Background
Breast cancer is the most common cancer in women and surgery is the primary treatment [
1]. Bleeding after primary breast cancer surgery is rare, and occurs in 2% to 4% of patients [
2,
3]. However, prescription medicines that affect platelet function may increase the risk of postsurgical bleeding, necessitating transfusion. Nonaspirin nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are frequently prescribed drugs that inhibit cyclooxygenase-1 (Cox-1), thereby preventing platelet aggregation. NSAIDs inhibit coagulation on a short-term basis, while aspirin inhibits clotting for up to 7 days after administration [
4,
5]. Use of NSAIDs is a well-established risk factor for gastrointestinal bleeding and also may have an impact on postsurgical bleeding [
6‐
8]. Selective serotonin reuptake inhibitors (SSRIs) decrease platelet serotonin storage and platelet function and are correlated with increased risk of both gastrointestinal and postsurgical bleeding [
9‐
12]. Other frequently used drugs, such as statins, may increase the risk of bleeding through a potential direct antiplatelet effect and an antithrombotic effect unrelated to cholesterol-lowering activity [
13,
14].
We have previously studied the association of prescriptions for SSRIs and glucocorticoids and the risk of re-operation due to postsurgical bleeding after breast cancer primary surgery [
11,
15]. Previous research has investigated predictors of red blood cell (RBC) transfusion in cardiac and hip fracture surgery patients [
16,
17]. However, no previous studies have examined the association of these drugs with the risk of RBC transfusion after breast cancer surgery. Prescription medications represent potentially modifiable risk factors that could be intervened upon to reduce the risk of RBC transfusion. Therefore, in a population-based cohort of Danish breast cancer patients, we investigated the association of prescription use of aspirin, NSAIDs, SSRIs, and statins with the risk of RBC transfusion. Here, we investigated the association of the most frequently used prescription drugs – aspirin, NSAIDs, statins, and SSRIs – with the risk of RBC transfusion as a proxy for postoperative bleeding in a population-based cohort of Danish breast cancer patients.
Results
Our study included 22,238 women aged ≥ 35 years with incident breast cancer who underwent surgery for their cancer between 2005 and 2012. Table
1 shows baseline characteristics of the cohort according to aspirin, NSAID, SSRI, and statin use. Overall, 45% were aged below 60 years at diagnosis, 85% had a CCI score of 0, and about 70% underwent BCS as primary breast cancer surgery. Over 40% had no preoperative measurement of hemoglobin concentration. There was no notable difference in the characteristics of patients with and without information on preoperative hemoglobin levels. Among women with information available on their preoperative hemoglobin level, about 5% had anemia [< 12 g/dL (7.4 mmol/L)]. Overall 1336 (6.0%) patients used aspirin, 1774 (8.0%) used NSAIDs, 1080 (4.9%) used SSRIs, and 2029 (9.1%) used statins. Compared with nonusers, users of these drugs were older, were more likely to have anemia, and had higher CCI scores. More users of aspirin, NSAIDs, SSRIs, and statins underwent mastectomy compared with nonusers of each drug type (Table
1). The most frequent comorbidities among users and nonusers of the four drugs were chronic pulmonary disease, diabetes, and cerebrovascular disease (see Additional file
2: Table S2).
Table 1
Baseline characteristics of 22,238 breast cancer surgery patients according to use of selected prescription drugs, Denmark, 2005–2012
Total | 22,238 | 100.0 | 20,902 | 100.0 | 1336 | 100.0 | 20,464 | 100.0 | 1774 | 100.0 | 21,158 | 100.0 | 1080 | 100.0 | 20,209 | 100.0 | 2029 | 100.0 |
Age at diagnosis (years) |
35–49 | 3794 | 17.1 | 3778 | 18.1 | 16 | 1.2 | 3606 | 17.6 | 188 | 10.6 | 3648 | 17.2 | 146 | 13.5 | 3743 | 18.5 | 51 | 2.5 |
50–59 | 6102 | 27.4 | 5958 | 28.5 | 144 | 10.8 | 5661 | 27.7 | 441 | 24.9 | 5806 | 27.4 | 296 | 27.4 | 5734 | 28.4 | 368 | 18.1 |
60–69 | 7831 | 35.2 | 7335 | 35.1 | 496 | 37.1 | 7209 | 35.2 | 622 | 35.1 | 7467 | 35.3 | 364 | 33.7 | 6843 | 33.9 | 988 | 48.7 |
70–79 | 3233 | 14.5 | 2808 | 13.4 | 425 | 31.8 | 2844 | 13.9 | 389 | 21.9 | 3051 | 14.4 | 182 | 16.9 | 2748 | 13.6 | 485 | 23.9 |
> =80 | 1278 | 5.7 | 1023 | 4.9 | 255 | 19.1 | 1144 | 5.6 | 134 | 7.6 | 1186 | 5.6 | 92 | 8.5 | 1141 | 5.6 | 137 | 6.8 |
Stage |
I | 10,161 | 45.7 | 9580 | 45.8 | 581 | 43.5 | 9347 | 45.7 | 814 | 45.9 | 9689 | 45.8 | 472 | 43.7 | 9192 | 45.5 | 969 | 47.8 |
II | 9587 | 43.1 | 8992 | 43.0 | 595 | 44.5 | 8842 | 43.2 | 745 | 42.0 | 9118 | 43.1 | 469 | 43.4 | 8739 | 43.2 | 848 | 41.8 |
III | 2490 | 11.2 | 2330 | 11.1 | 160 | 12.0 | 2275 | 11.1 | 215 | 12.1 | 2351 | 11.1 | 139 | 12.9 | 2278 | 11.3 | 212 | 10.4 |
Charlson comorbidity score |
0 | 18,863 | 84.8 | 18,131 | 86.7 | 732 | 54.8 | 17,405 | 85.1 | 1458 | 82.2 | 18,064 | 85.4 | 799 | 74.0 | 17,500 | 86.6 | 1363 | 67.2 |
1–2 | 3074 | 13.8 | 2560 | 12.2 | 514 | 38.5 | 2782 | 13.6 | 292 | 16.5 | 2829 | 13.4 | 245 | 22.7 | 2498 | 12.4 | 576 | 28.4 |
> =3 | 301 | 1.4 | 211 | 1.0 | 90 | 6.7 | 277 | 1.4 | 24 | 1.4 | 265 | 1.3 | 36 | 3.3 | 211 | 1.0 | 90 | 4.4 |
Specific comobidities of interest |
Myocardial infarction | 197 | 0.9 | 96 | 0.5 | 101 | 7.6 | 185 | 0.9 | 12 | 0.7 | 178 | 0.8 | 19 | 1.8 | 116 | 0.6 | 81 | 4.0 |
Congestive heart failure | 211 | 0.9 | 146 | 0.7 | 65 | 4.9 | 189 | 0.9 | 22 | 1.2 | 194 | 0.9 | 17 | 1.6 | 164 | 0.8 | 47 | 2.3 |
Diabetes I and II | 652 | 2.9 | 484 | 2.3 | 168 | 12.6 | 589 | 2.9 | 63 | 3.6 | 595 | 2.8 | 57 | 5.3 | 392 | 1.9 | 260 | 12.8 |
Diabetes with end organ damage | 239 | 1.1 | 159 | 0.8 | 80 | 6.0 | 214 | 1.0 | 25 | 1.4 | 212 | 1.0 | 27 | 2.5 | 142 | 0.7 | 97 | 4.8 |
Pre-operative hemoglobin concentration |
No data | 9137 | 41.1 | 8603 | 41.2 | 534 | 40.0 | 8401 | 41.1 | 736 | 41.5 | 8672 | 41.0 | 465 | 43.1 | 8308 | 41.1 | 829 | 40.9 |
< 7.4 mmol/L | 660 | 3.0 | 578 | 2.8 | 82 | 6.1 | 577 | 2.8 | 83 | 4.7 | 602 | 2.8 | 58 | 5.4 | 578 | 2.9 | 82 | 4.0 |
> =7.4 mmol/L | 12,441 | 55.9 | 11,721 | 56.1 | 720 | 53.9 | 11,486 | 56.1 | 955 | 53.8 | 11,884 | 56.2 | 557 | 51.6 | 11,323 | 56.0 | 1118 | 55.1 |
Type of primary surgery |
Mastectomy | 6935 | 31.2 | 6406 | 30.6 | 529 | 39.6 | 6324 | 30.9 | 611 | 34.4 | 6551 | 31.0 | 384 | 35.6 | 6300 | 31.2 | 635 | 31.3 |
Breast-conserving surgery | 15,303 | 68.8 | 14,496 | 69.4 | 807 | 60.4 | 14,140 | 69.1 | 1163 | 65.6 | 14,607 | 69.0 | 696 | 64.4 | 13,909 | 68.8 | 1394 | 68.7 |
Overall, 279 (1.3%) women received at least one RBC transfusion within 14 days of surgery. Risk of receiving a RBC transfusion, according to prescriptions redeemed for aspirin, NSAIDs, SSRIs, and statins, are presented in Table
2. The risk of RBC transfusion was 3.5% among aspirin users versus 1.1% among aspirin nonusers (corresponding to an adjusted OR of 1.9, 95% CI: 1.4–2.7). The increased risk of RBC transfusion among aspirin users was unchanged in sensitivity analyses (see Additional file
2: Tables S2–S5). The number needed to harm (NNH) based on ≥ 1 prescription redeemed in the 60 days prior to surgery was 41.5 (95% CI: 29.4–70.9) for aspirin. Although we observed a slightly elevated risk of RBC transfusion among NSAID users compared with NSAID nonusers (adjusted OR = 1.4, 95% CI: 0.9–2.0), this association attenuated in sensitivity analysis (see Additional file
2: Table S3). The risks of RBC transfusion did not differ for users of SSRIs (adjusted OR = 1.2, 95% CI: 0.7–1.9) or statins (adjusted OR = 1.0, 95% CI: 0.7–1.4) compared with nonusers.
Table 2
Risk and crude and adjusted odds ratios for blood transfusion within 14 days of surgery among 22,238 breast cancer patients, according to use of selected prescription drugs
Aspirin |
Nonusers | 232 | 20,902 | 1.1 | 1.0 (ref) | 1.0 |
Users | 47 | 1336 | 3.5 | 3.2 (2.4–4.5) | 1.9 (1.4–2.7) |
NSAIDs |
Nonusers | 247 | 20,464 | 1.2 | 1.0 | 1.0 |
Users | 32 | 1774 | 1.8 | 1.5 (1.0–2.2) | 1.4 (0.9–2.0) |
SSRIs |
Nonusers | 260 | 21,158 | 1.2 | 1.0 | 1.0 |
Users | 19 | 1080 | 1.8 | 1.4 (0.9–2.3) | 1.2 (0.7–1.9) |
Statins |
Nonusers | 248 | 20,209 | 1.2 | 1.0 | 1.0 |
Users | 31 | 2029 | 1.5 | 1.2 (0.9–1.8) | 1.0 (0.7–1.4) |
Table
3 shows the risk of RBC transfusion according to prescriptions for each of the exposure drugs, stratified by surgery type. We found no evidence of multiplicative interaction between the estimates for mastectomy and breast-conserving surgery.
Table 3
Risk and crude and adjusted odds ratios for blood transfusion within 14 days of surgery among 22,238 breast cancer patients, according to use of selected prescription drugs and stratified by surgery type
Aspirin |
Non-users | 178 | 6406 | 2.8 | 1.0 (ref) | 1.0 | 54 | 14,496 | 0.4 | 1.0 | 1.0 |
p = 0.87 |
Users | 37 | 529 | 7.0 | 2.6 (1.8–3.8) | 1.9 (1.3–2.9) | 10 | 807 | 1.2 | 3.4 (1.7– 6.6) | 1.8 (0.9–3.8) |
NSAIDs |
Non-users | 187 | 6324 | 3.0 | 1.0 | 1.0 | 60 | 14,140 | 0.4 | 1.0 | 1.0 |
p = 0.23 |
Users | 28 | 611 | 4.6 | 1.6 (1.1–2.4) | 1.4 (1.0–2.2) | 4 | 1163 | 0.3 | 0.8 (0.3–2.2) | 0.7 (0.3–2.0) |
SSRIs |
Non-users | 198 | 6551 | 3.0 | 1.0 | 1.0 | 62 | 14,607 | 0.4 | 1.0 | 1.0 |
p = 0.23 |
Users | 17 | 384 | 4.4 | 1.5 (0.9–2.5) | 1.3 (0.8–2.2) | 2 | 696 | 0.3 | 0.7 (0.2– 2.8) | 0.5 (0.1–2.2) |
Statins |
Non-users | 189 | 6300 | 3.0 | 1.0 | 1.0 | 59 | 13,909 | 0.4 | 1.0 | 1.0 |
p = 0.29 |
Users | 26 | 635 | 4.1 | 1.4 (0.9–2.1) | 1.1 (0.7–1.7) | 5 | 1394 | 0.4 | 0.8 (0.3–2.1) | 0.6 (0.2–1.6) |
Discussion
Primary breast cancer surgery among women with nonmetastatic breast cancer was associated with low risk of RBC transfusion. Our findings suggest that use of aspirin correlates with an increased risk of RBC transfusion. For every 42 women who filled ≥ 1 prescription in the 60 days prior to surgery, one patient underwent RBC transfusion within 14 days after surgery. We also found a potentially higher risk of RBC transfusion among NSAID users, compared with nonusers of these drugs. The risk of RBC transfusion did not differ among SSRI and statin users compared with nonusers.
Several factors should be considered when interpreting our results. Study strengths include its population-based registry setting, with availability of complete prescription and follow-up data. This reduced the risk of misclassification due to differential loss to follow-up. The unique CPR number facilitated accurate individual-level linkage across the Danish registry network. Use of prospectively collected data from prescription records, whose completeness approaches 100%, ensured an unbiased assessment of exposure before breast cancer diagnosis and eliminated recall bias [
29]. We had access to comprehensive information on potential confounders, including comorbid diseases.
We had no information on prescription compliance. Still, noncompliance would result in misclassification of nonusers as users and therefore could not account for any increased risk of RBC transfusion related to drug use. Some women defined as users may not have taken their medication right up to the day of surgery, however, misclassification would bias our findings to the null. Another concern is that our information on prescription drug exposure relied entirely on registration of dispensed prescriptions rather than actual consumption of the pills. However, as patients have to pay a portion of the cost of their redeemed prescriptions, our estimates are likely to reflect actual drug use. Over-the-counter use of aspirin and NSAIDs is an additional concern, because this is not covered by registry data. However, over-the-counter drug use would result in misclassification of users as nonusers and again bias our findings to the null. Research has suggested that nonprescription use of low-dose aspirin accounts for only 8% of all low-dose aspirin use in Denmark [
30]. As patients are reimbursed for a portion of the cost of prescribed medicines, long-term and continuous use of aspirin is likely to be via prescription. We had no information on medication use during hospitalization. However, breast cancer surgery is primarily an elective procedure, with a short amount of time from hospital admission to surgery (0.57 days in our study population). Thus patients are likely to be vulnerable to the effects of medication taken prior to hospitalization.
We used a “prevalent user design”, comparing current users with nonusers of the exposure drugs. This design may have introduced selection bias via a “healthy user effect”. Individuals who adhere to preventive medication may be more likely to see their doctor on a regular basis, stop smoking, exercise, eat a healthy diet, and have more engagement with the health-care system resulting in better outcomes. This has been seen in studies of statin use with large protective effects [
31]. To address this potential healthy user bias, we restricted the study population to new users of the prescription drugs (those with a first prescription for the exposure drugs up to 60 days prior to breast cancer primary surgery). However, the number of patients transfused in each group was too low to provide meaningful estimates. Nonetheless, we note that previous research suggests that Danish statin users are not healthier than the background population [
32].
While we adjusted for comorbidities, we had no information on the severity of conditions included in the CCI. We also lacked information on comorbid conditions diagnosed in primary care, but which may not be sufficiently severe to warrant a hospital diagnosis. These limitations may have resulted in residual confounding. Our findings may also be prone to confounding by indication. Unknown or unmeasured factors related to clinical characteristics or medical conditions may have triggered aspirin use, and at the same time, increased the risk of RBC transfusion. We note that aspirin users had a higher frequency of specific comorbidities including myocardial infarction, congestive heart failure, and diabetes. Cardiovascular disease (CVD) is a major indication for low-dose aspirin use, and the threshold for RBC transfusion is lower in patients with cardiovascular disease [
33]. However, CVD also correlates with statin use, which was not associated with an increased risk of RBC transfusion in our study, so confounding by indication is likely minimal. We had no registry data on lifestyle factors. Therefore, unmeasured confounding could contribute to the association between use of aspirin, NSAIDs, SSRIs, or statins and the risk of postoperative RBC transfusion if lifestyle factors differed between breast cancer patients who were users versus nonusers.
We had no data on the extent of postoperative bleeding and preoperative hemoglobin levels in over 40% of patients due to missing data in the DTDB. However, we note similar characteristics of patients with and without information on preoperative hemoglobin levels (data not presented). We could have imputed missing hemoglobin data, but hemoglobin may be an intermediate factor in the association between use of prescription drugs and the risk of postoperative RBC transfusion. We excluded 2653 patients who did not undergo surgery within 1 month of diagnosis. Thus patients who underwent neo-adjuvant chemotherapy were also excluded. Therefore, our findings may not be generalizable to all nonmetastatic breast cancer patients.
To the best of our knowledge, this is the first population-based study to investigate the use of common prescription drugs and the risk of postoperative RBC transfusion after primary breast cancer surgery. Studies have shown that aspirin use increases the risk of postoperative bleeding and possibly the need for blood transfusion, and that it depends on extent of surgery in addition to patient factors [
34,
35]. Studies across multiple surgical specialties, including heart surgery, surgery for gastric cancer, and colonoscopic polypectomy, also have reported increased risk of blood transfusion associated with aspirin use [
34‐
36]. However, other studies suggest no increased risk of bleeding associated with preoperative aspirin use among patients undergoing nephrectomy, prostate cancer surgery, and lung cancer surgery [
37‐
39]. Our findings also contrast with those from the STRATAGEM clinical trial, which randomized 291 patients to aspirin or placebo for noncardiac elective surgeries. STRATAGEM found no evidence of increased bleeding risk associated with aspirin use, but breast cancer surgery was not included in the trial [
40].
Although our overall analyses suggested an elevated risk of postoperative RBC transfusion among users of NSAIDs, this was not evident in sensitivity analyses. This finding concurs with two previous meta-analyses – one investigating the association of NSAIDs with the risk of postoperative bleeding in patients undergoing plastic surgery [
7], and the other, focused on the association of NSAIDs with bleeding risk after tonsillectomy [
8].
We observed little evidence of an association between SSRI use and postoperative RBC transfusion. This agrees with previous studies on patients undergoing coronary artery bypass surgery (CABG), which reported that use of preoperative SSRIs was not associated with any substantial risk of blood transfusion and bleeding [
41,
42]. Nonetheless, this finding seems at odds with our previous research, showing an increased risk of reoperation due to postsurgical bleeding in breast cancer patients [
11]. It also contrasts with the increased risk of bleeding events associated with SSRI use among patients undergoing breast biopsy [
43]. Taken together, this suggests that SSRIs may correlate with bleeding, but are unlikely to induce bleeding severe enough to warrant a blood transfusion.
We did not find an association between statin use and postoperative RBC transfusion. To our knowledge, no previous studies have investigated this association. Our findings agree with those observed among patients with gastrointestinal hemorrhage or bleeding in general, although we note that statin therapy has been associated with increased risk of spontaneous intracerebral hemorrhage [
44‐
46].
Breast cancer surgery is soft tissue surgery, and often characterized by extensive dissection, increasing the risk of blood loss. Although RBC transfusion is rare, it induces substantial morbidity and can delay further cancer-directed treatment [
11,
47]. The balance between the risk of bleeding associated with aspirin, and thrombotic events due to aspirin withdrawal, should be assessed carefully when choosing a surgical procedure appropriate for an individual patient. Our findings, therefore, may help to guide decision making and counseling for breast cancer patients who use prescription medications.