Content uploaded by Finn Egil Skjeldestad
Author content
All content in this area was uploaded by Finn Egil Skjeldestad on Dec 29, 2015
Content may be subject to copyright.
A preview of the PDF is not available
The increased risk of venous thromboembolism by advancing age cannot be attributed to the higher incidence of cancer in the elderly: The Tromsø study
Abstract and Figures
Unlabelled:
Whether the high incidence of venous thromboembolism (VTE) in the elderly can be attributed to cancer is not well studied. We assessed the impact of cancer on risk of VTE in young, middle-aged and elderly. 26,094 subjects without a history of cancer or VTE were recruited from the Tromsø study. Incident cancer (n = 2,290) and VTE (n = 531) were recorded from baseline (1994-1995) through December 31st, 2009. Cox regression with cancer as time-varying exposure was used to calculate hazard ratios with 95 % confidence intervals (CI). Overt cancer was associated with a fivefold (95 %CI 4.3, 6.7) increased risk of VTE, with an age-dependent gradient from 26-fold (95 %CI 12.1, 56.5) increased in the young, ninefold (95 % CI 6.6, 12.7) increased in the middle-aged, and threefold (95 % CI 2.5, 4.5) increased risk in the elderly. The population attributable risks were 14, 27 and 18 %, respectively.
Conclusion:
The relative risk of VTE by cancer were higher in young compared to elderly subjects, but the proportion of VTEs in the population due to cancer did not differ much across age groups. Our findings indicate that the increased risk of VTE by advancing age cannot be attributed to higher incidence of cancer in the elderly.
Figures - uploaded by Finn Egil Skjeldestad
Author content
All figure content in this area was uploaded by Finn Egil Skjeldestad
Content may be subject to copyright.
... VTE occurs predominantly in the elderly (> 85) and obesity (BMI > 35Kg/m 2 ) tends to play an adjuvant role for the development of VTE in this population (4,23,24). In our study, over 90% had a BMI < 35Kg/m 2 and 78.4% were below 60 years. ...
Background
Tamoxifen therapy is an effective and mainstay adjuvant treatment for estrogen-positive breast cancer patients. However, it has partial estrogen receptor agonist activity that causes hypercoagulation of blood and consequently venous thrombus formation. Patients who are being treated with tamoxifen require monitoring, because of the increased risk for developing deep venous thrombosis (DVT) and pulmonary embolism that could increase morbidity and mortality if left undiagnosed. This study sought to determine the prevalence and associated factors of lower limb DVT among breast cancer patients on tamoxifen, in Uganda.
Methods
This was a cross-sectional study done among patients receiving tamoxifen therapy who attended the breast clinic at the Uganda Cancer Institute. Clinical evaluation, mean platelet volume (MPV) and bilateral lower limb compression and Doppler ultrasound scans were done to screen for DVT. Univariate analysis was used to summarize continuous variables as mean and corresponding standard deviations, and categorical variables as proportions.
Results
Of the 180 participants, 170 (94.4%) were females, 141 (78.3%) were below 60 years. More than 95% were neither diabetic nor smokers and 163 (90.6%) of them had a BMI of < 35Kg/m². The prevalence of DVT was 0.6%. The statistical significance of the associated factors could not be elucidated at bivariate or multivariate analysis due to the very low prevalence of DVT.
Conclusion
The prevalence of DVT among breast cancer patients on tamoxifen at the Uganda cancer institute was very low (0.6%). The patients with normal MPV findings are unlikely to have DVT despite the intermediate risk on clinical assessment, therefore a routine sonographic examination for younger Ugandan patients on tamoxifen may not be necessary.
... Smoking was reported as an independent risk factor for VTE in all populations, especially in younger female patients (55,56). A population-based study concluded that the relative risk of VTE in the presence of cancer was highest in patients <50 years of age (57), whilst a study of female patients between the ages of 10 and 29 with PE suggested that oral contraceptive use, pregnancy and postpartum status were predominant factors (58). Other previous studies also demonstrated pregnancy, puerperium, estrogen and oral contraceptive use, family history of VTE and a history of trauma to be more prevalent in younger patients with PE (65) heart failure; venous insufficiency; increasing levels of blood plasma fibrinogen and plasminogen activator inhibitor-1 (ages in three articles were between 21-50 years, 18-40 years and <40 years, respectively) (32,59,60). ...
Pulmonary embolism (PE) is a serious, life-threatening condition that affects young populations (>18 and <50 years old, according to most literature reviews) with improved recognition of its clinical manifestations and the widespread use of sensitive imaging techniques, PE is increasingly diagnosed in younger patients. At present, there is limited understanding of the clinical features and adequate anticoagulant treatment options for this population. Most studies to date have yet to demonstrate significant differences in PE pathophysiology or symptoms between young and elderly patients. Although the overall incidence of PE is lower in young populations compared with elderly patients, important risk factors also apply for young patients. Hereditary thrombophilia is common and is a major cause of PE in younger patients. Immobilization, trauma, obesity, smoking and infection are also becoming increasingly frequent in young patients with PE. Among female patients, oral contraceptive use, pregnancy and postpartum status are predominant risk factors underlying PE. Rivaroxaban is a direct oral anticoagulant with a rapid onset of action that is associated with less drug-drug interactions compared with other therapies. Because the drug is administered at fixed doses with no requirement for routine coagulation monitoring, it is becoming an attractive option for anticoagulation treatment in young patients with PE. Therefore, the present literature review focuses on the clinical characteristics of PE and rivaroxaban therapy in younger patients.
... The proportion of VTE that would not occur if cancer was eliminated in the population (i.e. the population attributable risk fraction) was however similar in the young and elderly age groups (14% and 18%, respectively). 136 In the general population, the effect of sex on the risk of VTE is dependent of age. In a French population based study, IRs of VTE increased with increasing age, however women had a higher IR of VTE than men when younger than 40 years of age and older than 75. ...
The Ph.D. thesis is based on four epidemiological studies where associations between cancer
specific factors and VTE were investigated in different groups of cancer patietns. Study
1 showed that for some cancer types the degree of metastasis is associated with the risk
of VTE in the sense that regional and/or distant metastasis increases the risk of VTE
compared with localized disease, while for other cancer types the risk is high even in
localized disease or conversely low regardless of stage. Study 3 showed that the risk of
VTE in cancer patients who survive the acute effects of cancer, associated treatments
and hospitalizations without VTE decrease to the level of the background population,
except for patients with hematological cancer. Study 2 showed that especially myeloma
patietns and chronic lymphocytic leukemia patients have a higher risk of VTE
than the background population years after the diagnosis of hematological cancer. In
study 4, the association between chronic lymphocytic leukemia and VTE was further
investigated. Patients with chronic lymphocytic leukemia had a higher risk of VTE
mostly because of additional cancer after the diagnosis, but biological markers of the
prognosis of chronic lymphocytic leukemia were also associated with the risk of VTE.
In their entirety, the studies in this Ph.D. dissertation contributes to a more detailed
understanding of when and which cancer patients are at highest risk of VTE. With
other scientific contributions, the presented studies can aid in development of more
personalized efforts against cancer-associated VTE.
For full text go to:
https://vbn.aau.dk/da/publications/venous-thromboembolism-in-solid-and-hematological-cancers-cancer-
... Recently, Blix et al. calculated age-specific population attributable risks of VT due to cancer based on incidences of cancer and VT in the Tromsø Study and found a smaller actual difference than postulated between the young (<50 years, population attributable risk 14%) and the elderly (>70 years, population attributable risk 18%). 262 These findings show that malignancy does not explain a substantial proportion of the VT events in the elderly, and, most importantly, that studies focusing on risk factors in the elderly are urgently needed, because extrapolations do not suffice. A limited number of studies have investigated the impact of age-specific risk factor on VT risk, and prelimi-EHA Roadmap for European Hematology Research haematologica | 2016; 101(2) Figure 7. Venous thrombosis (VT) incidence increases with age. ...
The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
... Other tools could have been used to assess absolute treatment effect (attributable fraction [28] or risk [29]) or additive interaction (relative excess risk due to interaction [30,31]). Importantly, very simple tools can sometimes be useful to assess additive interaction, such as the direct comparison of probabilities, which we previously used in a re-analysis of published data of a clinical trial [1]. ...
Background:
In both observational and randomized studies, associations with overall survival are by and large assessed on a multiplicative scale using the Cox model. However, clinicians and clinical researchers have an ardent interest in assessing absolute benefit associated with treatments. In older patients, some studies have reported lower relative treatment effect, which might translate into similar or even greater absolute treatment effect given their high baseline hazard for clinical events.
Methods:
The effect of treatment and the effect modification of treatment were respectively assessed using a multiplicative and an additive hazard model in an analysis adjusted for propensity score in the context of coronary surgery.
Results:
The multiplicative model yielded a lower relative hazard reduction with bilateral internal thoracic artery grafting in older patients (Hazard ratio for interaction/year = 1.03, 95%CI: 1.00 to 1.06, p = 0.05) whereas the additive model reported a similar absolute hazard reduction with increasing age (Delta for interaction/year = 0.10, 95%CI: -0.27 to 0.46, p = 0.61). The number needed to treat derived from the propensity score-adjusted multiplicative model was remarkably similar at the end of the follow-up in patients aged < = 60 and in patients >70.
Conclusions:
The present example demonstrates that a lower treatment effect in older patients on a relative scale can conversely translate into a similar treatment effect on an additive scale due to large baseline hazard differences. Importantly, absolute risk reduction, either crude or adjusted, can be calculated from multiplicative survival models. We advocate for a wider use of the absolute scale, especially using additive hazard models, to assess treatment effect and treatment effect modification.
The incidence of venous thromboembolism in cancer patients may have changed in the past decade, possibly due to novel cancer therapies, improved survival, and high-resolution imaging. Danish medical registries were used to identify 499,092 patients with a first-time cancer diagnosis between 1997 and 2017, who were matched to 1,497,276 comparison individuals without cancer from the general population. We computed cumulative incidences of venous thromboembolism 6 and 12 months after the diagnosis/index date. Hazard ratios (HRs) were calculated using Cox regression. Risk factors were examined by computing subdistribution hazard ratios (SHRs) in a competing risk analysis. Cumulative incidence of venous thromboembolism 12 months after the cancer diagnosis/index date was 2.3% (95% confidence interval (CI), 2.2%-2.3%) in the cancer cohort and 0.35% (95% CI, 0.34%-0.36%) in the comparison cohort (HR, 8.5; 95% CI, 8.2-8.8). Important risk factors for cancer patients were prior venous thromboembolism (SHR, 7.6; 95% CI, 7.2-8.0), distant metastasis (SHR, 3.2; 95% CI, 2.9-3.4), and use of chemotherapy (SHR, 3.4; 95% CI, 3.1-3.7), protein kinase inhibitors (SHR, 4.1; 95% CI 3.4-4.9), anti-angiogenic therapy (SHR, 4.4; 95% CI, 3.8-5.2), and immunotherapy (SHR, 3.6; 2.8-4.6). Twelve-month incidence in the cancer cohort increased from 1.0% (95% CI, 0.9%-1.2%) in 1997 to 3.4% (95% CI, 2.9%-4.0%) in 2017, which was paralleled by improved 12-month survival and increased use of computed tomography (CT) scans, chemotherapy, and targeted therapies. In conclusion, the risk of venous thromboembolism in cancer patients is increasing steadily and is 9-fold higher than in the general population.
Background: Venous thromboembolism (VTE) is a frequent yet potentially preventable complication that increases morbidity and mortality among cancer patients. Chronic Lymphocytic Leukemia (CLL) is a heterogeneous hematological cancer. Patient specific factors (age, gender, performance status) and CLL specific markers (e.g. IgHV mutational status, Binet stage, and beta 2-microglobulin (B2M) levels) influence the clinical course of CLL. A considerable proportion of CLL patients are diagnosed with additional cancer after the CLL diagnosis. The risk of VTE in CLL is higher than the background population throughout the clinical course of CLL in contrast to solid tumors where VTE typically develops within the first few months after cancer diagnosis.
Aim: To investigate the risk of VTE in CLL patients according to patient specific factors, CLL specific markers, CLL treatment and additional cancer after the CLL diagnosis.
Methods: The Danish National CLL Registry provided prospectively collected clinical data from all CLL patients diagnosed in Denmark since 2008. These data were linked at person level by the unique civil registration number to the Danish National Patient Registry for information on VTE and additional cancers, to the Danish National Prescription Database for information on prescribed and reimbursed anticoagulation treatment and to the Danish Civil Registration System for information on vital status and emigration. Study entry was date of CLL diagnosis; subjects were followed until VTE, death, emigration or administrative censoring. Cumulative incidence of VTE according to Binet stage, B2M levels, IgHV mutational status and additional cancers diagnosed later than CLL were calculated. Additional cancer after the CLL diagnosis was defined as a time-varying exposure. Subjects contributed to the number being at risk of VTE in the "no additional cancer" group until the possible date of additional cancer at which they shifted to the "additional cancer after CLL" group. Death and additional cancer were treated as competing risks by use of the Aalen-Johansen estimator. In Cox proportional hazard models, we estimated the hazard ratios (HR) of VTE; WHO-performance score, previous VTE and sex were included in the models as categorical variables, age was included as a continuous variable and anticoagulation treatment and additional cancer were included as time-varying covariates in the appropriate models.
Results: From 2008 through 2015, 3609 subjects were diagnosed with CLL, 60.1% were males and the median age at CLL diagnosis was 70.4 years. Median follow-up was 2.6 years. During the study period, 12.7% (461) were diagnosed with an additional cancer and 19.9% (721) died. Anticoagulation treatment was given to 6.3% (227) of the CLL patients in the study period. The majority of the CLL patients had mutated IgHV, and B2M levels below 4mg/L (Table 1). A VTE was registered in 92 CLL patients during the study period. The cumulative incidence of VTE was highest in CLL patients exposed to additional cancer followed by CLL patients with B2M levels above 4 mg/L and unmutated IgHV. (Figure 1). CLL patients with additional cancer after the CLL diagnosis had a 3-4 fold higher risk of VTE compared with CLL patients without additional cancer. Previous VTE increased the risk of VTE after the CLL diagnosis by 5 fold. This was to some extent because a larger proportion of CLL patients with previous VTE were exposed to an additional cancer after the CLL diagnosis (23.9%) compared with the total study population (12.8%). The HR of VTE in case of previous VTE however, remained high after adjustment for additional cancer cancer and other risk factors (Table 1). Unmutated IgHV and B2M level >4 mg/L increased the risk of VTE, these associations persisted after adjustment for additional cancer (Table 1). CLL treatment tended to increase the risk of VTE, patient related factors and CLL specific markers did not affect the association markedly.
Conclusion: The risk of VTE was especially high in CLL patients with additional cancer. Previous VTE was also a substantial (expected) risk factor whereas high age and CLL specific markers (B2M level > 4 mg/L, unmutated IgHV) were significant but less strong risk factors of VTE.
Disclosures
No relevant conflicts of interest to declare.
Venous thromboembolism (VTE) is associated with inferior survival in cancer patients. The risk of VTE and its effect on survival in chronic lymphocytic leukemia (CLL) patients remains unclear. The present study investigated the impact of patient-related factors, CLL prognostic markers, and CLL treatment on the risk of VTE and assessed overall survival relative to VTE. All patients in the Danish National CLL Registry (2008-2015) were followed from the date of CLL diagnosis to death, VTE, emigration, or administrative censoring. Hazard ratios (HRs) were estimated using Cox models, and second primary cancers and anticoagulation treatment were included as time-varying exposures. During a median follow-up of 2.6 years, 92 VTEs occurred among 3609 CLL patients, corresponding to a total incidence rate of 8.2 VTEs per 1000 person-years (95% confidence interval [CI], 6.7-10.1). A history of VTE or second primary cancer was associated with HRs of VTE of 5.09 (95% CI, 2.82-9.17) and 3.72 (95% CI, 2.15-6.34), respectively, while β2-microglobulin >4 mg/L, unmutated immunoglobulin HV and unfavorable cytogenetics had lower HRs. CLL patients with VTE had marginally higher mortality, which was most pronounced among patients <60 years of age (HR, 7.74; 95% CI, 2.12-28.29). Our findings suggest that markers of unfavorable CLL prognosis contribute to an increased risk of VTE; however, previous VTE or a second primary cancer is more strongly associated with the risk of VTE than any CLL-specific marker. Focusing attention on this preventable complication may improve survival in young CLL patients.
Purpose:
Data concerning specific manifestations of pulmonary embolism (PE) among younger patients are scarce. We aimed to evaluate differences in clinical presentation, PE prediction rules, thrombolytic treatment use and PE outcomes in younger (<50 years of age) compared to older patients.
Material/methods:
We studied 238 consecutive patients with proven PE who were retrospectively categorized into three PE probability subgroups according to the revised Geneva score (RGS) and Wells score (WS). Duration of follow-up was up to 115 months.
Results:
Younger patients accounted for 19.7% of the study cohort. Obesity and smoking were significantly more common, while comorbidities were less common (P<0.05) in the younger patients. According to RGS and WS, younger patients were more often categorized into the low PE probability subgroup and rarely into the high probability subgroup (P<0.05). We found no differences in clinical signs, symptoms, and treatment between the two groups. In-hospital (2% vs. 13%) and long-term (12% vs. 36%) mortality rates were significantly lower in younger patients (P=0.003).
Conclusions:
In younger PE patients, despite differences in predisposing factors and PE probability grading as assessed by RGS and WS, clinical features at admission and treatment were similar compared to the older group. Our findings confirmed lower mortality among younger compared to older patients.
Objective:
The relationship between serum levels of calcium, parathyroid hormone (PTH) and risk of venous thromboembolism (VTE) has not been addressed in population-based cohorts. We investigated the associations between serum levels of calcium and PTH, with future risk of VTE in a general adult population.
Design:
Population-based cohort Methods: A total of 27,712 subjects (25-87 years) who participated in Tromsø 4 (1994-95) and Tromsø 5 (2001-02) surveys were included in the study, and total calcium and PTH were measured in 27,685 and 8,547 subjects, respectively. Incident VTE was recorded through December 31, 2012. Cox-regression models with calcium and PTH as time-varying exposures were used to calculate hazard ratios (HR) of VTE by quartiles of calcium and PTH. Quartiles of calcium and PTH were also combined in order to assess the effect of discordants of both PTH and calcium (e.g. highest and lowest quartiles of both calcium and PTH) on VTE risk using the middle two quartiles as reference.
Results:
There were 712 VTEs during 15.0 years of median follow-up. Serum levels of calcium and PTH were not associated with risk of VTE. However, subjects with discordant high serum levels of both calcium and PTH (calcium ≥2.45mmol/L and PTH ≥4.0pmol/L) had increased risk of VTE compared to subjects with normal calcium and PTH (multivariable HR 1.78, 95% CI 1.12-2.84).
Conclusions:
Serum levels of calcium and PTH separately were not associated with future risk of VTE, but subjects with high levels of both calcium and PTH had increased risk of VTE compared to subjects with normal levels.
People with cancer are known to be at increased risk of venous thromboembolism (VTE), and this risk is believed to vary according to cancer type, stage of disease, and treatment modality. Our purpose was to summarise the existing literature to determine precisely and accurately the absolute risk of VTE in cancer patients, stratified by malignancy site and background risk of VTE.
We searched the Medline and Embase databases from 1 January 1966 to 14 July 2011 to identify cohort studies comprising people diagnosed with one of eight specified cancer types or where participants were judged to be representative of all people with cancer. For each included study, the number of patients who developed clinically apparent VTE, and the total person-years of follow-up were extracted. Incidence rates of VTE were pooled across studies using the generic inverse variance method. In total, data from 38 individual studies were included. Among average-risk patients, the overall risk of VTE was estimated to be 13 per 1,000 person-years (95% CI, 7 to 23), with the highest risk among patients with cancers of the pancreas, brain, and lung. Among patients judged to be at high risk (due to metastatic disease or receipt of high-risk treatments), the risk of VTE was 68 per 1,000 person-years (95% CI, 48 to 96), with the highest risk among patients with brain cancer (200 per 1,000 person-years; 95% CI, 162 to 247). Our results need to be considered in light of high levels of heterogeneity, which exist due to differences in study population, outcome definition, and average duration of follow-up between studies.
VTE occurs in greater than 1% of cancer patients each year, but this varies widely by cancer type and time since diagnosis. The absolute VTE risks obtained from this review can aid in clinical decision-making about which people with cancer should receive anticoagulant prophylaxis and at what times.
Venous thromboembolism (VTE) is a common complication in patients with malignant disease. First recognised by Bouillard in 1823 and later described by Trousseau in 1844, multiple studies have since provided considerable evidence for a clinical association between VTE and cancer. Across all cancers, the risk for VTE is elevated 7-fold; in certain malignancies, the risk for VTE may be increased up to 28-fold. Venous thromboembolism is the second leading cause of death in patients with cancer; among survivors, complications commonly include recurrent VTE and post-thrombotic syndrome, and (more rarely) chronic thromboembolic pulmonary hypertension, which are costly, and have a profound impact on the patient's quality of life. Tumour cells can activate blood coagulation through multiple mechanisms, including production of procoagulant, fibrinolytic, and proaggregating activities, release of proinflammatory and proangiogenic cytokines, and interacting directly with host vascular and blood cells (e.g., endothelial cells, leukocytes, and platelets) through adhesion molecules. Increasing evidence suggests that elements of the haemostatic system also have a direct role in eliciting or enhancing angiogenesis, cell survival, and metastasis. Despite the problem posed by VTE in the setting of cancer, it is evident that a significant number of oncologists do not recognise the link between cancer, its treatment, and thrombogenesis. On 22 May 2009, a group of UK-based physicians met in London, UK, to evaluate recent data on cancer thrombosis. This article (1 of 4) briefly reviews key data on the epidemiology and pathophysiology of VTE as a context for a discussion and consensus statement developed by meeting attendees, on the implications of this information for UK clinical practice.
With explanatory covariates, the standard analysis for competing risks data involves modeling the cause-specific hazard functions via a proportional hazards assumption. Unfortunately, the cause-specific hazard function does not have a direct interpretation in terms of survival probabilities for the particular failure type. In recent years many clinicians have begun using the cumulative incidence function, the marginal failure probabilities for a particular cause, which is intuitively appealing and more easily explained to the nonstatistician. The cumulative incidence is especially relevant in cost-effectiveness analyses in which the survival probabilities are needed to determine treatment utility. Previously, authors have considered methods for combining estimates of the cause-specific hazard functions under the proportional hazards formulation. However, these methods do not allow the analyst to directly assess the effect of a covariate on the marginal probability function. In this article we propose a novel semiparametric proportional hazards model for the subdistribution. Using the partial likelihood principle and weighting techniques, we derive estimation and inference procedures for the finite-dimensional regression parameter under a variety of censoring scenarios. We give a uniformly consistent estimator for the predicted cumulative incidence for an individual with certain covariates; confidence intervals and bands can be obtained analytically or with an easy-to-implement simulation technique. To contrast the two approaches, we analyze a dataset from a breast cancer clinical trial under both models.
Thrombophilia is a well-established risk factor for a venous thromboembolic event (VTE), and it has been proposed that hereditary thrombophilia may substantially contribute to the development of VTE in young patients. We aimed to analyse the prevalence of thrombophilia with special regard to the age of VTE manifestation. The study cohort consisted of 1490 patients (58% females) with a median age 43 years at the time of their first VTE. At least one thrombophilic disorder was identified in 50·1% of patients. The probability of detecting a hereditary thrombophilia declined significantly with advancing age (from 49·3% in patients aged 20 years and younger to 21·9% in patients over the age of 70 years; P < 0·001). This may be primarily attributed to the decreasing frequencies of the F5 R506Q (factor V Leiden) mutation and deficiencies of protein C or protein S with older age at the time of the initial VTE event. Moreover, thrombophilia was more prevalent in unprovoked compared with risk-associated VTE (57·7% vs. 47·7%; P = 0·001). The decline in the prevalence of hereditary thrombophilia with older ages supports the use of a selected thrombophilia screening strategy dependent on age and the presence or absence of additional VTE risk factors.
Study Question: What are the outcomes of patients with cancer complicated by deep venous thrombosis (DVT)?Methods: The initial medical records and outcome of 529 consecutive cancer patients in whom DVT developed from January 1, 1994, through December 31, 1997, were tracked until December 31, 2000. The study was conducted in a major cancer center, and the cost of hospitalization was obtained from the hospital’s cost-accounting system and inflated to 2002 US dollars using the Consumer Price Index for Medical Care. Logistic regression was used to identify factors associated with a high risk of poor outcomes.Results: The mean age was 55 years, and 52% were women. Seventy-seven percent of DVT cases presented as outpatients, 15% had a previous bout of DVT, and 13% developed within 30 days of a surgical procedure. Over 70% had the diagnosis established within 24 h of symptoms onset, although 20% had symptoms for at least 2 weeks; 50% were lower extremity and 40% were a major central vein alone or with an extremity. The latter were more often associated with central venous catheters (51% with vs. 35% without, p<0.001). Ninety-three percent received anticoagulants (95% received heparin). The most common complication of DVT was bleeding, which occurred in 13% of patients. Pulmonary embolus occurred in 4%. Five patients (1%) died of complications of DVT and 5 (1%) of complications of anticoagulation. Recurrence of DVT was common (17% overall), particularly among those who had inferior vena cava filters (32%, p<0.001) or a previous episode of DVT (p=0.03). All but 4 patients were hospitalized for initial anticoagulation therapy, for a mean of 11 days. The mean cost of hospitalization was 2002 US $20,065.Conclusions: Among patients with cancer, DVT frequently is associated with serious clinical outcomes. Its treatment is resource intensive and costly. More effective agents and less costly management strategies could have a significant impact on the outcomes and cost of DVT in this population.Perspective: This study demonstrates the very high rate of recurrence of DVT in cancer patients, and as with other studies that question the efficacy of IVC filters. The latter may be selection bias, but also could infer that the presence of the filter increases the risk of distant thrombosis. Unfortunately, the data cannot be used to draw any specific therapeutic conclusions. MR
With explanatory covariates, the standard analysis for competing risks data involves modeling the cause-specific hazard functions via a proportional hazards assumption. Unfortunately, the cause-specific hazard function does not have a direct interpretation in terms of survival probabilities for the particular failure type. In recent years many clinicians have begun using the cumulative incidence function, the marginal failure probabilities for a particular cause, which is intuitively appealing and more easily explained to the nonstatistician. The cumulative incidence is especially relevant in cost-effectiveness analyses in which the survival probabilities are needed to determine treatment utility. Previously, authors have considered methods for combining estimates of the cause-specific hazard functions under the proportional hazards formulation. However, these methods do not allow the analyst to directly assess the effect of a covariate on the marginal probability function. In this article we propose a novel semiparametric proportional hazards model for the subdistribution. Using the partial likelihood principle and weighting techniques, we derive estimation and inference procedures for the finite-dimensional regression parameter under a variety of censoring scenarios. We give a uniformly consistent estimator for the predicted cumulative incidence for an individual with certain covariates; confidence intervals and bands can be obtained analytically or with an easy-to-implement simulation technique. To contrast the two approaches, we analyze a dataset from a breast cancer clinical trial under both models.
Although the association between malignancy and thromboembolic disease is well established, the relative risk of developing initial and recurrent deep vein thrombosis (DVT) or pulmonary embolism (PE) among patients with malignancy versus those without malignancy has not been clearly defined. The Medicare Provider Analysis and Review Record (MEDPAR) database was used for this analysis. Patients hospitalized during 1988-1990 with DVT/PE alone, DVT/PE and malignancy, malignancy alone, or 1 of several nonmalignant diseases (other than DVT/PE) were studied. The association of malignancy and nonmalignant disease with an initial episode of DVT/PE, recurrent DVT/PE, and mortality were analyzed. The percentage of patients with DVT/PE at the initial hospitalization was higher for those with malignancy compared with those with nonmalignant disease (0.6% versus 0.57%, p = 0.001). The probability of readmission within 183 days of initial hospitalization with recurrent thromboembolic disease was 0.22 for patients with prior DVT/PE and malignancy compared with 0.065 for patients with prior DVT/PE and no malignancy (p = 0.001). Among those patients with DVT/PE and malignant disease, the probability of death within 183 days of initial hospitalization was 0.94 versus 0.29 among those with DVT/PE and no malignancy (p = 0.001). The relative risk of DVT/PE among patients with specific types of malignancy is described. This study demonstrates that patients with concurrent DVT/PE and malignancy have a more than threefold higher risk of recurrent thromboembolic disease and death (from any cause) than patients with DVT/PE without malignancy. An alternative management strategy may be indicated for such patients.
Background:
Accurate population-based data are needed on the incidence of venous thromboembolism (VTE) in patients with different cancers in order to inform guidelines on which hospitalised and ambulatory cancer patients should receive VTE prophylaxis.
Methods:
We conducted a cohort study using data from the Clinical Practice Research Datalink, linked to Hospital Episode Statistics, Cancer Registry data and Office for National Statistics cause of death data. We determined the incidence rates (cases per 1000 person-years) of VTE separately for 24 cancer sites. To determine relative risk, incidence rates were compared to frequency-matched controls (by age) with no record of cancer.
Findings:
We identified 83,203 cancer patients and 577,207 controls. New cases of VTE were diagnosed in 3352 cancer patients, and 6353 controls. The absolute rate of VTE in all cancers was 13.9 per 1000 person-years (95% confidence interval [CI] 13.4-14.4), corresponding to an age, sex and calendar year adjusted hazard-ratio of 4.7 (CI 4.5-4.9) between cancer patients and the general population. Rates varied greatly by cancer site (range; 98 (CI 80-119) in pancreatic cancer to 3.1 (CI 1.5-6.5) in thyroid cancer), age (range; 16.9 for patients over 80 years to 4.9 for those under 30 years) and time from diagnosis (range; 75 in the first three months to 8.4, >1 year after diagnosis).
Interpretation:
VTE is strongly linked to cancer, but the annual rate varies greatly by cancer site, proximity to diagnosis and age. Prophylaxis guidelines should take account of cancer site and such intervention should also be targeted towards the three months following diagnosis.
In recent years, clinical investigation in the field of cancer-associated thrombosis has identified a number of potential biomarkers to predict the risk of developing a thrombotic event. Similarly, large randomized clinical trials have demonstrated the benefit of low molecular weight heparins in the treatment as well as prevention of venous thromboembolic events (VTE) in cancer patients. However, the most common statistical methodology to evaluate the occurrence of VTE has been the Kaplan-Meier approach. When used to estimate the cumulative incidence of VTE in cancer studies, the Kaplan-Meier method over-estimates the cumulative incidence function due to failure to account for death as a competing risk for the development of VTE. A more appropriate statistical estimate of cumulative incidence of VTE in cancer studies is the competing risk model. This review describes the theoretical and mathematical basis for estimating the cumulative incidence function by the competing risk model for the analysis of VTE outcomes in cancer-associated thrombosis.