progestin to the blood.2678

Use of systemic non-aspirin NSAIDs has additionally been positively related to the event of thrombogenic illness, together with venous thromboembolic occasions.3 Each use of conventional NSAIDs, equivalent to ibuprofen, diclofenac, and naproxen, and use of newer extremely selective cyclo-oxygenase-2 inhibitors have been linked to an elevated threat of each arterial and venous thromboses.39 By way of their focused inhibition of cyclo-oxygenase enzymes, NSAIDs promote platelet aggregation,10 which contributes to activation of the coagulation system and thereby doubtlessly to the formation of a venous thrombosis.11 A lot of the current proof experiences on the affiliation between NSAID use and threat of arterial thrombogenic illness. Meta-analyses primarily based on randomised managed trials and observational research each assist an elevated threat of arterial thrombogenic illness with use of NSAIDs,912 main the US Meals and Drug Administration and European Drugs Company to require that the abstract of product traits of any systemic non-aspirin NSAID ought to carry a warning of an elevated threat of coronary heart assaults and strokes. Much less proof exists on the danger of venous thromboembolism with use of NSAIDs, however observational research and meta-analyses of those report a optimistic affiliation, together with for conventional NSAIDs.313

Though each hormonal contraceptives and NSAIDs include lively components that will have an effect on blood coagulability, how concomitant use of the 2 drug lessons impacts the danger of improvement of venous thromboembolism in ladies of reproductive age stays to be explored. Contemplating the worldwide prevalent use of those medicine and the severity of venous thromboembolic illness, this is a vital public well being matter. We report a nationwide pharmacoepidemiological evaluation of the incidence of venous thromboembolism in ladies utilizing hormonal contraception and NSAIDs concurrently.

Strategies

Research design and inhabitants

We performed a nationwide historic cohort examine, together with all 15-49 yr previous ladies residing in Denmark between 1996 and 2017 with no medical historical past of any venous or arterial thrombotic occasion, most cancers (besides non-melanoma pores and skin most cancers), thrombophilia, hysterectomy, bilateral oophorectomy, sterilisation, or infertility remedy. Ladies had been adopted from 1 January 1996 or from their fifteenth birthday if this occurred after the beginning of the examine. To make sure data on eligibility, ladies who immigrated entered the cohort one yr after the date of immigration. Ladies had been censored at 31 December 2017, loss of life, emigration, or the incidence of any exclusion criterion.

We recognized examine members and their follow-up occasions through the use of the Civil Registration System, the Nationwide Registry of Causes of Demise, the Nationwide Affected person Registry, and the Nationwide Registry of Medicinal Product Statistics.14151617 We used the non-public identification quantity given to all Danish residents at start or immigration to reliably hyperlink the registries. Actual definitions of the exclusion and censoring standards are outlined in supplementary desk A.

Hormonal contraception and NSAIDs

Time up to date, particular person degree data on buy of hormonal contraception and systemic non-aspirin NSAIDs was offered by the Nationwide Registry of Medicinal Product Statistics, which holds data on all prescriptions crammed by the Danish inhabitants since 1995.17 The registry receives its data electronically from the digital accounting methods of Danish pharmacies that primarily use the methods to safe reimbursement from the Nationwide Well being Service.17 The knowledge contains knowledge on date of redemption of the prescription and quantity and kind of redeemed drug.17

We outlined time uncovered to hormonal contraception from the date of the crammed prescription. For hormonal contraceptives administrated orally or by patch, injection, or vaginal ring, we decided period of use by quantity of outlined day by day doses bought. We assumed period of utilization of intrauterine methods and implants to be one yr lower than the utmost accepted period of utilization to account for the potential for early discontinuation. We prolonged all publicity intervals by 28 days to account for delays in initiation of use.

On the idea of findings reported within the literature, we categorised use of hormonal contraception in accordance with the affiliation with venous thromboembolism into use of excessive threat hormonal contraceptives, medium threat hormonal contraceptives, and low/no threat hormonal contraceptives. Thus, primarily based on findings from earlier research, excessive threat hormonal contraceptives included mixed oestrogen and progestin patch, vaginal ring, and tablets containing 50 µg ethinyl oestradiol, or the progestins desogestrel, gestodene, drospirenone, or the anti-androgen cyproterone. Medium threat hormonal contraception included all different mixed oral contraceptives in addition to the medroxyprogesterone injection. We thought-about progestin-only tablets, implants, and hormone intrauterine units to be low/no threat hormonal contraceptives.126 Supplementary desk B offers an in depth record of all hormonal contraceptives accessible through the examine interval.

We assumed time uncovered to systemic non-aspirin NSAIDs (Anatomical Therapeutic Chemical (ATC) code M01A, besides glucosamine M01AX05) to final one week from the date of the crammed prescription, as 98% of prescriptions for NSAIDs redeemed by the cohort consisted of a single package deal of most 30 tablets. As a sensitivity evaluation, we expanded the publicity window for NSAIDs to 30 days from crammed prescription. Supplementary desk C offers an in depth record of all systemic non-aspirin NSAIDs out there through the examine interval. When time uncovered to hormonal contraception overlapped with time uncovered to NSAIDs, we thought-about the lady to be a concomitant consumer.

Venous thromboembolism

We used the Nationwide Affected person Registry and the Nationwide Registry of Causes of Demise for the identification of all main venous thromboembolic occasions, outlined as a primary prognosis (categorized in accordance with the worldwide classification of ailments, tenth revision) of any decrease limb deep venous thrombosis (I801-3) or pulmonary embolism (I26).1516 We thought-about diagnoses that had been completely made within the emergency division with out subsequently being repeated by a medical division to be tentative and due to this fact didn’t embody them.

We did a sensitivity evaluation together with completely diagnoses both given after related imaging (Danish Classification of Examinations and Scientific Physiology and Nuclear Drugs, code UXUG (ultrasonography of decrease extremity), UXCC/UXAC, UXCG/UXAG (computed tomography scan/angiography of thorax or decrease extremity), WLHGS/WLHSS (lung scintigraphy)) or adopted by redemption of a prescription for an anticoagulant (ATC B01). We selected this affirmation technique to make sure legitimate affirmation of diagnoses of venous thromboembolic occasions all through all the examine interval, as imaging examinations weren’t coded firstly of the examine interval and subsequent anticoagulative remedy was not offered by prescription within the final a part of the interval.

Confounding variables

Time up to date data on age, calendar time, instructional degree, being pregnant, surgical procedure, hypertension, diabetes, polycystic ovary syndrome, endometriosis, migraine, systemic connective tissue problems, and inflammatory polyarthropathies and use of oral tranexamic acid was out there for all the examine inhabitants (supplementary desk A). Ladies had been censored quickly through the incidence of non permanent confounding components. A girl was censored quickly throughout being pregnant and for six months after supply and 12 weeks after different sorts of being pregnant terminations. The Danish Medical Beginning Registry and the Registry of Legally Induced Abortions maintain data on all births and induced abortions in Denmark since 1973, respectively, together with date of start/abortion and gestational age at start/abortion, permitting calculation of the estimated date of conception and thereby the non permanent censoring of girls throughout and after being pregnant.1819 Equally, miscarriages, extrauterine pregnancies, and pregnancies with unknown places identified or handled in a hospital setting are registered within the Nationwide Affected person Registry with date of termination and gestational age at termination.16 The Nationwide Affected person Registry additionally holds data on all surgical procedures undergone in Danish hospitals since 1976.16 If a surgical procedure resulted in hospital admission for at the very least someday, a girl could be censored quickly for eight weeks from the day of discharge. Each hormonal contraceptives and NSAIDs could also be used within the remedy of heavy menstrual bleeding. To keep away from overlap with use of the doubtless thrombogenic drug tranexamic acid,20 which can also be used within the administration of heavy menstrual bleeding, ladies had been quickly censored for eight weeks from the date of redemption of a prescription for tranexamic acid.

Quickly censored time intervals didn’t contribute with individual time or venous thromboembolic occasions within the analyses, and girls experiencing an occasion, loss of life, emigration, or any exclusion criterion throughout a quickly censored time interval had been completely censored from the date of such incident. Information on each physique mass index and smoking standing simply earlier than being pregnant had been out there for parous ladies from the calendar yr 2004, because it was recorded on the first go to to a midwife within the Medical Beginning Registry (supplementary desk A).19

Statistical evaluation

Utilizing Poisson regression, we calculated adjusted incidence price ratios of venous thromboembolism in accordance with consumer standing of hormonal contraception and NSAIDs. The primary analyses included an publicity variable with eight classes: no use of hormonal contraception and NSAIDs, excessive threat hormonal contraception use solely, medium threat hormonal contraception use solely, low/no threat hormonal contraception use solely, use of (any) NSAIDs alone, concomitant use of excessive threat hormonal contraception and any NSAID, concomitant use of medium threat hormonal contraception and any NSAID, and concomitant use of low/no threat hormonal contraception and any NSAID.

In a sensitivity evaluation, use of NSAIDs was additional divided in accordance with lively ingredient (ibuprofen, diclofenac, naproxen, others, a number of). In one other sensitivity evaluation, ibuprofen use was divided in accordance with drug unit dimension into use of ≥600 mg tablets and use of ≤400 mg tablets.

To compute a P worth for every of the three interplay phrases of curiosity (NSAID*excessive threat hormonal contraception, NSAID*medium threat hormonal contraception, and NSAID*low/no threat hormonal contraception), we did three probability ratio exams evaluating a mannequin together with the publicity as 4 binary unbiased variables (NSAID use, sure/no; excessive threat hormonal contraception use, sure/no; medium threat hormonal contraception use, sure/no; and low/no threat hormonal contraception use, sure/no) with three fashions every additionally together with one of many interplay phrases of curiosity.

Utilizing the distribution of age, calendar time, instructional degree, hypertension, diabetes, polycystic ovary syndrome, endometriosis, migraine, systemic connective tissue problems, and inflammatory polyarthropathies in all the cohort as the usual, we calculated standardised incidence price variations of venous thromboembolism per 100 000 ladies over the primary week of NSAID remedy in contrast with non-use of NSAIDs in accordance with consumer standing for hormonal contraception. As well as, we repeated the principle statistical analyses in a subpopulation restricted to ladies with no historical past of comorbidities equivalent to cardiovascular ailments and musculoskeletal problems. Exclusion and censoring standards defining this subcohort are outlined in supplementary desk D. We managed knowledge with SAS software program, model 9.4, and analysed them utilizing R software program model 4.2.1.

Affected person and public involvement

Aside from the ladies of reproductive age within the analysis group, no sufferers or members of the general public had been concerned within the design, evaluation, or writing up of the examine, because the analysis challenge was undertaken with out funds for affected person and public involvement measures. The outcomes of the examine will, nevertheless, be disseminated to the general public and well being professionals by press releases and displays at scientific conferences.

Outcomes

From 1996 by way of 2017, we adopted 2 029 065 ladies aged 15 to 49 years for a median of 10.0 (interquartile vary 4.3-16.5) years (fig 1). Throughout a complete of 21.0 million individual years, 8710 incident venous thromboembolisms occurred. Of those, 2715 (31.2%) had been coded as pulmonary embolisms and the remaining had been registered as remoted deep venous thromboses of the decrease extremity. A complete of 7043 (81%) of the 8710 final result diagnoses had been made after related imaging or had been adopted by redemption of a prescription for anticoagulation remedy. A complete of 228 (2.6%) ladies died inside 30 days of their prognosis of venous thromboembolic. Desk 1 reveals the traits of the examine inhabitants.

Fig 1

Movement diagram of formation of examine cohort

Desk 1

Traits of examine inhabitants. Values are numbers (percentages)* except said in any other case

Hormonal contraception and NSAIDs had been used concomitantly by 529 704 ladies. Of the full quantity of threat time through which concomitant use was noticed, 58% was contributed by the mixture of NSAIDs and excessive threat hormonal contraception, 23% by concomitant use with medium threat hormonal contraception, and 19% by concomitant use with low/no threat hormonal contraception.

In concomitant customers, the median variety of redeemed prescriptions of NSAIDs was 2 (interquartile vary 1-4), and 93-95% had been redeemed at the very least one yr after initiation of hormonal contraception throughout the three teams of hormonal contraception. Ibuprofen was essentially the most regularly used NSAID (60%), adopted by diclofenac (20%) and naproxen (6%). Ibuprofen was primarily prescribed as tablets of 400-600 mg, diclofenac as 50 mg tablets, and naproxen as 500-550 mg tablets (supplementary desk E). The mode of administration of hormonal contraception was primarily oral for top threat and medium threat hormonal contraception use (97-98%); use of low/no threat hormonal contraception was principally accounted for by way of the levonorgestrel releasing intrauterine system (89%) (supplementary desk F). We noticed comparable drug use patterns in customers of monotherapy (supplementary tables E and F). Of all NSAID prescriptions redeemed by all the cohort, 98% had been for a single package deal containing a most of 30 tablets.

Desk 2 reveals the adjusted incidence price ratios of venous thromboembolism in accordance with publicity standing with non-use of each hormonal contraceptives and NSAIDs because the reference group. The age, calendar yr, and schooling adjusted incidence price ratios had been 4.2 (95% confidence interval 4.0 to 4.4) for top threat hormonal contraception use solely, 3.0 (2.8 to three.2) for medium threat hormonal contraception use solely, 1.1 (1.0 to 1.3) for low/no threat hormonal contraception use solely, and eight.1 (6.9 to 9.6) to be used of NSAIDs alone (desk 2). We noticed a optimistic affiliation for ibuprofen, diclofenac, and naproxen, with the strongest affiliation occurring with use of diclofenac (desk 2). We discovered no distinction in threat when evaluating use of ≥600 mg tablets with ≤400 mg tablets of ibuprofen (0.9, 0.7 to 1.2).

Desk 2

Adjusted incidence price ratios of venous thromboembolism in accordance with hormonal contraception use solely, NSAID use solely, and concomitant use of hormonal contraception and NSAIDs, with non-use as reference

The corresponding price ratios had been 50.6 (44.2 to 57.8), 26.1 (19.6 to 34.7), and 5.7 (3.3 to 10.1) for concomitant use of NSAIDs and excessive threat, medium threat, and low/no threat hormonal contraception, respectively (desk 2). The associations continued after additional adjustment for the incidence of migraine, connective tissue dysfunction, inflammatory polyarthropathies, endometriosis, polycystic ovary syndrome, hypertension, and diabetes (desk 2). The P values for interplay phrases had been <0.001, 0.42, and 0.01 for the interplay between NSAID use and excessive threat, medium threat, and low/no threat hormonal contraception, respectively.

Within the subcohort restricted to the 1 709 341 wholesome ladies with no historical past of those ailments, the adjusted incidence price ratios elevated to five.7 (5.2 to six.2) for top threat hormonal contraception use solely and 4.1 (3.6 to 4.6) for medium threat hormonal contraception use solely, whereas the null affiliation continued for low/no threat hormonal contraception use solely (1.1, 0.8 to 1.5) (supplementary desk G). In contrast with the adjusted price ratios estimated in all the cohort, the speed ratios of venous thromboembolism related to NSAID use elevated round twofold within the subcohort of wholesome ladies to fifteen.0 (10.8 to twenty.8) to be used of NSAIDs alone and to 111.7 (89.6 to 139.3), 43.2 (25.0 to 74.6), and 13.0 (3.2 to 51.9) for concomitant use of NSAIDs and excessive threat, medium threat, and low/no threat hormonal contraception, respectively (supplementary desk G). Though non-significant, the stronger affiliation of diclofenac with the danger of venous thromboembolism in contrast with ibuprofen remained, whereas no occasions occurred through the 1533 individual years of naproxen use within the subcohort of wholesome ladies (supplementary desk G). The adjusted price ratios of venous thromboembolism in accordance with use of hormonal contraception and NSAIDs estimated in all the cohort and within the wholesome subcohort remained comparable in sensitivity analyses completely together with confirmed venous thromboembolic occasions.

Determine 2 reveals the adjusted incidence price ratios of venous thromboembolism with use of NSAIDs in contrast with non-use of NSAIDs in accordance with consumer standing of hormonal contraception. In contrast with ladies not utilizing hormonal contraception, the speed ratio of venous thromboembolism with NSAID use in contrast with non-use was increased amongst ladies utilizing excessive threat hormonal contraception and decrease in ladies utilizing low/no threat hormonal contraception (fig 2). The elevated threat of venous thromboembolism with NSAID use in contrast with non-use remained considerably increased in excessive threat hormonal contraception customers in contrast with non-users of hormonal contraception in sensitivity analyses of solely confirmed occasions and when increasing the publicity window of NSAIDs to 30 days from crammed prescription (supplementary desk H). Equally, the ratio was decrease in concomitant customers of low/no threat hormonal contraception all through sensitivity analyses (supplementary desk H).

Fig 2
Fig 2

Adjusted incidence price ratios of venous thromboembolism and variety of further venous thromboembolic occasions in non-steroidal anti-inflammatory drug (NSAID) customers versus non-users in accordance with use of hormonal contraception. *Incidence price ratios adjusted for age, calendar time, instructional degree, hypertension, diabetes, polycystic ovary syndrome, endometriosis, migraine, systemic connective tissue problems, and inflammatory polyarthropathies. †Standardised incidence price variations per 100 000 individual weeks; standardised in accordance with distribution of age, calendar time, instructional degree, hypertension, diabetes, polycystic ovary syndrome, endometriosis, migraine, systemic connective tissue problems, and inflammatory polyarthropathies in whole cohort. CI=confidence interval

In contrast with non-use of NSAIDs, the adjusted variety of further venous thromboembolic occasions per 100 000 ladies over the primary week of NSAID remedy was 4 (95% confidence interval 3 to five) in ladies not utilizing hormonal contraception (fig 2). Though the quantity remained comparable in ladies concomitantly utilizing low/no threat hormonal contraception (3, 0 to five), it elevated to 23 (19 to 27) in ladies concomitantly utilizing excessive threat hormonal contraception and 11 (7 to fifteen) with concomitant use of medium threat hormonal contraception (fig 2). The elevated variety of further venous thromboembolisms with NSAID use versus non-use remained increased throughout concomitant use of excessive threat hormonal contraception in contrast with non-use of hormonal contraception for ibuprofen, diclofenac, and naproxen (fig 2).

Dialogue

In a nationwide cohort of girls of reproductive age, we discovered use of NSAIDs to be positively related to the event of venous thromboembolism, with the magnitude of the elevated threat being depending on the consumer standing for hormonal contraception. Most concomitant use occurred as incident NSAID use in prevalent customers of hormonal contraception. In contrast with non-use of hormonal contraception, the affiliation between NSAID use and venous thromboembolism was stronger in ladies utilizing excessive threat hormonal contraception and decrease in customers of low/no threat hormonal contraception.

Strengths and limitations of examine

Utilizing prime quality, linkable, nationwide registries, this nationwide examine provides new data on the danger of a doubtlessly deadly occasion throughout concomitant use of two drug lessons typically prescribed to in any other case wholesome ladies. First time prognosis of deep venous thrombosis or pulmonary embolism within the Danish Nationwide Affected person Registry has beforehand been proven to have a excessive optimistic predictive worth of 80-90%.21 On this examine, 81% of diagnoses of venous thromboembolism in decrease extremities or lungs had been made after related imaging or had been adopted by subsequent buy of anticoagulants, and all findings continued after we restricted the result to confirmed diagnoses.

The Nationwide Registry of Medicinal Product Statistics offered legitimate, day by day up to date, particular person degree data on buy of hormonal contraception and NSAIDs, thereby eliminating recall bias.17 Particular person degree knowledge on over-the-counter NSAID purchases weren’t out there. Nevertheless, a Danish examine on the impact of misclassification of over-the-counter NSAID use as non-use concluded that such misclassification is minor and has negligible affect on estimates of associations with NSAID use, making the Danish Nationwide Registry of Medicinal Product Statistics a sound knowledge supply for assessing results of NSAID use.22

The fastened day by day dose of hormonal contraceptives and the shelling out by way of repetitive redemption of prescriptions allowed dependable estimation of time of publicity utilizing data on date of shelling out and kind and quantity of hormonal contraception bought. However, the NSAID dosage could range amongst customers, and data on dosage regimens was not out there from the Nationwide Registry of Medicinal Product Statistics. However, the belief that NSAIDs had been used inside the first week from redemption of the prescription appears cheap contemplating that 98% of all prescriptions for NSAIDs redeemed by all the cohort had been for a single package deal containing a most of 30 tablets, that the median variety of redeemed NSAID prescriptions was two for NSAID customers all through a median follow-up time of 10 years, and the overall good well being of girls of reproductive age, all indicative of NSAIDs getting used for brief time period reduction of an acute, non permanent ache. Reassuringly, the elevated threat of venous thromboembolism with NSAID use and the adjustments within the magnitude of the affiliation in accordance with hormonal contraception use continued after we expanded the publicity window to 30 days from redemption of prescription, though the probably misclassification of time of non-use as use, occurring with such a large publicity window, contributed to a dilution of the associations. The opportunity of learning a dose impact for NSAIDs was hampered by the quite slim vary of really helpful doses and predominantly remoted prescriptions.

We had been capable of management for a wealth of potential confounding components by design and statistical changes, however publicity, being primarily based on actual world knowledge, was not randomised, leaving the opportunity of residual confounding and unmeasured confounding. Though we had details about smoking and weight problems for 355 086 ladies, this data was lacking for a lot of the included individual time, which hampered adjustment for these components. Nevertheless, in Denmark, smoking and weight problems are extremely correlated with instructional standing, and we adjusted for schooling in all our analyses. Moreover, for hormonal contraception, our incidence price ratios had been just like these reported in research that did regulate for smoking and weight problems.1 Lastly, smoking and weight problems are unlikely to trigger the noticed variations within the magnitude of the impact of NSAID use on threat of venous thrombosis throughout hormonal contraception use.

Confounding by indication and protopathic bias might happen when the affiliation between NSAID use and venous thromboembolic occasions is studied. We tried to get rid of confounding by indication as a lot as potential by way of management of indications for NSAIDs, equivalent to persistent ache or inflammatory situations, which can be doubtlessly thrombogenic themselves or enhance the probability of immobilisation. Though residual confounding by indication could happen, the indications for the very brief time period NSAID use noticed on this inhabitants of quite wholesome younger ladies appear unlikely to clarify the sevenfold increased threat of venous thromboembolism noticed throughout NSAID use in contrast with non-use. The variety of individual years with heart problems or persistent ache/inflammatory situations was restricted, lowering the potential affect of a collider bias. That protopathic bias could be otherwise distributed in accordance with hormonal contraception use additionally appears unlikely, and this could have to be the case to clarify the noticed variations within the affiliation between NSAID use and threat of venous thromboembolism in customers of various hormonal contraceptives.

Comparability with different research

Within the largest examine on the affiliation between NSAID use and unprovoked venous thromboembolism, Schmidt et al discovered use of NSAIDs to be related to a twofold increased threat of venous thromboembolism in contrast with non-use.13 Schmidt et al confirmed that the optimistic affiliation continued in long run customers, lowering the probability of protopathic bias, and in strata in accordance with the indication for NSAID use, minimising the impact of confounding by indication.13 Contemplating the overall excellent well being standing of girls of reproductive age and their sparse use of NSAIDs, we didn’t have the info basis to review the affiliation in such illness strata or in long run customers.

Schmidt et al assumed that use of NSAIDs occurred inside 60 days after buy, which probably precipitated misclassification of time of non-use as time of use and thereby a dilution of the particular affiliation. Such dilution with the growth of publicity window was confirmed in sensitivity analyses of their examine in addition to in ours.13 Moreover, Schmidt et al’s examine inhabitants included older and extra morbid members than these in our examine, inflicting the reference group to have a a lot increased baseline threat of venous thromboembolism in contrast with the wholesome, younger ladies included in our examine.13 This confounding by baseline price was additionally observable in our examine, because the associations doubled within the subcohort from which ladies with cardiovascular comorbidities had been excluded.

A meta-analysis of observational research from 2015 confirmed the findings of Schmidt et al of a twofold increased threat of venous thromboembolism amongst customers of NSAIDs.3 Once more, the broad time window of publicity and the inclusion of older members at cardiovascular threat could clarify the smaller relative affiliation noticed on this examine in contrast with ours.3 A latest examine by Kinsey et al (2020) additionally discovered a better threat of venous thromboembolism amongst customers of NSAIDs in contrast with non-users, however the affiliation turned null when the comparator was use of paracetamol.23 The authors interpret this discovering as indicative of the existence of confounding by indication or baseline traits of analgesic customers inflicting a better cardiovascular threat profile in contrast with non-users.23 Nevertheless, this examine outlined publicity time by extrapolating yearly collected data on use of analgesics. Whether or not such a technique would end in a sound definition of time of use of NSAIDs solely and paracetamol solely, securing non-overlapping use, is questionable. Moreover, use of paracetamol can’t be thought-about a sound damaging publicity management, as its pharmacodynamics have been proven to incorporate inhibition of the cyclo-oxygenase enzyme (just like NSAIDs) and it has been linked to elevated dangers of cardiovascular ailments.2425 Equally, we didn’t think about use of stronger analgesics, equivalent to opioids, as damaging publicity controls to be legitimate, as indications for these differ from widespread indications to be used of NSAIDs and will create confounding by indication.

A meta-analysis of 280 trials of NSAIDs versus placebo (124 513 members; 68 342 individual years) and 474 trials of 1 NSAID versus one other NSAID (229 296 members; 165 456 individual years) concluded that diclofenac specifically was related to elevated cardiovascular threat and had the same cardiovascular threat profile to the withdrawn cyclo-oxygenase-2 inhibitor rofecoxib.9 In our examine, the affiliation with venous thromboembolism was stronger for diclofenac than for ibuprofen or naproxen. Diclofenac is a standard NSAID like ibuprofen and naproxen however has comparable affinity/selectivity to newer cyclo-oxygenase-2 inhibitors for cyclo-oxygenase-2, which is believed to advertise platelet aggregation and activation of coagulation when inhibited.10

Because the pharmacodynamics of each hormonal contraception and NSAIDs embody an impact on the coagulation system,51011 the noticed superadditive joint impact between excessive/medium threat hormonal contraception and NSAIDs might signify a synergistic drug interplay between the drug lessons. Nevertheless, additional analysis is warranted to find out the potential existence and mechanism of such drug interplay.

Conclusion and implications

In conclusion, we discovered the affect of NSAID use on venous thromboembolic threat to be considerably better in ladies utilizing excessive threat hormonal contraception in contrast with no use of hormonal contraception and smaller in ladies utilizing low/no threat hormonal contraception. Nevertheless, additional analysis is required to make clear whether or not these findings signify an precise drug interplay.

Regardless of the excessive incidence price ratios, absolutely the threat of venous thromboembolic occasion within the first week after NSAID buy remained low even in customers of excessive threat hormonal contraception (0.02%). Nevertheless, contemplating the extremely prevalent indications to be used of hormonal contraception and of NSAIDs, learning this affiliation additional could be of public curiosity, particularly in common customers of NSAIDs, who may profit from a low/no threat hormonal contraceptive quite than a excessive/medium threat hormonal contraceptive.

What’s already recognized on this subject

  • Use of mixed hormonal contraceptives is an acknowledged threat issue for venous thromboembolism

  • Observational research and meta-analyses have reported an elevated threat of venous thromboembolism with use of non-steroidal anti-inflammatory medicine (NSAIDs)

  • Proof is missing on the venous thromboembolic threat with concomitant use of hormonal contraception and NSAIDs

What this examine provides

  • On this nationwide examine of girls of reproductive age, use of NSAIDs was related to an elevated threat of venous thromboembolism

  • The magnitude of the elevated threat trusted the consumer standing of hormonal contraception

  • In contrast with non-use of hormonal contraception, the affiliation between NSAID use and venous thromboembolism was stronger in ladies utilizing excessive threat hormonal contraception

Ethics statements

Moral approval

In accordance with Danish legislation, research primarily based on the nationwide Danish registries should not required to realize affected person consent or moral approval. This examine was accepted by the Danish Well being Information Board (approval ID: FSEID-00005931) and the Danish Information Safety Company (approval ID: P-2019-280).

Information availability assertion

Uncooked knowledge used to conduct this examine are accessible solely by way of approval from the Danish Information Safety Company and the Danish Well being Information Board. Though anonymised, the info had been out there at a person degree, making knowledge sharing restricted by the Basic Information Safety Regulation of EU legislation.

Footnotes

  • Contributors: CTP initiated the examine. AM designed the examine, with contributions from all co-authors. AM performed the info administration. AM did the analyses, with contribution from RKS and TAG. All authors, led by AM, had been concerned in knowledge interpretation and the writing of the manuscript. AM is the guarantor. The corresponding writer attests that each one listed authors meet the authorship standards and that no others assembly the factors have been omitted.

  • Funding: The examine was supported by the Danish Coronary heart Basis. The Danish Coronary heart Basis didn’t contribute to any a part of examine conduct or publication.

  • Competing pursuits: All authors have accomplished the ICMJE uniform disclosure kind at https://www.icmje.org/disclosure-of-interest/ and declare: assist from the Danish Coronary heart Basis, which funded AM’s wage, together with this examine; LSM has obtained grants from the medical health insurance organisation “Denmark,” the Danish Most cancers Society’s Scientific Committee, and Novo Nordisk for analysis unrelated to the current examine; CTP has obtained grants from Novo Nordisk and Bayer outdoors the present examine; no different relationships or actions that would seem to have influenced the submitted work.

  • The lead writer affirms that the manuscript is an sincere, correct, and clear account of the examine being reported; that no vital points of the examine have been omitted; and that any discrepancies from the examine as initially deliberate (and, if related, registered) have been defined.

  • Dissemination to members and associated affected person and public communities: We plan to disseminate outcomes to related medical societies within the type of press releases from the authors’ departments.

  • Provenance and peer evaluate: Not commissioned; externally peer reviewed.

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