Aromatase Inhibitors and the Risk of Cardiovascular Outcomes in Women With Breast Cancer: A Population-Based Cohort Study
Abstract
Background:
The association between aromatase inhibitors and cardiovascular outcomes among women with breast cancer is controversial. Given the discrepant findings from randomized controlled trials and observational studies, additional studies are needed to address this safety concern.
Methods:
We conducted a population-based cohort study using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. The study population consisted of women newly diagnosed with breast cancer initiating hormonal therapy with aromatase inhibitors or tamoxifen between April 1, 1998, and February 29, 2016. We usedCox proportional hazards models with inverse probability of treatment and censoring weighting to estimate hazard ratios (HRs) with 95% CIs comparing new users of aromatase inhibitors with new users of tamoxifen for each of the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality).
Results:
The study population consisted of 23 525 patients newly diagnosed with breast cancer, of whom 17 922 initiated treatment with either an aromatase inhibitor or tamoxifen (8139 and 9783, respectively). The use of aromatase inhibitors was associated with a significantly increased risk of heart failure (incidence rate, 5.4 versus 1.8 per 1000 person-years; HR, 1.86 [95% CI, 1.14–3.03]) and cardiovascular mortality (incidence rate, 9.5 versus 4.7 per 1000 person-years; HR, 1.50 [95% CI, 1.11–2.04]) compared with the use of tamoxifen. Aromatase inhibitors were associated with elevated HRs, but with CIs including the null value, for myocardial infarction (incidence rate, 3.9 versus 1.8 per 1000 person-years; HR, 1.37 [95% CI, 0.88–2.13]) and ischemic stroke (incidence rate, 5.6 versus 3.2 per 1000 person-years; HR, 1.19 [95% CI, 0.82–1.72]).
Conclusions:
In this population-based study, aromatase inhibitors were associated with increased risks of heart failure and cardiovascular mortality compared with tamoxifen. There were also trends toward increased risks, although nonsignificant, of myocardial infarction and ischemic stroke. The increased risk of cardiovascular events associated with aromatase inhibitors should be balanced with their favorable clinical benefits compared with tamoxifen.
Clinical Perspective
What Is New?
•
Some randomized controlled trials have associated aromatase inhibitors with an increased risk of cardiovascular outcomes, but to date, the few real-world studies on the topic have generated conflicting results.
•
In this population-based cohort study of 17 922 women with breast cancer, the use of aromatase inhibitors was associated with increased risks of heart failure and cardiovascular mortality and trends toward increased risks of myocardial infarction and ischemic stroke compared with the use of tamoxifen.
What Are the Clinical Implications?
•
In this population-based study, the use of aromatase inhibitors was associated with an increased risk of cardiovascular outcomes compared with tamoxifen.
•
This possible increased cardiovascular risk with aromatase inhibitors should be balanced with their favorable clinical profile compared with tamoxifen.
Introduction
Aromatase inhibitors (AIs) have become the preferred adjuvant treatment for postmenopausal women with estrogen receptor–positive breast cancer.1 These drugs have been associated with favorable clinical outcomes, including decreased risks of all-cause and breast cancer–related mortality, compared with tamoxifen.2 However, their safety has been a contentious issue, with some meta-analyses of randomized controlled trials (RCTs) reporting an increased risk of cardiovascular events compared with tamoxifen.3–5 However, the biological mechanism behind this possible association remains uncertain. Although some RCTs associated the use of AIs with hypercholesterolemia,6,7 others reported no effects on serum cholesterol levels.8–12 Moreover, some evidence suggests that tamoxifen may reduce cholesterol levels.12–16
To date, few observational studies have examined the cardiovascular effects of AIs.17–20 In 1 study, AIs were associated with an increased risk of myocardial infarction,17 whereas 3 other studies did not observe an association with this outcome.18–20 With respect to other cardiovascular outcomes, only 2 studies investigated stroke and heart failure,19,20 and none examined cardiovascular mortality. As a result, the response from regulatory agencies has also been mixed. The US Food and Drug Administration imposed a label change to certain AIs (anastrozole) to include a possible increased risk of ischemic heart disease among women with established cardiovascular disease,21 whereas other agencies such as the European Medicine Agency have not indicated this concern in their product assessment.22,23
Given the increasing use of AIs1 and continued concerns related to their cardiovascular safety,24 we conducted a population-based cohort study to examine the association between these drugs and the risk of myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality among women with breast cancer.
Methods
Data Sources
The analytical methods and study materials will be available to other researchers on request for replicating the procedures and reproducing the results in this article. This study was conducted by linking the UK Clinical Practice Research Datalink (CPRD) with the Hospital Episode Statistics (HES) and the Office for National Statistics (ONS) databases.
The CPRD includes information on medical diagnoses and procedures, lifestyle variables, anthropometric measurements, and prescriptions written by general practitioners.25 The patient population enrolled in the CPRD has been shown to be representative of the UK population in terms of age, ethnicity, and body mass index.25 Diagnoses have been shown to be well recorded in the CPRD.26,27 These include validation studies reporting high concordance rates between breast cancer diagnoses recorded in the CPRD compared with the National Cancer Data Repository (96%–97%)28,29 and medical profile reviews (98%).28–30 The HES repository includes information on all inpatient and outpatient hospital admissions, primary and secondary diagnoses, and procedures.31 Last, the ONS database includes the electronic death certificates of all residents in the United Kingdom.32
The study protocol was approved by the Independent Scientific Advisory Committee of the CPRD (protocol 17_072RA) and by the Research Ethics Board of the Jewish General Hospital, Montreal, Quebec, Canada.
Study Population
Using the CPRD, we identified a cohort of women at least 50 years of age with a first-ever diagnosis of breast cancer between April 1, 1998, and February 29, 2016. We excluded patients with <1 year of medical history before their first breast cancer diagnosis and those with evidence of metastatic disease (using diagnostic Read codes corresponding to secondary malignancy, recurrence, or metastases). In addition, we excluded patients with prescriptions of AIs or tamoxifen before their breast cancer diagnosis to minimize the inclusion of prevalent users.
From this cohort, we used a new-user, active-comparator design in which we identified patients newly treated with either an AI (anastrozole, letrozole, exemestane) or tamoxifen after their breast cancer diagnosis. Cohort entry was defined by the date of the first prescription of either drug class during the study period. We then excluded patients prescribed an AI and tamoxifen on the same day and patients prescribed >1 AI at cohort entry. Patients meeting the inclusion criteria were followed up from cohort entry until an incident diagnosis of 1 of the study outcomes (subsequently defined in detail), treatment discontinuation (subsequently defined in detail), death, end of registration with the general practice, or end of the study period (February 29, 2016), whichever occurred first.
Exposure Definition
We used an as-treated exposure definition in which patients were followed up while they were continuously exposed to the study drugs. According to this exposure definition, patients were censored at discontinuation of initial treatment or at a switch between tamoxifen or AIs (or vice versa). Patients were considered continuously exposed if the duration of 1 prescription plus a 30-day grace period overlapped with the date of the next prescription of the same drug class. Thus, treatment discontinuation corresponded to the end of a 30-day grace period in the event of no overlapping subsequent prescription. The date of censoring resulting from a treatment switch was defined by the date of a switch between prescriptions from different drug classes (tamoxifen to AI or vice versa).
Outcome Ascertainment
We considered the following 4 outcomes, which were assessed independently in the analyses, with separate follow-up durations determined for each: myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality (9th and 10th revisions of International Classification of Diseases codes are provided in Table I in the online-only Data Supplement). The HES repository was used to identify hospitalized events (in primary position), whereas the ONS was used to identify deaths for which a cardiovascular event was deemed to be the underlying cause. These outcomes have been shown to be well recorded in the HES, with myocardial infarction having a positive predictive value of 92%,33 diagnoses of coronary heart disease having a specificity and negative predictive value of 96%,34 and stroke having a perfect specificity and negative predictive value (100%).34
Potential Confounders
Overall, we considered 45 potential confounders assessed before or at cohort entry; these variables included lifestyle and anthropometric measures, comorbidities, prescriptions, and breast cancer–related variables. The variables measured at cohort entry included the following: age, body mass index (<25, 25–30, ≥30 kg/m2, unknown), Townsend Deprivation Index, ethnicity (white, other, unknown), smoking status (current, past, never, unknown), and alcohol-related disorders. We also included the following comorbidities measured at any time before cohort entry: myocardial infarction, stroke (ischemic or hemorrhagic) or transient ischemic attack, heart failure, peripheral vascular disease, venous thromboembolism, chronic obstructive pulmonary disease, chronic kidney disease, cancers (other than breast and nonmelanoma skin cancer), and non–breast cancer surgeries in the year before cohort entry. We also considered use of the following prescription drugs measured in the year before cohort entry: anticoagulants, antidepressants, antidiabetic drugs, antihypertensive drugs, bisphosphonates, nonsteroidal anti-inflammatory drugs, opioids, acetylsalicylic acid, non–acetylsalicylic acid antiplatelets, statins, and hormone replacement therapy. Last, the model included the following breast cancer–related variables measured between the breast cancer diagnosis date and cohort entry: receipt of chemotherapy, radiation therapy, breast cancer surgery, and time since the breast cancer diagnosis (defined as the time between the breast cancer diagnosis and cohort entry). Age and time since breast cancer diagnosis were modeled flexibly as restricted cubic splines with 5 interior knots.35 We did not include calendar time in the model because it acted as an instrumental variable and generated unstable weights36 as a result of its strong association with the exposure and relatively weak association with the outcomes.
Statistical Analysis
We used descriptive statistics (means and proportions) to summarize characteristics of each exposure group. We used absolute standardized differences to compare characteristics of patients initiating treatment on AIs and tamoxifen. For each exposure group, we calculated crude incidence rates for each outcome, with corresponding 95% CIs based on the Poisson distribution. We used Cox proportional hazards models with inverse probability of treatment and censoring weighting to estimate marginal hazard ratios (HRs) and 95% CIs using robust variance estimators for the outcomes of interest, comparing the use of AIs with the use of tamoxifen (details of this method are outlined in Methods I in the online-only Data Supplement).37 We generated weighted cumulative incidence curves, with duration of follow-up as the time axis, for each of the 4 outcomes. In secondary analyses, we assessed effect measure modification by stratifying on the presence of cardiovascular disease before cohort entry (using Read and 9th and 10th revisions of International Classification of Diseases diagnosis codes) and type of AI (anastrozole and letrozole; analyses for exemestane were not performed because of the low number of exposed patients [n=47]).
Sensitivity Analyses
We conducted 6 sensitivity analyses to assess the robustness of our findings. First, we extended the grace period between consecutive prescriptions to 60 days. Second, we changed the outcome definition to hospitalized events recorded in primary and secondary positions and deaths recorded in ONS. Third, we restricted the study population to patients at least 55 years of age to minimize the inclusion of premenopausal women. Fourth, to further assess residual confounding at baseline, we regenerated the inverse probability of treatment weights using the high-dimensional propensity score algorithm (described in detail in Methods II in the online-only Data Supplement).38 Fifth, to account for residual confounding and informative censoring resulting from time-varying covariates, we constructed marginal structural models with inverse probability of treatment and censoring weights with covariates updated at monthly intervals (described in detail in Methods III in the online-only Data Supplement).37 Last, we assessed the effect of variables with missing information (ie, body mass index, Townsend deprivation score, smoking status, and ethnicity) by conducting multiple imputation and a complete case analysis. For the former, 10 imputations were performed, and the resulting data sets were analyzed with weighted Cox proportional hazard models with the results combined using the Rubin rule to compute standard errors.39 All analyses were conducted with SAS version 9.4 (SAS Institute, Cary, NC) and R (R Foundation for Statistical Computing, Vienna, Austria).
Results
Of the 23 525 patients newly diagnosed with nonmetastatic breast cancer during the study period, 17 922 (76.2%) were newly treated with either an AI (n=8139) or tamoxifen (n=9783; Figure 1). The most commonly used AI was anastrozole (n=4700, 57.7%), followed by letrozole (n=3392, 41.7%) and exemestane (n=47, 0.6%).
The unweighted and weighted baseline characteristics of AI and tamoxifen users are shown in Table 1. Before weighting, AI users were older, had a higher body mass index, and were more likely to have alcohol-related disorders and to have smoked compared with tamoxifen users. They were also more likely to have comorbidities and to have used prescription drugs. The proportion of missing data was low (0.1% for Townsend deprivation score, 3% for ethnicity, 3% for smoking status, and 10% for body mass index). The baseline characteristics were well balanced between the groups after weighting (Table 1 and Tables II–IVin the online-only Data Supplement).
| Characteristic | Before Weighting | After Weighting* | ||||
|---|---|---|---|---|---|---|
| Aromatase Inhibitors (n=8139) | Tamoxifen (n=9783) | Standardized Difference (Absolute) | Aromatase Inhibitors | Tamoxifen | Standardized Difference (Absolute) | |
| Age, mean (SD), y | 70.8 (11.2) | 66.2 (11.5) | 0.41 | 68.1 (11.4) | 67.3 (10.9) | 0.07 |
| Body mass index, n (%) | ||||||
| <25 kg/m2 | 2574 (31.6) | 3581 (36.6) | 0.11 | 36.1 | 36.7 | 0.01 |
| 25–30 kg/m2 | 2630 (32.3) | 2887 (29.5) | 0.06 | 29.6 | 30.1 | 0.01 |
| ≥30 kg/m2 | 2265 (27.8) | 2091 (21.4) | 0.15 | 22.2 | 21.5 | 0.02 |
| Unknown | 670 (8.2) | 1224 (12.5) | 0.14 | 12.1 | 11.7 | 0.01 |
| Townsend deprivation score, n (%) | ||||||
| Quintile 1 | 2057 (25.3) | 2570 (26.3) | 0.02 | 25.0 | 25.8 | 0.02 |
| Quintile 2 | 2075 (25.5) | 2595 (26.5) | 0.02 | 27.0 | 27.7 | 0.02 |
| Quintile 3 | 1814 (22.3) | 2117 (21.6) | 0.02 | 21.1 | 20.7 | 0.01 |
| Quintile 4 | 1418 (17.4) | 1665 (17.0) | 0.01 | 17.7 | 16.9 | 0.02 |
| Quintile 5 | 768 (9.4) | 831 (8.5) | 0.03 | 9.1 | 8.7 | 0.01 |
| Unknown | 7 (0.1) | 5 (0.1) | 0.01 | 0.1 | 0.2 | 0.02 |
| Ethnicity, n (%) | ||||||
| White | 7696 (94.6) | 9184 (93.9) | 0.03 | 94.5 | 95.0 | 0.02 |
| Other | 230 (2.8) | 223 (2.3) | 0.03 | 2.6 | 2.5 | 0.01 |
| Unknown | 213 (2.6) | 376 (3.8) | 0.07 | 3.0 | 2.6 | 0.02 |
| Smoking status, n (%) | ||||||
| Current | 1130 (13.9) | 1528 (15.6) | 0.05 | 15.7 | 15.3 | 0.01 |
| Past | 2925 (35.9) | 2540 (26.0) | 0.22 | 4.5 | 4.9 | 0.02 |
| Never | 3974 (48.8) | 5201 (53.2) | 0.09 | 51.5 | 52.7 | 0.02 |
| Unknown | 110 (1.4) | 514 (5.3) | 0.22 | 28.3 | 27.1 | 0.02 |
| Comorbidities, n (%) | ||||||
| Alcohol-related disorders | 682 (8.4) | 480 (4.9) | 0.14 | 5.5 | 4.9 | 0.02 |
| Myocardial infarction | 277 (3.4) | 167 (1.7) | 0.11 | 2.6 | 2.2 | 0.02 |
| Stroke or transient ischemic attack | 503 (6.2) | 286 (2.9) | 0.16 | 4.6 | 4.1 | 0.03 |
| Heart failure | 313 (3.8) | 229 (2.3) | 0.09 | 2.8 | 2.4 | 0.03 |
| Peripheral vascular disease | 231 (2.8) | 160 (1.6) | 0.08 | 2.3 | 2.2 | 0.01 |
| Venous thromboembolism | 839 (10.3) | 457 (4.7) | 0.22 | 7.5 | 7.5 | 0.00 |
| Chronic obstructive pulmonary disease | 493 (6.1) | 310 (3.2) | 0.14 | 4.3 | 3.5 | 0.03 |
| Chronic kidney disease | 1127 (13.8) | 391 (4.0) | 0.35 | 7.0 | 5.8 | 0.04 |
| Other cancers | 905 (11.1) | 660 (6.7) | 0.15 | 8.9 | 8.0 | 0.03 |
| Non–breast cancer surgery | 2096 (25.8) | 2244 (22.9) | 0.07 | 25.3 | 25.5 | 0.01 |
| Anticoagulants, n (%) | ||||||
| Vitamin K antagonists | 561 (6.9) | 186 (1.9) | 0.25 | 4.1 | 4.0 | 0.01 |
| Direct oral anticoagulants | 22 (0.3) | Suppressed† | 0.07 | 0.1 | 0.0 | 0.01 |
| Heparin | 189 (2.3) | 47 (0.5) | 0.16 | 1.0 | 1.0 | 0.00 |
| Antidepressants, n (%) | ||||||
| Selective serotonin reuptake inhibitors | 887 (10.9) | 848 (8.7) | 0.08 | 9.4 | 8.6 | 0.03 |
| Serotonin and noradrenaline reuptake inhibitors | 92 (1.1) | 100 (1.0) | 0.01 | 1.5 | 1.4 | 0.00 |
| Tricyclic antidepressants | 854 (10.5) | 934 (9.5) | 0.03 | 10.7 | 10.4 | 0.01 |
| Other | 131 (1.6) | 98 (1.0) | 0.05 | 1.0 | 0.8 | 0.01 |
| Antidiabetic drugs, n (%) | ||||||
| Metformin | 509 (6.3) | 340 (3.5) | 0.13 | 4.6 | 4.1 | 0.02 |
| Sulfonylureas | 280 (3.4) | 227 (2.3) | 0.07 | 2.9 | 2.8 | 0.01 |
| Thiazolidinediones | 68 (0.8) | 48 (0.5) | 0.04 | 0.9 | 1.0 | 0.00 |
| Incretin-based drugs | 51 (0.6) | 13 (0.1) | 0.08 | 0.2 | 0.2 | 0.01 |
| Insulin | 175 (2.2) | 96 (1.0) | 0.09 | 1.6 | 1.5 | 0.01 |
| Other | 7 (0.1) | 7 (0.1) | 0.01 | 0.1 | 0.0 | 0.01 |
| Antihypertensive drugs, n (%) | ||||||
| Diuretics | 2578 (31.7) | 2547 (26.0) | 0.12 | 29.5 | 28.9 | 0.01 |
| β-Blockers | 1663 (20.4) | 1618 (16.5) | 0.10 | 18.6 | 19.1 | 0.01 |
| Calcium channel blockers | 1756 (21.6) | 1350 (13.8) | 0.20 | 16.6 | 16.0 | 0.02 |
| Angiotensin-converting enzyme inhibitors | 1704 (20.9) | 1268 (13.0) | 0.21 | 15.4 | 14.6 | 0.02 |
| Angiotensin II receptor blockers | 891 (10.9) | 577 (5.9) | 0.18 | 7.7 | 7.3 | 0.01 |
| Other | 532 (6.5) | 396 (4.0) | 0.11 | 5.5 | 5.1 | 0.02 |
| Other drugs, n (%) | ||||||
| Bisphosphonates | 524 (6.4) | 406 (4.2) | 0.10 | 5.1 | 4.3 | 0.04 |
| Nonsteroidal anti-inflammatory drugs | 1117 (13.7) | 1675 (17.1) | 0.09 | 18.3 | 19.0 | 0.02 |
| Opioids | 2680 (32.9) | 2555 (26.1) | 0.15 | 30.0 | 28.5 | 0.03 |
| Acetylsalicylic acid | 1584 (19.5) | 1276 (13.0) | 0.17 | 17.5 | 16.6 | 0.03 |
| Non–acetylsalicylic acid antiplatelets | 287 (3.5) | 121 (1.2) | 0.15 | 2.3 | 2.1 | 0.02 |
| Statins | 2361 (29.0) | 1370 (14.0) | 0.37 | 19.9 | 18.7 | 0.03 |
| Hormone replacement therapy | 548 (6.7) | 1605 (16.4) | 0.31 | 17.1 | 19.7 | 0.08 |
| Breast cancer–related variables, n (%) | ||||||
| Chemotherapy | 1424 (17.5) | 1060 (10.8) | 0.19 | 12.4 | 12.4 | 0.00 |
| Radiation therapy | 391 (4.8) | 433 (4.4) | 0.02 | 4.5 | 4.5 | 0.01 |
| Breast cancer surgery | 5702 (70.1) | 7959 (81.4) | 0.27 | 74.4 | 76.5 | 0.05 |
| Time since diagnosis, mean (SD), mo | 4.1 (9.3) | 3.0 (4.8) | 0.15 | 3.3 (6.9) | 3.3 (6.9) | 0.00 |
*
Baseline characteristics are displayed in the study population weighted for inverse probability of treatment and censoring weights with myocardial infarction as the outcome. Similar characteristics were observed with ischemic stroke, heart failure, and cardiovascular mortality as the outcome. Numbers correspond to percentage of patients.
†
Cells with <5 observations are not displayed per the confidentiality policies of the Clinical Practice Research Datalink.
Table 2 presents the results of the primary analyses for each of the study outcomes. Overall, users of AI and tamoxifen generated 15 425 to 15 486 and 18 590 to 18 618 person-years of follow-up, respectively. The median durations of follow-up for AI and tamoxifen users were 1.3 and 1.4 years, respectively.
| Outcome | Tamoxifen* | Aromatase Inhibitors* | ||||||
|---|---|---|---|---|---|---|---|---|
| No. of Events | Person-Years | Incidence Rate† (95% CI) | Weighted Hazard Ratio (95% CI) | No. of Events | Person-Years | Incidence Rate† (95% CI) | Weighted Hazard Ratio (95% CI) | |
| Myocardial infarction | 34 | 18 590 | 1.8 (1.3–2.6) | 1.00 (Reference) | 61 | 15 449 | 3.9 (3.0–5.1) | 1.37 (0.88–2.13) |
| Ischemic stroke | 59 | 18 594 | 3.2 (2.4–4.1) | 1.00 (Reference) | 86 | 15 440 | 5.6 (4.5–6.9) | 1.19 (0.82–1.72) |
| Heart failure | 33 | 18 603 | 1.8 (1.2–2.5) | 1.00 (Reference) | 83 | 15 425 | 5.4 (4.3–6.7) | 1.86 (1.14–3.03) |
| Cardiovascular mortality | 87 | 18 618 | 4.7 (3.7–5.8) | 1.00 (Reference) | 147 | 15 486 | 9.5 (8.0–11.2) | 1.50 (1.11–2.04) |
*
The aromatase inhibitor (n=8139) and tamoxifen (n=9783) exposure groups were weighted by inverse probability of treatment and censoring weights.
†
Per 1000 person-years.
Myocardial Infarction
During the follow-up period, there were 61 myocardial infarction events among AI users compared with 34 events among tamoxifen users, generating incidence rates of 3.9 (95% CI, 3.0–5.1) versus 1.8 (95% CI, 1.3–2.6) per 1000 person-years, respectively. This generated an elevated HR with a CI that included the null value (HR, 1.37 [95% CI, 0.88–2.13; Table 2). In secondary analyses, the cumulative incidence curves appeared to diverge after 2 years of use (Figure 2).
Ischemic Stroke
Overall, there were 86 ischemic stroke events among AI users compared with 59 cases among tamoxifen users. This yielded incidence rates of 5.6 (95% CI, 4.5–6.9) per 1000 person-years for AI users versus 3.2 (95% CI, 2.4–4.1) per 1000 person-years for tamoxifen users. This generated a slightly elevated HR with a CI that included the null value (HR, 1.19 [95% CI, 0.82–1.72]). The cumulative incidence curves appeared to diverge after 2 years of use (Figure 2).
Heart Failure
There were 83 cases of heart failure among AI users compared with 33 cases among tamoxifen users, generating incidence rates of 5.4 (95% CI, 4.3–6.7) versus 1.8 (95% CI, 1.2–2.5) per 1000 person-years. The use of AIs was associated with an 86% increased risk of heart failure compared with the use of tamoxifen (HR, 1.86 [95% CI, 1.14–3.03]). The cumulative incidence curves diverged 3 months after treatment initiation (Figure 2).
Cardiovascular Mortality
There were 147 cardiovascular deaths among AI users compared with 87 events among tamoxifen users, generating incidence rates of 9.5 (95% CI, 8.0–11.2) versus 4.7 (95% CI, 3.7–5.8) per 1000 person-years. The use of AIs was associated with a 50% increased risk of cardiovascular mortality compared with the use of tamoxifen (HR, 1.50 [95% CI, 1.11–2.04]). The cumulative incidence curves diverged after 2 years of use (Figure 2).
Secondary Analyses
Overall, there were no significant differences between anastrozole and letrozole and risk of cardiovascular outcomes, although the number of events was low for these stratified analyses (Figure 3 and Table V in the online-only Data Supplement). Stratification by history of cardiovascular disease led to overlapping HRs that included the null, with exception of heart failure, for which the use of AIs was associated with a significantly increased risk among patients without a history of cardiovascular disease (HR, 2.80 [95% CI, 1.29–6.08]; Figure 3 and Table VI in the online-only Data Supplement).
Sensitivity Analyses
The results of sensitivity analyses are summarized in Tables VII through XIII in the online-only Data Supplement. Lengthening the grace period and changing the outcome definition to include hospitalized events recorded in both primary or secondary positions along with deaths recorded in ONS led to point estimates that were consistent with those observed in the primary analyses (Tables VII and VIII in the online-only Data Supplement, respectively). Similarly, restricting the patient population to those at least 55 years of age yielded point estimates that were consistent with those of the primary analyses (Table IX in the online-only Data Supplement). Likewise, generating treatment and censoring weights using high-dimensional propensity scores (investigator-selected covariates and 200 additional covariates) led to similar findings (Table X in the online-only Data Supplement), as did the marginal structural models assessing the potential impact of time-varying confounding, albeit with wider CIs (Table XI in the online-only Data Supplement). Last, both multiple imputation and complete case analyses for variables with missing information led to results that were concordant with those of the primary analyses (Tables XII and XIII in the online-only Data Supplement).
Discussion
In this population-based study of women with breast cancer, initiation of an endocrine treatment with an AI was associated with an 86% increased risk of heart failure and a 50% increased risk of cardiovascular mortality. There was also a trend toward an increased risk of myocardial infarction and ischemic stroke. These findings remained consistent across several sensitivity analyses.
Overall, our results are consistent with those of 3 meta-analyses of RCTs that demonstrated that AIs are associated with an increased the risk of ischemic events (such as myocardial infarction) compared with tamoxifen.3–5 Furthermore, our heart failure finding corroborates the signal observed in the BIG 1-98 trial (Breast International Group) of letrozole, in which a significantly increased risk of severe heart failure was reported (letrozole, 26 of 3975 versus tamoxifen, 13 of 3988).8 To date, the 4 observational studies that examined the association between AIs and different cardiovascular outcomes have reported inconsistent findings.17–20 In a study conducted using the Ontario health insurance databases, AIs were associated with doubling of the risk of myocardial infarction (HR, 2.02 [95% CI, 1.16–3.53]) compared with tamoxifen among women at least 65 years of age.17 In contrast, a study using the Kaiser Permanente health insurance database did not find an increased risk of cardiac ischemia (HR, 0.97 [95% CI, 0.78–1.22]), stroke (HR, 0.97 [95% CI, 0.70–1.33]), or a combined end point of heart failure and cardiomyopathy (HR, 1.10 [95% CI, 0.86–1.40]) among women without a history of cardiovascular disease.20 However, this study did find an association between AIs and other cardiovascular events defined as a composite end point of dysrhythmia, valvular dysfunction, and pericarditis (HR, 1.29 [95% CI, 1.11–1.50]).20 Similarly, a recent study using the Surveillance, Epidemiology, and End Results–Medicare database among women at least 67 years of age did not find an association between use of AIs and myocardial infarction compared with tamoxifen (HR, 1.01 [95% CI, 0.72–1.42]).18 One study using HealthCore Integrated Research Databases found that among women at least 50 years of age, AIs were not associated with increased risks of myocardial infarction (HR, 0.90 [95% CI, 0.65–1.25]) or ischemic stroke (HR, 0.71 [95% CI, 0.49–1.03]) compared with women without breast cancer.19
Overall, the inconsistent findings across these studies may be the result of heterogeneity in the study populations. This includes the inconsistent inclusion of patients with or without a history of cardiovascular disease and the use of individual versus composite outcome definitions. In contrast, our study included patients with and without a history of cardiovascular disease and captured younger postmenopausal women diagnosed with breast cancer. Some of these previous studies had other limitations, including the use of an intention-to-treat exposure definition, which may lead to nondifferential exposure misclassification and a dilution of the effect estimate,17,20 informative censoring resulting from discontinuation and switching between treatments,18 and potential confounding by indication.19
Two hypothesized mechanisms can explain an association between AIs and cardiovascular ischemic events. The first hypothesis involves a mechanism by which AIs increase the risk of cardiovascular events by increasing low-density lipoprotein cholesterol levels.3 In the ATAC trial (Anastrozole Tamoxifen Alone or in Combination), the use of anastrozole was associated with increased low-density lipoprotein cholesterol levels compared with tamoxifen.6,7 However, other RCTs have not observed important changes in cholesterol levels with anastrozole, letrozole, or exemestane.8–10 Similarly, in extended adjuvant trials, there were no changes in low-density lipoprotein cholesterol or triglyceride levels when AIs were compared with placebo or no treatment.9,11,12 There was also no increased risk of ischemic events.5,40,41
The second hypothesis involves a possible cardioprotective effect of tamoxifen. Indeed, tamoxifen has been shown to have favorable effects on serum lipid levels, with decreases of up to 39 mg/dL for total cholesterol and 31 mg/dL for low-density lipoprotein cholesterol from baseline to 3 months of follow-up; this effect was shown to persist up to 1 year after treatment initiation.10,13,16,42 Another study reported that a reduction in total cholesterol occurred only during the treatment period, not after treatment discontinuation.13 Thus, the increased risk of cardiovascular mortality observed with AIs in our study may be a result, at least in part, of the cardioprotective effects of tamoxifen.5,43 This hypothesis is supported by meta-analyses of RCTs that showed that compared with placebo or no treatment, tamoxifen is associated with a 34% decreased risk of ischemic events, 26% decreased risk of myocardial infarction, and a 45% decreased risk of fatal myocardial infarction.5,44 With respect to the increased risk of heart failure observed with AIs, it is possible that this results from the anti-inflammatory and antioxidant properties of tamoxifen.13–16 In addition, some studies suggest that tamoxifen may improve endothelial function by increasing flow-mediated dilation and decreasing carotid intima-media thickness.45 However, a more recent study suggests that AIs may be associated with vascular injury and attenuated peripheral endothelial function.46
Our study has several strengths. To the best of our knowledge, this is the largest observational study to have directly compared the risk of cardiovascular outcomes between AIs and tamoxifen among women with breast cancer. In addition, this study comprehensively examined the association between AIs and clinically relevant end points, including myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality. Second, linkage to the HES and ONS databases likely minimized outcome misclassification.33,34 Third, the new-user, active-comparator design likely reduced confounding at the design stage while eliminating prevalent-user bias.47 Fourth, our results remained consistent across sensitivity analyses meant to address different sources of bias. Last, given the population-based nature of our study, our study population is likely to represent patients treated in the real-world setting.
Our study has some limitations. First, prescriptions in the CPRD represent those issued by general practitioners; thus, misclassification of exposure is possible if patients did fully adhere with the treatment regimen or if they were treated by specialists. However, in our study, ≈76% of the cohort initiated treatment with either an AI or tamoxifen, a finding that is consistent with the prevalence of hormone receptor–positive breast cancer reported in other studies.48 In addition, general practitioners in the United Kingdom are extensively involved in the management and treatment of patients with breast cancer, which includes the administration of endocrine therapy to postmenopausal women with hormone receptor–positive breast cancer.49,50 Second, residual confounding is possible given the observational nature of this study. However, the models considered a wide range of potential confounders, ranging from demographic, lifestyle (eg, smoking), anthropometric (eg, body mass index), comorbidities, cardiovascular history, prescription drug, and breast cancer–related variables (including previous breast surgery, chemotherapy, and radiation therapy as proxies for breast cancer severity). Furthermore, the decision to initiate treatment with either an AI versus tamoxifen is typically influenced by hormone receptor status, not cardiovascular risk profile.49,50 Third, the results for myocardial infarction and ischemic stroke generated wider CIs that included the null value, which may have resulted from the lower number of exposed events. Similarly, some of our secondary analyses such as those assessing the association with specific AIs and stratification by history of cardiovascular disease had limited statistical power. Thus, further large studies are required to corroborate our findings and to investigate the risk of cardiovascular outcomes by AI type and history of cardiovascular disease.
Conclusions
In this population-based study, the use of AIs was associated with an 86% increased risk of heart failure and a 50% increased risk of cardiovascular mortality compared with the use of tamoxifen. There was also a trend toward an increased risk of myocardial infarction and ischemic stroke. The increased risk of cardiovascular events associated with AIs should be balanced with their favorable clinical benefits compared with tamoxifen.
Acknowledgments
F. Khosrow-Khavar is the recipient of a doctoral award from the Fonds de recherche du Québec–Santé (FRQS). Dr Filion holds a Chercheur-Boursier Junior 2 award from the FRQS and is the recipient of a William Dawson Scholar award from McGill University. Dr Suissa is the recipient of a James McGill award from McGill University. Dr Azoulay holds a Senior Chercheur-Boursier career award from the FRQS and is the recipient of a William Dawson Scholar award from McGill University. The authors acknowledge Hui Yin for her assistance in conducting sensitivity analyses for this study.
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References
1.
Kelly E, Lu CY, Albertini S, Vitry A. Longitudinal trends in utilization of endocrine therapies for breast cancer: an international comparison. J Clin Pharm Ther. 2015;40:76–82. doi: 10.1111/jcpt.12227
2.
Early Breast Cancer Trialists’ Collaborative Group, Dowsett M, Forbes JF, Bradley R, Ingle J, Aihara T, Bliss J, Boccardo F, Coates A, Coombes RC, Cuzick J, et al. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386:1341–1352.
3.
Amir E, Seruga B, Niraula S, Carlsson L, Ocaña A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst. 2011;103:1299–1309. doi: 10.1093/jnci/djr242
4.
Cuppone F, Bria E, Verma S, Pritchard KI, Gandhi S, Carlini P, Milella M, Nisticò C, Terzoli E, Cognetti F, et al. Do adjuvant aromatase inhibitors increase the cardiovascular risk in postmenopausal women with early breast cancer? Meta-analysis of randomized trials. Cancer. 2008;112:260–267. doi: 10.1002/cncr.23171
5.
Khosrow-Khavar F, Filion KB, Al-Qurashi S, Torabi N, Bouganim N, Suissa S, Azoulay L. Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal women with breast cancer: a systematic review and meta-analysis of randomized controlled trials. Ann Oncol. 2017;28:487–496. doi: 10.1093/annonc/mdw673
6.
Bundred NJ. The effects of aromatase inhibitors on lipids and thrombosis. Br J Cancer. 2005;93(suppl 1):S23–S27. doi: 10.1038/sj.bjc.6602692
7.
Buzdar A, Howell A, Cuzick J, Wale C, Distler W, Hoctin-Boes G, Houghton J, Locker GY, Nabholtz JM. Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncol. 2006;7:633–643.
8.
Mouridsen H, Keshaviah A, Coates AS, Rabaglio M, Castiglione-Gertsch M, Sun Z, Thürlimann B, Mauriac L, Forbes JF, Paridaens R, et al. Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: safety analysis of BIG 1-98 trial. J Clin Oncol. 2007;25:5715–5722. doi: 10.1200/JCO.2007.12.1665
9.
Markopoulos C, Chrissochou M, Michailidou A, Tzoracoleftherakis E, Xepapadakis G, Papadiamantis J, Misitzis J, Zobolas V, Bafaloukos D, Gogas H. Effect of exemestane on the lipidemic profile of post-menopausal operable breast cancer patients following 5–7 years of adjuvant tamoxifen: preliminary results of the ATENA substudy. Anticancer Drugs. 2005;16:879–883. doi: 10.1097/01.cad.0000173478.12981.e1
10.
Hozumi Y, Suemasu K, Takei H, Aihara T, Takehara M, Saito T, Ohsumi S, Masuda N, Ohashi Y. The effect of exemestane, anastrozole, and tamoxifen on lipid profiles in Japanese postmenopausal early breast cancer patients: final results of National Surgical Adjuvant Study BC 04, the TEAM Japan sub-study. Ann Oncol. 2011;22:1777–1782. doi: 10.1093/annonc/mdq707
11.
Wasan KM, Goss PE, Pritchard PH, Shepherd L, Palmer MJ, Liu S, Tu D, Ingle JN, Heath M, Deangelis D, et al. The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Ann Oncol. 2005;16:707–715. doi: 10.1093/annonc/mdi158
12.
Younus M, Kissner M, Reich L, Wallis N. Putting the cardiovascular safety of aromatase inhibitors in patients with early breast cancer into perspective: a systematic review of the literature. Drug Saf. 2011;34:1125–1149. doi: 10.2165/11594170-000000000-00000
13.
Dewar JA, Horobin JM, Preece PE, Tavendale R, Tunstall-Pedoe H, Wood RA. Long term effects of tamoxifen on blood lipid values in breast cancer. BMJ. 1992;305:225–226. doi: 10.1136/bmj.305.6847.225
14.
Grainger DJ, Schofield PM. Tamoxifen for the prevention of myocardial infarction in humans: preclinical and early clinical evidence. Circulation. 2005;112:3018–3024. doi: 10.1161/CIRCULATIONAHA.104.531178
15.
Guetta V, Lush RM, Figg WD, Waclawiw MA, Cannon RO Effects of the antiestrogen tamoxifen on low-density lipoprotein concentrations and oxidation in postmenopausal women. Am J Cardiol. 1995;76:1072–1073. doi: 10.1016/s0002-9149(99)80302-6
16.
Love RR, Wiebe DA, Feyzi JM, Newcomb PA, Chappell RJ. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women after 5 years of treatment. J Natl Cancer Inst. 1994;86:1534–1539. doi: 10.1093/jnci/86.20.1534
17.
Abdel-Qadir H, Amir E, Fischer HD, Fu L, Austin PC, Harvey PJ, Rochon PA, Lee DS, Anderson GM. The risk of myocardial infarction with aromatase inhibitors relative to tamoxifen in post-menopausal women with early stage breast cancer. Eur J Cancer. 2016;68:11–21. doi: 10.1016/j.ejca.2016.08.022
18.
Kamaraju S, Shi Y, Smith E, Nattinger AB, Laud P, Neuner J. Are aromatase inhibitors associated with higher myocardial infarction risk in breast cancer patients? A Medicare population-based study. Clin Cardiol. 2019;42:93–100. doi: 10.1002/clc.23114
19.
Ligibel JA, James O’Malley A, Fisher M, Daniel GW, Winer EP, Keating NL. Risk of myocardial infarction, stroke, and fracture in a cohort of community-based breast cancer patients. Breast Cancer Res Treat. 2012;131:589–597. doi: 10.1007/s10549-011-1754-1
20.
Haque R, Shi J, Schottinger JE, Chung J, Avila C, Amundsen B, Xu X, Barac A, Chlebowski RT. Cardiovascular disease after aromatase inhibitor use. JAMA Oncol. 2016;2:1590–1597. doi: 10.1001/jamaoncol.2016.0429
21.
US Food and Drug Administration. Arimidex (anastrozole) tablet label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020541s026lbl.pdf. Accessed May 15, 2019.
22.
European Medicines Agency. Arimidex–article 30 referral–annex III. https://www.ema.europa.eu/en/medicines/human/referrals/arimidex. Accessed May 15, 2019.
23.
European Medicines Agency. Femara–article 30 referral–assessment report.ttps://www.ema.europa.eu/en/documents/referral/femara-article-30-referral-assessment-report_en.pdf. Accessed May 15, 2019.
24.
Foglietta J, Inno A, de Iuliis F, Sini V, Duranti S, Turazza M, Tarantini L, Gori S. Cardiotoxicity of aromatase inhibitors in breast cancer patients. Clin Breast Cancer. 2017;17:11–17. doi: 10.1016/j.clbc.2016.07.003
25.
Herrett E, Gallagher AM, Bhaskaran K, Forbes H, Mathur R, van Staa T, Smeeth L. Data resource profile: Clinical Practice Research Datalink (CPRD). Int J Epidemiol. 2015;44:827–836. doi: 10.1093/ije/dyv098
26.
Herrett E, Thomas SL, Schoonen WM, Smeeth L, Hall AJ. Validation and validity of diagnoses in the General Practice Research Database: a systematic review. Br J Clin Pharmacol. 2010;69:4–14. doi: 10.1111/j.1365-2125.2009.03537.x
27.
Herrett EL, Thomas SL, Smeeth L. Validity of diagnoses in the general practice research database. Br J Gen Pract. 2011;61:438–439. doi: 10.3399/bjgp11X583092
28.
Arhi CS, Bottle A, Burns EM, Clarke JM, Aylin P, Ziprin P, Darzi A. Comparison of cancer diagnosis recording between the Clinical Practice Research Datalink, Cancer Registry and Hospital Episodes Statistics. Cancer Epidemiol. 2018;57:148–157. doi: 10.1016/j.canep.2018.08.009
29.
Boggon R, van Staa TP, Chapman M, Gallagher AM, Hammad TA, Richards MA. Cancer recording and mortality in the General Practice Research Database and linked cancer registries. Pharmacoepidemiol Drug Saf. 2013;22:168–175. doi: 10.1002/pds.3374
30.
Margulis AV, Fortuny J, Kaye JA, Calingaert B, Reynolds M, Plana E, McQuay LJ, Atsma WJ, Franks B, de Vogel S, et al. Validation of cancer cases using primary care, cancer registry, and hospitalization data in the United Kingdom. Epidemiology. 2018;29:308–313. doi: 10.1097/EDE.0000000000000786
31.
NHS Digital. Hospital Episode Statistics (HES). https://digital.nhs.uk/data-and-information/data-tools-and-services/data-services/hospital-episode-statistics Accessed June 1, 2019.
32.
Office for National Statistics website. https://www.ons.gov.uk/ Accessed June 1, 2019.
33.
Herrett E, Shah AD, Boggon R, Denaxas S, Smeeth L, van Staa T, Timmis A, Hemingway H. Completeness and diagnostic validity of recording acute myocardial infarction events in primary care, hospital care, disease registry, and national mortality records: cohort study. BMJ. 2013;346:f2350. doi: 10.1136/bmj.f2350
34.
Kivimäki M, Batty GD, Singh-Manoux A, Britton A, Brunner EJ, Shipley MJ. Validity of cardiovascular disease event ascertainment using linkage to UK hospital records. Epidemiology. 2017;28:735–739. doi: 10.1097/EDE.0000000000000688
35.
Durrleman S, Simon R. Flexible regression models with cubic splines. Stat Med. 1989;8:551–561. doi: 10.1002/sim.4780080504
36.
Wyss R, Girman CJ, LoCasale RJ, Brookhart AM, Stürmer T. Variable selection for propensity score models when estimating treatment effects on multiple outcomes: a simulation study. Pharmacoepidemiol Drug Saf. 2013;22:77–85. doi: 10.1002/pds.3356
37.
Hernán MA, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiology. 2000;11:561–570. doi: 10.1097/00001648-200009000-00012
38.
Schneeweiss S, Rassen JA, Glynn RJ, Avorn J, Mogun H, Brookhart MA. High-dimensional propensity score adjustment in studies of treatment effects using health care claims data. Epidemiology. 2009;20:512–522. doi: 10.1097/EDE.0b013e3181a663cc
39.
Rubin, D. Multiple Imputation for Nonresponse in Surveys. New York, NY: John Wiley & Sons; 1987.
40.
Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005;97:1262–1271. doi: 10.1093/jnci/dji250
41.
Goss PE, Ingle JN, Pritchard KI, Robert NJ, Muss H, Gralow J, Gelmon K, Whelan T, Strasser-Weippl K, Rubin S, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med. 2016;375:209–219. doi: 10.1056/NEJMoa1604700
42.
Sahebkar A, Serban MC, Penson P, Gurban C, Ursoniu S, Toth PP, Jones SR, Lippi G, Kotani K, Kostner K, et al; Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. The effects of tamoxifen on plasma lipoprotein(a) concentrations: systematic review and meta-analysis. Drugs. 2017;77:1187–1197. doi: 10.1007/s40265-017-0767-4
43.
Matthews A, Stanway S, Farmer RE, Strongman H, Thomas S, Lyon AR, Smeeth L, Bhaskaran K. Long term adjuvant endocrine therapy and risk of cardiovascular disease in female breast cancer survivors: systematic review. BMJ. 2018;363:k3845. doi: 10.1136/bmj.k3845
44.
Braithwaite RS, Chlebowski RT, Lau J, George S, Hess R, Col NF. Meta-analysis of vascular and neoplastic events associated with tamoxifen. J Gen Intern Med. 2003;18:937–947. doi: 10.1046/j.1525-1497.2003.20724.x
45.
Stamatelopoulos KS, Lekakis JP, Poulakaki NA, Papamichael CM, Venetsanou K, Aznaouridis K, Protogerou AD, Papaioannou TG, Kumar S, Stamatelopoulos SF. Tamoxifen improves endothelial function and reduces carotid intima-media thickness in postmenopausal women. Am Heart J. 2004;147:1093–1099. doi: 10.1016/j.ahj.2003.12.029
46.
Maor R, Sara JDS, Wanous AA, Maor E, Pruthi S, Lerman A, Sandhu NP. Attenuated peripheral endothelial function among women treated with aromatase inhibitors for breast cancer. Coron Artery Dis. 2018;29:687–693. doi: 10.1097/MCA.0000000000000666
47.
Lund JL, Richardson DB, Stürmer T. The active comparator, new user study design in pharmacoepidemiology: historical foundations and contemporary application. Curr Epidemiol Rep. 2015;2:221–228. doi: 10.1007/s40471-015-0053-5
48.
Kohler BA, Sherman RL, Howlader N, Jemal A, Ryerson AB, Henry KA, Boscoe FP, Cronin KA, Lake A, Noone AM, et al. Annual report to the nation on the status of cancer, 1975-2011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state. J Natl Cancer Inst. 2015;107:djv048. doi: 10.1093/jnci/djv048
49.
National Institute for Clinical Excellence. Improving outcomes in breast cancer. www.nice.org.uk/guidance/csg1/resources/improving-outcomes-in-breast-cancer-update-pdf-773371117 Accessed June 15, 2019.
50.
National Institute for Health and Care Excellence. Early and locally advanced breast cancer: diagnosis and management. https://www.nice.org.uk/guidance/ng101/chapter/Recommendations#endocrine-therapy Accessed June 15, 2019.
Information & Authors
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© 2020 American Heart Association, Inc.
History
Received: 29 August 2019
Accepted: 20 November 2019
Published online: 17 February 2020
Published in print: 18 February 2020
Keywords
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Authors
Disclosures
Dr Bouganim served as a consultant from Amgen, Novartis, and Roche. Dr Suissa has received research funding from and participated in advisory board meetings or as a speaker for AstraZeneca, Boehringer-Ingelheim, Novartis, Pfizer, and Merck. Dr Azoulay has received consulting fees from Janssen and Pfizer. The other authors report no conflicts.
Sources of Funding
This study was funded by a Foundation Scheme Grant from the Canadian Institutes of Health Research (FDN-14328). The funding source had no influence on the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; and decision to submit the article for publication.
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