Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0205.
Lung Cancer
Predictors of Venous Thromboembolism and Early Mortality in Lung Cancer: Results from a Global Prospective Study (CANTARISK) NICOLE M. KUDERER,a,b MAREK S. PONIEWIERSKI,a EVA CULAKOVA,c GARY H. LYMAN,a,b ALOK A. KHORANA,d INGRID PABINGER,e GIANCARLO AGNELLI,f HOWARD A. LIEBMAN,g ERIC VICAUT,h GUY MEYER,h FRANCES A. SHEPHERDi a
Disclosures of potential conflicts of interest may be found at the end of this article.
Key Words. Venous thromboembolism
•
Lung neoplasms
•
Risk factors
•
Risk prediction model
•
Mortality
•
Prognosis
ABSTRACT Background. Patients with lung cancer are known to be at increased risk for venous thromboembolism (VTE). Venous thromboembolism is associated with increased risk for early mortality. However, there have been no studies performing a comprehensive assessment of risk factors for VTE or early mortality in lung cancer patients undergoing systemic chemotherapy in a global real-world setting. Materials and Methods. CANTARISK is a prospective, global, noninterventional cohort study including patients with lung cancer initiating a new cancer therapy. Clinical data were collected until 6-month follow-up. The impact of patient-, disease-, and treatment-related factors on the occurrence of VTE and early mortality was evaluated in univariable and multivariable Cox regression analyses. A previously validated VTE risk score (VTE-RS) was also calculated (also known as Khorana score). Results. Of 1,980 patients with lung cancer who were enrolled from 2011 to 2012, 84% had non-small cell lung cancer. During the first 6 months, 121 patients developed a VTE (6.1%), of which 47% had pulmonary embolism, 46% deep vein
thrombosis, 3% catheter-associated thrombosis, and 4% visceral thrombosis. Independent predictors for VTE included female sex, North America location, leg immobilization, and presence of a central venous catheter. The VTE-RS was not significantly associated with VTE in either univariable or multivariable analysis in this population. During the study period, 472 patients died, representing 20%, 24%, 36%, and 25% with VTE-RS 1, 2, 3, or unknown, respectively (p < .0001). Significant independent predictors of early mortality include older age, current/former smoking, chronic obstructive pulmonary disease, Eastern Cooperative Oncology Group performance status 2, no prior surgery, and metastatic disease, as well as the VTE-RS. Conclusion. In this global, prospective, real-world analysis, several demographic, geographic, and clinical factors are independent risk factors for VTE and early mortality in patients with lung cancer. The VTE-RS represents a significant independent predictor of early mortality but not for VTE in lung cancer in the era of targeted therapy. The Oncologist 2017;22:1–9
Implications for Practice: Multiple risk factors for both venous thromboembolism (VTE) and early mortality in patients with lung cancer receiving systemic chemotherapy should guide best practice by better informing clinical evaluation and treatment decisionmaking. The Khorana risk score is of value in assessing the risk of early all-cause mortality along with other clinical parameters in patients with lung cancer receiving systemic therapy. Further study is needed to fully evaluate the validity of the risk score in predicting the risk of VTE in the modern era of lung cancer therapy.
INTRODUCTION The risk of venous thromboembolism (VTE) is increased in patients with cancer, rising further during periods of treatment [1–3]. Venous thromboembolism has been associated with worsened short-term and long-term outcomes in patients with cancer in retrospective studies [4, 5]. Likewise, in prospective
studies, ambulatory patients with cancer who develop VTE experience a greater risk of early all-cause mortality than patients who do not develop VTE [6–9], including patients with lung cancer receiving chemotherapy [7, 8]. This association may be partly but not entirely accounted for by vascular events,
Correspondence: Gary H. Lyman, M.D., M.P.H., Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle Washington, 98109. Telephone: 206-667-6670; e-mail: [email protected] Received May 7, 2017; accepted for publication August 17, 2017. http:// dx.doi.org/10.1634/theoncologist.2017-0205
The Oncologist 2017;22:1–9 www.TheOncologist.com
c AlphaMed Press 2017 O
Downloaded from http://theoncologist.alphamedpress.org/ at Fudan University on September 28, 2017
Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; bDepartment of Medicine, University of Washington, Seattle, Washington, USA; cDepartment of Medicine, University of Rochester, Rochester, New York, USA; dDepartment of Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA; eDepartment of Medicine, Medical University of Vienna, Vienna, Austria; fDepartment of Internal Medicine, University of Perugia, Perugia, Italy; gDepartment of Medicine, University of Southern California, Los Angeles, California, USA; hDepartment of Medicine, Universite Paris Descartes, Paris, France; iCancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0205.
2
MATERIALS AND METHODS CANTARISK represents a global, prospective, noninterventional, real-world cohort study of patients with lung cancer or colorectal cancer initiating a new systemic cancer therapy. The objectives c AlphaMed Press 2017 O
were to evaluate VTE, bleeding, and mortality in patients initiating new systemic therapy. Patients aged 18 years or older with a confirmed histopathologic diagnosis of lung cancer were eligible. Chemotherapy treatment decisions were to be made prior to entry on this study and not linked to patient participation. Patients on studies necessitating treatment blinding were excluded. Each patient was to be followed for up to 6 months following enrollment and all patients provided written informed consent at enrollment. Patients were consented in 24 countries (including North and South America, Europe, and Asia). Patients unable to provide consent or with a life expectancy of less than 6 months were excluded from trial participation. Assessment regarding life expectancy was determined by the treating physician who was considered most knowledgeable about the patient and best able to assess the patient’s prognosis. The study has been conducted according to all national and international regulatory guidelines for clinical trial research and in accordance with the Declaration of Helsinki. Physicians were trained for participation in the study and were instructed to enroll consecutive eligible patients. Data collected using an electronic case report form created a priori included baseline data on patient demographics, medical history, cancer diagnosis and treatment history, history of thrombosis or bleeding, concomitant medication, and recent laboratory testing including complete blood count. Data inconsistencies generated automatic requests to which the treating clinician was required to respond. Data quality control was conducted within country by trained personnel at 10% of randomly selected active sites in each country and when specific quality issues were identified. Clinical data were collected at baseline and at 2-, 4- and 6month follow-up, and included subsequent cancer treatment details, bleeding and thromboembolic episodes, laboratory testing results, and cancer progression and survival data. Early mortality was defined as death within 6 months of enrollment, whereas VTE was based on clinical suspicion of a new event during clinical follow-up. Specific investigations to detect deep vein thrombosis (DVT) and PE were performed as indicated based on clinical symptoms or physical signs suggestive of VTE as determined by the treating physician. If the patient had both a diagnosis of PE and a concurrent lower-extremity DVT, they were counted only once and categorized as a PE. Incidental VTEs found on routine staging imaging studies were included, based on prior reports confirming that these are clinically as relevant as obviously symptomatic events in active cancer patients with a continuous prothrombotic state [29, 30, 35–39], and per recommendations by the American Society of Clinical Oncology practice guidelines [29, 30] and the International Society of Thrombosis and Haemostasis guidance document [35]. The validated VTE-RS was calculated at baseline for each patient based on cancer site, BMI, platelet count, and hemoglobin and leukocyte count (also known as Khorana score) [23]. The current report focuses on lung cancer patients. CANTARISK results for patients with colorectal cancer have been presented elsewhere [34].
Statistical Analysis The cumulative risk of VTE and survival were estimated by the method of Kaplan and Meier. Time to the occurrence of VTE was assessed from baseline until the first occurrence of VTE. Survival was estimated based on time from baseline until death or date of last follow-up. The impact of patient-, disease- and treatment-related factors and the VTE-RS on time to initial VTE
Downloaded from http://theoncologist.alphamedpress.org/ at Fudan University on September 28, 2017
such as pulmonary embolism (PE), directly leading to mortality [10]. In addition, the hemostatic system is activated by cancer cells, oncogenes, and oncogenic products that directly interact with malignant transformed cells, resulting in progression from a dormant, nonvascularized state to metastatic phenotypes [11, 12]. This association between factors denoting poor prognosis and VTE needs further detailed elucidation, but overall there appears to be a common pathogenesis underlying poor prognosis and cancer- associated VTE [8, 9, 12–16]. Rates of early mortality during the period of primary treatment vary widely based on the study population, cancer site, stage, and type of treatment, ranging upwards of 20% or more in patients with advanced cancer receiving systemic therapy [17–20]. Studies on risk factors for early mortality in advanced cancer including lung cancer are limited despite the high risk for early mortality, its direct impact on patients, and the difficulty of clinicians predicting survival in individual patients [21]. Previous studies of risk models for early mortality in cancer patients are more than 20 years old, with limited validity with modern treatment and supportive care [22]. A clinical risk model for VTE has previously been developed based on data from a large, prospective U.S. national cohort study of patients initiating a new chemotherapy regimen for solid tumors and lymphoma [23]. The resulting risk score relies on five clinical variables including primary cancer site, body mass index (BMI), pretreatment platelet and leukocyte counts, and hemoglobin and/or use of red cell growth factors. This model has now been validated by several independent investigators [24–27], integrated into clinical guidelines to aid in VTE risk assessment [28–31], and is being utilized for purposes of identifying high-risk patients in several prospective thromboprophylaxis trials. Patients with lung cancer are known to be at increased risk for VTE as well as a high rate of early all-cause mortality. However, no studies of risk factors for either VTE or early mortality in lung cancer patients undergoing systemic therapy exist in the era of targeted therapies in a prospective real-world setting and on a global scale. The previously developed and validated VTE risk model was shown to be significantly associated with the risk of VTE in patients with lung cancer in the original prospective study cohort (data not shown). Although validated across a range of solid tumors, the risk score has not previously been independently validated for VTE in patients with lung cancer. In fact, in the era of targeted therapies, other authors have been unable to demonstrate a significant association of the risk score with VTE in patients with lung cancer [32, 33]. More recently, this VTE risk score (VTE-RS) has been shown to be associated with early all-cause mortality in patients with cancer utilizing the original prospective cohort population [6]. The study presented here aimed to perform a comprehensive assessment of patient and clinical characteristics associated with both the occurrence of VTE as well as early all-cause mortality in a large, international, prospective cohort of real-world patients with lung cancer receiving systemic cancer therapy. CANTARISK results for patients with colorectal cancer have been presented elsewhere [34].
VTE and Early Mortality Predictors in Lung Cancer
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0205.
Kuderer, Poniewierski, Culakova et al.
3
Table 1. Patient demographics and clinical characteristics and primary study outcomes Risk of VTE (n 5 1,980)a, n (%)
Early mortality (n 5 1,980)a, n (%)
Overall rate
1,980 (100)
121 (6.1)
472 (23.8)
886 (44.7) 1,094 (55.3)
58 (6.5) 63 (5.8)
239 (27.0) 233 (21.3)
1,239 (62.6) 741 (37.4)
61 (4.9) 60 (8.1)
307 (24.8) 165 (22.3)
1,381 (70.0) 438 (22.2) 70 (3.5)
103 (7.5) 5 (1.1) 9 (12.9)
341 (24.7) 87 (19.9) 21 (30.0)
85 (4.3)
4 (4.7)
21 (18.7)
702 (35.5) 134 (6.8) 630 (31.8) 514 (26.0)
78 (11.1) 9 (6.7) 29 (4.6) 5 (1.0)
200 (28.5) 38 (28.4) 138 (21.9) 96 (18.7)
80 (4.1) 1,890 (95.9)
9 (11.3) 112 (5.9)
19 (23.8) 451 (23.9)
621 (31.9) 1,074 (55.2) 249 (12.8)
43 (6.9) 64 (6.0) 9 (3.6)
98 (15.8) 270 (25.1) 96 (38.6)
307 (15.5) 1,672 (84.5)
18 (5.9) 103 (6.2)
77 (25.1) 395 (23.6)
931 (47.0) 351 (17.7) 390 (19.7)
56 (6.0) 17 (4.8) 30 (7.7)
212 (22.8) 351 (26.2) 91 (23.3)
143 (7.2) 379 (19.1) 615 (31.1) 843 (42.6)
1 (0.7) 21 (5.5) 43 (7.0) 56 (6.6)
27 (18.9) 82 (21.6) 164 (26.7) 199 (23.6)
1,392 (70.4) 586 (29.6)
90 (6.5) 31 (5.3)
376 (27.0) 96 (16.4)
360 (18.3) 995 (50.5)
13 (3.6) 66 (6.6)
61 (16.9) 256 (25.7)
615 (31.2) 341 (17.6) 683 (35.2) 314 (15.9) 385 (20.3)
40 (6.5) 21 (6.2) 52 (7.6) 13 (4.1) 30 (7.8)
154 (25.0) 107 (31.4) 174 (25.5) 81 (25.8) 123 (31.9)
Age 65 years
Lung Cancer
Predictors of Venous Thromboembolism and Early Mortality in Lung Cancer: Results from a Global Prospective Study (CANTARISK) NICOLE M. KUDERER,a,b MAREK S. PONIEWIERSKI,a EVA CULAKOVA,c GARY H. LYMAN,a,b ALOK A. KHORANA,d INGRID PABINGER,e GIANCARLO AGNELLI,f HOWARD A. LIEBMAN,g ERIC VICAUT,h GUY MEYER,h FRANCES A. SHEPHERDi a
Disclosures of potential conflicts of interest may be found at the end of this article.
Key Words. Venous thromboembolism
•
Lung neoplasms
•
Risk factors
•
Risk prediction model
•
Mortality
•
Prognosis
ABSTRACT Background. Patients with lung cancer are known to be at increased risk for venous thromboembolism (VTE). Venous thromboembolism is associated with increased risk for early mortality. However, there have been no studies performing a comprehensive assessment of risk factors for VTE or early mortality in lung cancer patients undergoing systemic chemotherapy in a global real-world setting. Materials and Methods. CANTARISK is a prospective, global, noninterventional cohort study including patients with lung cancer initiating a new cancer therapy. Clinical data were collected until 6-month follow-up. The impact of patient-, disease-, and treatment-related factors on the occurrence of VTE and early mortality was evaluated in univariable and multivariable Cox regression analyses. A previously validated VTE risk score (VTE-RS) was also calculated (also known as Khorana score). Results. Of 1,980 patients with lung cancer who were enrolled from 2011 to 2012, 84% had non-small cell lung cancer. During the first 6 months, 121 patients developed a VTE (6.1%), of which 47% had pulmonary embolism, 46% deep vein
thrombosis, 3% catheter-associated thrombosis, and 4% visceral thrombosis. Independent predictors for VTE included female sex, North America location, leg immobilization, and presence of a central venous catheter. The VTE-RS was not significantly associated with VTE in either univariable or multivariable analysis in this population. During the study period, 472 patients died, representing 20%, 24%, 36%, and 25% with VTE-RS 1, 2, 3, or unknown, respectively (p < .0001). Significant independent predictors of early mortality include older age, current/former smoking, chronic obstructive pulmonary disease, Eastern Cooperative Oncology Group performance status 2, no prior surgery, and metastatic disease, as well as the VTE-RS. Conclusion. In this global, prospective, real-world analysis, several demographic, geographic, and clinical factors are independent risk factors for VTE and early mortality in patients with lung cancer. The VTE-RS represents a significant independent predictor of early mortality but not for VTE in lung cancer in the era of targeted therapy. The Oncologist 2017;22:1–9
Implications for Practice: Multiple risk factors for both venous thromboembolism (VTE) and early mortality in patients with lung cancer receiving systemic chemotherapy should guide best practice by better informing clinical evaluation and treatment decisionmaking. The Khorana risk score is of value in assessing the risk of early all-cause mortality along with other clinical parameters in patients with lung cancer receiving systemic therapy. Further study is needed to fully evaluate the validity of the risk score in predicting the risk of VTE in the modern era of lung cancer therapy.
INTRODUCTION The risk of venous thromboembolism (VTE) is increased in patients with cancer, rising further during periods of treatment [1–3]. Venous thromboembolism has been associated with worsened short-term and long-term outcomes in patients with cancer in retrospective studies [4, 5]. Likewise, in prospective
studies, ambulatory patients with cancer who develop VTE experience a greater risk of early all-cause mortality than patients who do not develop VTE [6–9], including patients with lung cancer receiving chemotherapy [7, 8]. This association may be partly but not entirely accounted for by vascular events,
Correspondence: Gary H. Lyman, M.D., M.P.H., Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle Washington, 98109. Telephone: 206-667-6670; e-mail: [email protected] Received May 7, 2017; accepted for publication August 17, 2017. http:// dx.doi.org/10.1634/theoncologist.2017-0205
The Oncologist 2017;22:1–9 www.TheOncologist.com
c AlphaMed Press 2017 O
Downloaded from http://theoncologist.alphamedpress.org/ at Fudan University on September 28, 2017
Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; bDepartment of Medicine, University of Washington, Seattle, Washington, USA; cDepartment of Medicine, University of Rochester, Rochester, New York, USA; dDepartment of Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA; eDepartment of Medicine, Medical University of Vienna, Vienna, Austria; fDepartment of Internal Medicine, University of Perugia, Perugia, Italy; gDepartment of Medicine, University of Southern California, Los Angeles, California, USA; hDepartment of Medicine, Universite Paris Descartes, Paris, France; iCancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0205.
2
MATERIALS AND METHODS CANTARISK represents a global, prospective, noninterventional, real-world cohort study of patients with lung cancer or colorectal cancer initiating a new systemic cancer therapy. The objectives c AlphaMed Press 2017 O
were to evaluate VTE, bleeding, and mortality in patients initiating new systemic therapy. Patients aged 18 years or older with a confirmed histopathologic diagnosis of lung cancer were eligible. Chemotherapy treatment decisions were to be made prior to entry on this study and not linked to patient participation. Patients on studies necessitating treatment blinding were excluded. Each patient was to be followed for up to 6 months following enrollment and all patients provided written informed consent at enrollment. Patients were consented in 24 countries (including North and South America, Europe, and Asia). Patients unable to provide consent or with a life expectancy of less than 6 months were excluded from trial participation. Assessment regarding life expectancy was determined by the treating physician who was considered most knowledgeable about the patient and best able to assess the patient’s prognosis. The study has been conducted according to all national and international regulatory guidelines for clinical trial research and in accordance with the Declaration of Helsinki. Physicians were trained for participation in the study and were instructed to enroll consecutive eligible patients. Data collected using an electronic case report form created a priori included baseline data on patient demographics, medical history, cancer diagnosis and treatment history, history of thrombosis or bleeding, concomitant medication, and recent laboratory testing including complete blood count. Data inconsistencies generated automatic requests to which the treating clinician was required to respond. Data quality control was conducted within country by trained personnel at 10% of randomly selected active sites in each country and when specific quality issues were identified. Clinical data were collected at baseline and at 2-, 4- and 6month follow-up, and included subsequent cancer treatment details, bleeding and thromboembolic episodes, laboratory testing results, and cancer progression and survival data. Early mortality was defined as death within 6 months of enrollment, whereas VTE was based on clinical suspicion of a new event during clinical follow-up. Specific investigations to detect deep vein thrombosis (DVT) and PE were performed as indicated based on clinical symptoms or physical signs suggestive of VTE as determined by the treating physician. If the patient had both a diagnosis of PE and a concurrent lower-extremity DVT, they were counted only once and categorized as a PE. Incidental VTEs found on routine staging imaging studies were included, based on prior reports confirming that these are clinically as relevant as obviously symptomatic events in active cancer patients with a continuous prothrombotic state [29, 30, 35–39], and per recommendations by the American Society of Clinical Oncology practice guidelines [29, 30] and the International Society of Thrombosis and Haemostasis guidance document [35]. The validated VTE-RS was calculated at baseline for each patient based on cancer site, BMI, platelet count, and hemoglobin and leukocyte count (also known as Khorana score) [23]. The current report focuses on lung cancer patients. CANTARISK results for patients with colorectal cancer have been presented elsewhere [34].
Statistical Analysis The cumulative risk of VTE and survival were estimated by the method of Kaplan and Meier. Time to the occurrence of VTE was assessed from baseline until the first occurrence of VTE. Survival was estimated based on time from baseline until death or date of last follow-up. The impact of patient-, disease- and treatment-related factors and the VTE-RS on time to initial VTE
Downloaded from http://theoncologist.alphamedpress.org/ at Fudan University on September 28, 2017
such as pulmonary embolism (PE), directly leading to mortality [10]. In addition, the hemostatic system is activated by cancer cells, oncogenes, and oncogenic products that directly interact with malignant transformed cells, resulting in progression from a dormant, nonvascularized state to metastatic phenotypes [11, 12]. This association between factors denoting poor prognosis and VTE needs further detailed elucidation, but overall there appears to be a common pathogenesis underlying poor prognosis and cancer- associated VTE [8, 9, 12–16]. Rates of early mortality during the period of primary treatment vary widely based on the study population, cancer site, stage, and type of treatment, ranging upwards of 20% or more in patients with advanced cancer receiving systemic therapy [17–20]. Studies on risk factors for early mortality in advanced cancer including lung cancer are limited despite the high risk for early mortality, its direct impact on patients, and the difficulty of clinicians predicting survival in individual patients [21]. Previous studies of risk models for early mortality in cancer patients are more than 20 years old, with limited validity with modern treatment and supportive care [22]. A clinical risk model for VTE has previously been developed based on data from a large, prospective U.S. national cohort study of patients initiating a new chemotherapy regimen for solid tumors and lymphoma [23]. The resulting risk score relies on five clinical variables including primary cancer site, body mass index (BMI), pretreatment platelet and leukocyte counts, and hemoglobin and/or use of red cell growth factors. This model has now been validated by several independent investigators [24–27], integrated into clinical guidelines to aid in VTE risk assessment [28–31], and is being utilized for purposes of identifying high-risk patients in several prospective thromboprophylaxis trials. Patients with lung cancer are known to be at increased risk for VTE as well as a high rate of early all-cause mortality. However, no studies of risk factors for either VTE or early mortality in lung cancer patients undergoing systemic therapy exist in the era of targeted therapies in a prospective real-world setting and on a global scale. The previously developed and validated VTE risk model was shown to be significantly associated with the risk of VTE in patients with lung cancer in the original prospective study cohort (data not shown). Although validated across a range of solid tumors, the risk score has not previously been independently validated for VTE in patients with lung cancer. In fact, in the era of targeted therapies, other authors have been unable to demonstrate a significant association of the risk score with VTE in patients with lung cancer [32, 33]. More recently, this VTE risk score (VTE-RS) has been shown to be associated with early all-cause mortality in patients with cancer utilizing the original prospective cohort population [6]. The study presented here aimed to perform a comprehensive assessment of patient and clinical characteristics associated with both the occurrence of VTE as well as early all-cause mortality in a large, international, prospective cohort of real-world patients with lung cancer receiving systemic cancer therapy. CANTARISK results for patients with colorectal cancer have been presented elsewhere [34].
VTE and Early Mortality Predictors in Lung Cancer
Published Ahead of Print on September 26, 2017 as 10.1634/theoncologist.2017-0205.
Kuderer, Poniewierski, Culakova et al.
3
Table 1. Patient demographics and clinical characteristics and primary study outcomes Risk of VTE (n 5 1,980)a, n (%)
Early mortality (n 5 1,980)a, n (%)
Overall rate
1,980 (100)
121 (6.1)
472 (23.8)
886 (44.7) 1,094 (55.3)
58 (6.5) 63 (5.8)
239 (27.0) 233 (21.3)
1,239 (62.6) 741 (37.4)
61 (4.9) 60 (8.1)
307 (24.8) 165 (22.3)
1,381 (70.0) 438 (22.2) 70 (3.5)
103 (7.5) 5 (1.1) 9 (12.9)
341 (24.7) 87 (19.9) 21 (30.0)
85 (4.3)
4 (4.7)
21 (18.7)
702 (35.5) 134 (6.8) 630 (31.8) 514 (26.0)
78 (11.1) 9 (6.7) 29 (4.6) 5 (1.0)
200 (28.5) 38 (28.4) 138 (21.9) 96 (18.7)
80 (4.1) 1,890 (95.9)
9 (11.3) 112 (5.9)
19 (23.8) 451 (23.9)
621 (31.9) 1,074 (55.2) 249 (12.8)
43 (6.9) 64 (6.0) 9 (3.6)
98 (15.8) 270 (25.1) 96 (38.6)
307 (15.5) 1,672 (84.5)
18 (5.9) 103 (6.2)
77 (25.1) 395 (23.6)
931 (47.0) 351 (17.7) 390 (19.7)
56 (6.0) 17 (4.8) 30 (7.7)
212 (22.8) 351 (26.2) 91 (23.3)
143 (7.2) 379 (19.1) 615 (31.1) 843 (42.6)
1 (0.7) 21 (5.5) 43 (7.0) 56 (6.6)
27 (18.9) 82 (21.6) 164 (26.7) 199 (23.6)
1,392 (70.4) 586 (29.6)
90 (6.5) 31 (5.3)
376 (27.0) 96 (16.4)
360 (18.3) 995 (50.5)
13 (3.6) 66 (6.6)
61 (16.9) 256 (25.7)
615 (31.2) 341 (17.6) 683 (35.2) 314 (15.9) 385 (20.3)
40 (6.5) 21 (6.2) 52 (7.6) 13 (4.1) 30 (7.8)
154 (25.0) 107 (31.4) 174 (25.5) 81 (25.8) 123 (31.9)
Age 65 years
