Thrombosis Research 134 (2014) 1008–1013
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Regular Article
Statins are Associated with Low Risk of Venous Thromboembolism in Patients with Cancer: A Prospective and Observational Cohort Study☆ Felix Lötsch a, Oliver Königsbrügge a, Florian Posch a, Christoph Zielinski b, Ingrid Pabinger a, Cihan Ay a,⁎ a b
Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18 – 20, A-1090 Vienna, Austria Clincial Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18 – 20, A-1090 Vienna, Austria
a r t i c l e
i n f o
Article history: Received 11 June 2014 Received in revised form 5 August 2014 Accepted 1 September 2014 Available online 6 September 2014 Keywords: Neoplasms Statins Simvastatin Thrombosis Venous thromboembolism
a b s t r a c t Introduction: Patients with cancer are at risk of venous thromboembolism (VTE). Statin-use has been shown to be associated with low risk of VTE in patients without cancer, but data in cancer patients is scarce. The objective of this study was to evaluate the association of statins with risk of VTE in cancer patients in a prospective observational cohort study. Materials and Methods: Patients with newly diagnosed cancer or progression of disease after remission were included and prospectively followed for a maximum of 2 years. Study endpoint was occurrence of symptomatic VTE. Results: Patients (n = 1434) were followed over a median observation period of 729 days. VTE occurred in 107 (7.5%) patients. At study inclusion, 170 (11.9%) patients took statins. Simvastatin (n = 96) and atorvastatin (n = 48) were the most frequently prescribed statins. VTE occurred in 6 (3.5%) patients with statins. Patients with statins had a lower risk of VTE than patients without (subhazard ratio 0.43, 95% confidence interval 0.19 to 0.98; p = 0.04). In competing risk analysis, the cumulative probability of VTE in patients with statins was 2.94% after 12 months and 3.54% after 24 months, compared to 7.13% and 8.13% in the group without statins (Gray’s test: p = 0.04). Conclusion: This study provides observational evidence for an association between statin use and low risk of VTE in patients with cancer. The role of statins for prevention of cancer-associated VTE needs to be confirmed in randomized, controlled trials. © 2014 Elsevier Ltd. All rights reserved.
Introduction The association between thrombosis and cancer has been recognized since the 19th century [1]. Today, malignancy is a well-established, independent and major risk factor of venous thromboembolism (VTE). The incidence of VTE is as high as 30% in certain subgroups [2] and depends largely on various cancer-, treatment-and patient-related risk factors [3–5]. Recently, risk stratification scores have been developed to improve individualized assessment of a cancer patient’s VTE risk [6–8]. These scores include clinical and laboratory parameters such as tumour entity, body mass index, haemoglobin levels, leucocyte and platelet count. An expanded version of this risk stratification score additionally comprises biomarkers such as D-dimer and sP-selectin [7]. In epidemiologic studies, statins have been shown to significantly reduce the risk of VTE in different populations. “The Heart and Estrogen/
☆ An abstract of this study was presented at the Annual Meeting of the Society for Thrombosis and Haemostasis Research (GTH) in February 2013 in Munich, Germany. ⁎ Corresponding author at: Comprehensive Cancer Center, Department of Medicine I, Clinical Division of Haematology and Haemostaseology, Waehringer Guertel 18-20, A1090 Vienna, Austria. Tel.: +43 1 40400 4410; fax: +43 1 40400 4030. E-mail address: [email protected] (C. Ay).
http://dx.doi.org/10.1016/j.thromres.2014.09.001 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
Progestin Replacement Study (HERS)” provided the first evidence that individuals using statins had a 50% risk reduction for VTE [9]. More recently, in a randomized controlled interventional trial for prevention of vascular events (JUPITER-trial), rosuvastatin significantly reduced the risk of VTE [10]. The association between statins and low risk of VTE has been corroborated in three meta-analyses [11–13]. However, the findings in the largest meta-analysis on the association of statins and risk of VTE by Rahimi et al. do not support a substantial risk reduction [14]. On the other side, specific data for patients with cancer are very scarce. In a retrospective evaluation of cancer patients, Khemasuwan et al. reported a lower frequency of VTE in patients on statins [15]. Statins are known to have pleiotropic effects on the cardiovascular system. As shown in the JUPITER trial, they effectively reduce Creactive protein (CRP), a marker of inflammation [16]. Furthermore, they improve endothelial function, mobilize endothelial progenitor cells [17], inhibit platelet activation [18], and enhance the stability of atherosclerotic plaques [19]. Statins also show antithrombotic effects. They affect the blood coagulation system through different pathways, including inhibition of plasmatic haemostasis and platelet activation [20]. Two key anti-thrombotic mechanisms of statins are the downregulation of tissue factor (TF) in endothelial cells and monocytes
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and the up-regulation of thrombomodulin [20,22–24], which are thought to be mediated by inhibition of the Rho/Rho kinase pathway [21]. Although each type of statin has been suggested to exert antithrombotic effects, clinical and epidemiologic studies have not elaborated so far, whether all types of statins show the same efficacy in preventing VTE. Thus, our aim was to investigate the association of statins with the risk of cancer-associated VTE in a prospective and observational cohort study. Methods Study population The study population consisted of patients recruited between October 2003 and April 2011 in the framework of the Vienna Cancer and Thrombosis study (CATS), an on-going prospective observational cohort-study conducted at the Medical University of Vienna, Austria, with approval of the local ethics committee and in agreement with the Declaration of Helsinki (ID of approval: 126/2003). Participants were randomly recruited and gave written, informed consent prior to study inclusion. The detailed methods of CATS have been described in previous publications [25,26]. In summary, the study included patients with newly diagnosed cancer or with progressive disease after remission. Exclusion criteria were overt bacterial or viral infection, recent chemotherapy and recent arterial or venous thromboembolism (within the last 3 months), radiotherapy or surgery (within the last 2 weeks) and continuous anticoagulation with vitamin K antagonists or lowmolecular-weight heparins (LMWH). Patients receiving drugs such as aspirin, clopidogrel or short-term anticoagulation with LMWH (e.g. for thromboprophylaxis during hospitalisation) were allowed to participate. Patients were observed for a maximum period of two years or until the occurrence of VTE, death, loss of follow-up or withdrawal of consent. At study inclusion blood samples were taken for laboratory analyses. Diagnosis of VTE Patients were instructed about the symptoms of VTE and requested to report when such symptoms occurred, but no active screening for VTE was conducted. In case of symptoms objective imaging methods were used to confirm or exclude the diagnosis of VTE [25–27]. In patients who had died during follow-up, death certificates and autopsy-reports, if available, were reviewed to establish or exclude the diagnosis of fatal PE or VTE. Then, all VTE events were presented to an independent adjudication committee including experts in the fields of angiology, radiology and nuclear medicine. The adjudication committee confirmed or rejected the diagnosis. Accidentally detected VTE was considered as event, if the committee decided that the respective event was of clinical significance.
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Laboratory analyses The methodology of taking blood samples and the applied laboratory methods for measurement of D-dimer, soluble P-selectin (sP-selectin) and factor VIII (FVIII) activity have been described in previous publications [25–27]. Blood count parameters were routinely determined with Sysmex XE-2100 haematology analyzer. CRP serum levels were measured by an immunonephelometric assay (Olympus Diagnostics, Southall, UK) on an AU 2700 chemistry analyzer [28]. Reference ranges are presented in supplementary Table 1. Statistical analysis All statistical analyses were performed using Stata (Windows version 12.0, Stata Corp., TX, USA) and R (Windows version 3.0.1, The R Foundation for Statistical Computing). Median, 25th and 75th percentile were used to describe continuous variables. T-test, X-squared test and Fisher’s exact test were applied to compare the distribution of laboratory and demographic parameters between different groups. A Competing risk (CR) analysis incorporating all-cause mortality as the competing event was used to investigate the association between the use of statins and time-to-VTE. In detail, the cumulative incidences of VTE over time and their 95% CI were computed according to the estimators of Marubini & Valsecchi (Stata’s stcompet suite). Cumulative incidence functions were compared between groups using Gray’s test (R library cmprsk) [29]. Uni- and multivariable competing risk regression models according to Fine & Gray were fitted to model the subhazard ratio (SHR) of VTE [30]. First, a univariable model with statin-use as the only variable was fitted. Then several multivariable analyses were modelled to adjust for possible confounders, such as use of antiplatelet drugs, certain comorbidities, laboratory-parameters predictive for VTE and unequally distributed demographic variables. As patients with and without statins differed with respect to several baseline variables (Table 1), we performed a sensitivity analysis using propensity score methods. These methods aim towards a more causal analysis of treatment effect in observational studies than regular covariate adjustment. We first estimated a propensity score (i.e. the probability to be in the statin group) for each patient using multivariable logistic regression with the predictor variables tumour site, tumour stage, use of antiplatelet drugs, age, BMI, prior history of myocardial infarction, diabetes at baseline, proton-pump inhibitor use at baseline and allopurinol use at baseline. We then stratified Gray’s test according to quintiles of this propensity score, and included the quintiles as covariates in the uni- and multivariable Fine & Gray models. Further sensitivity analyses included stratifying the Fine & Gray models on quintiles of the propensity score, and using inverse probability of treatment weighting (IPTW) on the propensity score (not shown, highly comparable results obtained) [31]. No propensity score analyses were performed for the statin-type subgroup comparisons. A p-value b 0.05 was considered to indicate statistical significance. Results
Identification of patients with use of statin Patients During the structured interview at study inclusion all study investigators placed great emphasis on taking a correct and complete medical history. In particular, patients were asked about their current medication including the information on the use of statins and the specific type of statin that was used. Additionally, medical reports of patients in a time-frame between one month before and three months after study inclusion were reviewed to complete the data and verify the information on the use and type of statin. Also the records of regular follow-up protocols, telephone conversations with patients, family members, treating oncologist/haemato-oncologist and general practitioners that were made during follow-up were searched for the use of statins.
In total, 1434 patients were observed over a median observation time of 729 days (25th to 75th percentile: 227 to 731) in the current study. Of those, 801 were men and 633 women. The median age of the study population was 61 years (25th to 75th percentile: 52 to 68). The most frequent cancer sites were lymphoma (n = 237), lung (n = 215), breast (n = 199), brain (n = 182), prostate (n = 148) and colon (n = 146). In the total study population, 170 (11.9%) patients with use of statin were identified, of whom 96 received simvastatin (56.5% of statin users), 48 atorvastatin (28.2%), 14 pravastatin (8.2%), 6 rosuvastatin (3.5%), 5 fluvastatin (2.9%) and 1 patient received lovastatin (0.6%).
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Table 1 Baseline demographic and clinical characteristic of the study population (n = 1434). Variable
n (% missing)
Overall (Q1; Q3)
Statin-users (Q1; Q3)
Non-statin user (Q1; Q3)
p-value
Age (years) BMI (kg/m2) Female Gender Newly diagnosed cancer (yes) High or very high-risk tumour site+ (yes) Tumor site Lymphoma Lung Breast Brain Prostate Colon Pancreas Stomach Kidney Multiple Myeloma Other site Use of antiplatelet drugs Platelet count (G/L) Leukocyte count (G/L) CRP (mg/L) D-Dimer (μg/mL) sP-selectin (ng/mL) FVIII (% activity) Haemoglobin (g/dL) Prior history of VTE Prior myocardial infarction Diabetes Khorana Score
1434 (0.0%) 1432 (0.1%) 1434 (0.0%) 1434 (0.0%) 1434 (0.0%) 1434 (0.0%) / / / / / / / / / / / 1434 (0.0%) 1428 (0.4%) 1428 (0.4%) 1323 (7.7%) 1368 (4.6%) 1430 (0.3%) 1362 (5.0%) 1428 (0.4%) 1434 (0.0%) 1434 (0.0%) 1434 (0.0%) 1434 (0.0%)
61 (52; 68) 25 (22; 28) 633 (44.1%) 1029 (71.8%) 854 (59.6%) / 237 (16.5%) 215 (15.0%) 199 (13.9%) 182 (12.7%) 148 (10.3%) 146 (10.2%) 85 (5.9%) 57 (4.0%) 40 (2.8%) 38 (2.6%) 87 (6.1%) 213 (14.9%) 244 (193; 304) 7.15 (5.62; 9.56) 0.51 (0.16; 1.67) 0.66 (0.34; 1.40) 40.5 (31.1; 51.6) 183 (142; 234) 13.1 (11.8; 14.1) 75 (5.2%) 64 (4.5%) 170 (11.9%) 1 (0; 1)
65 (61; 70) 27 (24; 40) 56 (32.9%) 131 (77.1%) 99 (58.2%) / 17 (10.0%) 38 (22.4%) 18 (10.6%) 20 (11.8%) 27 (15.9%) 14 (8.2%) 8 (4.7%) 6 (3.5%) 7 (4.1%) 3 (1.8%) 12 (7.1%) 87 (51.2%) 235 (184; 282) 7.07 (5.86; 9.11) 0.58 (0.16; 1.35) 0.61 (0.34; 1.42) 39.9 (30.1; 52.6) 194 (157; 239) 13.3 (11.9; 14.3) 14 (8.2%) 36 (21.2%) 41 (24.1%) 1 (0; 1)
60 (51; 67) 25 (22; 28) 577 (45.7%) 888 (70.3%) 755 (59.7%) / 220 (17.4) 177 (14.0%) 181 (14.3%) 162 (12.8%) 121 9.6%) 132 (10.4%) 77 (6.1%) 51 (4.0% 33 (2.6%) 35 (2.8%) 75 (6.0%) 126 (10.0%) 245 (195; 308) 7.15 (5.61; 9.58) 0.5 (0.17; 1.71) 0.67 (0.34; 1.39) 40.6 (31.4 - 51.5) 181 (139; 234) 13 (11.7; 14) 61 (4.8%) 28 (2.2%) 129 (10.2%) 1 (0; 1)
b0.001 b0.001 0.002 0.07 0.71 / / / / / / / / / / / / b0.001 b0.001 0.68 0.20 0.77 0.86 0.03 0.16 0.06 b0.001 b0.001 0.08
+
Kidney, lung, lymphoma, myeloma, brain, pancreas and stomach.
Venous thromboembolism VTE occurred in 107 patients (7.5% of overall study population). The VTE events were classified as deep vein thrombosis (DVT) (n = 46), pulmonary embolism (PE) (n = 36), combined DVT and PE (n = 7), portal vein thrombosis (n = 3), sinus vein thrombosis (n = 1), fatal PE (n = 4), combined DVT of arm and portal vein (n = 1), PE combined with DVT of arm (n = 1), DVT of arm (n = 4), thrombosis of the vena cava inferior (n = 1) and thrombosis of the jugular vein (n = 3). The cumulative incidence of VTE in the overall population in the presence of competing mortality was 5.42%, 6.63% and 7.58% after 6, 12 and 24 months, respectively. Statins and demographic & laboratory parameters Patients with statins (total group of statins) were found to be significantly older (median: 65 vs. 60 years, p b 0.001), had a higher BMI (median: 27 vs. 25 kg/m2; p b 0.001), had a higher likelihood to be male (67.1% vs. 54.3%; p = 0.002), to use antiplatelet drugs (51.2% vs. 10.0%; p b 0.001), to be diabetic (24.1% vs. 10.2%; p b 0.001) and to have had an myocardial infarction (21.2% vs 2.2%; p b 0.001). Their median platelet count was lower (235 vs. 245; p b 0.001), whereas their median FVIII levels were higher (194 vs. 181; p b 0.03). There was no statistically significant difference with regard to newly diagnosed cancer vs. progression after remission, high-risk tumour site, leukocyte count, CRP-levels, D-dimer levels, sP-selectin levels, prior history of VTE and Khorana score (see also Table 1). Statins and risk of VTE In patients with statins, 6 VTE events (3.5% of all patients with statins) were recorded, as opposed to 101 events (8.0%) in patients without statins. In the patient group using statins, 1 patient with simvastatin developed VTE, 4 patients with atorvastatin and 1 patient with pravastatin. In competing risk analysis, the cumulative probability of VTE in patients with statins was 2.94% after 6 months, 2.94% after
12 months and 3.54% after 24 months, compared to 5.76%, 7.13% and 8.13% in the group without statins. The difference was statistically significant (Gray’s test: p = 0.04) (see Fig. 1). No difference was observed for a different distribution of competing mortality between statin-users and non-statin-users (Gray’s test: p = 0.14). In a univariable Fine & Gray proportional subhazards model, statin use was associated with a 57% decrease in the risk of VTE (subhazard ratio (SHR) = 0.43, 95% CI: 0.19 to 0.98; p = 0.04). This association appeared to be independent of concomitant use of antiplatelet drugs, such as low-dose ASS and clopidogrel, and platelet count (SHR = 0.44, 95% CI: 0.19 to 1.00, p = 0.05). In an extended model including use of antiplatelet drugs, biomarkers predictive for VTE (FVIII and sP-selectin), the variable high-risk or very high-risk site and the unequally distributed variables age, BMI, diabetes and anamnestic myocardial infarction, the association prevailed (SHR = 0.39, 95% CI: 0.16 to 0.92; p = 0.03) (see Table 2). In a subgroup analysis, the incidence of VTE in patients with simvastatin was lower than in patients with other statins (1 of 96 [1.04%] vs. 5 of 74 [6.76%]; see Fig. 2). In competing risks regression, simvastatin was associated with a lower risk of VTE compared to patients without statins (SHR 0.12; 95% CI 0.02 to 0.89; p = 0.04), whereas use of other statins was not (SHR 0.83; 95% CI 0.34 to 2.07; p = 0.70). The univariable SHR for patients with simvastatin compared to other statins was 0.15 (95% CI 0.08 to 1.23; p = 0.08). Sensitivity analysis with propensity score methods The difference in cumulative incidences of VTE between the statin and non-statin group prevailed after stratifying Gray’s test on quintiles of the propensity score (p = 0.04). Next, a univariate Fine & Gray regression of baseline statin use on time-to-VTE, accounting for competing risk of mortality and using quintiles of the propensity score as a covariate, was fitted. Here, it emerged that the association between statin use and lower VTE risk was robust to the inclusion of the propensity score (SHR = 0.43, 95% CI: 0.19 to 0.97, p = 0.04). Extending this model with variables predictive for VTE such as FVIII-levels and high-
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Fig. 1. Cumulative incidence of VTE in patients with and without statins incorporating death as a competing risk. Footnote: 5 patients died on the same day as they were recruited into the study. 2 patients were immediately lost to follow-up. Thus 7 patients in total did not contribute any follow-up time and do therefore not appear in the figure.
risk tumor site, the association prevailed both with respect to effect size and statistical significance (SHR = 0.39, 95% CI: 0.17 to 0.90; p = 0.03) (see Table 3). Discussion In this prospective cohort study, we investigated the association of statins with the risk of VTE in patients with cancer. We found baseline statin use to be associated with a 57% lower VTE risk during the twoyear follow-up period. The overall prevalence of statin use was 11.9% in our study population. Although there is no exact data available for the prevalence of statin-use in the general Austrian population, the Organisation for Economic Co-operation and Development (OECD) reports that in 2013 the defined daily doses (DDDs) for anticholesterol drugs in Europe were between 32 (Estonia) and 130 DDDs per 1000 patients (UK). Thus, we assume that the prevalence of statin use found in our cancer-specific study population is comparable to the prevalence in the general population. The effect of statins on risk of VTE in a general population is still discussed controversially. Our data align with the results from the largest single prospective interventional trial in non-cancer patients, the JUPITER trial. During a median observation time of 1.9 years in that Table 2 Multivariable Fine & Gray regression of time to VTE incorporating death as a competing risk. Variable
SHR
95% CI
p
Statin-use Higha& very high-risk siteb Antiplatelet drugs FVIII (per 10% activity) sP-selectin (per 10 ng/L) Age (per year) BMI (per kg/m2) Myocardial Infarction Diabetes
0.39 2.07 0.96 1.04 1.19 0.99 1.04 1.04 0.88
0.16 – 0.92 1.33 – 3.23 0.50 – 1.84 1.02 – 1.06 1.11 – 1.28 0.98 – 1.01 1.00 – 1-08 0.37 – 2.96 0.46 – 1.67
0.031 0.001 0.891 b0.001 b0.001 0.503 0.037 0.936 0.697
a b
Kidney, lung, lymphoma and myeloma. Brain, pancreas and stomach.
study by Glynn et al., the rates of VTE were 0.18 and 0.32 events per 100 person years of follow up in the rosuvastatin and placebo groups, respectively [10]. Also, three previous meta-analyses on the association of statin-use with the risk of VTE in non-cancer patients showed that the odds ratio (OR) for occurrence of VTE in statin-users was between 0.59 and 0.81 [11–13]. On the other side, a recent large meta-analysis could not confirm a substantial risk reduction [14]. However, it has to be considered that our results originate from a cancer-specific population. At present, there is a lack of specific data on the association of statins and cancer-associated VTE. Hence, our data allow us to carefully hypothesize that statins may play a role in the primary prevention of cancerassociated VTE. As outlined in the introduction, several favourable pleiotropic effects have been attributed to statins. These might explain some of the antithrombotic properties of statins leading to a clinically relevant reduction in the risk of cancer-associated VTE. Statins can be regarded as very safe with negligibly low rates of severe complications such as rhabdomyolysis [32]. Furthermore, statins do not pose an increased bleeding risk. Compared to treatment with LMWH or Vitamin K antagonists, this would represent an important advantage for patients with cancer, who are at higher risk of haemorrhage during anticoagulant therapy than patients without cancer [33]. There is evidence that statins may even reduce cancer-related mortality [34]. Whenever reporting beneficial effects of chronic medication, the question of therapy adherence also has to be raised. As extensively reported in literature, therapy adherence for such drugs is low [35]. In the case of statins, as shown by Benner et al. in a cohort of elderly patients, it can be expected that only about half of the patients will still take their medication after 6 months [36]. However, this also means that a possible potential of statins to decrease VTE might even be larger. In a subgroup analysis for hypothesis generation, we found that the incidence of VTE was very low in patients with simvastatin. Also Khemasuwan et al. reported a similar phenomenon in their cohort of patients with cancer [15]. We want to strictly point out that due to the low numbers of patients in these subgroups, this might have been merely by chance, but we think it would be interesting to investigate differences in the antithrombotic potential of different statins in future studies.
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Fig. 2. Cumulative incidence of VTE in patients with simvastatin, patients with other statins (atorva-, prava-, rosuva-, fluva- and lovastatin) and patients without statins incorporating death as a competing risk. Footnote: 5 patients died on the same day as they were recruited into the study. 2 patients were immediately lost to follow-up. Thus 7 patients in total did not contribute any follow-up time and do therefore not appear in the figure.
We tried to adjust carefully to possible confounding factors. Acetylsalicylic acid was recently shown to be useful in preventing VTE recurrences [37,38]. In our cohort the variable “antiplatelet drug”, which was low-dose acetylsalicylic acid in 99.1% of the cases, was unevenly distributed between patients with and without statins (51.2 vs. 10.0%). However, in our study population the use of antiplatelet drugs was not associated with a lower risk of VTE (see Table 2). Also in univariable analysis, use of antiplatelet drugs was not associated with a lower risk of VTE (data not shown). After adjusting for antiplatelet use in the multivariable analysis, we could show that in our study population the association between use of statins and low risk of VTE was independent of use of antiplatelet drugs. When demographic and biochemical parameters between patients with and without statins, such as cancer site, BMI, FVIII, D-dimer, sP-selectin, haemoglobin, leukocyte count and platelet count were compared, we found that statin-users were older and had a higher BMI than patients without statins. Interestingly, FVIII was higher in patients with statins. This stands in contrast to previous publications [39]. However, none of these studies were conducted in a cancer-specific cohort. Platelet count was lower in statin users. There was no significant difference with regard to high- & very high-risk cancer sites, levels of D-dimer, sP-selectin, CRP, haemoglobin and leukocyte count between the two groups. Although it is well established that statins decrease CRP levels [16], it is difficult to compare Table 3 Multivariable Fine & Gray proportional subhazards model of time to VTE accounting for all-cause-mortality as a competing risk, stratifying on quintiles of the propensity score. Variable
SHR
95% CI
P
Statin-use Higha& very high-risk siteb FVIII (per 10% activity) sP-selectin (per 10 ng/mL) Quintiles of propensity score 2 3 4 5
0.39 2.07 1.04 1.17
0.17 – 0.90 1.32 – 3.24 1.02 – 1.06 1.10 – 1.24
0.028 0.002 b0.001 b0.001
1.22 1.00 0.88 1.11
0.68 – 2.21 0.54 – 1.85 0.46 – 1.68 0.59 – 2.11
0.506 0.996 0.704 0.743
a b
Kidney, lung, lymphoma and myeloma. Brain, pancreas and stomach.
our data to existing studies, because our study was conducted in a specific cohort of cancer patients and cancer itself has an important impact on inflammation [40] and the haemostatic system, increasing the risk of thrombophilia [41]. Patients with simvastatin had higher levels of haemoglobin, but lower levels of CRP than patients with other statins. Both, low levels of haemoglobin and high levels of CRP, are associated with an increased risk of VTE in cancer patients [42,43], although the latter finding is currently regarded as controversial [28]. Some limitations of this study should be mentioned. First of all, the number of patients with statins with 170 patients and six events was relatively low. However, as mentioned in the first paragraph of the discussion, the prevalence of statin use in our study population might be comparable to the general Austrian population. Thus, the relatively low number of patients with statins might be due to the fact that patients were recruited randomly. Nevertheless, a larger sample size would make the results more reliable. A second important limitation is that we did not have information neither on dosages, nor on how long patients took the statins. It has been shown that antithrombotic effects of statins are probably dose-dependent [44]. The results of this study might also have been influenced by certain types of selection bias: As we used prevalent rather than incident statin use as our exposure, patients in the statin group will have - as defined by our inclusion criteria - lived at least three months under statin-therapy without experiencing VTE prior to study inclusion and may thus feature milder disease phenotypes (“survivorship bias”). Additionally, patients who receive chronic, preventive therapy are also more likely to seek other health care services or to exercise other healthy behaviours ("healthy user effect") [45]. Collectively, these selection biases would lead to an accumulation of patients with a lower a priori VTE risk in the statin group, and thus exaggerate VTE-protective effects of statin therapy. Patients in our study were randomly recruited. Due to logistical reasons, a consecutive recruitment was not possible. We were also not able to collect data on a possible short-term use of heparins during follow-up, which could have influenced the result. Although patients with longterm anticoagulation and recent surgery or arterial or venous thromboembolism were not allowed to participate, we cannot exclude that some patients received a short-term course of heparins for other reasons during the course of their disease (e.g. hospitalisation with acute medical
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illness). Although our multivariable analysis adjusted for high-VTE-risk tumour types and paid meticulous statistical attention to the nonrandom allocation of statin-therapy (propensity score methods), there might have been residual uncontrolled confounding. Some strengths of this study should likewise be discussed. Comedication and comorbidities were specifically addressed at the study inclusion interview, which facilitated a careful covariate adjustment and propensity score analysis. Additionally, data on co-medication and comorbidities was completed by medical reports as a second independent source. Furthermore, VTE was confirmed by an independent expert-committee, which approved or disapproved suspected VTE. Conclusion This prospective study provides first observational evidence that statins are associated with a decreased risk of VTE in patients with cancer. A possible role for statins in the prevention of cancerassociated thrombosis should be explored in a future randomized controlled trial. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.thromres.2014.09.001. Statement of Conflict of Interest The authors declare no conflict of interest. All authors state that they had full access to all data, that the manuscript has been read and approved for submission to Thrombosis Research. Funding This study was supported by funds of the “Oesterreichische Nationalbank” (Anniversary Fund, project numbers 12739 and 14744). The funding source had no role in the design of this study and its execution, analyses, interpretation of the data, or decision to submit results. Acknowledgements We thank Tanja Altreiter (Clinical Division of Haematology and Haemostaseology, Department of Medicine I, MUV) for proof-reading this manuscript. References [1] Trousseau A. Phlegmasia alba dolens. Cln Med Hotel Dieu de Paris 1865;3:94–6. [2] Zangari M, Anaissie E, Barlogie B, Badros A, Desikan R, Gopal AV, et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 2001;98:1614–5. [3] Khorana AA, Connolly GC. Assessing risk of venous thromboembolism in the patient with cancer. J Clin Oncol 2009;27:4839–47. [4] Sousou T, Khorana A. Identifying cancer patients at risk for venous thromboembolism. Hamostaseologie 2009;29:121–4. [5] Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton 3rd LJ. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000;160:809–15. [6] Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111:4902–7. [7] Ay C, Dunkler D, Marosi C, Chiriac AL, Vormittag R, Simanek R, et al. Prediction of venous thromboembolism in cancer patients. Blood 2010;116:5377–82. [8] Thaler J, Ay C, Pabinger I. Venous thromboembolism in cancer patients - risk scores and recent randomised controlled trials. Thromb Haemost 2012;108:1042–8. [9] Herrington DM, Vittinghoff E, Lin F, Fong J, Harris F, Hunninghake D, et al. Statin therapy, cardiovascular events, and total mortality in the Heart and Estrogen/Progestin Replacement Study (HERS). Circulation 2002;105:2962–7. [10] Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009;360:1851–61. [11] Agarwal V, Phung OJ, Tongbram V, Bhardwaj A, Coleman CI. Statin use and the prevention of venous thromboembolism: a meta-analysis. Int J Clin Pract 2010;64: 1375–83. [12] Squizzato A, Galli M, Romualdi E, Dentali F, Kamphuisen PW, Guasti L, et al. Statins, fibrates, and venous thromboembolism: a meta-analysis. Eur Heart J 2010;31: 1248–56.
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Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Statins are Associated with Low Risk of Venous Thromboembolism in Patients with Cancer: A Prospective and Observational Cohort Study☆ Felix Lötsch a, Oliver Königsbrügge a, Florian Posch a, Christoph Zielinski b, Ingrid Pabinger a, Cihan Ay a,⁎ a b
Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18 – 20, A-1090 Vienna, Austria Clincial Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18 – 20, A-1090 Vienna, Austria
a r t i c l e
i n f o
Article history: Received 11 June 2014 Received in revised form 5 August 2014 Accepted 1 September 2014 Available online 6 September 2014 Keywords: Neoplasms Statins Simvastatin Thrombosis Venous thromboembolism
a b s t r a c t Introduction: Patients with cancer are at risk of venous thromboembolism (VTE). Statin-use has been shown to be associated with low risk of VTE in patients without cancer, but data in cancer patients is scarce. The objective of this study was to evaluate the association of statins with risk of VTE in cancer patients in a prospective observational cohort study. Materials and Methods: Patients with newly diagnosed cancer or progression of disease after remission were included and prospectively followed for a maximum of 2 years. Study endpoint was occurrence of symptomatic VTE. Results: Patients (n = 1434) were followed over a median observation period of 729 days. VTE occurred in 107 (7.5%) patients. At study inclusion, 170 (11.9%) patients took statins. Simvastatin (n = 96) and atorvastatin (n = 48) were the most frequently prescribed statins. VTE occurred in 6 (3.5%) patients with statins. Patients with statins had a lower risk of VTE than patients without (subhazard ratio 0.43, 95% confidence interval 0.19 to 0.98; p = 0.04). In competing risk analysis, the cumulative probability of VTE in patients with statins was 2.94% after 12 months and 3.54% after 24 months, compared to 7.13% and 8.13% in the group without statins (Gray’s test: p = 0.04). Conclusion: This study provides observational evidence for an association between statin use and low risk of VTE in patients with cancer. The role of statins for prevention of cancer-associated VTE needs to be confirmed in randomized, controlled trials. © 2014 Elsevier Ltd. All rights reserved.
Introduction The association between thrombosis and cancer has been recognized since the 19th century [1]. Today, malignancy is a well-established, independent and major risk factor of venous thromboembolism (VTE). The incidence of VTE is as high as 30% in certain subgroups [2] and depends largely on various cancer-, treatment-and patient-related risk factors [3–5]. Recently, risk stratification scores have been developed to improve individualized assessment of a cancer patient’s VTE risk [6–8]. These scores include clinical and laboratory parameters such as tumour entity, body mass index, haemoglobin levels, leucocyte and platelet count. An expanded version of this risk stratification score additionally comprises biomarkers such as D-dimer and sP-selectin [7]. In epidemiologic studies, statins have been shown to significantly reduce the risk of VTE in different populations. “The Heart and Estrogen/
☆ An abstract of this study was presented at the Annual Meeting of the Society for Thrombosis and Haemostasis Research (GTH) in February 2013 in Munich, Germany. ⁎ Corresponding author at: Comprehensive Cancer Center, Department of Medicine I, Clinical Division of Haematology and Haemostaseology, Waehringer Guertel 18-20, A1090 Vienna, Austria. Tel.: +43 1 40400 4410; fax: +43 1 40400 4030. E-mail address: [email protected] (C. Ay).
http://dx.doi.org/10.1016/j.thromres.2014.09.001 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
Progestin Replacement Study (HERS)” provided the first evidence that individuals using statins had a 50% risk reduction for VTE [9]. More recently, in a randomized controlled interventional trial for prevention of vascular events (JUPITER-trial), rosuvastatin significantly reduced the risk of VTE [10]. The association between statins and low risk of VTE has been corroborated in three meta-analyses [11–13]. However, the findings in the largest meta-analysis on the association of statins and risk of VTE by Rahimi et al. do not support a substantial risk reduction [14]. On the other side, specific data for patients with cancer are very scarce. In a retrospective evaluation of cancer patients, Khemasuwan et al. reported a lower frequency of VTE in patients on statins [15]. Statins are known to have pleiotropic effects on the cardiovascular system. As shown in the JUPITER trial, they effectively reduce Creactive protein (CRP), a marker of inflammation [16]. Furthermore, they improve endothelial function, mobilize endothelial progenitor cells [17], inhibit platelet activation [18], and enhance the stability of atherosclerotic plaques [19]. Statins also show antithrombotic effects. They affect the blood coagulation system through different pathways, including inhibition of plasmatic haemostasis and platelet activation [20]. Two key anti-thrombotic mechanisms of statins are the downregulation of tissue factor (TF) in endothelial cells and monocytes
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and the up-regulation of thrombomodulin [20,22–24], which are thought to be mediated by inhibition of the Rho/Rho kinase pathway [21]. Although each type of statin has been suggested to exert antithrombotic effects, clinical and epidemiologic studies have not elaborated so far, whether all types of statins show the same efficacy in preventing VTE. Thus, our aim was to investigate the association of statins with the risk of cancer-associated VTE in a prospective and observational cohort study. Methods Study population The study population consisted of patients recruited between October 2003 and April 2011 in the framework of the Vienna Cancer and Thrombosis study (CATS), an on-going prospective observational cohort-study conducted at the Medical University of Vienna, Austria, with approval of the local ethics committee and in agreement with the Declaration of Helsinki (ID of approval: 126/2003). Participants were randomly recruited and gave written, informed consent prior to study inclusion. The detailed methods of CATS have been described in previous publications [25,26]. In summary, the study included patients with newly diagnosed cancer or with progressive disease after remission. Exclusion criteria were overt bacterial or viral infection, recent chemotherapy and recent arterial or venous thromboembolism (within the last 3 months), radiotherapy or surgery (within the last 2 weeks) and continuous anticoagulation with vitamin K antagonists or lowmolecular-weight heparins (LMWH). Patients receiving drugs such as aspirin, clopidogrel or short-term anticoagulation with LMWH (e.g. for thromboprophylaxis during hospitalisation) were allowed to participate. Patients were observed for a maximum period of two years or until the occurrence of VTE, death, loss of follow-up or withdrawal of consent. At study inclusion blood samples were taken for laboratory analyses. Diagnosis of VTE Patients were instructed about the symptoms of VTE and requested to report when such symptoms occurred, but no active screening for VTE was conducted. In case of symptoms objective imaging methods were used to confirm or exclude the diagnosis of VTE [25–27]. In patients who had died during follow-up, death certificates and autopsy-reports, if available, were reviewed to establish or exclude the diagnosis of fatal PE or VTE. Then, all VTE events were presented to an independent adjudication committee including experts in the fields of angiology, radiology and nuclear medicine. The adjudication committee confirmed or rejected the diagnosis. Accidentally detected VTE was considered as event, if the committee decided that the respective event was of clinical significance.
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Laboratory analyses The methodology of taking blood samples and the applied laboratory methods for measurement of D-dimer, soluble P-selectin (sP-selectin) and factor VIII (FVIII) activity have been described in previous publications [25–27]. Blood count parameters were routinely determined with Sysmex XE-2100 haematology analyzer. CRP serum levels were measured by an immunonephelometric assay (Olympus Diagnostics, Southall, UK) on an AU 2700 chemistry analyzer [28]. Reference ranges are presented in supplementary Table 1. Statistical analysis All statistical analyses were performed using Stata (Windows version 12.0, Stata Corp., TX, USA) and R (Windows version 3.0.1, The R Foundation for Statistical Computing). Median, 25th and 75th percentile were used to describe continuous variables. T-test, X-squared test and Fisher’s exact test were applied to compare the distribution of laboratory and demographic parameters between different groups. A Competing risk (CR) analysis incorporating all-cause mortality as the competing event was used to investigate the association between the use of statins and time-to-VTE. In detail, the cumulative incidences of VTE over time and their 95% CI were computed according to the estimators of Marubini & Valsecchi (Stata’s stcompet suite). Cumulative incidence functions were compared between groups using Gray’s test (R library cmprsk) [29]. Uni- and multivariable competing risk regression models according to Fine & Gray were fitted to model the subhazard ratio (SHR) of VTE [30]. First, a univariable model with statin-use as the only variable was fitted. Then several multivariable analyses were modelled to adjust for possible confounders, such as use of antiplatelet drugs, certain comorbidities, laboratory-parameters predictive for VTE and unequally distributed demographic variables. As patients with and without statins differed with respect to several baseline variables (Table 1), we performed a sensitivity analysis using propensity score methods. These methods aim towards a more causal analysis of treatment effect in observational studies than regular covariate adjustment. We first estimated a propensity score (i.e. the probability to be in the statin group) for each patient using multivariable logistic regression with the predictor variables tumour site, tumour stage, use of antiplatelet drugs, age, BMI, prior history of myocardial infarction, diabetes at baseline, proton-pump inhibitor use at baseline and allopurinol use at baseline. We then stratified Gray’s test according to quintiles of this propensity score, and included the quintiles as covariates in the uni- and multivariable Fine & Gray models. Further sensitivity analyses included stratifying the Fine & Gray models on quintiles of the propensity score, and using inverse probability of treatment weighting (IPTW) on the propensity score (not shown, highly comparable results obtained) [31]. No propensity score analyses were performed for the statin-type subgroup comparisons. A p-value b 0.05 was considered to indicate statistical significance. Results
Identification of patients with use of statin Patients During the structured interview at study inclusion all study investigators placed great emphasis on taking a correct and complete medical history. In particular, patients were asked about their current medication including the information on the use of statins and the specific type of statin that was used. Additionally, medical reports of patients in a time-frame between one month before and three months after study inclusion were reviewed to complete the data and verify the information on the use and type of statin. Also the records of regular follow-up protocols, telephone conversations with patients, family members, treating oncologist/haemato-oncologist and general practitioners that were made during follow-up were searched for the use of statins.
In total, 1434 patients were observed over a median observation time of 729 days (25th to 75th percentile: 227 to 731) in the current study. Of those, 801 were men and 633 women. The median age of the study population was 61 years (25th to 75th percentile: 52 to 68). The most frequent cancer sites were lymphoma (n = 237), lung (n = 215), breast (n = 199), brain (n = 182), prostate (n = 148) and colon (n = 146). In the total study population, 170 (11.9%) patients with use of statin were identified, of whom 96 received simvastatin (56.5% of statin users), 48 atorvastatin (28.2%), 14 pravastatin (8.2%), 6 rosuvastatin (3.5%), 5 fluvastatin (2.9%) and 1 patient received lovastatin (0.6%).
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Table 1 Baseline demographic and clinical characteristic of the study population (n = 1434). Variable
n (% missing)
Overall (Q1; Q3)
Statin-users (Q1; Q3)
Non-statin user (Q1; Q3)
p-value
Age (years) BMI (kg/m2) Female Gender Newly diagnosed cancer (yes) High or very high-risk tumour site+ (yes) Tumor site Lymphoma Lung Breast Brain Prostate Colon Pancreas Stomach Kidney Multiple Myeloma Other site Use of antiplatelet drugs Platelet count (G/L) Leukocyte count (G/L) CRP (mg/L) D-Dimer (μg/mL) sP-selectin (ng/mL) FVIII (% activity) Haemoglobin (g/dL) Prior history of VTE Prior myocardial infarction Diabetes Khorana Score
1434 (0.0%) 1432 (0.1%) 1434 (0.0%) 1434 (0.0%) 1434 (0.0%) 1434 (0.0%) / / / / / / / / / / / 1434 (0.0%) 1428 (0.4%) 1428 (0.4%) 1323 (7.7%) 1368 (4.6%) 1430 (0.3%) 1362 (5.0%) 1428 (0.4%) 1434 (0.0%) 1434 (0.0%) 1434 (0.0%) 1434 (0.0%)
61 (52; 68) 25 (22; 28) 633 (44.1%) 1029 (71.8%) 854 (59.6%) / 237 (16.5%) 215 (15.0%) 199 (13.9%) 182 (12.7%) 148 (10.3%) 146 (10.2%) 85 (5.9%) 57 (4.0%) 40 (2.8%) 38 (2.6%) 87 (6.1%) 213 (14.9%) 244 (193; 304) 7.15 (5.62; 9.56) 0.51 (0.16; 1.67) 0.66 (0.34; 1.40) 40.5 (31.1; 51.6) 183 (142; 234) 13.1 (11.8; 14.1) 75 (5.2%) 64 (4.5%) 170 (11.9%) 1 (0; 1)
65 (61; 70) 27 (24; 40) 56 (32.9%) 131 (77.1%) 99 (58.2%) / 17 (10.0%) 38 (22.4%) 18 (10.6%) 20 (11.8%) 27 (15.9%) 14 (8.2%) 8 (4.7%) 6 (3.5%) 7 (4.1%) 3 (1.8%) 12 (7.1%) 87 (51.2%) 235 (184; 282) 7.07 (5.86; 9.11) 0.58 (0.16; 1.35) 0.61 (0.34; 1.42) 39.9 (30.1; 52.6) 194 (157; 239) 13.3 (11.9; 14.3) 14 (8.2%) 36 (21.2%) 41 (24.1%) 1 (0; 1)
60 (51; 67) 25 (22; 28) 577 (45.7%) 888 (70.3%) 755 (59.7%) / 220 (17.4) 177 (14.0%) 181 (14.3%) 162 (12.8%) 121 9.6%) 132 (10.4%) 77 (6.1%) 51 (4.0% 33 (2.6%) 35 (2.8%) 75 (6.0%) 126 (10.0%) 245 (195; 308) 7.15 (5.61; 9.58) 0.5 (0.17; 1.71) 0.67 (0.34; 1.39) 40.6 (31.4 - 51.5) 181 (139; 234) 13 (11.7; 14) 61 (4.8%) 28 (2.2%) 129 (10.2%) 1 (0; 1)
b0.001 b0.001 0.002 0.07 0.71 / / / / / / / / / / / / b0.001 b0.001 0.68 0.20 0.77 0.86 0.03 0.16 0.06 b0.001 b0.001 0.08
+
Kidney, lung, lymphoma, myeloma, brain, pancreas and stomach.
Venous thromboembolism VTE occurred in 107 patients (7.5% of overall study population). The VTE events were classified as deep vein thrombosis (DVT) (n = 46), pulmonary embolism (PE) (n = 36), combined DVT and PE (n = 7), portal vein thrombosis (n = 3), sinus vein thrombosis (n = 1), fatal PE (n = 4), combined DVT of arm and portal vein (n = 1), PE combined with DVT of arm (n = 1), DVT of arm (n = 4), thrombosis of the vena cava inferior (n = 1) and thrombosis of the jugular vein (n = 3). The cumulative incidence of VTE in the overall population in the presence of competing mortality was 5.42%, 6.63% and 7.58% after 6, 12 and 24 months, respectively. Statins and demographic & laboratory parameters Patients with statins (total group of statins) were found to be significantly older (median: 65 vs. 60 years, p b 0.001), had a higher BMI (median: 27 vs. 25 kg/m2; p b 0.001), had a higher likelihood to be male (67.1% vs. 54.3%; p = 0.002), to use antiplatelet drugs (51.2% vs. 10.0%; p b 0.001), to be diabetic (24.1% vs. 10.2%; p b 0.001) and to have had an myocardial infarction (21.2% vs 2.2%; p b 0.001). Their median platelet count was lower (235 vs. 245; p b 0.001), whereas their median FVIII levels were higher (194 vs. 181; p b 0.03). There was no statistically significant difference with regard to newly diagnosed cancer vs. progression after remission, high-risk tumour site, leukocyte count, CRP-levels, D-dimer levels, sP-selectin levels, prior history of VTE and Khorana score (see also Table 1). Statins and risk of VTE In patients with statins, 6 VTE events (3.5% of all patients with statins) were recorded, as opposed to 101 events (8.0%) in patients without statins. In the patient group using statins, 1 patient with simvastatin developed VTE, 4 patients with atorvastatin and 1 patient with pravastatin. In competing risk analysis, the cumulative probability of VTE in patients with statins was 2.94% after 6 months, 2.94% after
12 months and 3.54% after 24 months, compared to 5.76%, 7.13% and 8.13% in the group without statins. The difference was statistically significant (Gray’s test: p = 0.04) (see Fig. 1). No difference was observed for a different distribution of competing mortality between statin-users and non-statin-users (Gray’s test: p = 0.14). In a univariable Fine & Gray proportional subhazards model, statin use was associated with a 57% decrease in the risk of VTE (subhazard ratio (SHR) = 0.43, 95% CI: 0.19 to 0.98; p = 0.04). This association appeared to be independent of concomitant use of antiplatelet drugs, such as low-dose ASS and clopidogrel, and platelet count (SHR = 0.44, 95% CI: 0.19 to 1.00, p = 0.05). In an extended model including use of antiplatelet drugs, biomarkers predictive for VTE (FVIII and sP-selectin), the variable high-risk or very high-risk site and the unequally distributed variables age, BMI, diabetes and anamnestic myocardial infarction, the association prevailed (SHR = 0.39, 95% CI: 0.16 to 0.92; p = 0.03) (see Table 2). In a subgroup analysis, the incidence of VTE in patients with simvastatin was lower than in patients with other statins (1 of 96 [1.04%] vs. 5 of 74 [6.76%]; see Fig. 2). In competing risks regression, simvastatin was associated with a lower risk of VTE compared to patients without statins (SHR 0.12; 95% CI 0.02 to 0.89; p = 0.04), whereas use of other statins was not (SHR 0.83; 95% CI 0.34 to 2.07; p = 0.70). The univariable SHR for patients with simvastatin compared to other statins was 0.15 (95% CI 0.08 to 1.23; p = 0.08). Sensitivity analysis with propensity score methods The difference in cumulative incidences of VTE between the statin and non-statin group prevailed after stratifying Gray’s test on quintiles of the propensity score (p = 0.04). Next, a univariate Fine & Gray regression of baseline statin use on time-to-VTE, accounting for competing risk of mortality and using quintiles of the propensity score as a covariate, was fitted. Here, it emerged that the association between statin use and lower VTE risk was robust to the inclusion of the propensity score (SHR = 0.43, 95% CI: 0.19 to 0.97, p = 0.04). Extending this model with variables predictive for VTE such as FVIII-levels and high-
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Fig. 1. Cumulative incidence of VTE in patients with and without statins incorporating death as a competing risk. Footnote: 5 patients died on the same day as they were recruited into the study. 2 patients were immediately lost to follow-up. Thus 7 patients in total did not contribute any follow-up time and do therefore not appear in the figure.
risk tumor site, the association prevailed both with respect to effect size and statistical significance (SHR = 0.39, 95% CI: 0.17 to 0.90; p = 0.03) (see Table 3). Discussion In this prospective cohort study, we investigated the association of statins with the risk of VTE in patients with cancer. We found baseline statin use to be associated with a 57% lower VTE risk during the twoyear follow-up period. The overall prevalence of statin use was 11.9% in our study population. Although there is no exact data available for the prevalence of statin-use in the general Austrian population, the Organisation for Economic Co-operation and Development (OECD) reports that in 2013 the defined daily doses (DDDs) for anticholesterol drugs in Europe were between 32 (Estonia) and 130 DDDs per 1000 patients (UK). Thus, we assume that the prevalence of statin use found in our cancer-specific study population is comparable to the prevalence in the general population. The effect of statins on risk of VTE in a general population is still discussed controversially. Our data align with the results from the largest single prospective interventional trial in non-cancer patients, the JUPITER trial. During a median observation time of 1.9 years in that Table 2 Multivariable Fine & Gray regression of time to VTE incorporating death as a competing risk. Variable
SHR
95% CI
p
Statin-use Higha& very high-risk siteb Antiplatelet drugs FVIII (per 10% activity) sP-selectin (per 10 ng/L) Age (per year) BMI (per kg/m2) Myocardial Infarction Diabetes
0.39 2.07 0.96 1.04 1.19 0.99 1.04 1.04 0.88
0.16 – 0.92 1.33 – 3.23 0.50 – 1.84 1.02 – 1.06 1.11 – 1.28 0.98 – 1.01 1.00 – 1-08 0.37 – 2.96 0.46 – 1.67
0.031 0.001 0.891 b0.001 b0.001 0.503 0.037 0.936 0.697
a b
Kidney, lung, lymphoma and myeloma. Brain, pancreas and stomach.
study by Glynn et al., the rates of VTE were 0.18 and 0.32 events per 100 person years of follow up in the rosuvastatin and placebo groups, respectively [10]. Also, three previous meta-analyses on the association of statin-use with the risk of VTE in non-cancer patients showed that the odds ratio (OR) for occurrence of VTE in statin-users was between 0.59 and 0.81 [11–13]. On the other side, a recent large meta-analysis could not confirm a substantial risk reduction [14]. However, it has to be considered that our results originate from a cancer-specific population. At present, there is a lack of specific data on the association of statins and cancer-associated VTE. Hence, our data allow us to carefully hypothesize that statins may play a role in the primary prevention of cancerassociated VTE. As outlined in the introduction, several favourable pleiotropic effects have been attributed to statins. These might explain some of the antithrombotic properties of statins leading to a clinically relevant reduction in the risk of cancer-associated VTE. Statins can be regarded as very safe with negligibly low rates of severe complications such as rhabdomyolysis [32]. Furthermore, statins do not pose an increased bleeding risk. Compared to treatment with LMWH or Vitamin K antagonists, this would represent an important advantage for patients with cancer, who are at higher risk of haemorrhage during anticoagulant therapy than patients without cancer [33]. There is evidence that statins may even reduce cancer-related mortality [34]. Whenever reporting beneficial effects of chronic medication, the question of therapy adherence also has to be raised. As extensively reported in literature, therapy adherence for such drugs is low [35]. In the case of statins, as shown by Benner et al. in a cohort of elderly patients, it can be expected that only about half of the patients will still take their medication after 6 months [36]. However, this also means that a possible potential of statins to decrease VTE might even be larger. In a subgroup analysis for hypothesis generation, we found that the incidence of VTE was very low in patients with simvastatin. Also Khemasuwan et al. reported a similar phenomenon in their cohort of patients with cancer [15]. We want to strictly point out that due to the low numbers of patients in these subgroups, this might have been merely by chance, but we think it would be interesting to investigate differences in the antithrombotic potential of different statins in future studies.
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Fig. 2. Cumulative incidence of VTE in patients with simvastatin, patients with other statins (atorva-, prava-, rosuva-, fluva- and lovastatin) and patients without statins incorporating death as a competing risk. Footnote: 5 patients died on the same day as they were recruited into the study. 2 patients were immediately lost to follow-up. Thus 7 patients in total did not contribute any follow-up time and do therefore not appear in the figure.
We tried to adjust carefully to possible confounding factors. Acetylsalicylic acid was recently shown to be useful in preventing VTE recurrences [37,38]. In our cohort the variable “antiplatelet drug”, which was low-dose acetylsalicylic acid in 99.1% of the cases, was unevenly distributed between patients with and without statins (51.2 vs. 10.0%). However, in our study population the use of antiplatelet drugs was not associated with a lower risk of VTE (see Table 2). Also in univariable analysis, use of antiplatelet drugs was not associated with a lower risk of VTE (data not shown). After adjusting for antiplatelet use in the multivariable analysis, we could show that in our study population the association between use of statins and low risk of VTE was independent of use of antiplatelet drugs. When demographic and biochemical parameters between patients with and without statins, such as cancer site, BMI, FVIII, D-dimer, sP-selectin, haemoglobin, leukocyte count and platelet count were compared, we found that statin-users were older and had a higher BMI than patients without statins. Interestingly, FVIII was higher in patients with statins. This stands in contrast to previous publications [39]. However, none of these studies were conducted in a cancer-specific cohort. Platelet count was lower in statin users. There was no significant difference with regard to high- & very high-risk cancer sites, levels of D-dimer, sP-selectin, CRP, haemoglobin and leukocyte count between the two groups. Although it is well established that statins decrease CRP levels [16], it is difficult to compare Table 3 Multivariable Fine & Gray proportional subhazards model of time to VTE accounting for all-cause-mortality as a competing risk, stratifying on quintiles of the propensity score. Variable
SHR
95% CI
P
Statin-use Higha& very high-risk siteb FVIII (per 10% activity) sP-selectin (per 10 ng/mL) Quintiles of propensity score 2 3 4 5
0.39 2.07 1.04 1.17
0.17 – 0.90 1.32 – 3.24 1.02 – 1.06 1.10 – 1.24
0.028 0.002 b0.001 b0.001
1.22 1.00 0.88 1.11
0.68 – 2.21 0.54 – 1.85 0.46 – 1.68 0.59 – 2.11
0.506 0.996 0.704 0.743
a b
Kidney, lung, lymphoma and myeloma. Brain, pancreas and stomach.
our data to existing studies, because our study was conducted in a specific cohort of cancer patients and cancer itself has an important impact on inflammation [40] and the haemostatic system, increasing the risk of thrombophilia [41]. Patients with simvastatin had higher levels of haemoglobin, but lower levels of CRP than patients with other statins. Both, low levels of haemoglobin and high levels of CRP, are associated with an increased risk of VTE in cancer patients [42,43], although the latter finding is currently regarded as controversial [28]. Some limitations of this study should be mentioned. First of all, the number of patients with statins with 170 patients and six events was relatively low. However, as mentioned in the first paragraph of the discussion, the prevalence of statin use in our study population might be comparable to the general Austrian population. Thus, the relatively low number of patients with statins might be due to the fact that patients were recruited randomly. Nevertheless, a larger sample size would make the results more reliable. A second important limitation is that we did not have information neither on dosages, nor on how long patients took the statins. It has been shown that antithrombotic effects of statins are probably dose-dependent [44]. The results of this study might also have been influenced by certain types of selection bias: As we used prevalent rather than incident statin use as our exposure, patients in the statin group will have - as defined by our inclusion criteria - lived at least three months under statin-therapy without experiencing VTE prior to study inclusion and may thus feature milder disease phenotypes (“survivorship bias”). Additionally, patients who receive chronic, preventive therapy are also more likely to seek other health care services or to exercise other healthy behaviours ("healthy user effect") [45]. Collectively, these selection biases would lead to an accumulation of patients with a lower a priori VTE risk in the statin group, and thus exaggerate VTE-protective effects of statin therapy. Patients in our study were randomly recruited. Due to logistical reasons, a consecutive recruitment was not possible. We were also not able to collect data on a possible short-term use of heparins during follow-up, which could have influenced the result. Although patients with longterm anticoagulation and recent surgery or arterial or venous thromboembolism were not allowed to participate, we cannot exclude that some patients received a short-term course of heparins for other reasons during the course of their disease (e.g. hospitalisation with acute medical
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illness). Although our multivariable analysis adjusted for high-VTE-risk tumour types and paid meticulous statistical attention to the nonrandom allocation of statin-therapy (propensity score methods), there might have been residual uncontrolled confounding. Some strengths of this study should likewise be discussed. Comedication and comorbidities were specifically addressed at the study inclusion interview, which facilitated a careful covariate adjustment and propensity score analysis. Additionally, data on co-medication and comorbidities was completed by medical reports as a second independent source. Furthermore, VTE was confirmed by an independent expert-committee, which approved or disapproved suspected VTE. Conclusion This prospective study provides first observational evidence that statins are associated with a decreased risk of VTE in patients with cancer. A possible role for statins in the prevention of cancerassociated thrombosis should be explored in a future randomized controlled trial. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.thromres.2014.09.001. Statement of Conflict of Interest The authors declare no conflict of interest. All authors state that they had full access to all data, that the manuscript has been read and approved for submission to Thrombosis Research. Funding This study was supported by funds of the “Oesterreichische Nationalbank” (Anniversary Fund, project numbers 12739 and 14744). The funding source had no role in the design of this study and its execution, analyses, interpretation of the data, or decision to submit results. Acknowledgements We thank Tanja Altreiter (Clinical Division of Haematology and Haemostaseology, Department of Medicine I, MUV) for proof-reading this manuscript. References [1] Trousseau A. Phlegmasia alba dolens. Cln Med Hotel Dieu de Paris 1865;3:94–6. [2] Zangari M, Anaissie E, Barlogie B, Badros A, Desikan R, Gopal AV, et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 2001;98:1614–5. [3] Khorana AA, Connolly GC. Assessing risk of venous thromboembolism in the patient with cancer. J Clin Oncol 2009;27:4839–47. [4] Sousou T, Khorana A. Identifying cancer patients at risk for venous thromboembolism. Hamostaseologie 2009;29:121–4. [5] Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton 3rd LJ. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000;160:809–15. [6] Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111:4902–7. [7] Ay C, Dunkler D, Marosi C, Chiriac AL, Vormittag R, Simanek R, et al. Prediction of venous thromboembolism in cancer patients. Blood 2010;116:5377–82. [8] Thaler J, Ay C, Pabinger I. Venous thromboembolism in cancer patients - risk scores and recent randomised controlled trials. Thromb Haemost 2012;108:1042–8. [9] Herrington DM, Vittinghoff E, Lin F, Fong J, Harris F, Hunninghake D, et al. Statin therapy, cardiovascular events, and total mortality in the Heart and Estrogen/Progestin Replacement Study (HERS). Circulation 2002;105:2962–7. [10] Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009;360:1851–61. [11] Agarwal V, Phung OJ, Tongbram V, Bhardwaj A, Coleman CI. Statin use and the prevention of venous thromboembolism: a meta-analysis. Int J Clin Pract 2010;64: 1375–83. [12] Squizzato A, Galli M, Romualdi E, Dentali F, Kamphuisen PW, Guasti L, et al. Statins, fibrates, and venous thromboembolism: a meta-analysis. Eur Heart J 2010;31: 1248–56.
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