Conclusions In the present study, transdermal treatment was the safest type of hormone replacement therapy when risk of venous thromboembolism was assessed. Transdermal treatment appears to be underused, with the overwhelming preference still for oral preparations.

Results Overall, 5795 (7.2%) women who had venous thromboembolism and 21 670 (5.5%) controls had been exposed to hormone replacement therapy within 90 days before the index date. Of these two groups, 4915 (85%) and 16 938 (78%) women used oral therapy, respectively, which was associated with a significantly increased risk of venous thromboembolism compared with no exposure (adjusted odds ratio 1.58, 95% confidence interval 1.52 to 1.64), for both oestrogen only preparations (1.40, 1.32 to 1.48) and combined preparations (1.73, 1.65 to 1.81). Estradiol had a lower risk than conjugated equine oestrogen for oestrogen only preparations (0.85, 0.76 to 0.95) and combined preparations (0.83, 0.76 to 0.91). Compared with no exposure, conjugated equine oestrogen with medroxyprogesterone acetate had the highest risk (2.10, 1.92 to 2.31), and estradiol with dydrogesterone had the lowest risk (1.18, 0.98 to 1.42). Transdermal preparations were not associated with risk of venous thromboembolism, which was consistent for different regimens (overall adjusted odds ratio 0.93, 95% confidence interval 0.87 to 1.01).

Our case-control study, based on the general female population in the UK, aimed to assess the associations between VTE risk and all available types of HRT in the UK between 1998 and 2017. The study performed additional analyses of subgroups of women based on age and body mass index.

Oral HRT formulations can be oestrogen only (unopposed) using conjugated equine oestrogen or estradiol, or oestrogen combined with a progestogen (opposed). Progestogens in combined formulations include medroxyprogesterone acetate or newer agents such as norgestrel, dydrogesterone, or drospirenone. Previous studies assessing the VTE risk associated with different HRT treatments either have not distinguished between the types of oestrogen or progestogen, or were powered to analyse only the most common preparations. 4 5 Findings from randomised controlled trials summarised in a Cochrane systematic review 4 were based mainly on the Women’s Health Initiative trial of women in the United States, who were predominantly in relatively good health. 6 The review reported that increased risk was associated with oestrogen only oral preparations, and with oral combinations of conjugated equine oestrogen and medroxyprogesterone acetate. Other preparations have become available in the past 20 years and across other countries, but observational studies on these treatments, which have been summarised in a meta-analysis, did not have consistent definitions of outcome and were not sufficiently powered to investigate individual types of HRT. 5 Therefore, there is insufficient information on VTE risk associated with specific HRT formulations for clinicians and women to make informed choices about treating menopausal symptoms.

Venous thromboembolism (VTE) is a rare but serious risk associated with hormone replacement therapy (HRT). HRT is used to prevent a range of symptoms experienced by many women during the menopause, such as hot flushes and night sweats. In 2015, in response to a halving of HRT use after two large studies 1 2 had raised concerns about the safety profile of HRT (including VTE risk), the National Institute for Health and Care Excellence (NICE) published its first guideline on diagnosis and management of menopausal symptoms in the United Kingdom. 3 A central theme was the need to inform women of the risks and benefits of HRT so that they can make appropriate treatment choices; but the recommendations relate to overall use of HRT, distinguishing only between oral and transdermal preparations. 3 The guideline recommends further research on the risks of HRT containing different types of progestogens in combination with oestrogen. The guideline also notes that the VTE risk appears greater for oral preparations than for transdermal treatment. The guideline is likely to result in an increase in HRT use in women with menopausal symptoms, increasing the need for detailed studies of the long term risks of different HRT regimens.

This study was unfunded, so patient and public involvement initially envisaged in anticipation of funding was not possible. No patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for design or implementation of the study. No patients were asked to aid in interpreting or disseminating the results. There are no plans to disseminate the results of the research to the relevant patient community.

For ease of comparisons with other studies, we conducted four additional analyses. Firstly, we ran an analysis on women with a VTE diagnosis supported by hospital admissions or mortality records, or with anticoagulant prescriptions six weeks before or after the VTE diagnosis. We used only practices with linked data for this analysis. Secondly, we ran an additional analysis on idiopathic participants who did not have any of the comorbidities or recent medical events associated with an increased risk of VTE. We also conducted two subgroup analyses using two clinically important variables to stratify risk: age (categories 40-54, 55-64, 65-79 years), and body mass index (categories: not overweight or obese, <25; overweight, 25-30; and obese, >30). These analyses investigated whether associations differed among the subgroups.

We ran three sensitivity analyses to address a number of assumptions. Firstly, to assess the assumption that previous use of anticoagulants was not related to an unrecorded VTE event, we ran an analysis excluding all women with previous exposure to anticoagulants. Secondly, we conducted a sensitivity analysis because of a difference in the data sources between QResearch and CPRD. All QResearch practices are linked to hospital admissions, mortality, and Townsend deprivation data whereas only 56% of CPRD practices (61% of included patients) are linked. For the main analysis, we used data from all the CPRD practices, but for this sensitivity analysis we only included linked CPRD practices. We also excluded participants with previous VTE events on hospital records from this second sensitivity analysis. Thirdly, to assess the plausibility of the missing at random assumption, we performed an analysis on women with complete data for body mass index, smoking status, and alcohol consumption.

We used the number needed to harm to estimate the magnitude of VTE risk in women exposed to oral HRT 13 ; this was based on the adjusted odds ratios from the combined analysis and the VTE rate in the unexposed population. We obtained this rate using CPRD data by following the cohort until the first prescription of HRT. Because exposure to HRT is highest in women aged 55-64 and VTE risk increases with age, we calculated the overall risk and the risk by age. To account for multiple comparisons, we chose a 1% significance level. We calculated 95% confidence intervals to allow comparison with other studies. Stata version 15 was used for all analyses.

We conducted analyses of QResearch and CPRD separately, but tried to keep the study designs as similar as possible (identical when data availability allowed). Adjusted estimates from the databases were combined by a meta-analysis technique. The findings were consistently similar between the databases; we did not expect or detect any heterogeneity. Therefore, we used a fixed effect model to combine the results of the two analyses, and we report only combined adjusted odds ratios in the text and figures. We present adjusted odds ratios for the separate QResearch and CPRD analyses in the tables and supplementary tables.

We used conditional logistic regression adjusted for the confounders to estimate odds ratios and to assess associations between HRT exposure and VTE risk. We assumed missing values for body mass index, smoking status, and alcohol consumption were missing at random and used imputation by chained equations. We created 10 imputed datasets and the imputation model included all listed confounders, current and past exposure, and the case-control indicator. We combined the odds ratios from each imputed dataset using Rubin’s rule. 12

We adjusted the analyses for confounding factors, which might have influenced whether doctors prescribed HRT or what specific HRT treatment was chosen. These factors are listed in table 1 and include lifestyle factors such as smoking status and body mass index, family history of VTE, comorbidities, and acute conditions associated with increased VTE risk. 11 Comorbidities had to be recorded at any time before the index date, and included asthma, atrial fibrillation, cancer, cardiovascular disease, chronic obstructive pulmonary disease, chronic renal disease, coagulation disturbances, congestive cardiac failure, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, and varicose veins. We considered acute conditions to be confounders if they were recorded in the six months before the index date; these conditions were gall bladder surgery, hip fracture or hip replacement operation, pregnancy, respiratory infection, and urinary tract infection. The analysis also included hospital admissions between two and six months before the index date. Other drugs that could be prescribed to women using HRT were included, either as current use (within 90 days before the index date) or past use (91-365 days before the index date). These were antipsychotics, antidepressants (tricyclic, selective serotonin reuptake inhibitors, and others), aspirin, tamoxifen, oral contraceptives, and progestogen only preparations.

Our analysis also included other preparations with oestrogen or progestogen that are used as topical (cream) or vaginal (pessaries) treatments. In addition, we included two other drugs that do not contain oestrogen: tibolone for menopausal symptoms and raloxifene for osteoporosis.

The dose was categorised as low (≤0.625 mg for oral conjugated equine oestrogen, ≤1 mg for oral estradiol, ≤50 μg for transdermal estradiol) or high. We assessed exposure duration in the year before the index date by adding up the days of prescriptions plus any periods between prescriptions of shorter than 90 days. Duration was categorised as short term (≤84 days) or long term (>84 days). No use of HRT in the past year was the reference category for all analyses.

We also analysed different regimens—cyclical or continuous—overall and separately for preparations with a sufficient number of cases (estradiol combined with norethisterone, and estradiol combined with dydrogesterone).

We classified exposure based on the most recent HRT prescription in the 90 days before the index date. Oral HRT included oestrogen only preparations (conjugated equine oestrogen and estradiol) and combined preparations (oestrogen with medroxyprogesterone acetate, dydrogesterone, norethisterone acetate, norgestrel/levonorgestrel, or drospirenone). Because of low numbers of participants exposed to norgestrel/levonorgestrel or to drospirenone, we analysed these preparations as one type of drug—that is, other progestogens structurally related to testosterone. 10 Transdermal HRT included oestrogen only and combined estradiol and we analysed this route of administration separately. We removed participants from the analysis if they had prescriptions for two different types of oestrogen or progestogen in the last 90 days issued on the same date. A few women had switched to another HRT within the last 90 days, so we added a switch indicator to the analysis.

We used HRT prescription information for the last year before the index date and included types of oestrogen and progestogen, dosage, and duration of exposure. We defined overall exposure to HRT as any exposure to oral or transdermal (patch, subcutaneous, or gel formulation) preparations containing estradiol. Oral and transdermal exposures were analysed separately. We identified a few treatments that included both tablets and patches; in such instances, the patient was considered to have been exposed to both oral and transdermal HRT. Exposure was categorised as recent (within 90 days before the index date), past (91-365 days), or no exposure. The study’s main focus was on recent exposure to HRT, because a previous study showed that past exposure is not associated with increased risk of VTE. 9 All included women had records for the one year before the index date; therefore, if women had no HRT prescriptions in this period, it meant that they were not exposed in terms of this study definition.

For the QResearch database, we identified cases of incident VTE recorded between January 1998 and February 2017 in the general practice records, or in hospital admissions or mortality records. For the CPRD analysis, we identified cases by using only the general practice records. We used incidence density sampling for both databases to match each case to up to five controls from the same practice and by year of birth. 8 The first date of diagnosis of VTE for cases became the index date for matched controls.

Full details of the study design have been published elsewhere. 7 In summary, we conducted nested case-control studies using the two UK primary care research databases QResearch and Clinical Practice Research Datalink (CPRD) and included all practices, which had contributed data for at least a year. We identified two open cohorts of women aged 40-79 years and registered with study practices between January 1998 and February 2017. We excluded women with previous records of VTE or with less than one year of medical records.

Results

We identified 52 137 cases from the QResearch database between 2 January 1998 and 5 February 2017 (the latest available data linkage date) using general practice, hospital admissions, or mortality records. We identified 28 259 cases from the CPRD database between 2 January 1998 and 22 February 2017 using general practice records. Of the CPRD cases, 16 638 were also linked to hospital admissions and mortality data between 2 January 1998 and 31 March 2016; these cases were used in a sensitivity analysis (fig 1).

Fig 1 Flow of included cases and controls for QResearch and Clinical Practice Research Datalink (CPRD) analyses with numbers excluded and reasons for exclusion. VTE=venous thromboembolism

Table 1 presents the characteristics of the study participants across the databases. More than half of the women who had VTE were aged 65 or older; they were also more likely to have comorbidities than controls (overall, 56% v 36%), such as cancer (21% v 7%), cardiovascular disease (13% v 9%), or chronic renal disease (8% v 5%). Women who had VTE were more likely than controls to have recent medical events than controls (27% v 12%), such as respiratory or urinary infection (20% v 10%), hip fracture or operation (3.4% v 0.3%), or hospital admission (7% v 1%), and to use antidepressants (24% v 14%; table 1).

Exposure (main analysis) When combining CPRD and QResearch results, we found that 5795 (7.2%) women with VTE and 21 670 (5.5%) controls were exposed to HRT in the 90 days before the index date. Figure 2 presents all available preparations and the numbers of exposed cases (for controls supplementary eFigure 1). In women exposed to HRT, 4915 (85%) cases and 16 938 (78%) controls used oral preparations, including 102 (1.8%) cases and 312 (1.4%) controls who also had transdermal preparations; 880 (14%) cases and 4731 (19%) controls used transdermal HRT only. Most of the transdermal preparations were prescribed in the form of patches (87% (n=858) in cases, 88% (n=4460) in controls), with only small proportions of women having subcutaneous and gel preparations (fig 2 and supplementary eFigure 1). Fig 2 Hormone replacement therapy (HRT) preparations available in the UK and number of women with venous thromboembolism exposed to HRT from QResearch and Clinical Practice Research Datalink (CPRD) databases. Some treatments comprised tablets and patches; 60 women in the oestrogen only group and 42 in the combined group were prescribed these treatments. CEE=conjugated equine oestrogen; E2=estradiol; MPA=medroxyprogesterone acetate; NEA=norethisterone acetate; other=dydrogesterone or levonorgestrel Supplementary eTable 1 presents the number of study participants unexposed and exposed to oral and transdermal HRT across the confounding factors to highlight differences in prescribing. Women in the two younger age groups were more likely to have been exposed to HRT than women in the oldest group. Women exposed to HRT were less likely to be obese and have comorbidities such as cardiovascular disease, chronic renal disease, and cancer, but more likely to have used antidepressants. Women using transdermal HRT were more likely to have had oophorectomy or hysterectomy than women on oral HRT (73% (n=714) cases and 67% (n=3407) controls v 45% (n=2185) cases and 43% (n=7278) controls); these women were also slightly older and had more comorbidities (supplementary eTable 1). Table 2 shows the number of study participants exposed to all types of HRT and adjusted odds ratios by database and for the combined analysis, compared with no exposure (unadjusted odds ratios are presented in supplementary eTable 2). Table 3 presents information for direct comparisons between different types of HRT. Overall exposure to HRT in the past 90 days was associated with a 43% increased VTE risk (adjusted odds ratio 1.43, 95% confidence interval 1.38 to 1.48; table 2) compared with no HRT use in the past year. Use of oral preparations was associated with a significantly increased VTE risk (1.58, 1.52 to 1.64), whereas transdermal HRT was not associated with VTE risk (0.93, 0.87 to 1.01; table 2). Compared with transdermal HRT, oral HRT was associated with a 70% increased risk of VTE (1.70, 1.56 to 1.85; table 3). Table 2 Exposure to different types of HRT and adjusted odds ratios for venous thromboembolism risk by database and combined analysis View this table: Table 3 Direct comparisons between different types of hormone replacement therapy (HRT). Values are adjusted odds ratios (95% confidence intervals) View this table: Oral oestrogen only and oral combined preparations were associated with increased VTE risk (adjusted odds ratio 1.40, 95% confidence interval 1.32 to 1.48, and 1.73, 1.65 to 1.81, respectively; table 2). Different types of oestrogen were associated with different risks. Oestrogen only preparations using conjugated equine oestrogen had higher VTE risks than preparations using estradiol (fig 3). Compared with oestrogen only conjugated equine oestrogen, use of oestrogen only estradiol was associated with a 15% reduction in VTE risk (0.85, 0.76 to 0.95; table 3). For combined oral preparations, the risks were significantly increased for conjugated equine oestrogen (1.91, 1.79 to 2.05) and estradiol preparations (1.59, 1.49 to 1.69; table 2) compared with no HRT use in the past year. Direct comparison between the types of oestrogen showed a 17% lower risk for combined estradiol than for combined conjugated equine oestrogen (0.83, 0.76 to 0.91; table 3). Fig 3 Adjusted odds ratios for different types of hormone replacement therapy (HRT) and different doses of oestrogen. Odds ratios are adjusted for current use of conjugated equine oestrogen cream, estradiol pessaries, oral progestogen, progesterone cream or vaginal preparations, past use of HRT, smoking status, alcohol consumption, Townsend deprivation fifth (QResearch only), body mass index, comorbidities, recent events, current and past use of antidepressants, antipsychotics, aspirin, oral contraceptives, tamoxifen, and years of data. Cases are matched to controls by age, general practice, and index date. *P<0.01 For oral combined HRT, conjugated equine oestrogen with medroxyprogesterone acetate was associated with the highest risk of VTE (adjusted odds ratio 2.10, 95% confidence interval 1.92 to 2.31), and estradiol with dydrogesterone with the lowest risk (1.18, 0.98 to 1.42; table 2 and fig 3). Compared with conjugated equine oestrogen with medroxyprogesterone, estradiol with dydrogesterone and estradiol with norethisterone were associated with 44% and 20% lower VTE risks, respectively (0.56, 0.45 to 0.69, P<0.001, and 0.80, 0.71 to 0.89, P<0.001, respectively; table 3). Overall, continuous and cyclical regimens for combined oral preparations were associated with an increased risk of VTE compared with no HRT use (adjusted odds ratio 1.55, 95% confidence interval 1.44 to 1.66, and 1.88, 1.77 to 1.99, respectively; table 2). However, not all combinations and age groups were equally covered. Younger women were more likely to be prescribed cyclical preparations and older women continuous preparations (supplementary eTable 3). Not all combined preparations were prescribed for cyclical and continuous regimens; conjugated equine oestrogen with medroxyprogesterone acetate was available mostly as a continuous regimen, whereas conjugated equine oestrogen with norgestrel was generally cyclical (fig 2 and supplementary eFigure 1). Only two preparations, estradiol with dydrogesterone and estradiol with norethisterone, had sufficient observations to assess the effect of the regimen. Neither cyclical nor continuous estradiol with dydrogesterone were associated with a statistically significantly increased VTE risk (1.21, 0.95 to 1.53, and 1.13, 0.84 to 1.53, respectively; table 2). Cyclical and continuous use of estradiol with norethisterone were associated with increased VTE risk compared with no HRT use (1.44, 1.28 to 1.63, and 1.80, 1.66 to 1.95, respectively; table 2). A large proportion of women using transdermal HRT had oestrogen only preparations (80% (n=781) in cases and 76% (n=3850) in controls (table 2). For combined preparations, norethisterone was the most common progestogen, with very low numbers for levonorgestrel and dydrogesterone, and most of the transdermal preparations had a lower dose of estradiol (fig 2). None of the transdermal preparations (oestrogen only or combined, low dose or high dose, combined cyclical or continuous) was associated with an increased VTE risk (table 2). Only a small proportion of women (about 10%) had a short exposure of fewer than 84 days, and we did not detect any differences in risk compared with longer exposure (supplementary eTable 4). Tibolone was used by 368 women with VTE and 1859 controls, and its use was not associated with VTE risk (adjusted odds ratio 1.02, 95% confidence interval 0.90 to 1.15; table 2). A small number of women (180 cases and 631 controls) used raloxifene, which was associated with a significantly increased VTE risk (1.49, 1.24 to 1.79; table 2). Use of conjugated equine oestrogen cream or estradiol vaginal preparations was not associated with VTE risk (table 2). Past exposures to HRT in the 91-365 days before the index date were not significantly associated with increased VTE risk (supplementary eTable 5).

Numbers needed to harm and excess risk of VTE The rate of VTE for the unexposed population based on the CPRD cohort was 16.0 per 10 000 women years. The rate differed among age groups: 9.0 per 10 000 women years for age 40-54, 22.2 for age 55-64, and 35.1 for age 65-79. Additional VTE cases were expected because of the increased VTE risk for users of most oral preparations (table 4). Table 4 Numbers needed to harm and excess risk of VTE per 10 000 women for different types of HRT over one year View this table: For overall oral HRT use across all age groups, the number needed to harm was 1076 (95% confidence interval 974 to 1196) and the number of extra VTE cases was nine per 10 000 women years (95% confidence interval 8 to 10; table 4). The highest number of extra cases was for conjugated equine oestrogen with medroxyprogesterone acetate (18 per 10 000 women years, 15 to 21), but this also increased with age (8 per 10 000, 5 to 13, for age 40-54; 37 per 10 000, 26 to 50, for age 64-79; table 4).