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Risk and Cause of Death in Patients Diagnosed With Myeloproliferative Neoplasms in Sweden Between 1973 and 2005: A Population-Based Study
Both M.H. and S.R.W. contributed equally to this work as co-first authors.
Abstract
Myeloproliferative neoplasms (MPNs) are associated with a shortened life expectancy. We assessed causes of death in patients with MPN and matched controls using both relative risks and absolute probabilities in the presence of competing risks.
From Swedish registries, we identified 9,285 patients with MPN and 35,769 matched controls. A flexible parametric model was used to estimate cause-specific hazard ratios (HRs) of death and cumulative incidence functions, each with 95% CIs.
In patients with MPN, the HRs of death from hematologic malignancies and infections were 92.8 (95% CI, 70.0 to 123.1) and 2.7 (95% CI, 2.4 to 3.1), respectively. In patients age 70 to 79 years at diagnosis (the largest patient group), the HRs of death from cardiovascular and cerebrovascular disease were 1.5 (95% CI, 1.4 to 1.7) and 1.5 (95% CI, 1.3 to 1.8), respectively; all were statistically significantly elevated compared with those of controls. In the same age group, no difference was observed in the 10-year probability of death resulting from cardiovascular disease in patients with MPN versus controls (16.8% v 15.2%) or cerebrovascular disease (5.6% v 5.2%). In patients age 50 to 59 years at diagnosis, the 10-year probability of death resulting from cardiovascular and cerebrovascular disease was elevated, 4.2% versus 2.1% and 1.9% versus 0.4%, respectively. Survival in patients with MPN increased over time, mainly because of decreased probabilities of dying as a result of hematologic malignancies, infections, and, in young patients, cardiovascular disease.
The myeloproliferative neoplasms (MPNs)—polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)—are often associated with reduced life expectancy.1–3 Despite improved understanding of the molecular bases of MPN as well as improvements in risk stratification and management,4–9 patients with MPNs have an elevated risk of thromboembolic events, of progression to myelofibrosis, and of transformation to acute myeloid leukemia (AML).10–12 In a recent, large, population-based study, patients with all MPN subtypes, including ET, had inferior relative survival.3 Relative survival improved with time, particularly in patients with PV and ET, but excess mortality was still observed in patients with MPN compared with the general population during 2001 to 2008.3
In randomized controlled trials and observational studies involving mainly patients with PV and PMF, cardiovascular disease and transformation to AML represent the most common causes of death.11,13–15 ET is often considered to be a more benign disease, and information about causes of death is limited.16–18 In addition, causes of death in patients with MPN have seldom been compared with those of the general population. To further improve our understanding of the excess mortality in MPNs, we used information on causes of death and applied a competing risk model to a large cohort of patients with diagnosed MPNs in Sweden from 1973 to 2005 and compared the findings with those of matched controls.
Sweden, a country of 9.5 million people, provides universal medical care for the entire population. The population-based nationwide Swedish Cancer Register, which was established in 1958,19 gathers information about all incident cases of malignant disorders in Sweden. It is mandatory for every physician to report each new diagnosis of MPN to the register.19 All dates and causes of death are recorded in the Cause of Death Register.20
In Sweden, from the mid-1970s to the early 2000s, the Polycythemia Vera Study Group criteria were used for diagnosing PV, ET, and PMF.3,19,21,22 Beginning in 2001, the World Health Organization criteria has gradually replaced this system.23 MPN-unclassifiable was introduced in the Swedish Cancer Register in 1993.12
We identified all patients with diagnosed MPN who were reported to the Swedish Cancer Register from 1973 to 2005. Although the Swedish Cancer Register has a high level of coverage, a certain degree of underreporting exists for patients with MPN.12,24 Therefore, we also retrieved information about patients with MPN through the Swedish Myeloproliferative Neoplasm Study Group, which comprises hematology and oncology centers in Sweden, to include patients who were not reported to the cancer register. For each patient with MPN, we randomly selected four controls matched by sex, year of birth, and county of residency from the Swedish Total Population Register using stratified simple random sampling (see Appendix, online only). All controls had to be alive and free from hematologic malignancy at the time of diagnosis for the corresponding patient with MPN. If fewer than four matched controls were found, we chose to include fewer controls per patient rather than imperfectly matched ones. Patients and controls were followed from the date of MPN diagnosis (entry for controls) until death, emigration, or end of follow-up (December 31, 2007), whichever occurred first. From the Cause of Death Register, information about causes of death was collected from January 1, 1973, to December 31, 2007.
Causes of death were classified into six categories: infection, solid tumor, hematologic malignancy, cardiovascular disease, cerebrovascular disease, and other disorders. The category hematologic malignancy included deaths resulting from AML or myelodysplastic syndrome, deaths resulting from myelofibrosis, and a few deaths resulting from hematologic malignancies (eg, lymphoma). The underlying cause of death was considered primary, with two exceptions: If the underlying cause was MPN, the first contributing cause was considered to be the primary cause of death; or, if AML was listed as a cause of death, AML was considered to be the primary cause. Cardiovascular disease included arterial thromboembolism, whereas venous thromboembolism, congestive heart failure, and cardiac arrhythmias were included in other disorders. Deaths resulting from accidents or suicide were included in other disorders.
The study was approved by the Regional Ethical Review Board in Stockholm. Informed consent was waived because we had no contact with study participants.
A flexible parametric survival model was used to estimate cause-specific mortality rates for the six causes of death in patients with MPN compared with matched controls.25,26 This model allows the underlying shape of the hazard function to vary among the different causes.25 Results are presented as hazard ratios (HRs) with 95% CIs. In the main analysis, we considered all subtypes combined, and results are presented for all MPN subtypes together, if not specified otherwise. Age was categorized into five groups: 18 to 49, 50 to 59, 60 to 69, 70 to 79, or 80 years and older at diagnosis. Calendar period of diagnosis was categorized as 1973 to 1982, 1983 to 1992, 1993 to 2000, or 2001 to 2005. Two-way interactions were assessed by using likelihood ratio tests. A detailed description of the fitted model appears in the Appendix. The final model included the variables patient status (patient with MPN or matched control), sex, age group, calendar period of diagnosis, and an interaction term between patient status and age group. The different causes of death were treated as competing events, and the probability of death from each of the six causes was estimated as a function of time. This is known as the cumulative incidence function and can be obtained through transformation of the cause-specific mortality rates obtained from the flexible parametric model.26
Additional analyses were performed to evaluate the cumulative incidence function for the subtypes PV, ET, and PMF. Because MPN-unclassifiable was not introduced until 1993 and therefore does not cover all four periods, it was not considered in the subtype analysis. All analyses were carried out by using STATA (version 12; http://www.stata.com/stata12).
A total of 9,285 patients with MPN and 35,769 matched controls were included. Of these, 7,938 patients with MPN were identified from the Swedish Cancer Register and 1,347 from the MPN network cohort. Because of the narrow matching criteria for controls, 10.8% of patients with MPN were matched with three controls and 1.9% of patients with MPN were matched with one or two. Forty-seven percent were male, and the median age at diagnosis was 69 years (Table 1). During the first 10 years after diagnosis of MPN, 4,842 (52.1%) patients with MPN and 11,393 (31.9%) controls died.
|
| Characteristic | Calendar Period | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 1973 to 1982 | 1983 to 1992 | 1993 to 2000 | 2001 to 2005 | All | ||||||
| Patients | Controls | Patients | Controls | Patients | Controls | Patients | Controls | Patients | Controls | |
| All, No. | 1,643 | 6,353 | 2,556 | 9,739 | 3,222 | 12,406 | 1,864 | 7,271 | 9,285 | 35,769 |
| Age, No. | ||||||||||
| 18 to 49 years | 125 | 499 | 246 | 980 | 441 | 1,761 | 210 | 839 | 1,022 | 4,079 |
| 50 to 59 years | 238 | 942 | 299 | 1,184 | 452 | 1,798 | 309 | 1,231 | 1,298 | 5,155 |
| 60 to 69 years | 459 | 1,798 | 647 | 2,522 | 697 | 2,749 | 401 | 1,597 | 2,204 | 8,666 |
| 70 to 79 years | 586 | 2,249 | 956 | 3,582 | 1,024 | 3,905 | 521 | 2,029 | 3,087 | 11,765 |
| ≥ 80 years | 235 | 865 | 408 | 1,471 | 608 | 2,193 | 423 | 1,575 | 1,674 | 6,104 |
| Median age, years | 69 | 69 | 70 | 70 | 69 | 70 | 69 | 70 | 69 | 70 |
| Sex, No. | ||||||||||
| Male | 819 | 3,181 | 1,208 | 4,616 | 1,473 | 5,695 | 878 | 3,422 | 4,378 | 16,914 |
| Female | 824 | 3,172 | 1,348 | 5,123 | 1,749 | 6,711 | 986 | 3,849 | 4,907 | 18,885 |
| MPN subtype, No. | ||||||||||
| PV | 1,249 | 1,410 | 1,206 | 901 | 4,766 | |||||
| ET | 155 | 773 | 1,237 | 460 | 2,625 | |||||
| PMF | 239 | 373 | 309 | 174 | 1,095 | |||||
| MPN-U* | 470 | 329 | 799 | |||||||
Abbreviations: ET, essential thrombocythemia; MPN, myeloproliferative neoplasm; MPN-U, MPN unclassified; PMF, primary myelofibrosis; PV, polycythemia vera.
*MPN-U was not included in the Swedish Cancer Register until 1993.
The cause-specific mortality rate was higher in patients with MPN than in matched controls (HRs > 1.0) for most causes of death and age groups (Table 2). The HRs for death from hematologic malignancies was 92.8 (95% CI, 70.0 to 123.1), and from infections, 2.7 (95% CI, 2.4 to 3.1), in the MPN cohort compared with controls. In patients with MPN aged 70 to 79 years at diagnosis, the HR for death from cardiovascular disease was 1.5 (95% CI, 1.4 to 1.7), from cerebrovascular disease 1.5 (1.3 to 1.8), from solid tumor 1.2 (95% CI, 1.0 to 1.3), and from other disorders 2.4 (95% CI, 2.1 to 2.6) compared with corresponding controls. In the younger age groups, relative differences in the risk of dying from vascular diseases between patients with MPN and controls were greater. HRs for death from cardiovascular disease and cerebrovascular disease in patients with MPN aged 50 to 59 years at diagnosis were 2.2 (95% CI, 1.6 to 3.1) and 5.1 (95% CI, 2.8 to 9.4), respectively, compared with matched controls (Table 2).
|
| Age or Cause | Age of Patient at Diagnosis | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | HR | 95% CI | HR | 95% CI | HR | 95% CI | HR | 95% CI | |
| Age of patient with MPN at diagnosis, years | 18 to 49 | 50 to 59 | 60 to 69 | 70 to 79 | ≥ 80 | |||||
| Infection | 2.7 | 2.4 to 3.1 | ||||||||
| Hematologic malignancy | 92.8 | 70.0 to 123.1 | ||||||||
| Solid tumor | 2.5 | 1.3 to 4.7 | 1.4 | 1.0 to 2.0 | 1.1 | 0.9 to 1.4 | 1.2 | 1.0 to 1.3 | 1.0 | 0.8 to 1.2 |
| Cardiovascular disease | 8.8 | 3.9 to 19.6 | 2.2 | 1.6 to 3.1 | 1.8 | 1.5 to 2.2 | 1.5 | 1.4 to 1.7 | 1.6 | 1.4 to 1.8 |
| Cerebrovascular disease | 8.7 | 0.8 to 96.3 | 5.1 | 2.8 to 9.4 | 2.8 | 2.1 to 3.7 | 1.5 | 1.3 to 1.8 | 1.4 | 1.2 to 1.7 |
| Other disorders | 5.1 | 3.1 to 8.6 | 4.2 | 3.2 to 5.6 | 3.8 | 3.2 to 4.4 | 2.4 | 2.1 to 2.6 | 1.8 | 1.6 to 2.0 |
NOTE. All HRs are adjusted for sex and calendar period of diagnosis. Because of interactions, HRs are shown separately for the different age groups except for infection and hematologic malignancy for which, as a result of a small number of controls dying as a result of these causes, HRs are shown for all ages.
Abbreviations: HR, hazard ratio; MPN, myeloproliferative neoplasm.
Results from the cumulative incidence functions, including competing risks, were illustrated by using the largest patient group, eg, male patients in whom MPN was diagnosed between the ages 70 and 79 years during 1993 to 2000. These patients had an overall 10-year probability of death of 75.0% compared with 49.0% in matched controls (Fig 1A). The 10-year probabilities of death were higher in patients with MPN versus matched controls for infections (4.6% v 2.3%), hematologic malignancies (13.6% v 0.2%), and other disorders (24.9% v 14.8%). However, no large difference was observed between patients and controls in the 10-year probabilities of dying from cardiovascular diseases (16.8% v 15.2%), cerebrovascular diseases (5.6% v 5.2%), or solid tumors (9.7% v 11.4%; Fig 1A). In female patients with MPN of the same age group and calendar period, the distribution of causes of death was similar, but the overall 10-year probability of death was lower, namely, 61.0% for patients with MPN and 36.3% for matched controls (Fig 1B). Overall, 7.2% of deaths in patients with MPN were caused by AML.
Fig 1. Stacked cumulative probabilities of dying as a result of six different causes of death in (A) male and (B) female patients with myeloproliferative neoplasms (MPNs; a) age 70 to 79 years when MPNs were diagnosed from 1993 to 2000; (b) matched controls. The 10-year probability (%) with 95% CIs of dying as a result of each of the causes of death is given in the tables.
In the younger age groups, the 10-year probability of death from cardiovascular and cerebrovascular disease was higher in patients with MPN than in matched controls. For male patients with MPN aged 50 to 59 years at diagnosis from 1993 to 2000, 10-year mortality from cardiovascular disease was 4.2% versus 2.1% for controls and from cerebrovascular disease, 1.9% versus 0.4%, respectively. The 10-year probability of death for each of the six causes are presented for patients with MPN and controls for all age groups, sex, and calendar periods in Appendix Tables A1 and A2 (online only).
Regarding the MPN subtypes, again in male patients with MPN aged 70 to 79 years at diagnosis during 1993 to 2000, the 10-year probabilities of death was 70.7% in patients with PV, 67.2% in those with ET, and 89.7% in patients with PMF (Fig 2). The most common cause of death was cardiovascular disease in patients with PV (18.9%) and ET (16.3%), whereas patients with PMF had an increased probability of dying from hematologic malignancies (20.1%).
Fig 2. Stacked cumulative probabilities of dying from the six different causes of death in patients aged 70 to 79 years when (A) polycythemia vera (PV), (B) essential thrombocythemia (ET), or (C) primary myelofibrosis (PMF) was diagnosed in 1993 to 2000. The 10-year probability (%) with 95% CIs of the causes of death is given in the table.
Ten-year mortality decreased for the recent cohorts, more so in patients with MPN than in matched controls primarily because of reduced probabilities of death from infections and hematologic malignancies. However, the observed decrease in mortality from hematologic malignancies was mainly explained by changes between the first (1973-1982) and second (1983-1999) calendar periods; thereafter, the decrease was less pronounced (Fig 3A). A similar pattern of decline in cardiovascular mortality occurred over time in male patients with MPN aged 70 to 79 and in matched controls (Fig 3A). In men age 50 to 59 at diagnosis, 10-year probabilities of death from cardiovascular and cerebrovascular diseases decreased more in patients with MPN than in their matched controls (Fig 3B).
Fig 3. Probability (%) of dying as a result of six causes of death in relation to calendar period of diagnosis for male patients with myeloproliferative neoplasms (MPNs) age (A) 70 to 79 or (B) 50 to 59 years at diagnosis and their matched controls. The table presents the difference in probability of cause-specific death from between 1973 to 1982 and 2001 to 2005 in percentages with 95% CIs.
The most common causes of death among other disorders were congestive heart failure, arrhythmias, pulmonary diseases, and dementia. Venous thrombosis was a less frequent cause of death in this category.
In this population-based study of 9,285 patients with MPN and more than 35,000 matched controls, mortality rates from all six causes of death were higher in patients than in controls. The excess mortality in patients was mainly explained by death from hematologic malignancy, infections, and other disorders. The probability of dying from cardiovascular disease was elevated in younger patients with MPN, whereas no significant difference was observed in older patients with MPN compared with their corresponding controls when we accounted for competing risks. Ten-year survival improved in later cohorts of patients with MPN primarily because of reduced probabilities of dying from hematologic malignancy, infection, and, in younger patients, cardiovascular disease. Importantly, the probability of death resulting from hematologic malignancy decreased, but there is nonetheless a persisting need for better disease-specific treatment.
The excess mortality in patients with MPN was largely attributed to death from hematologic malignancies. During the study period, use of hydroxyurea increased whereas use of potentially leukemogenic treatments, such as alkylating agents and radioactive phosphorus, decreased. The less frequent use of leukemogenic treatments may partly explain the reduced probability of dying from hematologic malignancies between the first and second calendar periods.12,27 Except for the introduction of allogeneic stem-cell transplantation for selected patients, strategies for cytoreductive treatment did not undergo any major changes during recent calendar periods.28,29 The modern specific treatments, including Janus kinase 2 (JAK2) inhibitors, were not in use during the study period. Ruxolitinib, the first approved JAK2 inhibitor, was recently shown to improve survival in patients with PMF.30,31 The JAK2 inhibitors and other novel therapies now in clinical studies will, we hope, lead to further improvements in the quality of life and survival of patients with MPN.
Risk of death from infections was elevated in patients with MPNs. Most deaths in this category resulted from bacterial infections. Patients with MPNs may be more susceptible than others to infectious diseases either because of the disease itself or because of long-term therapy with cytoreductive agents. The risk of death from infections decreased over time, a finding which may reflect improved diagnostics and treatment of infectious complications. The role of infections in patients with MPN needs to be further elucidated as infections are becoming increasingly important in the era of novel immunomodulatory agents.
Patients with MPN had significantly higher mortality rates from cardiovascular and cerebrovascular disease than did those of matched controls when comparing cause-specific mortality rates (HRs). However, when we accounted for competing risks, increased 10-year mortality from cardiovascular and cerebrovascular disease was observed in young patients, whereas no significant difference was observed between older patients with MPN and their corresponding controls. In the younger age groups, the decrease in 10-year mortality from cardiovascular and cerebrovascular disease over time was larger in patients with MPN than in controls, whereas the pattern of decrease over time was similar in older patients with MPN and their corresponding controls. Advances in MPN treatment, such as prophylactic low-dose aspirin and more stringent criteria for phlebotomy,32,33 has most likely contributed to the improved survival in patients with MPN. In addition, general improvements—for example, reduced smoking rates, more optimal treatment of hyperlipidemia, and better acute management of vascular events—have contributed to decreased mortality from cardiovascular disease in both patients with MPN and in controls.34,35 The higher cardiovascular death rate in young patients with MPN compared with controls is an important finding that needs further assessment. Young patients with MPN are currently considered to have a low risk of thrombosis, and cytoreductive therapy is not generally recommended.29,36–38 Our findings imply that further optimization of thromboprophylaxis in MPNs is of great importance, and that enhanced risk stratification measures to identify and treat high-risk patients younger than 60 years are needed.
Mortality rates from solid tumors tended to be higher in patients with MPN than in controls. An elevated risk of nonhematologic cancers and lymphoproliferative disorders in patients with MPN has previously been reported.39–41 Treatment with potentially DNA-mutagenic cytoreductive agents as well as a possible inherited propensity to develop malignant diseases may be important, especially in patients with MPN aged 18 to 49 years in whom the mortality rate from solid tumors was significantly elevated.
In the subtype analysis, all subtypes including ET were associated with an elevated 10-year mortality in patients compared with controls. Patients with PV and ET had a high risk of death from cardiovascular disease and cerebrovascular disease. In PV, these results are supported by results of previous studies.10,13,42,43 However, some investigators found transformation to AML to be the leading cause of death in PV.44,45 Although ET has been associated with a high risk of thrombosis,37,46,47 it is often considered a more benign disease, and the few studies on causes of death have shown varying results.48–51 However, during the earlier calendar periods of this study, there may have been a certain selective reporting of only the patient with more severe ET to the cancer register. We cannot exclude some degree of misclassification of early PMF as ET, which may have led to an overestimation of deaths resulting from hematologic malignancy in the ET group. In addition, changes in classification systems have gradually led to a more pure ET population in recent years, a population that most likely will have a better prognosis.52 PMF was associated with a high probability of death resulting from hematologic malignancies, reflecting the inherent higher risk of disease progression and transformation to AML and myelodysplastic syndromes compared with PV and ET.12,52 In addition, patients with PMF have an elevated risk of thromboembolic and hemorrhagic events, which contribute to the excess mortality.38,52,53 Despite possible uncertainties in subtype classification during the early calendar periods, MPNs are associated with disease progression and risk of thromboembolic events, which both need to be addressed to improve outcomes.
The strengths of this study are the population-based design on the basis of Swedish registries, which generally have a high level of coverage and accuracy,20,24 and the use of both relative risks and absolute probabilities in the presence of competing risks. Because of the competing causes of death, results from the two risk estimates differ slightly and need explanation. The cause-specific HRs of all of six causes of death were higher in patients with MPN than in the matched controls. However, in absolute terms, when we take into account that patients are at risk of dying from more than one cause, the proportion of deaths from each cause is not consistently higher in patients with MPN than in the controls. Also, by preventing patients from dying from certain causes, they will, over time, have a higher risk of dying from something else, hence the increase in deaths from other causes.
One of the limitations of this study is the quality of the Cause of Death Register, which is user dependent. In addition, the number of autopsies has decreased since the 1970s.20 We had no information about detailed clinical features or treatment, because this was not recorded in the Swedish Cancer Register at the time. Moreover, the observed excess mortality from other causes in patients with MPN may, to a certain degree, reflect various underlying medical illnesses that contributed to the medical work-up and that eventually led to the detection of the MPN. In addition, changes in classification systems, increased coverage of the cancer register, and earlier disease detection during recent calendar periods may influence the observed improvement in survival over time.3 All MPN subtype analyses were based on limited numbers of patients divided by age groups and calendar period of diagnosis and should, therefore, be interpreted with some caution.
In summary, the elevated 10-year mortality observed in patients with MPN compared with controls was explained by deaths from hematologic malignancies, infections, other disorders, and, in younger patients, cardiovascular and cerebrovascular diseases as well. Ten-year mortality from cardiovascular disease decreased over time, and the largest decrease was observed in younger patients with MPN. Mortality from hematologic malignancies declined primarily between the first and second calendar periods but was prominent throughout the study period. Our results underline the demand for disease-modifying treatments as well as improved prevention of thromboembolic and infectious complications in patients with MPN, something that it is hoped can be achieved with the emerging tailored treatments.
Supported by grants from the regional agreement concerning medical education and research in health and medical care between the Stockholm County Council and the Karolinska Institutet, Adolf H. Lundin Charitable Foundation, Blodcancerfonden, the Swedish Cancer Society, and the Karolinska Institutet Foundations.
Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.
Disclosures provided by the authors are available with this article at www.jco.org.
Conception and design: Malin Hultcrantz, Sally R. Wilkes, Sigurdur Y. Kristinsson, Therese M.-L. Andersson, Paul W. Dickman, Paul C. Lambert, Magnus Björkholm
Administrative support: Malin Hultcrantz, Magnus Björkholm
Provision of study materials or patients: Malin Hultcrantz, Sally R. Wilkes, Sigurdur Y. Kristinsson, Åsa R. Derolf, Jan Samuelsson, Ola Landgren, Magnus Björkholm
Collection and assembly of data: Malin Hultcrantz, Sally R. Wilkes, Sigurdur Y. Kristinsson, Therese M.-L. Andersson, Åsa R. Derolf, Jan Samuelsson, Paul C. Lambert
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
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For each patient with MPN, four population controls were randomly selected from the Swedish Total Population Register, an electronic register of all Swedish residents (including noncitizens) maintained by the Swedish Tax Agency. The selection was performed by the government agency Statistics Sweden (Statistiska Centralbyrån) using stratified simple random sampling. In detail, for each patient with MPN, a sampling frame comprising all eligible controls was constructed from the total population register. That is, all individuals with the same values of the matching variables (sex, year of birth, and county of residency) at the time MPN was diagnosed in the patient were identified. To be eligible, controls had to be alive and free of any hematologic malignancy at the time of diagnosis of the corresponding patient with MPN. Patients with MPN were removed from the sampling frame and were not eligible as controls. For each patient with MPN, four controls were then randomly selected from the eligible controls, such that each of the eligible controls had the same probability of being selected. If fewer than four eligible matched controls were found, we chose to include fewer controls per patient rather than imperfectly matched controls.
A flexible parametric survival model using restricted cubic splines was used to estimate the cause-specific mortality rates for each of the six different causes of death in patients with MPN compared with matched population controls during the first 10 years after diagnosis. The knot locations for the splines were selected separately for each of the six causes of death using the first and last death times along with the 25th, 50th, and 75th centiles of the death times to allow the underlying shape of the hazard function to vary between the different causes. The main analysis included all subtypes combined, and results are presented as all MPN subtypes together, if not specified otherwise. Age was categorized into the groups 18 to 49, 50 to 59, 60 to 69, 70 to 79, and 80 years and older. Calendar period of diagnosis was categorized as 1973 to 1982, 1983 to 1992, 1993 to 2000, and 2001 to 2005. All main effects (status of patient with MPN patient, age group, and calendar period) were included in the model. Two-way interactions were assessed by using likelihood ratio tests. The final model included the variables patient status (patient with MPN or matched control), age group, period of diagnosis, and sex. The 60-to-69 age group, the 1973-to-1982 calendar period of diagnosis, and males were chosen as the reference groups for age, period, and sex, respectively. Interaction terms between patient status (patient with MPN or control) and age group were also included in the final model for all causes except infection and hematologic malignancy. For sensitivity analysis, we fitted models with and without additional interactions to compare predictions of the cumulative incidence functions given different assumptions and observed no major differences in the predicted values. No time-dependent effects were found to be significant, and therefore, the proportional hazards assumption was assumed to be reasonable for all six causes of death.
|
| Group | 18 to 49 | 50 to 59 | 60 to 69 | 70 to 79 | ≥ 80 | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| 1973-1982 | ||||||||||
| Patient (n = 60) | Control (n = 239) | Patient (n = 126) | Control (n = 498) | Patient (n = 234) | Control (n = 921) | Patient (n = 305) | Control (n = 1,176) | Patient (n = 94) | Control (n = 347) | |
| Probability, % (95% CI) | ||||||||||
| Infection | 0.9 (0.4 to 1.4) | 0.4 (0.1 to 0.6) | 1.1 (0.6 to 1.7) | 0.5 (0.3 to 0.7) | 3.3 (2.6 to 4.1) | 1.7 (1.3 to 2.1) | 6.5 (5.4 to 7.6) | 3.8 (3.2 to 4.3) | 11.1 (9.1 to 13.1) | 7.5 (6.3 to 8.7) |
| Solid tumor | 2.4 (1.2 to 3.6) | 1.1 (0.7 to 1.5) | 4.6 (3.1 to 6.0) | 4.0 (3.3 to 4.7) | 7.1 (5.7 to 8.5) | 8.5 (7.6 to 9.5) | 9.0 (7.7 to 10.3) | 12.0 (10.9 to 13.1) | 5.5 (4.3 to 6.7) | 10.4 (9.2 to 11.6) |
| Hematologic malignancy | 8.6 (6.1 to 11.2) | 0.1 (0.1 to 0.1) | 12.7 (9.9 to 15.4) | 0.2 (0.1 to 0.2) | 18.0 (15.2 to 20.8) | 0.2 (0.2 to 0.3) | 17.2 (14.7 to 19.7) | 0.3 (0.2 to 0.3) | 14.9 (12.2 to 17.7) | 0.2 (0.2 to 0.3) |
| Cardiovascular disease | 4.5 (2.4 to 6.5) | 0.6 (0.2 to 0.9) | 8.3 (6.0 to 10.6) | 4.6 (3.7 to 5.5) | 16.2 (13.9 to 18.4) | 12.3 (11.2 to 13.5) | 27.0 (24.6 to 29.3) | 27.7 (26.1 to 29.3) | 32.4 (29.2 to 35.6) | 37.0 (34.8 to 39.3) |
| Cerebrovascular disease | 0.4 (0.0 to 0.9) | 0.0 (0.0 to 0.1) | 3.0 (1.7 to 4.2) | 0.7 (0.4 to 1.0) | 5.2 (4.0 to 6.4) | 2.6 (2.1 to 3.1) | 7.0 (5.8 to 8.2) | 7.5 (6.6 to 8.4) | 8.4 (6.8 to 10.0) | 11.1 (9.7 to 12.5) |
| Other disorders | 4.7 (3.1 to 6.3) | 1.0 (0.6 to 1.4) | 9.8 (7.8 to 11.9) | 2.8 (2.3 to 3.4) | 15.9 (14.0 to 17.8) | 6.0 (5.3 to 6.6) | 22.1 (20.1 to 24.1) | 15.0 (13.9 to 16.1) | 26.7 (24.0 to 29.3) | 28.1 (26.2 to 30.1) |
| Group | 1983-1992 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Patient (n = 128) | Control (n = 509) | Patient (n = 175) | Control (n = 693) | Patient (n = 325) | Control (n = 1,263) | Patient (n = 414) | Control (n = 1,548) | Patient (n = 166) | Control (n = 603) | |
| Probability, % (95% CI) | ||||||||||
| Infection | 0.8 (0.3 to 1.2) | 0.3 (0.1 to 0.5) | 1.0 (0.5 to 1.5) | 0.4 (0.2 to 0.6) | 3.1 (2.4 to 3.7) | 1.5 (1.2 to 1.8) | 6.4 (5.4 to 7.4) | 3.5 (3.0 to 4.0) | 11.6 (9.7 to 13.4) | 7.4 (6.4 to 8.5) |
| Solid tumor | 2.3 (1.1 to 3.4) | 1.0 (0.6 to 1.4) | 4.4 (3.0 to 5.8) | 3.7 (3.1 to 4.4) | 7.2 (5.9 to 8.6) | 8.2 (7.3 to 9.0) | 9.7 (8.4 to 11.0) | 12.1 (11.1 to 13.1) | 6.3 (5.0 to 7.7) | 11.3 (10.1 to 12.5) |
| Hematologic malignancy | 6.4 (4.6 to 8.3) | 0.1 (0.0 to 0.1) | 9.6 (7.5 to 11.7) | 0.1 (0.1 to 0.2) | 14.1 (12.0 to 16.3) | 0.2 (0.1 to 0.2) | 14.1 (12.1 to 16.0) | 0.2 (0.1 to 0.3) | 12.7 (10.5 to 14.9) | 0.2 (0.1 to 0.3) |
| Cardiovascular disease | 3.0 (1.6 to 4.4) | 0.4 (0.1 to 0.6) | 5.7 (4.1 to 7.4) | 3.0 (2.4 to 3.6) | 11.7 (10.0 to 13.4) | 8.4 (7.6 to 9.2) | 20.8 (18.9 to 22.7) | 20.0 (18.8 to 21.2) | 26.6 (23.9 to 29.2) | 28.7 (26.8 to 30.5) |
| Cerebrovascular disease | 0.3 (0.0 to 0.7) | 0.0 (0.0 to 0.1) | 2.3 (1.3 to 3.3) | 0.5 (0.3 to 0.8) | 4.2 (3.2 to 5.2) | 2.0 (1.6 to 2.4) | 6.1 (5.1 to 7.2) | 6.1 (5.4 to 6.8) | 7.8 (6.4 to 9.3) | 9.7 (8.6 to 10.9) |
| Other disorders | 4.8 (3.2 to 6.4) | 1.0 (0.6 to 1.4) | 10.3 (8.2 to 12.4) | 2.8 (2.3 to 3.4) | 17.5 (15.5 to 19.5) | 6.1 (5.5 to 6.8) | 26.0 (23.9 to 28.0) | 16.4 (15.4 to 17.5) | 33.3 (30.6 to 36.1) | 33.2 (31.3 to 35.1) |
| Group | 1993-2000 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Patient (n = 204) | Control (n = 814) | Patient (n = 239) | Control (n = 949) | Patient (n = 349) | Control (n = 1,376) | Patient (n = 468) | Control (n = 1,783) | Patient (n = 213) | Control (n = 773) | |
| Probability, % (95% CI) | ||||||||||
| Infection | 0.5 (0.2 to 0.8) | 0.2 (0.1 to 0.3) | 0.6 (0.3 to 0.9) | 0.3 (0.1 to 0.4) | 2.0 (1.6 to 2.5) | 0.9 (0.7 to 1.1) | 4.6 (3.8 to 5.3) | 2.3 (2.0 to 2.7) | 9.1 (7.6 to 10.6) | 5.5 (4.7 to 6.3) |
| Solid tumor | 2.0 (1.0 to 3.1) | 0.9 (0.5 to 1.2) | 4.0 (2.7 to 5.3) | 3.3 (2.7 to 3.9) | 6.8 (5.5 to 8.0) | 7.3 (6.6 to 8.1) | 9.7 (8.4 to 11.0) | 11.4 (10.5 to 12.4) | 7.0 (5.6 to 8.4) | 11.7 (10.5 to 12.9) |
| Hematologic malignancy | 5.7 (4.1 to 7.3) | 0.1 (0.0 to 0.1) | 8.6 (6.8 to 10.4) | 0.1 (0.1 to 0.1) | 13.0 (11.1 to 15.0) | 0.2 (0.1 to 0.2) | 13.6 (11.8 to 15.5) | 0.2 (0.1 to 0.2) | 13.1 (10.9 to 15.2) | 0.2 (0.1 to 0.3) |
| Cardiovascular disease | 2.1 (1.2 to 3.1) | 0.3 (0.1 to 0.4) | 4.2 (3.0 to 5.3) | 2.1 (1.7 to 2.6) | 8.8 (7.5 to 10.1) | 6.0 (5.4 to 6.6) | 16.8 (15.2 to 18.4) | 15.2 (14.2 to 16.2) | 23.7 (21.3 to 26.1) | 24.0 (22.4 to 25.7) |
| Cerebrovascular disease | 0.2 (0.0 to 0.5) | 0.0 (0.0 to 0.1) | 1.9 (1.1 to 2.7) | 0.4 (0.2 to 0.6) | 3.6 (2.7 to 4.4) | 1.6 (1.3 to 1.9) | 5.6 (4.6 to 6.5) | 5.2 (4.6 to 5.8) | 7.9 (6.4 to 9.3) | 9.2 (8.1 to 10.3) |
| Other disorders | 4.0 (2.7 to 5.4) | 0.8 (0.5 to 1.2) | 8.8 (7.0 to 10.6) | 2.4 (1.9 to 2.8) | 15.6 (13.8 to 17.4) | 5.2 (4.6 to 5.8) | 24.9 (23.0 to 26.8) | 14.8 (13.8 to 15.7) | 35.4 (32.7 to 38.2 | 33.1 (31.3 to 34.9) |
| Group | 2001-2008 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Patient (n = 104) | Control (n = 415) | Patient (n = 156) | Control (n = 622) | Patient (n = 209) | Control (n = 829) | Patient (n = 242) | Control (n = 929) | Patient (n = 167) | Control (n = 627) | |
| Probability, % (95% CI) | ||||||||||
| Infection | 0.4 (0.2 to 0.7) | 0.2 (0.1 to 0.3) | 0.6 (0.3 to 0.8) | 0.2 (0.1 to 0.4) | 1.8 (1.3 to 2.4) | 0.8 (0.6 to 1.1) | 4.2 (3.1 to 5.2) | 2.1 (1.6 to 2.6) | 8.5 (6.6 to 10.5) | 5.1 (4.0 to 6.3) |
| Solid tumor | 2.0 (1.0 to 3.0) | 0.8 (0.5 to 1.2) | 3.9 (2.6 to 5.2) | 3.2 (2.5 to 3.9) | 6.6 (5.2 to 8.0) | 7.1 (6.1 to 8.2) | 9.7 (8.0 to 11.3) | 11.3 (9.9 to 12.7) | 7.1 (5.5 to 8.7) | 11.8 (10.2 to 13.4) |
| Hematologic malignancy | 5.7 (3.9 to 7.5) | 0.1 (0 to 0.1) | 8.7 (6.5 to 10.8) | 0.1 (0.1 to 0.1) | 13.2 (10.6 to 15.8) | 0.2 (0.1 to 0.2) | 13.9 (11.3 to 16.5) | 0.2 (0.1 to 0.2) | 13.6 (10.9 to 16.3) | 0.2 (0.1 to 0.3) |
| Cardiovascular disease | 1.7 (0.9 to 2.4) | 0.2 (0.1 to 0.3) | 3.2 (2.3 to 4.2) | 1.7 (1.3 to 2.0) | 6.9 (5.7 to 8.1) | 4.7 (4.1 to 5.4) | 13.4 (11.6 to 15.1) | 12.0 (10.7 to 13.4) | 19.3 (16.7 to 21.9) | 19.4 (17.4 to 21.5 |
| Cerebrovascular disease | 0.2 (0.0 to 0.5) | 0.0 (0.0 to 0.1) | 1.8 (1.0 to 2.6) | 0.4 (0.2 to 0.6) | 3.5 (2.5 to 4.4) | 1.5 (1.2 to 1.9) | 5.5 (4.3 to 6.6) | 5.1 (4.2 to 6.0) | 8.0 (6.2 to 9.7) | 9.2 (7.6 to 10.7) |
| Other disorders | 4.2 (2.7 to 5.7) | 0.9 (0.5 to 1.2) | 9.2 (7.2 to 11.1) | 2.5 (1.9 to 3.0) | 16.4 (14.3 to 18.6) | 5.5 (4.8 to 6.2) | 26.6 (24.0 to 29.2) | 15.7 (14.3 to 17.1) | 38.9 (35.5 to 42.3) | 36.0 (33.3 to 38.6) |
Abbreviations: MPN, myeloproliferative neoplasm.
|
| Group | 18 to 49 | 50 to 59 | 60 to 69 | 70 to 79 | ≥ 80 | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| 1973-1982 | ||||||||||
| Patient (n = 65) | Control (n = 260) | Patient (n = 112) | Control (n = 444) | Patient (n = 225) | Control (n = 877) | Patient (n = 281) | Control (n = 1,073) | Patient (n = 141) | Control (n = 518) | |
| Probability, % (95% CI) | ||||||||||
| Infection | 0.6 (0.2 to 0.9) | 0.2 (0.1 to 0.4) | 0.8 (0.4 to 1.1) | 0.3 (0.2 to 0.5) | 2.4 (1.9 to 3.0) | 1.1 (0.9 to 1.4) | 5.4 (4.4 to 6.3) | 2.8 (2.3 to 3.2) | 10.3 (8.4 to 12.1) | 6.4 (5.4 to 7.4) |
| Solid tumor | 1.6 (0.8 to 2.3) | 0.7 (0.4 to 0.9) | 3.1 (2.1 to 4.0) | 2.5 (2.0 to 3.0) | 5.1 (4.1 to 6.1) | 5.6 (4.9 to 6.3) | 7.2 (6.2 to 8.3) | 8.6 (7.8 to 9.5) | 5.0 (3.9 to 6.1) | 8.6 (7.6 to 9.6) |
| Hematologic malignancy | 5.9 (4.1 to 7.7) | 0.1 (0.0 to 0.1) | 8.9 (6.9 to 11.0) | 0.1 (0.1 to 0.1) | 13.4 (11.2 to 15.7) | 0.2 (0.1 to 0.2) | 13.9 (11.7 to 16.0) | 0.2 (0.1 to 0.2) | 13.0 (10.6 to 15.3) | 0.2 (0.1 to 0.3) |
| Cardiovascular disease | 2.8 (1.5 to 4.0) | 0.3 (0.1 to 0.6) | 5.4 (3.8 to 6.9) | 2.8 (2.2 to 3.3) | 11.3 (9.6 to 13.0) | 7.8 (7.0 to 8.6) | 21.1 (19.1 to 23.1) | 19.3 (18.1 to 20.6) | 28.7 (25.8 to 31.6) | 29.8 (27.9 to 31.7) |
| Cerebrovascular disease | 0.3 (0.0 to 0.8) | 0.0 (0.0 to 0.1) | 2.7 (1.5 to 3.8) | 0.6 (0.3 to 0.9) | 5.1 (3.9 to 6.3) | 2.3 (1.9 to 2.7) | 7.8 (6.4 to 9.1) | 7.3 (6.5 to 8.2) | 10.6 (8.6 to 12.5) | 12.6 (11.1 to 14.1) |
| Other disorders | 3.6 (2.3 to 4.8) | 0.8 (0.5 to 1.0) | 7.8 (6.2 to 9.4) | 2.1 (1.7 to 2.5) | 13.7 (12.0 to 15.4) | 4.6 (4.1 to 5.2) | 21.5 (19.6 to 23.4) | 12.9 (11.9 to 13.9) | 29.4 (26.7 to 32.1) | 28.1 (26.2 to 30.0) |
| Group | 1983-1992 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Patient (n = 118) | Control (n = 471) | Patient (n = 124) | Control (n = 491) | Patient (n = 322) | Control (n = 1,259) | Patient (n = 542) | Control (n = 2,034) | Patient (n = 242) | Control (n = 868) | |
| Probability, % (95% CI) | ||||||||||
| Infection | 0.5 (0.2 to 0.8) | 0.2 (0.1 to 0.3) | 0.7 (0.4 to 1.0) | 0.3 (0.1 to 0.4) | 2.2 (1.7 to 2.7) | 1.0 (0.8 to 1.2) | 5.1 (4.2 to 5.9) | 2.5 (2.1 to 2.8) | 10.4 (8.7 to 12.0) | 6.1 (5.2 to 6.9) |
| Solid tumor | 1.5 (0.7 to 2.2) | 0.6 (0.4 to 0.9) | 2.9 (2.0 to 3.9) | 2.4 (1.9 to 2.8) | 5.1 (4.1 to 6.0) | 5.3 (4.7 to 5.9) | 7.5 (6.4 to 8.5) | 8.4 (7.7 to 9.2) | 5.6 (4.4 to 6.7) | 9.0 (8.0 to 9.9) |
| Hematologic malignancy | 4.4 (3.1 to 5.7) | 0.0 (0.0 to 0.1) | 6.7 (5.2 to 8.2) | 0.1 (0.0 to 0.1) | 10.3 (8.6 to 12.0) | 0.1 (0.1 to 0.2) | 11.0 (9.4 to 12.6) | 0.1 (0.1 to 0.2) | 10.8 (8.9 to 12.6) | 0.2 (0.1 to 0.2) |
| Cardiovascular disease | 1.9 (1.0 to 2.7) | 0.2 (0.1 to 0.4) | 3.6 (2.6 to 4.7) | 1.8 (1.5 to 2.2) | 7.9 (6.7 to 9.1) | 5.3 (4.7 to 5.8) | 15.6 (14.1 to 17.1) | 13.5 (12.6 to 14.4) | 22.7 (20.4 to 25.1) | 22.2 (20.7 to 23.6) |
| Cerebrovascular disease | 0.2 (0.0 to 0.6) | 0.0 (0.0 to 0.1) | 2.1 (1.2 to 2.9) | 0.4 (0.2 to 0.6) | 4.0 (3.1 to 5.0) | 1.7 (1.4 to 2.1) | 6.5 (5.4 to 7.6) | 5.8 (5.1 to 6.4) | 9.5 (7.8 to 11.2) | 10.7 (9.5 to 11.8) |
| Other disorders | 3.6 (2.4 to 4.9) | 0.8 (0.5 to 1.0) | 8.0 (6.4 to 9.7) | 2.1 (1.7 to 2.5) | 14.6 (12.9 to 16.3) | 4.7 (4.2 to 5.2) | 24.1 (22.2 to 25.9) | 13.7 (12.8 to 14.5) | 35.5 (32.8 to 38.2) | 31.8 (30.1 to 33.5) |
| Group | 1993-2000 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Patient (n = 237) | Control (n = 947) | Patient (n = 213) | Control (n = 849) | Patient (n = 348) | Control (n = 1,373) | Patient (n = 556) | Control (n = 2,122) | Patient (n = 395) | Control (n = 1,420) | |
| Probability, % (95% CI) | ||||||||||
| Infection | 0.3 (0.1 to 0.5) | 0.1 (0.0 to 0.2) | 0.4 (0.2 to 0.6) | 0.2 (0.1 to 0.2) | 1.4 (1.1 to 1.7) | 0.6 (0.5 to 0.7) | 3.5 (2.9 to 4.0) | 1.6 (1.3 to 1.9) | 7.8 (6.6 to 9.1) | 4.3 (3.7 to 4.9) |
| Solid tumor | 1.3 (0.6 to 1.9) | 0.5 (0.3 to 0.8) | 2.6 (1.8 to 3.4) | 2.1 (1.7 to 2.5) | 4.6 (3.7 to 5.5) | 4.7 (4.2 to 5.2) | 7.2 (6.2 to 8.2) | 7.8 (7.1 to 8.4) | 5.9 (4.7 to 7.1) | 8.9 (8.0 to 9.8) |
| Hematologic malignancy | 3.8 (2.7 to 5.0) | 0.0 (0.0 to 0.1) | 5.9 (4.6 to 7.2) | 0.1 (0.0 to 0.1) | 9.3 (7.9 to 10.8) | 0.1 (0.1 to 0.1) | 10.4 (8.9 to 11.8) | 0.1 (0.1 to 0.2) | 10.8 (9.1 to 12.6) | 0.2 (0.1 to 0.2) |
| Cardiovascular disease | 1.3 (0.7 to 1.9) | 0.2 (0.1 to 0.3) | 2.6 (1.9 to 3.4) | 1.3 (1.0 to 1.6) | 5.8 (5.0 to 6.7) | 3.7 (3.4 to 4.1) | 12.1 (10.9 to 13.3) | 10.0 (9.3 to 10.7) | 19.5 (17.5 to 21.5) | 17.8 (16.6 to 19.0) |
| Cerebrovascular disease | 0.2 (0.0 to 0.5) | 0.0 (0.0 to 0.1) | 1.6 (0.9 to 2.3) | 0.4 (0.2 to 0.5) | 3.3 (2.5 to 4.1) | 1.4 (1.1 to 1.6) | 5.6 (4.7 to 6.6) | 4.8 (4.2 to 5.3) | 9.2 (7.6 to 10.8) | 9.6 (8.6 to 10.6) |
| Other disorders | 3.0 (2.0 to 4.1) | 0.6 (0.4 to 0.9) | 6.8 (5.4 to 8.2) | 1.8 (1.4 to 2.1) | 12.7 (11.2 to 14.2) | 4.0 (3.5 to 4.4) | 22.1 (20.4 to 23.8) | 11.9 (11.2 to 12.7) | 36.2 (33.6 to 38.8) | 30.2 (28.7 to 31.8) |
| Group | 2001-2008 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Patient (n = 106) | Control (n = 424) | Patient (n = 153) | Control (n = 609) | Patient (n = 192) | Control (n = 768) | Patient (n = 279) | Control (n = 1,100) | Patient (n = 256) | Control (n = 948) | |
| Probability, % 95% CI | ||||||||||
| Infection | 0.3 (0.1 to 0.4) | 0.1 (0.0 to 0.2) | 0.4 (0.2 to 0.6) | 0.1 (0.1 to 0.2) | 1.3 (0.9 to 1.6) | 0.5 (0.4 to 0.7) | 3.1 (2.3 to 3.9) | 1.4 (1.1 to 1.8) | 7.3 (5.6 to 8.9) | 3.9 (3.0 to 4.8) |
| Solid tumor | 1.2 (0.6 to 1.9) | 0.5 (0.3 to 0.7) | 2.5 (1.7 to 3.4) | 2.0 (1.6 to 2.4) | 4.5 (3.5 to 5.5) | 4.6 (3.9 to 5.3) | 7.1 (5.9 to 8.3) | 7.6 (6.6 to 8.6) | 5.9 (4.6 to 7.3) | 8.8 (7.6 to 10.0) |
| Hematologic malignancy | 3.8 (2.6 to 5.1) | 0.0 (0.0 to 0.1) | 5.9 (4.4 to 7.5) | 0.1 (0.0 to 0.1) | 9.4 (7.4 to 11.4) | 0.1 (0.1 to 0.2) | 10.5 (8.5 to 12.6) | 0.1 (0.1 to 0.2) | 11.1 (8.9 to 13.3) | 0.2 (0.1 to 0.2) |
| Cardiovascular disease | 1.0 (0.5 to 1.5) | 0.1 (0.0 to 0.2) | 2.0 (1.4 to 2.6) | 1.0 (0.8 to 1.2) | 4.6 (3.7 to 5.4) | 2.9 (2.5 to 3.3) | 9.5 (8.2 to 10.8) | 7.8 (6.9 to 8.8) | 15.6 (13.5 to 17.8) | 14.1 (12.6 to 15.7) |
| Cerebrovascular disease | 0.2 (0.0 to 0.4) | 0.0 (0.0 to 0.1) | 1.6 (0.9 to 2.3) | 0.3 (0.2 to 0.5) | 3.2 (2.3 to 4.1) | 1.3 (1.0 to 1.6) | 5.5 (4.3 to 6.7) | 4.6 (3.8 to 5.4) | 9.1 (7.2 to 11.1) | 9.4 (7.9 to 11.0) |
| Other disorders | 3.1 (2.0 to 4.2) | 0.6 (0.4 to 0.9) | 7.1 (5.5 to 8.6) | 1.8 (1.4 to 2.2) | 13.3 (11.5 to 15.1) | 4.1 (3.6 to 4.7) | 23.4 (21.1 to 25.7) | 12.6 (11.4 to 13.8) | 39.1 (35.8 to 42.5) | 32.3 (29.9 to 34.8) |
Abbreviations: MPN, myeloproliferative neoplasm.
