BREAST

Tamoxifen (Selective Estrogen-Receptor

Modulators) and Aromatase Inhibitors as
Potential Perioperative Thrombotic Risk
Factors in Free Flap Breast Reconstruction
Michael N. Mirzabeigi, M.D.
Background: Selective estrogen-receptor modulators and aromatase inhibitors
Jonas A. Nelson, M.D.
have become ubiquitous in the treatment of breast cancer. However, hormone
John P. Fischer, M.D.
therapy is a well-established thromboembolic risk factor. The purpose of this
Steven J. Kovach, M.D. study is two-fold: (1) to further evaluate tamoxifen as a potential thrombotic
Joseph M. Serletti, M.D. risk factor and (2) to evaluate use of aromatase inhibitors as a potential novel
Liza C. Wu, M.D. risk factor.
Suhail Kanchwala, M.D. Methods: Abdominally based free flaps were reviewed from January of 2008
Philadelphia, Pa. to July of 2012. Preoperative records were used to identify patients receiv-
ing selective estrogen-receptor modulators (e.g., tamoxifen) or aromatase
inhibitors before reconstruction. Patients were instructed to cease tamoxi-
fen 2 weeks before surgery. Patients were not advised to cease their aroma-
tase inhibitor regimen. Univariate statistical analyses included Fisher’s exact
test and the Mann-Whitney U test. A value of p < 0.05 denoted statistical
significance.
Results: One thousand three hundred forty-seven flaps were performed on 858
patients. There were no statistically significant differences in thrombotic com-
plications or flap failure in comparing those that did not receive preoperative
hormone therapy versus those that did receive preoperative hormone therapy,
nor were there significant differences specific to those receiving tamoxifen
or aromatase inhibitors. A post hoc power analysis was performed with the
supposition that hormone therapy exposure results in a two-fold increase in
complication rate. The study power was found to be 0.863.
Conclusions: Tamoxifen may have been previously overestimated as a microvas-
cular thrombotic risk factor. At a minimum, these data suggest that withhold-
ing tamoxifen for 2 weeks before surgery can mitigate thrombotic risk.  (Plast.
Reconstr. Surg. 135: 670e, 2015.)

T
he interplay between the endocrine system
and breast tumor biology has been described
in the medical literature since the late nine-
teenth century, when the effects of oophorec-
tomy on breast cancer were first published. It is
From the Division of Plastic Surgery, University of Pennsylva-
nia Health System.
Received for publication August 6, 2014; accepted October
9, 2014.
Presented at the 25th Annual Meeting of the European Asso-
ciation of Plastic Surgeons, in Ischia, Italy, May 29 through
31, 2014; and the 31st Annual Meeting of the Northeastern
Society of Plastic Surgeons, in Providence, Rhode Island,
September 12 through 14, 2014.
Copyright © 2015 by the American Society of Plastic Surgeons
DOI: 10.1097/PRS.0000000000001127
estimated that 60 percent of premenopausal and
75 percent of postmenopausal women with breast
cancer demonstrate hormone (estrogen or pro-
gesterone) receptor–positive tumors on immuno-
chemistry.1 As a result, targeted hormone therapy
has become ubiquitous as adjuvant treatment for
breast cancer.
In broad and dichotomous terms, targeted
estrogen therapy is manifested as two categories
of agents. The first category of agents consists of
selective estrogen receptor modulators, including
tamoxifen and raloxifene. Tamoxifen, approved
by the U.S. Food and Drug Administration in
Disclosure: The authors have no financial interest
to declare in relation to the content of this article.

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Volume 135, Number 4 • Tamoxifen and Thrombotic Risk
1997, has emerged from studies with high-level
evidence as an effective treatment modality.2–6
The Early Breast Cancer Trialists’ Collaborative
Group, a collaborative meta-analysis of 20 trials,
demonstrated that 5 years of adjuvant tamoxifen
therapy reduces the 15-year risk of mortality and
local recurrence.2 There is more recent evidence
to suggest that 10 years, rather than 5, of adju-
vant tamoxifen therapy further improves rates of
recurrence and survival.7,8
The other category of commonly used hor-
mone therapy agents are known as aromatase
inhibitors. There have been three iterations of
aromatase inhibitors such that the current agents,
developed to be the most specific and efficacious,
are described as third-generation agents, includ-
ing anastrozole (nonsteroidal), letrozole (nonste-
roidal), and exemestane (steroidal).9–12 As with
tamoxifen, the efficacy of aromatase inhibitors
is well documented with large, prospective trials
that unequivocally support the administration of
aromatase inhibitors to lower local recurrence
rates and improve overall survival. Aromatase
inhibitors have been found to be as efficacious as
tamoxifen or, in some cases, more effective than
tamoxifen as adjuvant therapy.13–18 There is also
evidence to support sequential therapy, in which
patients receive aromatase inhibitors after multi-
ple years of tamoxifen, rather than monotherapy
treatment with either agent.19,20
Both selective estrogen-receptor modulators
and aromatase inhibitors have a side-effect profile
that has been similarly well described in multiple
prospective trials. Both agents have been impli-
cated in higher rates of venous thromboembolic
events, namely, deep venous thrombosis and pul-
monary embolism.21–29 Systematic reviews have
demonstrated that tamoxifen increases the rate of
venous thromboembolic events by 1.5 to 7.1 times
that of a similar cohort receiving a placebo treat-
ment.21,30–37 It is generally accepted that tamoxifen
is more prothrombotic in comparison with aroma-
tase inhibitors. Nonetheless, aromatase inhibitors
have been similarly associated with higher rates
of venous thromboembolic events. The increase
in the relative venous thromboembolic event
risk for aromatase inhibitors is estimated to be
approximately 1.5-fold, even when controlling for
the prothrombotic effects of chemotherapy and
breast cancer.38,39
In revisiting Virchow’s triad of stasis, endo-
thelial injury, and hypercoagulability, it is rea-
sonable to conclude that tamoxifen increases
thromboembolic risk by causing a resultant
hypercoagulable state. By extrapolating the
demonstrated increased risk of venous thrombo-
embolic events, it stands to reason that patients
receiving hormone therapy may be at higher
risk for microvascular thromboses following free
tissue transfer. Given this logical inference, the
effects of tamoxifen and microsurgical complica-
tions were directly examined by Kelley et al. in
2012.40 The level III data published by the Kel-
ley group demonstrated a two-fold increase in
microsurgical complications for those patients
receiving tamoxifen up to 1 month before sur-
gery. Given the study findings that suggested that
tamoxifen was associated with a doubled rate of
microsurgical complications, one can argue that
tamoxifen should be held for even greater than
1 month preoperatively.
There remains a paucity of data on the periop-
erative management of hormone therapy and free
flap breast reconstruction. The aforementioned
investigation of tamoxifen stands alone regard-
ing hormone therapy and breast reconstruction.
Furthermore, aromatase inhibitors have yet to be
discussed in the context of free tissue transfer and
potentially increased rates of thrombosis. Given
that the majority of women demonstrate hormone
receptor–positive breast cancer and the unre-
lenting evidence to support hormone therapy
administration, and newer guidelines increasing
treatment duration, it is incumbent on microsur-
geons to familiarize themselves with these increas-
ingly used and potentially prothrombotic agents.
Moreover, further investigation is required to
developed evidence-based guidelines for periop-
erative administration of hormone therapy. The
purpose of this study is two-fold: (1) to further
evaluate tamoxifen as a potential thrombotic risk
factor and (2) to evaluate use of aromatase inhibi-
tors as a potential novel risk factor for thrombosis
in free flap breast reconstruction.
PATIENTS AND METHODS
A retrospective review of records was per-
formed on all patients undergoing abdominally
based free flap breast reconstruction at the Divi-
sion of Plastic Surgery, University of Pennsylva-
nia Health System, from January of 2008 to July
of 2012. Transverse rectus abdominis myocuta-
neous, deep inferior epigastric perforator, and
superficial inferior epigastric perforator flaps
were all included in this study. Other commonly
used free flaps (e.g., gluteal or transverse upper
gracilis) were excluded from the study. Preop-
erative outpatient records were used to identify
patients receiving preoperative hormone therapy.
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A systemwide electronic medical record system
used by the medical oncologists, breast surgeons,
and plastic surgeons included a shared medica-
tion reconciliation record, which included details
of hormone therapy. Hospital records detailing
intraoperative care and immediate postoperative
course were used.
Rates of thrombosis and flap loss were calcu-
lated per flap, given that each flap has an indi-
vidualized risk for thrombosis, which can vary
from the contralateral side (e.g., vessel caliber,
ipsilateral irradiation, flap type). In addition to
performing calculations per flap, and given that
hormone therapy is a systemic treatment, we cal-
culated complications per patient as well.
Rates of thrombosis and flap loss were first cal-
culated for patients receiving any type of hormone
therapy (selective estrogen-receptor modulators
and aromatase inhibitors combined) preopera-
tively and compared to those patients not receiv-
ing any type of preoperative hormone therapy. A
similar analysis was performed comparing those
patients receiving tamoxifen versus those patients
not receiving any form of preoperative hormone
therapy. Raloxifene, although having previously
demonstrated a similar venous thromboembolic
event risk as tamoxifen, was excluded for homo-
geneity, given that the overwhelming majority of
patients in this study (and in general) received
tamoxifen.41 Lastly, rates of thrombosis and flap
loss were examined in comparing those patients
receiving any type of aromatase inhibitor preop-
eratively versus those not receiving hormone ther-
apy preoperatively.
Univariate statistical analyses included Fisher’s
exact test for categorical variables and the Mann-
Whitney U test for continuous variables. All tests
were two-sided, and a value of p ≤ 0.05 was used to
determine statistical significance. Statistical analysis
was performed using STATA IC 13.0 (StataCorp,
College Station, Texas).
Perioperative Hormone Therapy Instructions
All patients receiving selective estrogen-
receptor modulators (i.e., tamoxifen or raloxi-
fene) were instructed to cease administration for
2 weeks preoperatively and were instructed to
resume their selective estrogen-receptor modu-
lator regimen 2 weeks after surgery. Aromatase
inhibitors were not held preoperatively, and
patients were instructed to restart their respective
aromatase inhibitor regimen on discharge from
the hospital. In considering the limited plastic
surgery clinical data available, these institutional
guidelines were developed in conjunction with
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Plastic and Reconstructive Surgery • April 2015
the oncologist’s recommendations and the known
half-life of these agents. The half-life of aromatase
inhibitors is considerably shorter compared with
tamoxifen. Nonsteroidal agents such as anastro-
zole and letrozole have a half-life of 48 hours, or
27 hours for steroidal exemestane, whereas the
half-life of tamoxifen has been demonstrated to
be 2 weeks.10–12
Perioperative Anticoagulation Protocol
Patients undergoing surgery received 5000
units of subcutaneous heparin before induc-
tion and continued to receive subcutaneous
heparin every 8 hours until discharge to home.
All patients received bilateral intermittent
compression devices throughout their hospital
course as well.
RESULTS
A total of 1347 flaps were performed on 858
patients. One hundred fifty-two patients (17.7
percent) received hormone therapy treatment
preoperatively. Hormone therapy regimens are
described in Table 1. Tamoxifen was predomi-
nantly representative of the selective estrogen-
receptor modulator treatment group. Arimidex
(anastrozole) was the most commonly used aro-
matase inhibitor.
Venous Thromboembolic Events
Nine patients (1 percent) were diagnosed
with a perioperative deep venous thrombosis, and
three patients (0.4 percent) were diagnosed with
a perioperative pulmonary embolism. Given the
paucity of venous thromboembolic events, and
the well-described association with hormone ther-
apy, further analysis of these events was excluded
from this study.
Table 1.  Hormone Therapy Regimens of Patients
Undergoing Breast Reconstruction
No. (%)
Total no. of patients 858
Preoperative hormone therapy
 SERM 74 (8.7)
  Tamoxifen 67 (7.9)
  Raloxifene 7 (0.8)
 Aromatase inhibitors 78 (9.2)
  Anastrozole (Arimidex; AstraZeneca,
 Cambridge, United Kingdom) 50 (5.9)
  Letrozole (Femara; Novartis Pharmaceutical
  Corp., East Hanover, N.J.) 18 (2.1)
  Exemestane (Aromasin; Pfizer,
 New York, N.Y.) 10 (0.9)
SERM, selective estrogen receptor modulator.
Volume 135, Number 4 • Tamoxifen and Thrombotic Risk

All Preoperative Hormone Therapy (Selective Table 3.  Perioperative Outcomes for Patients Receiving
Estrogen-Receptor Modulators and Aromatase and Patients Not Receiving Hormone Therapy
Inhibitors Combined) No Preoperative Preoperative
Patient demographics and perioperative char- Hormone Hormone
acteristics are listed in Table 2. In comparing Therapy (%) Therapy (%) p
those not receiving hormone therapy versus those No. of flaps 1120 227
receiving hormone therapy before reconstruc- Flap outcomes
 Intraoperative
tion, patients receiving preoperative hormone   arterial thrombosis 29 (2.6) 7 (3.1) 0.67
therapy demonstrated significantly higher rates  Intraoperative
of preoperative radiation therapy (60.5 versus   venous thrombosis 5 (0.4) 2 (0.9) 0.34
 Intraoperative
22.5 percent; p < 0.001) and preoperative che-  any thrombosis 31 (2.8) 9 (4.0) 0.33
motherapy (71.7 versus 33.7 percent; p < 0.001).  Postoperative arterial
The group not receiving hormone therapy dem-  thrombosis 14 (1.3) 4 (1.8) 0.53
 Postoperative venous
onstrated higher rates of immediate reconstruc-  thrombosis 14 (1.3) 2 (0.9) 1
tion (87.4 versus 34.8 percent; p < 0.001) and  Postoperative any
bilateral reconstruction (58.6 versus 49.3 percent;  thrombosis 26 (2.3) 6 (2.6) 0.77
 Any arterial
p = 0.04). When comparing thrombotic complica-  thrombosis 43 (3.8) 11 (4.8) 0.48
tions—both venous and arterial—there were no  Any venous
statistically significant different rates of intraoper-  thrombosis 19 (1.7) 4 (1.8) 1
 Any thrombosis 56 (5.0) 15 (6.6) 0.32
ative or postoperative thrombosis between those  Flap loss (partial) 5 (0.4) 1 (0.4) 1
receiving hormone therapy and those not receiv-  Flap loss (total) 6 (0.5) 1 (0.4) 1
ing hormone therapy (Table 3).  Flap loss (any) 11 (1.0) 2 (0.9) 1
Flap type
 Muscle-sparing
Preoperative Tamoxifen Therapy  free TRAM 779 (69.6) 171 (75.3) 0.18
Patient demographics and perioperative char-  DIEP 296 (26.4) 53 (23.3)
 SIEA 33 (2.9) 3 (1.3)
acteristics are listed in Table 4. The tamoxifen
TRAM, transverse rectus abdominis myocutaneous; DIEP, deep inferior
cohort demonstrated a significantly lower mean epigastric perforator; SIEA, superficial inferior epigastric artery.
age (46.4 years versus 51.0 years; p = 0.0002). In
comparing those not receiving tamoxifen versus radiation therapy (71.6 versus 22.5 percent;
those receiving tamoxifen before reconstruction, p < 0.001) and preoperative chemotherapy (76.1
patients receiving preoperative tamoxifen demon- versus 33.7 percent; p < 0.001). The group not
strated significantly higher rates of preoperative

Table 2.  Patient Demographics for Patients Receiving Table 4.  Patient Demographics for Patients Receiving
and Patients Not Receiving Hormone Therapy Tamoxifen and Patients Not Receiving Hormone
Therapy
No Preoperative Preoperative
Hormone Hormone No
Therapy (%) Therapy (%) p Preoperative Preoperative
Hormone Tamoxifen
No. of patients 706 152 Therapy (%) (%) p
Patient
 demographics No. of patients 706 67
 Age, yr 51 (9.4) 51.3 (8.9) 0.49 Patient demographics
 BMI 28.9 (5.9) 29.1 (5.6) 0.44  Age, yr 51 (9.4) 46.4 (7.3) 0.0002
 Diabetes 46 (6.5) 8 (5.2) 0.58  BMI 28.9 (5.9) 29.2 (6.1) 0.66
 Hypertension 175 (24.8) 39 (25.6) 0.79  Diabetes 46 (6.5) 4 (6.0) 1
 Coronary artery  Hypertension 175 (24.8) 13 (19.4) 0.31
 disease 13 (1.8) 1 (0.7) 0.48  Coronary artery
 Peripheral  disease 13 (1.8) 0 (0) 0.62
 vascular disease 2 (0.3) 0 (0.0) 1  Peripheral
 Active smoking 71 (10.1) 13 (8.6) 0.53  vascular disease 2 (0.3) 0 (0) 1
 Preoperative  Active smoking 71 (10.1) 5 (7.5) 0.45
 chemotherapy 238 (33.7) 109 (71.7) <0.001  Preoperative
 Preoperative  chemotherapy 238 (33.7) 51 (76.1) <0.001
 radiotherapy 159 (22.5) 92 (60.5) <0.001  Preoperative
 Immediate  radiotherapy 159 (22.5) 48 (71.6) <0.001
 reconstruction* 979 (87.4) 79 (34.8) <0.001  Immediate
 Bilateral  reconstruction 979* (87.4) 40 (38.8) <0.001
 reconstruction 414 (58.6) 75 (49.3) 0.04  Bilateral reconstruction 414 (58.6) 36 (53.7) 0.44
BMI, body mass index. BMI, body mass index.
*Denominator = no. of reconstructions. *Total number of reconstructed breasts.

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 Plastic and Reconstructive Surgery • April 2015

receiving tamoxifen demonstrated higher rates Table 6.  Patient Demographics for Patients Receiving
of immediate reconstruction (87.4 versus 38.8 Aromatase Inhibitors and Patients Not Receiving
percent; p < 0.001). When comparing thrombotic Hormone Therapy
complications—both venous and arterial—there No
were no statistically significant different rates Preoperative Preoperative
of intraoperative or postoperative thrombosis Hormone Aromatase
Therapy (%) Inhibitor (%) p
between those receiving tamoxifen and those not
receiving tamoxifen (Table 5). No. of patients 706 78
Patient
 demographics
Preoperative Aromatase Inhibitors  Age, yr 51 (9.4) 55 (8.2) 0.0001
Patient demographics and perioperative  BMI 28.9 (5.9) 29.1 (5.3) 0.51
 Diabetes 46 (6.5) 4 (5.2) 0.81
characteristics are listed in Table 6. The aroma-  Hypertension 175 (24.8) 24 (31.2) 0.24
tase inhibitor cohort demonstrated a significantly  Coronary artery
higher mean age (55 years versus 51 years; p =  disease 13 (1.8) 1 (1.3) 1
 Peripheral
0.0001). In comparing those not receiving aroma-  vascular disease 2 (0.3) 0 (0) 1
tase inhibitors versus those receiving aromatase  Active smoking 71 (10.1) 7 (9.1) 0.58
inhibitors before reconstruction, patients receiv-  Preoperative
 chemotherapy 238 (33.7) 56 (72.7) <0.001
ing preoperative aromatase inhibitors demon-  Preoperative
strated significantly higher rates of preoperative  radiotherapy 159 (22.5) 42 (54.5) <0.001
radiation therapy (54.5 versus 22.5 percent; p <  Immediate
 reconstruction* 979 (87.4) 30 (39.0) <0.001
0.001), preoperative chemotherapy (72.7 versus  Bilateral
33.7 percent; p < 0.001), and bilateral reconstruc-  reconstruction 414 (58.6) 35 (44.9) 0.02
tion (58.6 versus 44.9; p = 0.02). The group not BMI, body mass index.
receiving aromatase inhibitors demonstrated *Denominator = reconstructions.
higher rates of immediate reconstruction (87.4
versus 39.0 percent; p < 0.001). When compar-
ing thrombotic complications—both venous and
Table 5.  Perioperative Outcomes for Patients Receiving arterial—there were no statistically significant
and Patients Not Receiving Hormone Therapy different rates of intraoperative or postoperative
No thrombosis between those receiving aromatase
Preoperative inhibitors and those not receiving aromatase
Hormone Preoperative
Therapy (%) Tamoxifen (%) p inhibitors (Table 7).
No. of flaps 1120 103
Flap outcomes Complications Calculated per Patient
 Intraoperative Complications were then analyzed per patient
 arterial thrombosis 29 (2.6) 5 (4.9) 0.2 (rather than per flap as above) as demonstrated
 Intraoperative
 venous thrombosis 5 (0.4) 0 (0) 1 in Table 8, which further demonstrated no differ-
 Intraoperative any ence in complications based on hormone therapy
 thrombosis 31 (2.8) 5 (4.9) 0.22 regimen or lack thereof.
 Postoperative arterial
 thrombosis 14 (1.3) 2 (1.9) 0.64
 Postoperative venous Post Hoc Power Analysis
 thrombosis 14 (1.3) 1 (1) 1
 Postoperative any A post hoc power analysis was performed with
 thrombosis 26 (2.3) 3 (2.9) 0.73 the supposition that hormone therapy exposure
 Any arterial results in a two-fold increase in complication rate.
 thrombosis 43 (3.8) 7 (6.8) 0.19
 Any venous The study power was found to be 0.863 (>0.800
 thrombosis 19 (1.7) 1 (1) 1 suggesting adequate study power and low likeli-
 Any thrombosis 56 (5.0) 8 (7.8) 0.23 hood of type II error).
 Flap loss (partial) 5 (0.4) 1 (1) 0.41
 Flap loss (total) 6 (0.5) 0 (0) 1
 Flap loss (any) 11 (1.0) 1 (1) 1 DISCUSSION
Flap type
 Muscle-sparing Hormone therapy, including selective estro-
 free TRAM 779 (69.6) 75 (72.8) 0.49 gen-receptor modulators and aromatase inhibi-
 DIEP 296 (26.4) 27 (26.2)
 SIEA 33 (2.9) 1 (1) tors, has become a critical component in the
TRAM, transverse rectus abdominis myocutaneous; DIEP, deep infe- treatment algorithm of breast cancer. Given the
rior epigastric perforator; SIEA, superficial inferior epigastric artery. increasingly compelling evidence as to the efficacy

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Volume 135, Number 4 • Tamoxifen and Thrombotic Risk

Table 7.  Perioperative Outcomes for Patients 1.2.42,43 Both selective estrogen-receptor modu-
Receiving Aromatase Inhibitor Therapy versus lators and aromatase inhibitors have been dem-
Patients Not Receiving Hormone Therapy onstrated to be efficacious, albeit through two
No distinctly different mechanisms.
Preoperative Preoperative Selective estrogen-receptor modulators inhibit
Hormone Aromatase tumor growth by means of competitive antago-
Therapy (%) Inhibitor (%) p
nism of estrogen at the receptor level and thus
No. of flaps 1120 113 are widely used for premenopausal women with
Flap outcomes
 Intraoperative maintained ovarian estrogen production. Selec-
 arterial thrombosis 29 (2.6) 2 (1.8) 1 tive estrogen-receptor modulators demonstrate
 Intraoperative mixed agonist and antagonist activity21,44,45 and
 venous thrombosis 5 (0.4) 2 (1.8) 0.23
 Intraoperative thus have the effect of preventing bone deminer-
 any thrombosis 31 (2.8) 4 (3.5) 0.77 alization and improving lipid profiles.9 Although
 Postoperative selective estrogen-receptor modulators function
 arterial thrombosis 14 (1.3) 1 (0.9) 1
 Postoperative at the receptor level, aromatase inhibitors func-
 venous thrombosis 14 (1.3) 1 (0.9) 1 tion by preventing peripheral tissue conversion
 Postoperative
 any thrombosis 26 (2.3) 2 (1.8) 1 of the adrenal androgen substrate androstene-
 Any arterial dione to estrogen. Aromatase, an enzyme of the
 thrombosis 43 (3.8) 3 (2.7) 0.79 cytochrome P450 family, has been found in sub-
 Any venous
 thrombosis 19 (1.7) 3 (2.7) 0.45 cutaneous fat, liver, muscle, brain, and breast.9
 Any thrombosis 56 (5.0) 6 (5.3) 0.82 In postmenopausal women, peripheral tissue
 Flap loss (partial) 5 (0.4) 0 (0) 1 conversion serves as the primary source of estro-
 Flap loss (total) 6 (0.5) 1 (0.9) 0.49
 Flap loss (any) 11 (1.0) 1 (0.9) 1 gen.46 Thus, these agents are used for women who
Flap type no longer demonstrate ovarian production of
 Muscle-sparing estrogen.
 free TRAM 779 (69.6) 88 (78.8) 0.18
 DIEP 296 (26.4) 22 (19.5) As an unintended byproduct of both these
 SIEA 33 (2.9) 2 (1.8) mechanisms, an increased rate of venous throm-
TRAM, transverse rectus abdominis myocutaneous; DIEP, deep infe- boembolic events has been reliably reproduced
rior epigastric perforator; SIEA, superficial inferior epigastric artery. in large, prospective trials of both tamoxifen
and aromatase inhibitors. The clinical findings
of these agents, the support to increase treatment have prompted closer examination as to the
duration, and the expanding role of hormone mechanism by which tamoxifen may cause a pro-
therapy, use of both selective estrogen-receptor thrombotic state. Hematologic studies have dem-
modulators and aromatase inhibitors will con- onstrated that tamoxifen decreases antithrombin
tinue to be more pervasive among those under- III, protein C, and protein S.28,47–52 However, there
going breast reconstruction. There has even been has been little evidence to suggest a change in
a well-described role for using hormone therapy markers of activated coagulation or fibrinolysis
prophylactically for those patients demonstrat- such as prothrombin F, fibrin degradation prod-
ing a relative risk of breast cancer of greater than ucts, or thrombin-antithrombin complex.28,47,49,52,53

Table 8.  Perioperative Complications Calculated per Patient

None Tamoxifen Aromatase Inhibitors
No. % No. % p No. % p
No. of patients 706 67 78
Intraoperative arterial thrombosis 27 3.8 5 7.5 0.15 2 2.6 0.76
Intraoperative venous thrombosis 5 0.7 0 0.0 1 2 2.6 0.15
Intraoperative any thrombosis 29 4.1 5 7.5 0.2 4 5.1 0.56
Postoperative arterial thrombosis 14 2.0 2 3.0 0.58 1 1.3 1
Postoperative venous thrombosis 12 1.7 1 1.5 1 1 1.3 1
Postoperative any thrombosis 24 3.4 3 4.5 0.72 2 2.6 1
Any arterial thrombosis 40 5.7 7 10.4 0.12 3 3.8 0.79
Any venous thrombosis 17 2.4 1 1.5 1 3 3.8 0.44
Any thrombosis 52 7.4 8 11.9 0.18 6 7.7 0.82
Flap loss (partial) 5 0.7 1 1.5 0.42 0 0.0 1
Flap loss (total) 6 0.8 0 0.0 1 1 1.3 0.52
Flap loss (any) 11 1.6 1 1.5 1 1 1.3 1

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Conversely, the mechanism by which aromatase
inhibitors may be prothrombotic is less well under-
stood. In the limited study of aromatase inhibitors,
there is evidence to suggest that aromatase inhibi-
tors do not similarly lower levels of antithrombin
III, protein C, and protein S.38 Nonetheless, the
clinical evidence does suggest that aromatase
inhibitors are prothrombotic, albeit to a lesser
degree than tamoxifen.
Tamoxifen reportedly increases the rate of
venous thromboembolic event by 1.5 to 7.1 times
that of a similar cohort receiving a placebo treat-
ment. Although a seven-fold increase stands as
an outlier in terms of relative risk increase, the
collective data seem to suggest an approximately
three-fold increase in venous thromboembolic
event risk.21,30,31,33–37,54 In comparing tamoxifen to
aromatase inhibitors, the prospectively designed
Arimidex, Tamoxifen Alone, or in Combination
trial of over 9000 women demonstrated that the
risk of venous thromboembolic event at 4 years is
higher with tamoxifen compared with anastrozole
(relative risk of 1.7 in comparison). In addition, in
comparing venous thromboembolic event risk of
aromatase inhibitors versus tamoxifen, there are
illuminating data from the Breast International
Group 1-98 trial of 8000 women. In the Breast
International Group 1-98 trial, the venous throm-
boembolic event relative risk of letrozole (1.5) was
similarly lower than the tamoxifen cohort (3.5).14
Considered together, the data would suggest that
aromatase inhibitors carry an increased venous
thromboembolic event risk of approximately 1.5
versus approximately 3 for tamoxifen.
Despite the well-established higher rates of
venous thromboembolic events, our data suggest
that those receiving preoperative hormone ther-
apy (with discontinuation 2 weeks before surgery)
were not predisposed to a higher risk of micro-
vascular thromboses or flap loss. At a minimum,
the data presented in this article would suggest
that 2 weeks of cessation from tamoxifen is ade-
quate to mitigate thrombotic risk. In addition, this
study represents the only investigation thus far
regarding aromatase inhibitors and microvascular
thrombotic risk. Aromatase inhibitors did not rep-
resent a perioperative thrombotic risk even when
administered until the day of surgery. Interest-
ingly, there were no statistically significant differ-
ences in complication rates despite higher rates of
preoperative irradiation, preoperative chemother-
apy, delayed reconstruction, and more advanced
age (aromatase inhibitor cohort only). Prior irra-
diation has been strongly implicated with higher
rates of thromboses, particularly intraoperative
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Plastic and Reconstructive Surgery • April 2015
thromboses.55,56 Noting this study bias and that the
thrombosis rate remains unaffected by hormone
therapy, one can argue that this further portends
to hormone therapy not contributing to throm-
botic risk.
At first glance, these data may seem contra-
dictory to the overwhelming evidence of venous
thromboembolic event risk and hormone ther-
apy. It is, however, a false equivalence to suggest
that venous thromboembolic event risk equates
to higher microsurgical thrombosis risk. First, all
patients in prospective trials examining venous
thromboembolic events are actively receiving the
hormone therapy at the time of their thrombo-
embolic event. Furthermore, these patients may
currently be receiving chemotherapy, which has
been found to have a synergistic thrombotic effect
with tamoxifen.57,58 In a trial of stage II and III
breast cancer patients, the incidence of venous
thromboembolic events was 1.4 percent versus
10.8 for tamoxifen alone and tamoxifen/chemo-
therapy, respectively.57 At the time of reconstruc-
tion, patients are not actively receiving hormone
therapy or chemotherapy.
Most critically, aside from well-established
venous thromboembolic event risk, one must rec-
oncile the data presented in this article with the
previously published data by Kelley et al., which
are essentially contradictory.40 Tamoxifen may in
fact be effectively prothrombotic at a microvascu-
lar level, as shown in the data reported by Kelley et
al.; however, this simply may not have manifested
in this patient series. Thrombosis is a demonstra-
tion of often multiple contributing factors. Those
contributing factors may then cross a threshold,
at which time a thrombotic event occurs. Par-
ticularly in less reliable flaps than those that are
abdominally based, this threshold effect may be
more pronounced.
Although the study by Kelley et al. was innova-
tive and important, it is not without flaw. As men-
tioned in the published discussion by Disa, the
role of nonabdominal flaps (e.g., gluteal flaps)
resulting in a higher rate of complications in
the tamoxifen group is not entirely addressed.59
Our group has published data to suggest that glu-
teal flaps themselves can exhibit higher rates of
microvascular complications.60 Tamoxifen was not
shown to be an independent risk factor for throm-
bosis or flap loss when controlling for flap type
in their heterogeneous series of flaps. Further-
more, patients in the tamoxifen group (similar
to our own study) had higher rates of preopera-
tive irradiation. In addition, in the study by Kel-
ley et al., complications were grouped together to
Volume 135, Number 4 • Tamoxifen and Thrombotic Risk
include potentially multifactorial or non sequitur
outcomes such as fat necrosis. Similarly, rates of
thrombosis were 1.5 percent, but flap loss was
higher, which may have been a result of alterna-
tive cause (e.g., intrinsic flap failure). For these
three reasons in particular—unaccounted vari-
ance in flap type, significantly higher rates of
preoperative irradiation in the tamoxifen group,
and grouped outcome variables—the effect of
preoperative tamoxifen may have been previously
overestimated.
Ultimately, this is an important matter that
requires further investigation. It is not conclu-
sively answered by our own investigation or oth-
ers to date. However, it is certainly important for
patient care. If the data by Kelley et al. are accepted
in which tamoxifen was held for 1 month before
surgery, one can argue that tamoxifen should be
held for greater than 1 month. If one includes the
preoperative period, the postoperative period of
cessation, and potential cessation for subsequent
revision procedures, patients may have hormone
therapy held for a significant portion of a calendar
year. There is no evidence available to correlate
cessation period and altered oncologic outcomes;
however, it is important to remember that the
Early Breast Cancer Trialists’ Collaborative Group
demonstrated a reduction in the 15-year mortal-
ity rate by at least one-third with full compliance
with tamoxifen therapy. Given the proven efficacy
in mortality, surgeons should maintain a high
threshold for withholding such agents.
Recommendations
This study suggests that withholding tamoxi-
fen for greater than 2 weeks does not improve
microvascular outcomes. We recommend with-
holding tamoxifen for no longer than 2 weeks
before surgery and suggest further study, as an
even shorter time interval may be appropriate.
Similarly, the data also suggest that aromatase
inhibitors may be continued until surgery without
deleterious effects.
Limitations
This study does suffer from particular limita-
tions. To adequately power the outcomes analysis,
aromatase inhibitors were grouped together. It
should be noted, however, that the rates of venous
thromboembolic event for agents are similar. In
focusing on three large prospective trials, the
rate of relative risk for venous thromboembolic
events is similar for anastrozole (1.6 in the Arimi-
dex, Tamoxifen Alone, or in Combination trial),
letrozole (1.5 in the Breast International Group
1-98 trial), and exemestane (1.3 in the Intergroup
Exemestane Study trial).14,39,61,62 In addition, there
is a time-dependent component of thrombotic
risk and the initiation of tamoxifen therapy.3 In
a Danish population-based cohort study of over
16,000 women, the initial 2 years of tamoxifen
portended to a 3.5-fold venous thromboembolic
event risk versus a 1.5-fold risk in years 3 through
5 of therapy.26 This study does not account for the
length of time for which women are treated.
CONCLUSIONS
Hormone therapy, when indicated, has
become the standard of care in breast cancer
therapy; however, selective estrogen-receptor
modulators and aromatase inhibitors have been
implicated in higher rates of venous thromboem-
bolic events. Despite these findings of increased
venous thromboembolic event rates, tamoxi-
fen may have been previously overestimated
as a microvascular thrombotic risk factor. At a
minimum, these data suggest that withholding
tamoxifen for 2 weeks before surgery can miti-
gate thrombotic risk. Aromatase inhibitors were
not found to increase thrombotic complications
despite continued perioperative administration.
Suhail Kanchwala, M.D.
Division of Plastic Surgery
10 Penn Tower
3400 Spruce Street
Philadelphia, Pa. 19104
suhail.kanchwala@uphs.upenn.edu
references
1. Williams N, Harris LN. The renaissance of endocrine ther-
apy in breast cancer. Curr Opin Obstet Gynecol. 2014;26:41–47.
2. Early Breast Cancer Trialists’ Collaborative Group
(EBCTCG). Relevance of breast cancer hormone recep-
tors and other factors to the efficacy of adjuvant tamoxi-
fen: Patient-level meta-analysis of randomized trials. Lancet
2011;378:771–784.
3. Onitilo AA, Doi SA, Engel JM, Glurich I, Johnson J, Berg R.
Clustering of venous thrombosis events at the start of tamoxi-
fen therapy in breast cancer: A population-based experience.
Thromb Res. 2012;130:27–31.
4. Cuzick J, Forbes JF, Sestak I, et al. Long-term results of
tamoxifen prophylaxis from breast cancer: 96 month fol-
low-up of the randomized IBIS-I trial. J Natl Cancer Inst.
2007;99:272–282.
5. Decensi A, Maisonneuve P, Rotmensz N, et al.; Italian
Tamoxifen Study Group. Effect of tamoxifen on venous
thromboembolic events in a breast cancer prevention trial.
Circulation 2005;111:650–656.
6. Ragaz J, Coldman A. Survival impact of adjuvant tamoxifen
on competing causes of mortality in breast cancer survivors,
with analysis of mortality from contralateral breast cancer,
677e

cardiovascular events, endometrial cancer, and thromboem-
bolic episodes. J Clin Oncol. 1998;16:2018–2024.
7. Davies C, Pan H, Godwin J, et al. Long-term effects of con-
tinuing adjuvant tamoxifen to 10 years versus stopping at 5
years after diagnosis of estrogen receptor-positive breast can-
cer: ATLAS, a randomized trial. Lancet 2013;381:805–816.
8. Gray RG, Rea D, Handley K, et al. aTTom: Long-term effects
of continuing adjuvant tamoxifen to 10 years versus stop-
ping at 5 years in 6953 women with early breast cancer. J Clin
Oncol. 2013;31(Suppl, abstr 5).
9. Altundag K, Ibrahim NK. Aromatase inhibitors in breast can-
cer: An overview. Oncologist 2006;11:553–562.
10. Lamb HM, Adkins JC. Letrozole: A review of its use in post-
menopausal women with advanced breast cancer. Drugs
1998;56:1125–1140.
11. Wiseman LR, Adkins JC. Anastrozole: A review of its use in
the management of postmenopausal women with advanced
breast cancer. Drugs Aging 1998;13:321–332.
12. Lønning PE. Pharmacological profiles of exemestane and
formestane, steroidal aromatase inhibitors used for treat-
ment of postmenopausal breast cancer. Breast Cancer Res
Treat. 1998;49(Suppl 1):S45–S52; discussion S73–S77.
13. Baum M, Buzdar A, Cuzick J, et al. Anastrozole alone or
in combination with tamoxifen versus tamoxifen alone for
adjuvant treatment of postmenopausal women with early-
stage breast cancer: Results of ATAC (Arimidex, Tamoxifen
Alone, or in Combination) trial efficacy and safety update
analyses. Cancer 2003;98:1802–1810.
14. Thurlimann B, Keshaviah A, Coates AS, et al. A comparison
of letrozole and tamoxifen in postmenopausal women with
early breast cancer. N Engl J Med. 2005;353:2747–2757.
15. Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast
cancer outcomes in adjuvant trials of aromatase inhibitors
versus tamoxifen. J Clin Oncol. 2010;28:509–518.
16. Chirgwin J, Sun Z, Smith I, et al. The advantage of letro-
zole over tamoxifen in the BIG 1-98 trial is consistent in
younger postmenopausal women and in those with che-
motherapy-induced menopause. Breast Cancer Res Treat.
2012;131:295–306.
17. Eiermann W, Paepke S, Appfelstaedt J, et al.; Letrozole
Neo-Adjuvant Breast Cancer Study Group. Preoperative
treatment of postmenopausal breast cancer patients with
letrozole: A randomized double-blind multicenter study.
Ann Oncol. 2001;12:1527–1532.
18. Cataliotti L, Buzdar A, Noguchi S, et al. Efficacy of Pre-
Operative Arimidex (anastrozole) Compared with
Tamoxifen (PROACT) as neoadjuvant therapy in postmeno-
pausal women with hormone receptor-positive breast cancer.
Eur J Cancer 2004;2(Suppl):A46.
19. Goss PE, Ingle JN, Martino S, 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.
20. Thurlimann BJ, Keshaviah A, Mouridsen A, et al. BIG 1-98:
Randomized double-blind phase III study to evaluate letro-
zole (L) versus tamoxifen (T) as adjuvant endocrine therapy
for postmenopausal women with receptor-positive breast
cancer. J Clin Oncol. 2005;23:6s.
21. Deitcher SR, Gomes MP. The risk of venous thromboembolic
disease associated with adjuvant hormone therapy for breast
carcinoma: A systematic review. Cancer 2004;101:439–449.
22. Nevasaari K, Heikkinen M, Taskinen PJ. Tamoxifen and
thrombosis. Lancet 1978;2:946–947.
23. Lipton A, Harvey HA, Hamilton RW. Venous thrombosis
as a side effect of tamoxifen treatment. Cancer Treat Rep.
1984;68:887–889.
678e
Plastic and Reconstructive Surgery • April 2015
24. Duggan C, Marriott K, Edwards R, Cuzick J. Inherited and
acquired risk factors for venous thromboembolic disease
among women taking tamoxifen to prevent breast cancer. J
Clin Oncol. 2003;21:3588–3593.
25. Goldhaber SZ. Tamoxifen: Preventing breast cancer and
placing the risk of deep vein thrombosis in perspective.
Circulation 2005;111:539–541.
26. Hernandez RK, Sørensen HT, Pedersen L, Jacobsen J, Lash
TL. Tamoxifen treatment and risk of deep venous thrombo-
sis and pulmonary embolism: A Danish population-based
cohort study. Cancer 2009;115:4442–4449.
27. Lee AY, Levine MN. Venous thromboembolism and cancer:
Risks and outcomes. Circulation 2003;107(Suppl 1):I17–I21.
28. Love RR, Wiebe DA, Feyzi JM, Newcomb PA, Chappell RJ.
Effects of tamoxifen on cardiovascular risk factors in post-
menopausal women after 5 years of treatment. J Natl Cancer
Inst. 1994;86:1534–1539.
29. Prandoni P, Falanga A, Piccioli A. Cancer and venous throm-
boembolism. Lancet Oncol. 2005;6:401–410.
30. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for
prevention of breast cancer: Report of the National Surgical
Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer
Inst. 1998;90:1371–1388.
31. Veronesi U, Maisonneuve P, Costa A, et al.; on behalf of the
Italian Tamoxifen Prevention Study. Prevention of breast
cancer with tamoxifen: Preliminary findings from the Italian
randomized trial among hysterectomised women. Lancet
1998;352:93–97.
32. Powles T, Eeles R, Ashley S, et al. Interim analysis of the
incidence of breast cancer in the Royal Marsden Hospital
tamoxifen randomised chemoprevention trial. Lancet
1998;352:98–101.
33. IBIS Investigators. First results from the International Breast
Cancer Intervention Study (IBIS-I): A randomized preven-
tion trial. Lancet 2002;360:817–824.
34. Saphner T, Tormey DC, Gray R. Venous and arterial throm-
bosis in patients who received adjuvant therapy for breast
cancer. J Clin Oncol. 1991;9:286–294.
35. Meier CR, Jick H. Tamoxifen and risk of idiopathic venous
thromboembolism. Br J Clin Pharmacol. 1998;45:608–612.
36. McDonald CC, Alexander FE, Whyte BW, Forrest AP,
Stewart HJ. Cardiac and vascular morbidity in women
receiving adjuvant tamoxifen for breast cancer in a ran-
domised trial: The Scottish Cancer Trials Breast Group.
BMJ 1995;311:977–980.
37. Rutqvist LE, Mattsson A. Cardiac and thromboembolic mor-
bidity among postmenopausal women with early-stage breast
cancer in a randomized trial of adjuvant tamoxifen: The
Stockholm Breast Cancer Study Group. J Natl Cancer Inst.
1993;85:1398–1406.
38. Costa LA, Kopreski MS, Demers LM, et al. Effect of the
potent aromatase inhibitor fadrozole hydrochloride (CGS
16949A) in postmenopausal women with breast carcinoma.
Cancer 1999;85:100–103.
39. Coombes RC, Hall E, Gibson JL, et al. A randomized trial of
exemestane after 2 to 3 years of tamoxifen therapy in post-
menopausal women with primary breast cancer. N Engl J Med.
2004;350:1081–1092.
40. Kelley BP, Valero V, Yi M, Kronowitz SJ. Tamoxifen increases
the risk of microvascular flap complications in patients
undergoing microvascular breast reconstruction. Plast
Reconstr Surg. 2012;129:305–314.
41. Cummings SR, Eckert S, Krueger KA, et al. The effect of
raloxifene on risk of breast cancer in postmenopausal
women: Results from the MORE randomized trial. JAMA
1999;281:2189–2197.
Volume 135, Number 4 • Tamoxifen and Thrombotic Risk
42. Vogel VG, Costantino JP, Wickerham DC, et al. Effects of
tamoxifen versus raloxifene on risk of developing invasive
breast cancer and other disease outcomes: The NSABP
study of tamoxifen and raloxifene (STAR) P-2 trial. JAMA
2006;295:2727–2741
43. Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for
breast cancer prevention in postmenopausal women. N Engl
J Med. 2011;364:2381–2391.
44. Riggs BL, Hartmann LC. Selective estrogen-receptor modu-
lators: Mechanisms of action and application to clinical prac-
tice. N Engl J Med. 2003;348:618–629.
45. O’Regan RM, Gradishar WJ. Selective estrogen-receptor
modulators in 2001. Oncology (Williston Park) 2001;15:1177–
1185, 1189.
46. Evans CT, Ledesma DB, Schulz TZ, Simpson ER, Mendelson
CR. Isolation and characterization of a complementary DNA
specific for human aromatase-system cytochrome P-450
mRNA. Proc Natl Acad Sci USA 1986;83:6387–6391.
47. Lycette JL, Luoh SW, Beer TM, Deloughery TG. Acute
bilateral pulmonary emboli occurring while on adju-
vant aromatase inhibitor therapy with anastrozole: Case
report and review of the literature. Breast Cancer Res Treat.
2006;99:249–255.
48. Mannucci PM, Bettega D, Chantarangkul V, Tripodi A,
Sacchini V, Veronesi U. Effect of tamoxifen on measure-
ments of hemostasis in healthy women. Arch Intern Med.
1996;156:1806–1810.
49. Jones AL, Powles TJ, Treleaven JG, et al. Haemostatic
changes and thromboembolic risk during tamoxifen therapy
in normal women. Br J Cancer 1992;66:744–747.
50. Cushman M, Costantino JP, Bovill EG, et al. Effect of tamoxi-
fen on venous thrombosis risk factors in women without
cancer: The Breast Cancer Prevention Trial. Br J Haematol.
2003;120:109–116.
51. Pemberton KD, Melissari E, Kakkar VV. The influence of
tamoxifen in vivo on the main natural anticoagulants and
fibrinolysis. Blood Coagul Fibrinolysis 1993;4:935–942.
52. Oberhoff C, Szymeczek J, Hoffmann O, Winkler UH, Kaiser
S, Schindler AE. Adjuvant antiestrogen treatment with
tamoxifen in postmenopausal women with breast cancer:
A longitudinal study of blood coagulation and fibrinolysis.
Breast Cancer Res Treat. 1998;50:73–81.
53. Cushman M, Costantino JP, Tracy RP, et al. Tamoxifen
and cardiac risk factors in healthy women: Suggestion of
an anti-inflammatory effect. Arterioscler Thromb Vasc Biol.
2001;21:255–261.
54. Powles T, Eeles R, Ashley S, et al. Interim analysis of the
incidence of breast cancer in the Royal Marsden Hospital
tamoxifen randomised chemoprevention trial. Lancet
1998;352:98–101.
55. Baumann DP, Crosby MA, Selber JC, et al. Optimal timing
of delayed free lower abdominal flap breast reconstruction
after postmastectomy radiation therapy. Plast Reconstr Surg.
2011;127:1100–1106.
56. Fosnot J, Fischer JP, Smartt JM Jr, et al. Does previous
chest wall irradiation increase vascular complications in
free autologous breast reconstruction? Plast Reconstr Surg.
2011;127:496–504.
57. Pritchard KI, Paterson AH, Paul NA, Zee B, Fine S, Pater J.
Increased thromboembolic complications with concurrent
tamoxifen and chemotherapy in a randomized trial of adju-
vant therapy for women with breast cancer: National Cancer
Institute of Canada Clinical Trials Group Breast Cancer Site
Group. J Clin Oncol. 1996;14:2731–2727.
58. Rickles FR, Levine MN. Venous thromboembolism in
malignancy and malignancy in venous thromboembolism.
Haemostasis 1998;28(Suppl 3):43–49.
59. Disa JJ. Discussion: Tamoxifen increases the risk of
microvascular flap complications in patients undergoing
microvascular breast reconstruction. Plast Reconstr Surg.
2012;129:315–316.
60. Mirzabeigi MN, Au A, Jandali S, Natoli N, Sbitany H, Serletti
JM. Trials and tribulations with the inferior gluteal artery
perforator flap in autologous breast reconstruction. Plast
Reconstr Surg. 2011;128:614e–624e.
61. Howell A, Cuzick J, Baum M, et al.; ATAC Trialists’ Group.
Results of the ATAC (Arimidex, Tamoxifen, Alone or in
Combination) trial after completion of 5 years’ adjuvant
treatment for breast cancer. Lancet 2005;365:60–62.
62. Baum M, Budzar AU, Cuzick J, et al.; ATAC Trialists’ Group.
Anastrozole alone or in combination with tamoxifen versus
tamoxifen alone for adjuvant treatment of postmenopausal
women with early breast cancer: First results of the ATAC
randomized trial. Lancet 2002;359:2131–2139.
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