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Statins, aspirin and risk of thromboembolic events in ovarian cancer patients
Gynecologic Oncology 133 (2014) 304–308
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Statins, aspirin and risk of thromboembolic events in ovarian cancer patients Ayelet Shai a,⁎, Hedy S. Rennert b, Gad Rennert b, Shlomi Sagi c, Michelle Leviov a, Ofer Lavie d a
Department of Oncology, Lin and Carmel Medical Centers, Clalit Health Services, Haifa, Israel Department of Community Medicine and Epidemiology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of Technology and Clalit Health Services National Cancer Control Center, Haifa, Israel c Department of Obstetrics and Gynecology, Bnai-Zion Medical Center, Haifa, Israel d Gynecology—Oncology Unit, Department of Obstetrics and Gynecology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa, Israel b
H I G H L I G H T S • We studied the association between statins and aspirin and risk of VTEs in patients with ovarian cancer. • Statin use was not associated with a reduced risk of VTEs in this cohort. • Aspirin use was associated with a decreased risk of VTEs that was marginally statistically significant.
a r t i c l e
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Article history: Received 5 November 2013 Accepted 4 March 2014 Available online 11 March 2014 Keywords: Ovarian cancer Statins Aspirin Venous thromboembolic events Deep vein thrombosis Pulmonary embolism
a b s t r a c t Objectives. Studies suggest that statins and low dose aspirin reduce risk of VTEs in the general population. We aimed to study the effect of these drugs on the incidence of VTEs in patients with ovarian cancer. Methods. Patients diagnosed with ovarian cancer between 2000 and 2011 were identified through the Clalit Health Services (CHS) chronic disease registry. Data were extracted from CHS database and from computerized pharmacy records. Use of medications was analyzed as a time dependent covariate in a Cox regression model. Results. Of 1746 patients 175 (10%) had a VTE during a median follow up of 3.13 years. 83 patients (5.6%) had a VTE within 2 years of diagnosis of ovarian cancer. Use of chemotherapy and stage 3 and 4 at presentation were associated with an increased risk for VTEs. Statins were used by 43.5% of the patients, and 32.3% used aspirin. Aspirin use was associated with a marginally significant reduction in incidence of VTEs within 2 years of diagnosis, HR 0.423 (95% CI 0.182–1.012, p-value 0.053). Statin use was not associated with risk of VTEs. Conclusion. This is the first study looking at the effect of statins and aspirin on the incidence of VTEs in ovarian cancer patients. In our cohort, statins did not decrease the risk for a VTE and aspirin use was associated with a reduced risk which was marginally significant. Our results might be explained by use of low potency statins and by alternate mechanisms for VTE formation in cancer patients. © 2014 Elsevier Inc. All rights reserved.
Introduction Ovarian cancer patients are at increased risk of venous thromboembolic events (VTEs) [1,2]. The incidence was reported to be about 3% in women recruited to randomized trials of first line chemotherapy [1], and as high as 10% in women treated outside a clinical trial [2–4]. VTEs are associated with increased risk of death in ovarian cancer patients [5,1], and patients treated for a VTE are also at increased risk of recurrent thromboembolism and bleeding [6]. ⁎ Corresponding author at: Department of Oncology, Lin and Carmel Medical Centers, Clalit Health Services, 35 Rotchild St., Haifa, Israel. Fax: +972 4 8568249. E-mail address: [email protected] (A. Shai).
http://dx.doi.org/10.1016/j.ygyno.2014.03.006 0090-8258/© 2014 Elsevier Inc. All rights reserved.
Statins are widely used to treat hypercholesterolemia. Several observational and case control studies have shown that use of statins is associated with a reduced risk for VTEs in the general population [7–12]. JUPITER was a randomized placebo controlled trial of rosuvastatin in adults with increased CRP level. Treatment with rosuvastatin decreased the incidence of symptomatic VTEs by 43% [13]. Several cohort studies did not find an association between statin use and risk of VTEs [14–16]. A recent metaanalysis of randomized trials of that used toxicity reporting to assess incidence of VTEs concluded that statins do not reduce the risk of these events [17]. The discrepancies between the different studies might be due to differences in statin strength and dose and in their design. Currently the effect of statins on VTE risk remains undetermined.
A. Shai et al. / Gynecologic Oncology 133 (2014) 304–308
Several mechanisms can explain the effect of statins on the risk of VTEs. Statins act by inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. This leads to inhibition of the Mevalonate pathway, affecting intracellular signaling pathways, resulting in anti-inflammatory, immune-modulatory, antioxidant and antithrombotic effects [18,19] and possibly anti-cancerous effects [20–23] as well. Low dose aspirin has been shown to reduce the risk of deep vein thrombosis and pulmonary embolism in surgical patients [24] and patients with a previous arterial occlusive event [25]. Randomized trials demonstrated that low dose aspirin reduces the risk of VTE recurrence after completion of oral anticoagulant treatment [26], and is as effective as low molecular weight heparin (LMWH) for VTE prophylaxis in multiple myeloma patients treated with thalidomide [27] or lenalidomide [28]. International guidelines do not support routine prophylactic use of anti-coagulants in ambulatory cancer patients [29]. Given their low cost and manageable safety profile, statins and aspirin could potentially serve as VTE prophylaxis in high risk patients with ovarian cancer. Statin use was shown to be associated with a decreased risk for a VTE in hospitalized patients with various solid tumors [30]. Our aim was to study the association between statins and aspirin and the incidence of VTEs in patients with ovarian cancer. Methods Study population Patients aged 18–90 years that were diagnosed with invasive epithelial ovarian cancer in Israel between 2000 and 2011 were identified through Clalit Health Services (CHS) chronic disease registry. Health care coverage in Israel is mandatory and is provided by four nonprofit organizations. Thus, all study participants had a similar basic health insurance plan and similar access to health services. Patients who took warfarin or LMWH for 3 months or longer were excluded. Patients were followed until study termination, death or diagnosis of VTE. The Institutional review board of Carmel Medical Center, Haifa, Israel, approved all procedures. Drug exposure data The use of statins, aspirin, warfarin and LMWH was determined on the basis of CHS pharmacy records that were available for all study participants. Chemotherapy use was determined on the basis of CHS pharmacy records and hospital and day-care admission data. The pharmacy records of CHS are a reliable source of use of medication data as co-payment for drugs is very low in Israel, making it unlikely that prescription medications were purchased in private, non-CHS pharmacies or as over the counter medications. Detailed prescription information enabled us to assess drug exposure over time and evaluate the risk of VTEs in relation to the time course of drug exposure. For the purpose of calculating exact exposure period to the drugs of interest we considered patients to be on statins until 1 month and on aspirin 1 week from the end of their last prescription. Chemotherapy exposure duration was defined as 1 month after each treatment day to avoid artificial gaps in treatment continuity caused by cycle delays. Additional data Diagnoses are coded based on tumor origin and histological subtype and stage at diagnosis is recorded as well. The Charlson comorbidity index predicts 10 year mortality for people with a wide range of medical conditions [31]. Comorbidities prior to the time of ovarian cancer diagnoses were retrieved from the CHS database. Patients were divided into two groups: Charlson index 0–2 vs 3 or more.
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End points The occurrence of deep vein thrombosis and/or pulmonary embolism was determined from the CHS database. Diagnoses assigned in the inpatient and outpatient setting are inserted to the database through hospital discharge records and by physicians working in the community setting. These diagnoses are coded and can thus be reliably retrieved. Patients were considered to have had an event if diagnosed with lower or upper extremity deep vein thrombosis and/or pulmonary embolism (ICD codes: 4511, 4442, 4512, 41511, 4151, 4511, 45111, 45119, 45181, 45340–2, 45184, 4532). Diagnoses of superficial vein thrombosis were not considered a VTE. Statistical analysis Statistical analysis was performed using SPSS (v 18). The use of medications was analyzed as a time dependent covariate in a Cox regression model. The incidence of events during drug exposure for the whole study population was compared to the incidence of events occurring at times without drug exposure. Results 1743 ovarian cancer patients were included in the study. Median follow up was 3.15 years, probably due to a high mortality rate in patients with ovarian cancer. Median age was 61.8 years. 168 (9.6%) patients had stage 1 disease at diagnosis, 318 (18.2%) had stage 2 disease, 981 (56.3%) had stage 3 or 4 and for 276 (15.8%) information regarding stage was missing. 759 (43.5%) patients used statins at any time during follow up and 563 (32.3%) used aspirin. Of aspirin users, 91% took 75–100 mg per day. 1532 (87.9%) were treated with chemotherapy. Of 981 patients with stage III and IV disease, 291 used statins and 387 used aspirin. 175 (10%) patients had a VTE during the follow up period. 83 (5.6%) patients had a VTE within 2 years of ovarian cancer diagnosis. The characteristics of patients that did and did not have a VTE are presented in Table 1. We analyzed the risk factors for VTEs within 2 years of diagnosis and throughout follow up. Factors included in the analysis were age, Charlson comorbidity Index, tumor stage, use of chemotherapy and statin and aspirin use. As shown in Table 2, on multivariate analysis only stage at diagnosis and chemotherapy use were associated with the risk for a VTE within 2 years of diagnosis and throughout follow up. The percentages of patients with VTEs according to stage at diagnosis are shown in Table 3. 30 patients had a VTE prior to diagnosis of ovarian cancer but were not treated by LMWH or warfarin and were thus included in the cohort. None of these patients had a VTE during follow up. Statin use was not associated with a reduced risk for VTEs within 2 years of diagnosis and throughout follow up. Use of aspirin was associated with a reduced risk of VTEs within 2 years of diagnosis Table 1 Characteristics of study participants. VTE—venous thromboembolic events.
Statins Aspirin Chemotherapy Stage 1 2 3+4 missing Charlson index 0–2 ≥3 Age (median)
With VTE (%)
Without VTE
71 (40.6) 51 (29.1) 171 (97.7)
688 (43.9) 512 (31.7) 1361 (86.6)
12 (7.7) 31 (19.9) 113 (64.6) 19 (10.9)
156 (11.9) 287 (21.9) 868 (55.4) 257 (16.4)
92 (52.6) 83 (47.4) 62.8
769 (49) 799 (51) 61.5
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A. Shai et al. / Gynecologic Oncology 133 (2014) 304–308
Table 2 Multivariate analysis of risk factors for VTE's within 2 years of diagnosis and throughout follow up. 2 years from diagnosis
Statins Aspirin Chemotherapy Age Charlson comorbidity index (0–2 vs 3) Stage 3 + 4
Throughout follow up
HR
95% CI
Pvalue
HR
95% C
Pvalue
1.419 0.429 3.113 1.014 1.17
0.867–2.234 0.182–1.012 1.919–5.052 0.990–1.038 0.678–2.02
0.164 0.053 N0.001 0.247 0.573
1.096 0.607 3.825 1.01 1.074
0.758–1.584 0.342–1.076 2.724–5.372 0.993–1.027 0.727–1.587
0.627 0.087 N0.001 0.269 0.719
3.439
1.075–11.067
1.84
1.004–3.372
0.049
0.037
which was marginally significant, with a hazard ratio of 0.429 (95% CI 0.182–1.012, p-value 0.053). The hazard ratio for risk of VTE at any time during follow up in aspirin users was 0.607 (95% CI 0.342–1.076, p-value 0.087). Fig. 1 depicts the types of statins that were used. Simvastatin was the most prevalent statin. 94.4% of users took simvastatin at least once, and 56.1% of statin prescriptions were for simvastatin. Additional 25.4% of prescriptions were for the lower potency statins of pravastatin and fluvastatin and only 16.6% of prescriptions were for the higher potency statins atorvastatin and rosuvastatin. 57.3% of simvastatin prescriptions were for 20 mg tablets, 26.3% were for 10 mg tablets, 15.5% for 40 mg and 0.9% for 80 mg. Since simvastatin was the predominant statin used we analyzed the association between the use of this drug and risk of VTEs. When compared to no statin use, simvastatin was not associated with a reduction in the risk of VTEs, with a HR of 1.203 (95% CI 0.682–2.114, p-value 0.52). Discussion Although statins and aspirin were shown by some to be associated with a reduced risk of VTEs in the general population (statins) and in high risk patients (aspirin), their effect on the incidence of VTEs in patients with ovarian cancer has not been studied. In previous studies statins and aspirin reduced the risk of VTEs by 30 to 50% [13–18,22,27, 28]. Our study had 97% power to detect a 50% reduction and 86% power to detect a 40% reduction in the incidence of VTEs among statin users. Among aspirin users, the study had 95% power to detect a 50% reduction and 80% power to detect a 40% reduction in the risk of VTEs. In contrast to most of the studies performed in the general population, our results suggest that in ovarian cancer patients, statin treatment does not reduce the risk of VTEs. It has been postulated that the protective effect of statins against VTEs is mediated by their anti-inflammatory properties [7,13] and possibly by their pro-fibrinolytic effects [32]. Cancer activates the coagulation system by various mechanisms, some of them, such as expression of cancer pro-coagulant [33] and abnormal expression of tissue factor [34] have been described only in malignant diseases. Exposure to chemotherapy is another risk factor unique to cancer patients. Statins might be less effective in preventing VTEs secondary to these mechanisms. One study reported that statin use is associated with a reduced incidence of VTEs in hospitalized cancer patients [30]. VTEs in hospitalized patients are often secondary to
Table 3 Percentage of patients with VTEs according to stage of disease at diagnosis.
Stage 1 Stage 2 Stage 3 + 4
VTE within 2 years (%)
VTE throughout follow up (%)
3/168 (1.8%) 15/318 (4.7%) 65/981 (6.6%)
12/168 (7.14%) 31/318 (9.75%) 113/981 (11.52%)
intercurrent illness such as infection and immobilization, potentially explaining the difference from our results. We have recently shown that statin use is not associated with a reduced risk of VTEs in ambulatory patients with breast cancer, further suggesting a differential effect of these drugs in patients with malignancy [35]. 56.1% of the prescriptions were for simvastatin and 27.3% for lower potency statins. Simvastatin use was not associated with a reduced risk for VTEs in our cohort. The use of simvastatin has been shown to be associated with a reduced risk of VTEs in the general population. A recent observational study showed that the association between simvastatin use and VTE risk is related to dose [36]. Hippesilley-Cox et al. found a marginal protective effect for simvastatin, larger effects for the higher potency statins atorvastatin and rosuvastatin, and lack of effect for lower potency statins [15]. However, although there is evidence supporting the protective effect of simvastatin on VTE risk we cannot rule out the possibility that use of higher potency statins is associated with a reduction in the incidence of VTEs in ovarian cancer patients. In our cohort use of aspirin was associated with a trend for decreased risk of VTEs within 2 years of ovarian cancer diagnosis. The association became weaker for events that occurred throughout follow up. This might be due to a greater number of patients relapsing with advanced disease over time and a reduced efficacy of aspirin in this scenario. 91% of patients used low dose aspirin (75–100 mg/d). Low dose aspirin has been shown to decrease the incidence of VTEs in several populations at risk [24,26,28,27,25]. It is possible however, that a higher dose of aspirin is needed to reduce the risk of VTEs in patients with ovarian cancer. Our previous study in patients with breast cancer did not show an association between aspirin use and reduced risk of VTEs [35]. Randomized trials would be needed to evaluate the effect of aspirin on the risk of VTEs in patients with ovarian cancer. Our cohort included all consecutive women diagnosed with invasive epithelial ovarian cancer in Israel between 2000 and 2011 that were insured by the largest health provider in Israel. The incidence of VTEs in our cohort is comparable to the incidence in other published series [2,1,3,4]. Tumor stage and chemotherapy treatment emerged as significant risk factors for VTE, in agreement with other published data [3,4]. This suggests that our cohort is representative of ovarian cancer patients treated in the general oncology setting. The association between drug use and VTE risk was analyzed as a time dependent covariate. This analysis compares the incidence of events during drug exposure in all patients to the incidence at times without drug exposure and is especially suitable for a retrospective study aiming to evaluate the effect of drugs on acute events like VTEs. In addition, our methodology avoids the possible bias of classifying patients as drug “users” and “non-users” based on medication used at study entry. Our study has several limitations. Obesity is a well recognized risk factor for VTEs in ovarian cancer patients [4,2] and is probably linked to statin and aspirin use. We had data on BMI for only 25% of patients, and thus omitted this variable from our analysis. It is possible that the observed effect of statins and aspirin was attenuated due to the lack of information regarding BMI in our study. Statins have been linked to reduced mortality from ovarian cancer. A borderline significant risk reduction was reported in a population study from Denmark [37] and two retrospective studies suggested that statin users have a better prognosis compared to non-users after cytoreduction and chemotherapy [23,38]. In the study by Lavie et al. only women who commenced statin treatment after diagnosis of ovarian cancer had improved survival [23]. Low dose aspirin is also associated with reduced cancer mortality. In an analysis of randomized trials of primary prevention for cardiovascular disease, treatment with low dose aspirin resulted in lower cancer death and metastasis, an effect that was more prominent in patients with adenocarcinoma [39,40]. We did not have data on disease recurrence in this study. Controlling for the use of chemotherapy in a time dependent manner accounted for cases that were treated with
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Fig. 1. Types of statins used. A: Percentage of prescriptions distributed. B: Percentage of users ever using each statin.
chemotherapy for recurrent disease, but we could not account for all recurrences. Since advanced stage disease is a risk factor for VTEs, it is possible that the effect of statins and aspirin on disease outcome acted as a confounder.
Conclusion In contrary to findings in the general population, statin use was not associated with a reduced risk for VTEs in our cohort of ovarian cancer patients. This might be due to alternate mechanisms for VTE formation in these patients, or to the prevalent use of low potency statins. Aspirin use was associated with a trend for a reduced risk for VTEs, which was more prominent within the first 2 years after diagnosis. Randomized trials are needed to confirm the effect of aspirin on VTE risk in ovarian cancer patients.
Conflict of interest statement All authors have no conflict of interests to declare.
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Statins, aspirin and risk of thromboembolic events in ovarian cancer patients Ayelet Shai a,⁎, Hedy S. Rennert b, Gad Rennert b, Shlomi Sagi c, Michelle Leviov a, Ofer Lavie d a
Department of Oncology, Lin and Carmel Medical Centers, Clalit Health Services, Haifa, Israel Department of Community Medicine and Epidemiology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of Technology and Clalit Health Services National Cancer Control Center, Haifa, Israel c Department of Obstetrics and Gynecology, Bnai-Zion Medical Center, Haifa, Israel d Gynecology—Oncology Unit, Department of Obstetrics and Gynecology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa, Israel b
H I G H L I G H T S • We studied the association between statins and aspirin and risk of VTEs in patients with ovarian cancer. • Statin use was not associated with a reduced risk of VTEs in this cohort. • Aspirin use was associated with a decreased risk of VTEs that was marginally statistically significant.
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Article history: Received 5 November 2013 Accepted 4 March 2014 Available online 11 March 2014 Keywords: Ovarian cancer Statins Aspirin Venous thromboembolic events Deep vein thrombosis Pulmonary embolism
a b s t r a c t Objectives. Studies suggest that statins and low dose aspirin reduce risk of VTEs in the general population. We aimed to study the effect of these drugs on the incidence of VTEs in patients with ovarian cancer. Methods. Patients diagnosed with ovarian cancer between 2000 and 2011 were identified through the Clalit Health Services (CHS) chronic disease registry. Data were extracted from CHS database and from computerized pharmacy records. Use of medications was analyzed as a time dependent covariate in a Cox regression model. Results. Of 1746 patients 175 (10%) had a VTE during a median follow up of 3.13 years. 83 patients (5.6%) had a VTE within 2 years of diagnosis of ovarian cancer. Use of chemotherapy and stage 3 and 4 at presentation were associated with an increased risk for VTEs. Statins were used by 43.5% of the patients, and 32.3% used aspirin. Aspirin use was associated with a marginally significant reduction in incidence of VTEs within 2 years of diagnosis, HR 0.423 (95% CI 0.182–1.012, p-value 0.053). Statin use was not associated with risk of VTEs. Conclusion. This is the first study looking at the effect of statins and aspirin on the incidence of VTEs in ovarian cancer patients. In our cohort, statins did not decrease the risk for a VTE and aspirin use was associated with a reduced risk which was marginally significant. Our results might be explained by use of low potency statins and by alternate mechanisms for VTE formation in cancer patients. © 2014 Elsevier Inc. All rights reserved.
Introduction Ovarian cancer patients are at increased risk of venous thromboembolic events (VTEs) [1,2]. The incidence was reported to be about 3% in women recruited to randomized trials of first line chemotherapy [1], and as high as 10% in women treated outside a clinical trial [2–4]. VTEs are associated with increased risk of death in ovarian cancer patients [5,1], and patients treated for a VTE are also at increased risk of recurrent thromboembolism and bleeding [6]. ⁎ Corresponding author at: Department of Oncology, Lin and Carmel Medical Centers, Clalit Health Services, 35 Rotchild St., Haifa, Israel. Fax: +972 4 8568249. E-mail address: [email protected] (A. Shai).
http://dx.doi.org/10.1016/j.ygyno.2014.03.006 0090-8258/© 2014 Elsevier Inc. All rights reserved.
Statins are widely used to treat hypercholesterolemia. Several observational and case control studies have shown that use of statins is associated with a reduced risk for VTEs in the general population [7–12]. JUPITER was a randomized placebo controlled trial of rosuvastatin in adults with increased CRP level. Treatment with rosuvastatin decreased the incidence of symptomatic VTEs by 43% [13]. Several cohort studies did not find an association between statin use and risk of VTEs [14–16]. A recent metaanalysis of randomized trials of that used toxicity reporting to assess incidence of VTEs concluded that statins do not reduce the risk of these events [17]. The discrepancies between the different studies might be due to differences in statin strength and dose and in their design. Currently the effect of statins on VTE risk remains undetermined.
A. Shai et al. / Gynecologic Oncology 133 (2014) 304–308
Several mechanisms can explain the effect of statins on the risk of VTEs. Statins act by inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. This leads to inhibition of the Mevalonate pathway, affecting intracellular signaling pathways, resulting in anti-inflammatory, immune-modulatory, antioxidant and antithrombotic effects [18,19] and possibly anti-cancerous effects [20–23] as well. Low dose aspirin has been shown to reduce the risk of deep vein thrombosis and pulmonary embolism in surgical patients [24] and patients with a previous arterial occlusive event [25]. Randomized trials demonstrated that low dose aspirin reduces the risk of VTE recurrence after completion of oral anticoagulant treatment [26], and is as effective as low molecular weight heparin (LMWH) for VTE prophylaxis in multiple myeloma patients treated with thalidomide [27] or lenalidomide [28]. International guidelines do not support routine prophylactic use of anti-coagulants in ambulatory cancer patients [29]. Given their low cost and manageable safety profile, statins and aspirin could potentially serve as VTE prophylaxis in high risk patients with ovarian cancer. Statin use was shown to be associated with a decreased risk for a VTE in hospitalized patients with various solid tumors [30]. Our aim was to study the association between statins and aspirin and the incidence of VTEs in patients with ovarian cancer. Methods Study population Patients aged 18–90 years that were diagnosed with invasive epithelial ovarian cancer in Israel between 2000 and 2011 were identified through Clalit Health Services (CHS) chronic disease registry. Health care coverage in Israel is mandatory and is provided by four nonprofit organizations. Thus, all study participants had a similar basic health insurance plan and similar access to health services. Patients who took warfarin or LMWH for 3 months or longer were excluded. Patients were followed until study termination, death or diagnosis of VTE. The Institutional review board of Carmel Medical Center, Haifa, Israel, approved all procedures. Drug exposure data The use of statins, aspirin, warfarin and LMWH was determined on the basis of CHS pharmacy records that were available for all study participants. Chemotherapy use was determined on the basis of CHS pharmacy records and hospital and day-care admission data. The pharmacy records of CHS are a reliable source of use of medication data as co-payment for drugs is very low in Israel, making it unlikely that prescription medications were purchased in private, non-CHS pharmacies or as over the counter medications. Detailed prescription information enabled us to assess drug exposure over time and evaluate the risk of VTEs in relation to the time course of drug exposure. For the purpose of calculating exact exposure period to the drugs of interest we considered patients to be on statins until 1 month and on aspirin 1 week from the end of their last prescription. Chemotherapy exposure duration was defined as 1 month after each treatment day to avoid artificial gaps in treatment continuity caused by cycle delays. Additional data Diagnoses are coded based on tumor origin and histological subtype and stage at diagnosis is recorded as well. The Charlson comorbidity index predicts 10 year mortality for people with a wide range of medical conditions [31]. Comorbidities prior to the time of ovarian cancer diagnoses were retrieved from the CHS database. Patients were divided into two groups: Charlson index 0–2 vs 3 or more.
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End points The occurrence of deep vein thrombosis and/or pulmonary embolism was determined from the CHS database. Diagnoses assigned in the inpatient and outpatient setting are inserted to the database through hospital discharge records and by physicians working in the community setting. These diagnoses are coded and can thus be reliably retrieved. Patients were considered to have had an event if diagnosed with lower or upper extremity deep vein thrombosis and/or pulmonary embolism (ICD codes: 4511, 4442, 4512, 41511, 4151, 4511, 45111, 45119, 45181, 45340–2, 45184, 4532). Diagnoses of superficial vein thrombosis were not considered a VTE. Statistical analysis Statistical analysis was performed using SPSS (v 18). The use of medications was analyzed as a time dependent covariate in a Cox regression model. The incidence of events during drug exposure for the whole study population was compared to the incidence of events occurring at times without drug exposure. Results 1743 ovarian cancer patients were included in the study. Median follow up was 3.15 years, probably due to a high mortality rate in patients with ovarian cancer. Median age was 61.8 years. 168 (9.6%) patients had stage 1 disease at diagnosis, 318 (18.2%) had stage 2 disease, 981 (56.3%) had stage 3 or 4 and for 276 (15.8%) information regarding stage was missing. 759 (43.5%) patients used statins at any time during follow up and 563 (32.3%) used aspirin. Of aspirin users, 91% took 75–100 mg per day. 1532 (87.9%) were treated with chemotherapy. Of 981 patients with stage III and IV disease, 291 used statins and 387 used aspirin. 175 (10%) patients had a VTE during the follow up period. 83 (5.6%) patients had a VTE within 2 years of ovarian cancer diagnosis. The characteristics of patients that did and did not have a VTE are presented in Table 1. We analyzed the risk factors for VTEs within 2 years of diagnosis and throughout follow up. Factors included in the analysis were age, Charlson comorbidity Index, tumor stage, use of chemotherapy and statin and aspirin use. As shown in Table 2, on multivariate analysis only stage at diagnosis and chemotherapy use were associated with the risk for a VTE within 2 years of diagnosis and throughout follow up. The percentages of patients with VTEs according to stage at diagnosis are shown in Table 3. 30 patients had a VTE prior to diagnosis of ovarian cancer but were not treated by LMWH or warfarin and were thus included in the cohort. None of these patients had a VTE during follow up. Statin use was not associated with a reduced risk for VTEs within 2 years of diagnosis and throughout follow up. Use of aspirin was associated with a reduced risk of VTEs within 2 years of diagnosis Table 1 Characteristics of study participants. VTE—venous thromboembolic events.
Statins Aspirin Chemotherapy Stage 1 2 3+4 missing Charlson index 0–2 ≥3 Age (median)
With VTE (%)
Without VTE
71 (40.6) 51 (29.1) 171 (97.7)
688 (43.9) 512 (31.7) 1361 (86.6)
12 (7.7) 31 (19.9) 113 (64.6) 19 (10.9)
156 (11.9) 287 (21.9) 868 (55.4) 257 (16.4)
92 (52.6) 83 (47.4) 62.8
769 (49) 799 (51) 61.5
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Table 2 Multivariate analysis of risk factors for VTE's within 2 years of diagnosis and throughout follow up. 2 years from diagnosis
Statins Aspirin Chemotherapy Age Charlson comorbidity index (0–2 vs 3) Stage 3 + 4
Throughout follow up
HR
95% CI
Pvalue
HR
95% C
Pvalue
1.419 0.429 3.113 1.014 1.17
0.867–2.234 0.182–1.012 1.919–5.052 0.990–1.038 0.678–2.02
0.164 0.053 N0.001 0.247 0.573
1.096 0.607 3.825 1.01 1.074
0.758–1.584 0.342–1.076 2.724–5.372 0.993–1.027 0.727–1.587
0.627 0.087 N0.001 0.269 0.719
3.439
1.075–11.067
1.84
1.004–3.372
0.049
0.037
which was marginally significant, with a hazard ratio of 0.429 (95% CI 0.182–1.012, p-value 0.053). The hazard ratio for risk of VTE at any time during follow up in aspirin users was 0.607 (95% CI 0.342–1.076, p-value 0.087). Fig. 1 depicts the types of statins that were used. Simvastatin was the most prevalent statin. 94.4% of users took simvastatin at least once, and 56.1% of statin prescriptions were for simvastatin. Additional 25.4% of prescriptions were for the lower potency statins of pravastatin and fluvastatin and only 16.6% of prescriptions were for the higher potency statins atorvastatin and rosuvastatin. 57.3% of simvastatin prescriptions were for 20 mg tablets, 26.3% were for 10 mg tablets, 15.5% for 40 mg and 0.9% for 80 mg. Since simvastatin was the predominant statin used we analyzed the association between the use of this drug and risk of VTEs. When compared to no statin use, simvastatin was not associated with a reduction in the risk of VTEs, with a HR of 1.203 (95% CI 0.682–2.114, p-value 0.52). Discussion Although statins and aspirin were shown by some to be associated with a reduced risk of VTEs in the general population (statins) and in high risk patients (aspirin), their effect on the incidence of VTEs in patients with ovarian cancer has not been studied. In previous studies statins and aspirin reduced the risk of VTEs by 30 to 50% [13–18,22,27, 28]. Our study had 97% power to detect a 50% reduction and 86% power to detect a 40% reduction in the incidence of VTEs among statin users. Among aspirin users, the study had 95% power to detect a 50% reduction and 80% power to detect a 40% reduction in the risk of VTEs. In contrast to most of the studies performed in the general population, our results suggest that in ovarian cancer patients, statin treatment does not reduce the risk of VTEs. It has been postulated that the protective effect of statins against VTEs is mediated by their anti-inflammatory properties [7,13] and possibly by their pro-fibrinolytic effects [32]. Cancer activates the coagulation system by various mechanisms, some of them, such as expression of cancer pro-coagulant [33] and abnormal expression of tissue factor [34] have been described only in malignant diseases. Exposure to chemotherapy is another risk factor unique to cancer patients. Statins might be less effective in preventing VTEs secondary to these mechanisms. One study reported that statin use is associated with a reduced incidence of VTEs in hospitalized cancer patients [30]. VTEs in hospitalized patients are often secondary to
Table 3 Percentage of patients with VTEs according to stage of disease at diagnosis.
Stage 1 Stage 2 Stage 3 + 4
VTE within 2 years (%)
VTE throughout follow up (%)
3/168 (1.8%) 15/318 (4.7%) 65/981 (6.6%)
12/168 (7.14%) 31/318 (9.75%) 113/981 (11.52%)
intercurrent illness such as infection and immobilization, potentially explaining the difference from our results. We have recently shown that statin use is not associated with a reduced risk of VTEs in ambulatory patients with breast cancer, further suggesting a differential effect of these drugs in patients with malignancy [35]. 56.1% of the prescriptions were for simvastatin and 27.3% for lower potency statins. Simvastatin use was not associated with a reduced risk for VTEs in our cohort. The use of simvastatin has been shown to be associated with a reduced risk of VTEs in the general population. A recent observational study showed that the association between simvastatin use and VTE risk is related to dose [36]. Hippesilley-Cox et al. found a marginal protective effect for simvastatin, larger effects for the higher potency statins atorvastatin and rosuvastatin, and lack of effect for lower potency statins [15]. However, although there is evidence supporting the protective effect of simvastatin on VTE risk we cannot rule out the possibility that use of higher potency statins is associated with a reduction in the incidence of VTEs in ovarian cancer patients. In our cohort use of aspirin was associated with a trend for decreased risk of VTEs within 2 years of ovarian cancer diagnosis. The association became weaker for events that occurred throughout follow up. This might be due to a greater number of patients relapsing with advanced disease over time and a reduced efficacy of aspirin in this scenario. 91% of patients used low dose aspirin (75–100 mg/d). Low dose aspirin has been shown to decrease the incidence of VTEs in several populations at risk [24,26,28,27,25]. It is possible however, that a higher dose of aspirin is needed to reduce the risk of VTEs in patients with ovarian cancer. Our previous study in patients with breast cancer did not show an association between aspirin use and reduced risk of VTEs [35]. Randomized trials would be needed to evaluate the effect of aspirin on the risk of VTEs in patients with ovarian cancer. Our cohort included all consecutive women diagnosed with invasive epithelial ovarian cancer in Israel between 2000 and 2011 that were insured by the largest health provider in Israel. The incidence of VTEs in our cohort is comparable to the incidence in other published series [2,1,3,4]. Tumor stage and chemotherapy treatment emerged as significant risk factors for VTE, in agreement with other published data [3,4]. This suggests that our cohort is representative of ovarian cancer patients treated in the general oncology setting. The association between drug use and VTE risk was analyzed as a time dependent covariate. This analysis compares the incidence of events during drug exposure in all patients to the incidence at times without drug exposure and is especially suitable for a retrospective study aiming to evaluate the effect of drugs on acute events like VTEs. In addition, our methodology avoids the possible bias of classifying patients as drug “users” and “non-users” based on medication used at study entry. Our study has several limitations. Obesity is a well recognized risk factor for VTEs in ovarian cancer patients [4,2] and is probably linked to statin and aspirin use. We had data on BMI for only 25% of patients, and thus omitted this variable from our analysis. It is possible that the observed effect of statins and aspirin was attenuated due to the lack of information regarding BMI in our study. Statins have been linked to reduced mortality from ovarian cancer. A borderline significant risk reduction was reported in a population study from Denmark [37] and two retrospective studies suggested that statin users have a better prognosis compared to non-users after cytoreduction and chemotherapy [23,38]. In the study by Lavie et al. only women who commenced statin treatment after diagnosis of ovarian cancer had improved survival [23]. Low dose aspirin is also associated with reduced cancer mortality. In an analysis of randomized trials of primary prevention for cardiovascular disease, treatment with low dose aspirin resulted in lower cancer death and metastasis, an effect that was more prominent in patients with adenocarcinoma [39,40]. We did not have data on disease recurrence in this study. Controlling for the use of chemotherapy in a time dependent manner accounted for cases that were treated with
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Fig. 1. Types of statins used. A: Percentage of prescriptions distributed. B: Percentage of users ever using each statin.
chemotherapy for recurrent disease, but we could not account for all recurrences. Since advanced stage disease is a risk factor for VTEs, it is possible that the effect of statins and aspirin on disease outcome acted as a confounder.
Conclusion In contrary to findings in the general population, statin use was not associated with a reduced risk for VTEs in our cohort of ovarian cancer patients. This might be due to alternate mechanisms for VTE formation in these patients, or to the prevalent use of low potency statins. Aspirin use was associated with a trend for a reduced risk for VTEs, which was more prominent within the first 2 years after diagnosis. Randomized trials are needed to confirm the effect of aspirin on VTE risk in ovarian cancer patients.
Conflict of interest statement All authors have no conflict of interests to declare.
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