Research objective
We aimed to investigate which time-scale (attained age or time since diagnosis) is more critical in increasing rates of first thrombosis post index date, and how the rates of thrombosis differ for MPN patients compared to matched population controls over two time-scales simultaneously.
Settings
Study design: matched-cohort, where to 1 MPN patient (age at diagnosis 18-90) were matched 10 controls, based on sex and year of birth, randomly selected with replacement from the Swedish population .
Data sources:
- the National Cancer Register (for MPN, other hematological malignancies)
- the National Inpatient Register (hospital admissions), the National Outpatient Register (specialist visits) (for MPN and thromboses)
- the National Causes of Deaths Register (for thromboses and other causes of deaths)
- the National Prescribed Drugs Register (for cytoreductive drugs and anticoagulants)
- the Total Population Register (for demographic data)
Study period: the MPN diagnoses were identified for the period January 1, 2001 - December 31, 2021. The follow-up was until December 31, 2022.
Index date: at 6 months post MPN date/matching date. Individuals were excluded if prior to the index date, they developed other hematological malignancy, or they emigrated, or they died. Any thromboses experienced prior to the index date were classified as “history of thrombosis”.
End of follow-up: individuals were followed until the outcome of interest (first thrombosis post index date) or censoring due to emigration, due to death from other causes, or due to the end of follow-up (December 31, 2022); whichever occurred first.
Main model
Fitted the following flexible parametric survival model on the log-hazard scale with two time-scales:
\[
\begin{align}
\log h & = s(t_1; \gamma_1) + s(t_2 \text{ at } MPN=1; \gamma_2) + \beta_{MPN} \cdot I_{MPN} \\
& + s(t_1; \gamma_3) \cdot I_{MPN} + s(t_1; \gamma_4) \cdot s(t_2; \gamma_5) \cdot I_{MPN}
\end{align}
\]
where \(t_1\) is attained age for all individuals, whereas \(t_2\) is time since index date only for individuals with MPN. Functions \(s\) represent restricted cubic splines with \(\gamma\) as corresponding parameters. Optimal number of knots for the spline functions were chosen based on AIC and BIC of the models.
Stata code for the model:
/* stset to define the first time-scale (attained age) */
stset eof_date, failure(status==1) scale(365.25) entry(t start_date) id(id) origin(t dob)
/* the fpm model where second time-scale (time since index date) is specified using option start(age_minus) */
stmt mpn, ///
time1(df(4) logtoff tvc(mpn) dftvc(mpn:2)) ///
time2(df(4) logtoff start(age_minus) indicator(mpn)) timeint(t1:t2 2:2)
Click here for stata code for predicting thrombosis rates
/* predict hazard rates for non-mpn and mpn; and hazard ratios for each time-point of time1, time2 and age0 */
local n=1
local datalist ""
forvalues a0= 30 30.25 : 90 {
qui clear
qui set obs 401
qui gen age_start =`a0' // a0: age at index
qui range time2 0 20 401 // t2: time on study
qui gen time1 = time2 + age_start // t1: attained age
qui gen _d = .
qui gen _t = .
qui gen mpn = .
foreach mpn in 0 1 {
qui predict h_mpn`mpn', h time1var(time1) time2var(time2) at(mpn `mpn') per(1000) ci
}
qui predictnl ln_hr = ln(predict(h time1var(time1) time2var(time2) at(mpn 1))) ///
- ln(predict(h time1var(time1) time2var(time2) at(mpn 0))), ///
ci(ln_hr_lci ln_hr_uci)
qui gen hr = exp(ln_hr)
qui gen hr_lci = exp(ln_hr_lci)
qui gen hr_uci = exp(ln_hr_uci)
qui tempfile temppred`n'
qui save `temppred`n''
local datalist `datalist' `temppred`n''
local n=`n'+1
}
qui clear
qui set obs 0
qui append using `datalist'
qui order age_start time2
keep time1 time2 age_start h*
Results
Cohort characteristics
Table 4.1: Characteristics of patients diagnosed during 2001-2021 with myeloproliferative neoplasms and population controls matched on sex and year of birth. MPN=myeloproliferative neoplasm, PV=polycythemia vera, ET=essential thrombocythemia, PMF=primary myelofibrosis, MPN-U=myeloproliferative neoplasm unclassifiable.
| MPN (N=17830) | Controls (N=172634) |
|---|
Sex |
|
|
Female | 9299 (52.2%) | 90204 (52.3%) |
Male | 8531 (47.8%) | 82430 (47.7%) |
Age at diagnosis |
|
|
Median (Q1, Q3) | 69.9 (59.0, 77.9) | 69.6 (58.7, 77.6) |
18-49 | 2296 (12.9%) | 22803 (13.2%) |
50-59 | 2505 (14.1%) | 24658 (14.3%) |
60-69 | 4137 (23.2%) | 40596 (23.5%) |
70-79 | 5482 (30.8%) | 53093 (30.8%) |
80-90 | 3398 (19.1%) | 31437 (18.2%) |
Calendar period of diagnosis |
|
|
2001-2010 | 7776 (43.6%) | 75267 (43.6%) |
2011-2021 | 10054 (56.4%) | 97367 (56.4%) |
History of thrombosis prior to MPN/matching date1 |
|
|
Yes | 3922 (22.0%) | 19525 (11.3%) |
No | 13908 (78.0%) | 153109 (88.7%) |
History of thrombosis prior to index date2 |
|
|
Yes | 4442 (24.9%) | 20655 (12.0%) |
No | 13388 (75.1%) | 151979 (88.0%) |
MPN subtype |
|
|
PV | 7071 (39.7%) | - |
ET | 6735 (37.8%) | - |
PMF | 1132 (6.3%) | - |
MPN-U | 2892 (16.2%) | - |
1Any thrombosis prior to the MPN date/matching date. |
2Any thrombosis prior to the index date (index date is at 6 months post MPN date/matching date). |
Total person-years and events
Table 4.2: For each type of event of interest, number of individuals, person-years, number of events for MPN-patients and matched controls, overall and by subtype, respectively.
Event | | All MPNs | Controls | PV | Controls | ET | Controls | PMF | Controls |
|---|
Any thrombosis | N | 17,830 | 172,634 | 7,071 | 68,287 | 6,735 | 65,458 | 1,132 | 10,977 |
Person-years | 108,570 | 1,279,090 | 42,728 | 504,502 | 44,171 | 477,283 | 4,812 | 67,761 |
Events | 4,282 | 31,217 | 1,963 | 13,083 | 1,370 | 10,364 | 212 | 1,836 |
Arterial thrombosis | N | 17,830 | 172,634 | 7,071 | 68,287 | 6,735 | 65,458 | 1,132 | 10,977 |
Person-years | 115,793 | 1,307,918 | 46,020 | 516,158 | 46,261 | 487,326 | 5,142 | 69,226 |
Events | 3,125 | 26,128 | 1,454 | 11,067 | 1,020 | 8,525 | 135 | 1,544 |
Venous thrombosis | N | 17,830 | 172,634 | 7,071 | 68,287 | 6,735 | 65,458 | 1,132 | 10,977 |
Person-years | 126,261 | 1,435,190 | 51,071 | 571,496 | 49,888 | 526,084 | 5,386 | 75,675 |
Events | 1,541 | 6,667 | 702 | 2,702 | 462 | 2,351 | 95 | 361 |
Thrombosis rates
Data
Below are few selected rows from the dataset containing estimated thrombosis rates and hazard ratios for all MPNs and subtypes for any thrombosis, arterial thrombosis and venous thrombosis. If you wish to see full data (size ~200 Mb), the following download link will provide the excel file: https://github.com/nurbatyr/Suppl-material-thrombosis-rates-in-MPNs-over-2ts/releases/download/thromb-rates-main/011_021_estimated_thrombosis_rates.xlsx
event | age_start | fu_time | attained_age | h_mpn0 | h_mpn0_lci | h_mpn0_uci | h_mpn1 | h_mpn1_lci | h_mpn1_uci | hr | hr_lci | hr_uci |
|---|
Any thromb | 65 | 0.00 | 65.00 | 12.461 | 12.149 | 12.780 | 71.528 | 64.079 | 79.843 | 5.740 | 5.135 | 6.417 |
Any thromb | 65 | 0.05 | 65.05 | 12.507 | 12.195 | 12.827 | 68.701 | 61.842 | 76.320 | 5.493 | 4.937 | 6.112 |
Any thromb | 65 | 0.10 | 65.10 | 12.553 | 12.240 | 12.874 | 65.993 | 59.677 | 72.976 | 5.257 | 4.746 | 5.823 |
Any thromb | 65 | 0.15 | 65.15 | 12.600 | 12.286 | 12.921 | 63.403 | 57.586 | 69.807 | 5.032 | 4.563 | 5.550 |
Any thromb | 65 | 0.20 | 65.20 | 12.646 | 12.332 | 12.968 | 60.930 | 55.566 | 66.811 | 4.818 | 4.386 | 5.292 |
Any thromb | 65 | 0.25 | 65.25 | 12.693 | 12.378 | 13.016 | 58.571 | 53.619 | 63.982 | 4.615 | 4.217 | 5.050 |
Any thromb | 65 | 0.30 | 65.30 | 12.740 | 12.424 | 13.063 | 56.326 | 51.742 | 61.316 | 4.421 | 4.054 | 4.822 |
Any thromb | 65 | 0.35 | 65.35 | 12.787 | 12.470 | 13.111 | 54.191 | 49.934 | 58.809 | 4.238 | 3.898 | 4.608 |
Any thromb | 65 | 0.40 | 65.40 | 12.834 | 12.517 | 13.159 | 52.163 | 48.196 | 56.456 | 4.065 | 3.748 | 4.408 |
Any thromb | 65 | 0.45 | 65.45 | 12.881 | 12.563 | 13.207 | 50.240 | 46.527 | 54.250 | 3.900 | 3.605 | 4.220 |
Hazard ratio for thrombosis in MPN vs non-MPN
HR table
Table 4.3: Hazard ratio (HR) with 95% confidence interval (CI) for thrombosis during follow-up in MPN patients relative to controls. Index date is at 6 months post MPN diagnosis date or matching date. MPN=myeloproliferative neoplasm, PV=polycythemia vera, ET=essential thrombocythemia, PMF=primary myelofibrosis, N₁ = number of events among MPN subjects, N₂ = number of events among controls
Attained age | Time since index date | All MPNs
HR (95% CI) | PV
HR (95% CI) | ET
HR (95% CI) | PMF
HR (95% CI) |
|---|
|
| Any thrombosis
N1=4282,
N2=31217 | Arterial thrombosis
N1=3125,
N2=26128 | Venous thrombosis
N1=1541,
N2=6667 | Any thrombosis
N1=1963,
N2=13083 | Arterial thrombosis
N1=1454,
N2=11067 | Venous thrombosis
N1=702,
N2=2702 | Any thrombosis
N1=1370,
N2=10364 | Arterial thrombosis
N1=1020,
N2=8525 | Venous thrombosis
N1=462,
N2=2351 | Any thrombosis
N1=212,
N2=1836 | Arterial thrombosis
N1=135,
N2=1544 | Venous thrombosis
N1=95,
N2=361 |
55 | 6 months | 7.53
(6.86, 8.25) | 5.20
(4.52, 5.98) | 11.26
(9.85, 12.87) | 8.27
(7.14, 9.58) | 5.34
(4.25, 6.71) | 13.13
(10.60, 16.26) | 5.29
(4.50, 6.21) | 4.42
(3.54, 5.53) | 6.51
(5.05, 8.38) | 8.12
(5.34, 12.37) | 4.53
(2.17, 9.45) | 15.66
(8.95, 27.42) |
1 year | 5.12
(4.67, 5.61) | 3.97
(3.49, 4.51) | 6.86
(5.98, 7.88) | 5.67
(4.91, 6.54) | 4.08
(3.32, 5.02) | 8.07
(6.49, 10.03) | 3.83
(3.29, 4.46) | 3.33
(2.71, 4.08) | 4.68
(3.72, 5.90) | 5.71
(3.69, 8.84) | 4.10
(2.12, 7.96) | 8.71
(4.64, 16.35) |
5 years | 2.39
(2.12, 2.69) | 2.29
(1.96, 2.67) | 2.98
(2.49, 3.55) | 2.79
(2.30, 3.38) | 2.44
(1.90, 3.13) | 3.60
(2.69, 4.82) | 1.88
(1.55, 2.29) | 1.97
(1.54, 2.50) | 2.32
(1.73, 3.10) | 4.13
(2.51, 6.81) | 2.75
(1.25, 6.04) | 6.41
(3.27, 12.58) |
60 | 6 months | 5.25
(4.84, 5.70) | 3.88
(3.47, 4.34) | 8.11
(7.15, 9.22) | 5.61
(4.95, 6.36) | 4.00
(3.36, 4.75) | 9.00
(7.41, 10.93) | 3.87
(3.33, 4.50) | 3.38
(2.80, 4.08) | 4.80
(3.73, 6.18) | 5.40
(3.80, 7.68) | 3.46
(2.04, 5.88) | 10.55
(6.47, 17.20) |
1 year | 3.67
(3.38, 3.99) | 3.00
(2.71, 3.33) | 5.12
(4.50, 5.84) | 3.96
(3.50, 4.48) | 3.10
(2.65, 3.63) | 5.74
(4.72, 6.99) | 2.87
(2.49, 3.30) | 2.56
(2.15, 3.04) | 3.57
(2.85, 4.47) | 3.83
(2.62, 5.60) | 3.04
(1.82, 5.07) | 5.96
(3.38, 10.51) |
5 years | 2.04
(1.86, 2.24) | 1.87
(1.66, 2.10) | 2.78
(2.40, 3.22) | 2.33
(2.02, 2.70) | 2.02
(1.68, 2.43) | 3.26
(2.59, 4.10) | 1.62
(1.38, 1.90) | 1.59
(1.31, 1.92) | 2.18
(1.69, 2.82) | 2.88
(1.92, 4.31) | 2.04
(1.15, 3.62) | 4.61
(2.61, 8.16) |
65 | 6 months | 3.85
(3.57, 4.16) | 3.03
(2.75, 3.35) | 6.06
(5.36, 6.85) | 4.04
(3.60, 4.54) | 3.12
(2.69, 3.61) | 6.54
(5.43, 7.87) | 2.96
(2.56, 3.42) | 2.69
(2.26, 3.19) | 3.66
(2.85, 4.69) | 3.79
(2.74, 5.23) | 2.75
(1.79, 4.22) | 7.34
(4.59, 11.75) |
1 year | 2.76
(2.56, 2.98) | 2.37
(2.16, 2.59) | 3.95
(3.49, 4.48) | 2.92
(2.61, 3.27) | 2.45
(2.15, 2.81) | 4.31
(3.58, 5.20) | 2.24
(1.96, 2.56) | 2.05
(1.75, 2.40) | 2.80
(2.24, 3.49) | 2.71
(1.89, 3.87) | 2.35
(1.51, 3.66) | 4.24
(2.45, 7.34) |
5 years | 1.79
(1.65, 1.94) | 1.58
(1.43, 1.74) | 2.62
(2.30, 3.00) | 2.01
(1.78, 2.27) | 1.73
(1.50, 2.00) | 2.99
(2.45, 3.66) | 1.43
(1.24, 1.66) | 1.33
(1.12, 1.58) | 2.07
(1.63, 2.64) | 2.12
(1.47, 3.05) | 1.58
(0.99, 2.50) | 3.60
(2.11, 6.13) |
70 | 6 months | 2.98
(2.78, 3.21) | 2.49
(2.27, 2.72) | 4.71
(4.19, 5.29) | 3.11
(2.79, 3.47) | 2.56
(2.23, 2.93) | 5.08
(4.26, 6.05) | 2.38
(2.08, 2.73) | 2.24
(1.90, 2.64) | 2.88
(2.27, 3.66) | 2.82
(2.08, 3.83) | 2.28
(1.54, 3.38) | 5.30
(3.37, 8.36) |
1 year | 2.19
(2.03, 2.35) | 1.96
(1.80, 2.13) | 3.16
(2.81, 3.56) | 2.30
(2.07, 2.56) | 2.04
(1.80, 2.31) | 3.44
(2.89, 4.10) | 1.83
(1.61, 2.08) | 1.72
(1.48, 2.00) | 2.26
(1.84, 2.78) | 2.03
(1.44, 2.86) | 1.92
(1.26, 2.92) | 3.15
(1.85, 5.39) |
5 years | 1.62
(1.50, 1.74) | 1.39
(1.27, 1.52) | 2.51
(2.21, 2.85) | 1.79
(1.60, 2.00) | 1.54
(1.35, 1.75) | 2.81
(2.32, 3.39) | 1.31
(1.14, 1.50) | 1.17
(1.00, 1.38) | 1.98
(1.57, 2.50) | 1.66
(1.18, 2.35) | 1.27
(0.84, 1.94) | 3.08
(1.85, 5.15) |
75 | 6 months | 2.46
(2.30, 2.62) | 2.15
(1.98, 2.34) | 3.82
(3.43, 4.26) | 2.58
(2.34, 2.84) | 2.22
(1.96, 2.52) | 4.24
(3.60, 4.99) | 2.02
(1.79, 2.29) | 1.97
(1.70, 2.28) | 2.37
(1.88, 2.97) | 2.25
(1.71, 2.97) | 2.00
(1.39, 2.86) | 4.00
(2.59, 6.18) |
1 year | 1.83
(1.72, 1.96) | 1.71
(1.58, 1.85) | 2.64
(2.36, 2.94) | 1.94
(1.76, 2.13) | 1.79
(1.59, 2.00) | 2.93
(2.49, 3.45) | 1.58
(1.41, 1.77) | 1.53
(1.33, 1.75) | 1.90
(1.57, 2.30) | 1.63
(1.18, 2.26) | 1.66
(1.11, 2.47) | 2.47
(1.47, 4.14) |
5 years | 1.51
(1.41, 1.62) | 1.28
(1.18, 1.39) | 2.43
(2.16, 2.74) | 1.66
(1.50, 1.84) | 1.42
(1.26, 1.61) | 2.69
(2.25, 3.21) | 1.23
(1.08, 1.40) | 1.09
(0.94, 1.27) | 1.91
(1.53, 2.37) | 1.41
(1.02, 1.94) | 1.08
(0.73, 1.60) | 2.94
(1.84, 4.72) |
80 | 6 months | 2.17
(2.03, 2.30) | 1.98
(1.83, 2.13) | 3.26
(2.89, 3.67) | 2.32
(2.11, 2.54) | 2.06
(1.84, 2.31) | 3.83
(3.23, 4.55) | 1.83
(1.63, 2.05) | 1.84
(1.61, 2.11) | 2.03
(1.58, 2.60) | 1.95
(1.49, 2.53) | 1.85
(1.34, 2.55) | 3.16
(1.94, 5.15) |
1 year | 1.64
(1.54, 1.74) | 1.59
(1.48, 1.70) | 2.29
(2.04, 2.58) | 1.76
(1.61, 1.93) | 1.67
(1.51, 1.85) | 2.68
(2.27, 3.17) | 1.44
(1.30, 1.60) | 1.44
(1.27, 1.62) | 1.66
(1.35, 2.04) | 1.41
(1.03, 1.93) | 1.53
(1.06, 2.23) | 2.05
(1.20, 3.51) |
5 years | 1.46
(1.37, 1.55) | 1.24
(1.15, 1.34) | 2.40
(2.15, 2.68) | 1.61
(1.46, 1.77) | 1.39
(1.24, 1.56) | 2.63
(2.23, 3.10) | 1.20
(1.07, 1.36) | 1.07
(0.93, 1.23) | 1.86
(1.51, 2.28) | 1.30
(0.97, 1.74) | 0.98
(0.68, 1.40) | 3.17
(2.09, 4.82) |
85 | 6 months | 2.05
(1.89, 2.22) | 1.94
(1.77, 2.12) | 2.91
(2.46, 3.43) | 2.27
(2.01, 2.55) | 2.05
(1.79, 2.35) | 3.74
(2.96, 4.73) | 1.76
(1.52, 2.04) | 1.84
(1.57, 2.15) | 1.81
(1.29, 2.54) | 1.82
(1.29, 2.58) | 1.82
(1.23, 2.69) | 2.61
(1.28, 5.33) |
1 year | 1.56
(1.45, 1.68) | 1.57
(1.44, 1.70) | 2.08
(1.79, 2.43) | 1.73
(1.55, 1.93) | 1.68
(1.49, 1.89) | 2.64
(2.12, 3.27) | 1.40
(1.23, 1.59) | 1.45
(1.26, 1.66) | 1.50
(1.12, 2.00) | 1.32
(0.92, 1.90) | 1.52
(1.01, 2.29) | 1.79
(0.90, 3.55) |
5 years | 1.46
(1.36, 1.56) | 1.26
(1.17, 1.36) | 2.39
(2.12, 2.70) | 1.62
(1.47, 1.79) | 1.43
(1.28, 1.60) | 2.63
(2.20, 3.15) | 1.23
(1.09, 1.38) | 1.12
(0.98, 1.28) | 1.82
(1.46, 2.28) | 1.31
(0.95, 1.80) | 0.94
(0.63, 1.39) | 3.82
(2.42, 6.02) |
Thrombosis rates by treatments in MPNs
We investigated further the patterns of thrombosis rates over two time-scales in MPN patients with cytoreductive and anticoagulant treatments.
The cytoreductive treatment constituted any of the following drugs that were collected after the MPN date and before the end of follow-up: Interferon (ATC: L03AB11, L03AB10), Hydroxyurea (ATC: L01XX05), Jakavi (ATC: L01EJ01), Anagrelide (ATC: L01XX35), Busulfan (ATC: L01AB01) .
For the anticoagulant treatment, we looked at antiplatelet drugs (Aspirin, ATC: B01AC06; Clopidogrel ATC: B01AC04) and at anticoagulants, which included any of the following drugs: Warfarin (ATC: B01AA03), Dabigatran (ATC: B01AE07), direct oral anticoagulants (ATC: B01AF01-B01AF03), Heparins (ATC: B01AB04-B01AB10).
Since the Prescribed Drugs Register was established in July 2005, we looked at MPN patients diagnosed during 2006-2021. Two time-varying treatment variables were created based on the following criteria:
For cytoreductive treatment: patients can go from treatment state ‘No cytoreductive treatment’ to treatment state ‘Cytoreductive treatment’; or can start from ‘Cytoreductive treatment’.
For anticoagulant treatment: patients can go from treatment state ‘No antiplatelet drugs, no anticoagulants’ to ‘Antiplatelet drugs’; from ‘No antiplatelet drugs, no anticoagulants’ to ‘Anticoagulants’; from ‘Antiplatelet drugs’ to ‘Anticoagulants’. Note: starting treatment state can be any of the above.
For the analysis, only treatment states that were at index date and beyond were included.
Cytoreductive treatment for all MPNs
Model
Fitted the following model:
\[
\begin{align}
\log h & = s(t_1; \gamma_1) + s(t_2; \gamma_2) + \beta_{Cyt} \cdot I_{Cyt} + s(t_1; \gamma_3) \cdot I_{Cyt} + s(t_2; \gamma_4) \cdot I_{Cyt}
\end{align}
\]
where \(t_1\) is attained age, \(t_2\) is time since index date and \(I_{Cyt}\) is a time-varying indicator variable for cytoreductive treatment.
Stata code for the model:
stmt trt_cyt, ///
time1(df(3) logtoff tvc(trt_cyt) dftvc(trt_cyt:1)) ///
time2(df(3) logtoff start(age_minus) tvc(trt_cyt) dftvc(trt_cyt:1))
Results
Table 5.1: MPN-patients with diagnosis during 2006-2021 at different treatment states after index date (6 months post MPN-diagnosis) during the follow-up where the event of interest is any thrombosis. Treatment state is a time-varying covariate, so patients can go from ‘No cytoreductive treatment’ to ‘Cytoreductive treatment’; or can start from ‘Cytoreductive treatment’.
Treatment state | Person-years | Number of events | N |
|---|
No cytoreductive treatment | 29,076 | 1,089 | 6,889 |
Cytoreductive treatment | 45,125 | 1,734 | 9,211 |
Total number of patients in the cohort N=14017. |
By attained age for times since index date
Data
Below are few selected rows from the dataset containing estimated thrombosis rates for all MPNs with exposure to cytoreductive treatment and for any thrombosis as event of interest. If you wish to see full data (size ~10 Mb), the following download link will provide the excel file: https://github.com/nurbatyr/Suppl-material-thrombosis-rates-in-MPNs-over-2ts/releases/download/thromb-rates-by-cyt-trt/061_estimated_thrombosis_rates_by_cyt_trt.xlsx
Note: trt0 = ‘No cytoreductive treatment’, trt1 = ‘Cytoreductive treatment’.
age_start | fu_time | attained_age | h_trt0 | h_trt0_lci | h_trt0_uci | h_trt1 | h_trt1_lci | h_trt1_uci |
|---|
65 | 0.00 | 65.00 | 64.10264 | 56.50680 | 72.71954 | 50.28367 | 44.27674 | 57.10555 |
65 | 0.05 | 65.05 | 62.29614 | 55.07600 | 70.46279 | 48.99265 | 43.28059 | 55.45858 |
65 | 0.10 | 65.10 | 60.54236 | 53.67730 | 68.28542 | 47.73621 | 42.30406 | 53.86589 |
65 | 0.15 | 65.15 | 58.84133 | 52.31104 | 66.18684 | 46.51466 | 41.34757 | 52.32746 |
65 | 0.20 | 65.20 | 57.19290 | 50.97742 | 64.16620 | 45.32817 | 40.41144 | 50.84311 |
65 | 0.25 | 65.25 | 55.59684 | 49.67665 | 62.22256 | 44.17687 | 39.49596 | 49.41254 |
65 | 0.30 | 65.30 | 54.05279 | 48.40884 | 60.35476 | 43.06076 | 38.60138 | 48.03530 |
65 | 0.35 | 65.35 | 52.56029 | 47.17407 | 58.56150 | 41.97978 | 37.72789 | 46.71085 |
65 | 0.40 | 65.40 | 51.11884 | 45.97242 | 56.84139 | 40.93380 | 36.87569 | 45.43851 |
65 | 0.45 | 65.45 | 49.72781 | 44.80388 | 55.19288 | 39.92264 | 36.04491 | 44.21753 |
Anticoagulant treatment for all MPNs
Model
Fitted the following model:
\[
\begin{align}
\log h & = s(t_1; \gamma_1) + s(t_2; \gamma_2) + \beta_{Ant1} \cdot I_{Ant1} + \beta_{Ant2} \cdot I_{Ant2} + \\
& + s(t_1; \gamma_3) \cdot (I_{Ant1} + I_{Ant2}) + s(t_2; \gamma_4) \cdot (I_{Ant1} + I_{Ant2})
\end{align}
\]
where \(t_1\) is attained age, \(t_2\) is time since index date, \(I_{Ant1}\) is a time-varying indicator variable for treatment state ‘Antiplatelet drugs’, and \(I_{Ant2}\) is a time-varying indicator for treatment state ‘Anticoagulants’.
Stata code for the model:
stmt trt_ant1 trt_ant2, ///
time1(df(3) logtoff tvc(trt_ant1 trt_ant2) dftvc(trt_ant1:1 trt_ant2:1)) ///
time2(df(3) logtoff start(age_minus) tvc(trt_ant1 trt_ant2) dftvc(trt_ant1:1 trt_ant2:1))
Results
Table 5.2: MPN-patients with diagnosis during 2006-2021 at different treatment states after index date (6 months post MPN-diagnosis) during the follow-up where the event of interest is any thrombosis. Treatment state is a time-varying covariate, so patients can go from ‘No antiplatelet drugs, no anticoagulants’ to ‘Antiplatelet drugs’; from ‘No antiplatelet drugs, no anticoagulants’ to ‘Anticoagulants’; from ‘Antiplatelet drugs’ to ‘Anticoagulants’. Note: starting treatment state can be any of the above.
Treatment state | Person-years | Number of events | N |
|---|
No antiplatelet drugs, no anticoagulants | 8,712 | 216 | 2,413 |
Antiplatelet drugs | 47,828 | 1,412 | 9,865 |
Anticoagulants | 17,661 | 1,195 | 4,821 |
Total number of patients in the cohort N=14017. |
By attained age for times since index date
Data
Below are few selected rows from the dataset containing estimated thrombosis rates for all MPNs with exposure to anticoagulant treatment and for any thrombosis as event of interest. If you wish to see full data (size ~15 Mb), the following download link will provide the excel file: https://github.com/nurbatyr/Suppl-material-thrombosis-rates-in-MPNs-over-2ts/releases/download/thromb-rates-by-anticoag-trt/071_estimated_thrombosis_rates_by_cyt_anticoag.xlsx
Note: trt0 = ‘No antiplatelet drugs, no anticoagulants’, trt1 = ‘Antiplatelet drugs’, trt2 = ‘Anticoagulants’.
age_start | fu_time | attained_age | h_trt0 | h_trt0_lci | h_trt0_uci | h_trt1 | h_trt1_lci | h_trt1_uci | h_trt2 | h_trt2_lci | h_trt2_uci |
|---|
65 | 0.00 | 65.00 | 46.29481 | 37.64192 | 56.93676 | 40.82849 | 35.98913 | 46.31858 | 145.4649 | 127.17651 | 166.3832 |
65 | 0.05 | 65.05 | 44.95722 | 36.65499 | 55.13988 | 39.69825 | 35.10191 | 44.89645 | 140.9155 | 123.57503 | 160.6892 |
65 | 0.10 | 65.10 | 43.65958 | 35.69196 | 53.40583 | 38.60044 | 34.23412 | 43.52365 | 136.5124 | 120.06725 | 155.2100 |
65 | 0.15 | 65.15 | 42.40188 | 34.75315 | 51.73400 | 37.53520 | 33.38605 | 42.19999 | 132.2547 | 116.65331 | 149.9426 |
65 | 0.20 | 65.20 | 41.18400 | 33.83881 | 50.12357 | 36.50253 | 32.55791 | 40.92507 | 128.1409 | 113.33311 | 144.8834 |
65 | 0.25 | 65.25 | 40.00574 | 32.94914 | 48.57363 | 35.50239 | 31.74988 | 39.69842 | 124.1695 | 110.10645 | 140.0286 |
65 | 0.30 | 65.30 | 38.86681 | 32.08428 | 47.08315 | 34.53465 | 30.96208 | 38.51944 | 120.3385 | 106.97292 | 135.3741 |
65 | 0.35 | 65.35 | 37.76684 | 31.24430 | 45.65102 | 33.59910 | 30.19462 | 37.38743 | 116.6460 | 103.93204 | 130.9152 |
65 | 0.40 | 65.40 | 36.70541 | 30.42925 | 44.27605 | 32.69550 | 29.44759 | 36.30163 | 113.0895 | 100.98322 | 126.6472 |
65 | 0.45 | 65.45 | 35.68203 | 29.63913 | 42.95697 | 31.82352 | 28.72101 | 35.26117 | 109.6668 | 98.12578 | 122.5653 |
Sensitivity analysis - no history of thrombosis before index date
For sensitivity analysis we excluded individuals with history of thrombosis prior to the index date. Note, history of thrombosis was classified as “any thrombosis until the index date”, where the index date is at 6 months post MPN diagnosis date or matching date. So for this analysis, patients had to survive at least 6 months post MPN/matching date, without developing any other hematological malignancy and have not experienced any thrombosis.
SA: Cohort characteristics
Table 6.1: Characteristics of patients diagnosed during 2001-2021 with myeloproliferative neoplasms and population controls matched on sex and year of birth while excluding individuals with history of thrombosis before the index date. MPN=myeloproliferative neoplasm, PV=polycythemia vera, ET=essential thrombocythemia, PMF=primary myelofibrosis, MPN-U=myeloproliferative neoplasm unclassifiable.
| MPN (N=13388) | Controls (N=151979) |
|---|
Sex |
|
|
Female | 7248 (54.1%) | 81157 (53.4%) |
Male | 6140 (45.9%) | 70822 (46.6%) |
Age at diagnosis |
|
|
Median (Q1, Q3) | 68.7 (57.2, 77.0) | 68.3 (57.1, 76.6) |
18-49 | 1968 (14.7%) | 22547 (14.8%) |
50-59 | 2065 (15.4%) | 23694 (15.6%) |
60-69 | 3152 (23.6%) | 37067 (24.4%) |
70-79 | 3931 (29.4%) | 44619 (29.4%) |
80-90 | 2262 (16.9%) | 24005 (15.8%) |
Calendar period of diagnosis |
|
|
2001-2010 | 5983 (44.7%) | 67449 (44.4%) |
2011-2021 | 7405 (55.3%) | 84530 (55.6%) |
MPN subtype |
|
|
PV | 5049 (37.7%) | - |
ET | 5271 (39.4%) | - |
PMF | 894 (6.7%) | - |
MPN-U | 2174 (16.2%) | - |
SA: Total person-years and events
Table 4.2: For each type of event of interest, number of individuals, person-years, number of events for MPN-patients and matched controls, overall and by subtype, respectively.
Event | | All MPNs | Controls | PV | Controls | ET | Controls | PMF | Controls |
|---|
Any thrombosis | N | 17,830 | 172,634 | 7,071 | 68,287 | 6,735 | 65,458 | 1,132 | 10,977 |
Person-years | 108,570 | 1,279,090 | 42,728 | 504,502 | 44,171 | 477,283 | 4,812 | 67,761 |
Events | 4,282 | 31,217 | 1,963 | 13,083 | 1,370 | 10,364 | 212 | 1,836 |
Arterial thrombosis | N | 17,830 | 172,634 | 7,071 | 68,287 | 6,735 | 65,458 | 1,132 | 10,977 |
Person-years | 115,793 | 1,307,918 | 46,020 | 516,158 | 46,261 | 487,326 | 5,142 | 69,226 |
Events | 3,125 | 26,128 | 1,454 | 11,067 | 1,020 | 8,525 | 135 | 1,544 |
Venous thrombosis | N | 17,830 | 172,634 | 7,071 | 68,287 | 6,735 | 65,458 | 1,132 | 10,977 |
Person-years | 126,261 | 1,435,190 | 51,071 | 571,496 | 49,888 | 526,084 | 5,386 | 75,675 |
Events | 1,541 | 6,667 | 702 | 2,702 | 462 | 2,351 | 95 | 361 |
SA: Thrombosis rates
Data
Below are few selected rows from the dataset containing estimated thrombosis rates and hazard ratios from sensitivity analysis for all MPNs and subtypes for any thrombosis, arterial thrombosis and venous thrombosis. If you wish to see full data (size ~200 Mb), the following download link will provide the excel file: https://github.com/nurbatyr/Suppl-material-thrombosis-rates-in-MPNs-over-2ts/releases/download/thromb-rates-SA/031_041_estimated_thrombosis_rates_SA.xlsx
event | age_start | fu_time | attained_age | h_mpn0 | h_mpn0_lci | h_mpn0_uci | h_mpn1 | h_mpn1_lci | h_mpn1_uci | hr | hr_lci | hr_uci |
|---|
Any thromb | 65 | 0.00 | 65.00 | 10.954 | 10.650 | 11.267 | 24.232 | 20.611 | 28.487 | 2.212 | 1.880 | 2.603 |
Any thromb | 65 | 0.05 | 65.05 | 10.994 | 10.689 | 11.307 | 24.166 | 20.656 | 28.272 | 2.198 | 1.877 | 2.574 |
Any thromb | 65 | 0.10 | 65.10 | 11.033 | 10.728 | 11.348 | 24.101 | 20.699 | 28.062 | 2.184 | 1.874 | 2.545 |
Any thromb | 65 | 0.15 | 65.15 | 11.074 | 10.767 | 11.388 | 24.036 | 20.740 | 27.857 | 2.171 | 1.871 | 2.518 |
Any thromb | 65 | 0.20 | 65.20 | 11.114 | 10.807 | 11.429 | 23.972 | 20.778 | 27.657 | 2.157 | 1.868 | 2.491 |
Any thromb | 65 | 0.25 | 65.25 | 11.154 | 10.846 | 11.470 | 23.909 | 20.814 | 27.464 | 2.144 | 1.864 | 2.465 |
Any thromb | 65 | 0.30 | 65.30 | 11.194 | 10.886 | 11.511 | 23.846 | 20.848 | 27.276 | 2.130 | 1.861 | 2.439 |
Any thromb | 65 | 0.35 | 65.35 | 11.235 | 10.926 | 11.552 | 23.784 | 20.878 | 27.095 | 2.117 | 1.856 | 2.414 |
Any thromb | 65 | 0.40 | 65.40 | 11.275 | 10.966 | 11.594 | 23.722 | 20.904 | 26.920 | 2.104 | 1.852 | 2.390 |
Any thromb | 65 | 0.45 | 65.45 | 11.316 | 11.006 | 11.635 | 23.661 | 20.927 | 26.752 | 2.091 | 1.847 | 2.367 |
SA: Hazard ratio for thrombosis in MPN vs non-MPN
HR table
Table 6.2: Hazard ratio (HR) with 95% confidence interval (CI) for thrombosis during follow-up in MPN patients relative to controls. Index date is at 6 months post MPN diagnosis date or matching date. MPN=myeloproliferative neoplasm, PV=polycythemia vera, ET=essential thrombocythemia, PMF=primary myelofibrosis, N₁ = number of events among MPN subjects, N₂ = number of events among controls
Attained age | Time since index date | All MPNs
HR (95% CI) | PV
HR (95% CI) | ET
HR (95% CI) | PMF
HR (95% CI) |
|---|
|
| Any thrombosis
N1=2602,
N2=24436 | Arterial thrombosis
N1=1945,
N2=20241 | Venous thrombosis
N1=870,
N2=5409 | Any thrombosis
N1=1160,
N2=10250 | Arterial thrombosis
N1=869,
N2=8590 | Venous thrombosis
N1=391,
N2=2196 | Any thrombosis
N1=858,
N2=8102 | Arterial thrombosis
N1=643,
N2=6586 | Venous thrombosis
N1=278,
N2=1908 | Any thrombosis
N1=142,
N2=1385 | Arterial thrombosis
N1=94,
N2=1157 | Venous thrombosis
N1=59,
N2=278 |
55 | 6 months | 3.04
(2.60, 3.57) | 2.59
(2.08, 3.23) | 3.94
(3.12, 4.97) | 2.91
(2.20, 3.85) | 2.29
(1.55, 3.38) | 4.44
(3.01, 6.55) | 2.56
(2.00, 3.28) | 2.21
(1.57, 3.12) | 2.94
(2.01, 4.31) | 4.18
(2.18, 8.01) | 3.14
(1.28, 7.67) | 5.85
(1.93, 17.67) |
1 year | 2.86
(2.50, 3.28) | 2.52
(2.09, 3.05) | 3.44
(2.82, 4.20) | 2.84
(2.24, 3.60) | 2.30
(1.64, 3.22) | 3.87
(2.77, 5.40) | 2.32
(1.88, 2.87) | 2.06
(1.53, 2.76) | 2.55
(1.84, 3.53) | 4.08
(2.30, 7.24) | 3.66
(1.74, 7.71) | 5.46
(2.11, 14.14) |
5 years | 2.02
(1.74, 2.35) | 2.01
(1.66, 2.42) | 2.16
(1.72, 2.72) | 2.44
(1.93, 3.09) | 2.18
(1.62, 2.94) | 2.90
(1.99, 4.23) | 1.52
(1.21, 1.92) | 1.78
(1.33, 2.38) | 1.45
(1.02, 2.06) | 4.06
(2.23, 7.39) | 3.22
(1.39, 7.43) | 5.82
(2.40, 14.11) |
60 | 6 months | 2.50
(2.19, 2.85) | 2.14
(1.80, 2.53) | 3.35
(2.71, 4.14) | 2.49
(2.01, 3.09) | 2.02
(1.52, 2.69) | 3.72
(2.66, 5.19) | 1.99
(1.59, 2.50) | 1.79
(1.34, 2.38) | 2.31
(1.58, 3.39) | 3.23
(1.94, 5.36) | 2.28
(1.15, 4.54) | 5.78
(2.65, 12.59) |
1 year | 2.37
(2.12, 2.65) | 2.08
(1.81, 2.41) | 2.97
(2.49, 3.56) | 2.42
(2.02, 2.90) | 2.02
(1.59, 2.57) | 3.29
(2.48, 4.36) | 1.83
(1.51, 2.22) | 1.67
(1.31, 2.12) | 2.05
(1.49, 2.83) | 3.17
(2.01, 5.00) | 2.61
(1.45, 4.67) | 5.30
(2.70, 10.40) |
5 years | 1.76
(1.56, 1.98) | 1.69
(1.46, 1.95) | 2.09
(1.73, 2.53) | 2.07
(1.72, 2.48) | 1.83
(1.46, 2.29) | 2.74
(2.05, 3.68) | 1.32
(1.09, 1.61) | 1.48
(1.17, 1.87) | 1.38
(1.02, 1.87) | 3.17
(2.00, 5.01) | 2.43
(1.31, 4.50) | 4.79
(2.42, 9.48) |
65 | 6 months | 2.11
(1.87, 2.38) | 1.81
(1.57, 2.10) | 2.91
(2.37, 3.57) | 2.18
(1.81, 2.62) | 1.82
(1.45, 2.29) | 3.20
(2.34, 4.38) | 1.62
(1.30, 2.02) | 1.50
(1.15, 1.95) | 1.90
(1.30, 2.78) | 2.57
(1.64, 4.02) | 1.77
(0.98, 3.20) | 5.30
(2.70, 10.38) |
1 year | 2.01
(1.82, 2.23) | 1.77
(1.57, 2.00) | 2.62
(2.21, 3.11) | 2.12
(1.82, 2.47) | 1.81
(1.50, 2.19) | 2.87
(2.21, 3.73) | 1.51
(1.26, 1.81) | 1.40
(1.13, 1.75) | 1.73
(1.26, 2.37) | 2.53
(1.68, 3.81) | 1.98
(1.18, 3.31) | 4.86
(2.71, 8.69) |
5 years | 1.56
(1.41, 1.74) | 1.46
(1.29, 1.65) | 2.04
(1.72, 2.42) | 1.80
(1.54, 2.11) | 1.58
(1.31, 1.90) | 2.62
(2.04, 3.38) | 1.19
(0.99, 1.42) | 1.28
(1.04, 1.57) | 1.34
(1.01, 1.78) | 2.53
(1.70, 3.76) | 1.89
(1.14, 3.13) | 4.12
(2.25, 7.56) |
70 | 6 months | 1.84
(1.64, 2.06) | 1.59
(1.39, 1.83) | 2.58
(2.12, 3.14) | 1.95
(1.63, 2.32) | 1.67
(1.36, 2.06) | 2.84
(2.10, 3.84) | 1.38
(1.12, 1.71) | 1.31
(1.02, 1.69) | 1.65
(1.15, 2.38) | 2.11
(1.38, 3.23) | 1.48
(0.86, 2.57) | 4.46
(2.29, 8.68) |
1 year | 1.76
(1.61, 1.94) | 1.57
(1.40, 1.75) | 2.36
(2.01, 2.77) | 1.90
(1.65, 2.19) | 1.66
(1.40, 1.97) | 2.58
(2.02, 3.30) | 1.30
(1.10, 1.55) | 1.24
(1.01, 1.52) | 1.53
(1.13, 2.05) | 2.08
(1.41, 3.07) | 1.62
(1.00, 2.63) | 4.15
(2.35, 7.34) |
5 years | 1.44
(1.30, 1.59) | 1.31
(1.17, 1.47) | 2.01
(1.71, 2.37) | 1.63
(1.41, 1.89) | 1.41
(1.19, 1.67) | 2.53
(1.99, 3.22) | 1.10
(0.93, 1.31) | 1.15
(0.95, 1.40) | 1.33
(1.01, 1.75) | 2.07
(1.42, 3.03) | 1.52
(0.96, 2.42) | 3.74
(2.07, 6.75) |
75 | 6 months | 1.65
(1.49, 1.83) | 1.46
(1.28, 1.66) | 2.36
(1.96, 2.83) | 1.79
(1.52, 2.11) | 1.58
(1.29, 1.92) | 2.62
(1.98, 3.46) | 1.25
(1.03, 1.52) | 1.21
(0.96, 1.53) | 1.53
(1.08, 2.15) | 1.81
(1.23, 2.67) | 1.36
(0.82, 2.24) | 3.40
(1.76, 6.58) |
1 year | 1.60
(1.47, 1.74) | 1.44
(1.30, 1.59) | 2.18
(1.89, 2.52) | 1.76
(1.54, 2.00) | 1.57
(1.34, 1.83) | 2.40
(1.92, 2.99) | 1.19
(1.02, 1.39) | 1.14
(0.95, 1.37) | 1.43
(1.09, 1.87) | 1.77
(1.24, 2.54) | 1.45
(0.92, 2.27) | 3.29
(1.89, 5.71) |
5 years | 1.36
(1.24, 1.50) | 1.23
(1.10, 1.37) | 2.01
(1.72, 2.35) | 1.53
(1.33, 1.76) | 1.33
(1.13, 1.56) | 2.47
(1.97, 3.11) | 1.07
(0.91, 1.26) | 1.09
(0.90, 1.31) | 1.34
(1.04, 1.74) | 1.75
(1.22, 2.50) | 1.28
(0.83, 1.98) | 3.59
(2.04, 6.32) |
80 | 6 months | 1.54
(1.40, 1.70) | 1.39
(1.24, 1.57) | 2.21
(1.84, 2.66) | 1.70
(1.46, 1.98) | 1.53
(1.27, 1.83) | 2.50
(1.89, 3.31) | 1.20
(1.00, 1.45) | 1.18
(0.96, 1.46) | 1.50
(1.06, 2.14) | 1.63
(1.13, 2.35) | 1.37
(0.87, 2.13) | 2.33
(1.09, 4.99) |
1 year | 1.51
(1.40, 1.62) | 1.38
(1.26, 1.51) | 2.07
(1.80, 2.39) | 1.67
(1.49, 1.88) | 1.53
(1.33, 1.75) | 2.31
(1.86, 2.86) | 1.15
(1.01, 1.33) | 1.12
(0.95, 1.32) | 1.42
(1.08, 1.86) | 1.57
(1.11, 2.22) | 1.42
(0.95, 2.14) | 2.38
(1.28, 4.45) |
5 years | 1.34
(1.23, 1.46) | 1.20
(1.09, 1.33) | 2.03
(1.76, 2.35) | 1.50
(1.32, 1.71) | 1.31
(1.12, 1.52) | 2.44
(1.97, 3.03) | 1.09
(0.94, 1.26) | 1.09
(0.92, 1.29) | 1.40
(1.10, 1.78) | 1.53
(1.10, 2.12) | 1.12
(0.75, 1.67) | 3.69
(2.19, 6.21) |
85 | 6 months | 1.50
(1.33, 1.69) | 1.40
(1.22, 1.60) | 2.13
(1.68, 2.71) | 1.66
(1.38, 2.00) | 1.52
(1.24, 1.88) | 2.49
(1.73, 3.57) | 1.24
(1.00, 1.54) | 1.23
(0.96, 1.56) | 1.58
(1.01, 2.46) | 1.53
(0.94, 2.49) | 1.52
(0.90, 2.59) | 1.44
(0.45, 4.64) |
1 year | 1.47
(1.34, 1.62) | 1.39
(1.25, 1.54) | 2.02
(1.66, 2.45) | 1.65
(1.43, 1.91) | 1.54
(1.31, 1.80) | 2.30
(1.71, 3.09) | 1.19
(1.01, 1.42) | 1.17
(0.97, 1.41) | 1.49
(1.04, 2.15) | 1.45
(0.94, 2.23) | 1.55
(0.97, 2.48) | 1.60
(0.61, 4.21) |
5 years | 1.37
(1.26, 1.50) | 1.24
(1.12, 1.37) | 2.09
(1.79, 2.43) | 1.54
(1.35, 1.76) | 1.36
(1.18, 1.58) | 2.45
(1.94, 3.08) | 1.16
(1.01, 1.35) | 1.15
(0.97, 1.36) | 1.49
(1.16, 1.92) | 1.39
(0.96, 2.00) | 1.03
(0.66, 1.60) | 4.02
(2.28, 7.11) |
Statistical Software
The statistical software used for the analysis was Stata 18.0 and R version 4.3.2.
