Keywords
seasonality - epidemiology - peak-to-trough ratio - venous thromboembolism
Introduction
Venous thromboembolism (VTE) typically manifests as deep vein thrombosis or pulmonary
embolism, but affects any venous circulation.[1] Occurrences at other sites include splanchnic vein thrombosis (encompassing thrombosis
of the portal, hepatic, mesenteric, and splenic veins) cerebral vein thrombosis, and
retinal vein thrombosis.[2]
VTE represents a growing global burden: the incidence rate is increasing due to changes
in demographics, increases in the prevalence of several risk factors, and improvements
in diagnostic imaging.[1] The risk of dying within 30 days following a VTE diagnosis is 5-, 80-, and 40-fold
higher in patients suffering from deep vein thrombosis, pulmonary embolism, or splanchnic
vein thrombosis compared with the general population.[3]
[4] The risks generally remain increased over the long term.[3]
[4]
Occurrence of cardiovascular diseases is unequally distributed throughout the year,
as is associated mortality.[5]
[6] But most evidence regarding seasonality relates to atherosclerotic disease rather
than to VTE.[6] The existing literature on the seasonality of VTE is conflicting, with some studies
reporting excess risk during the winter,[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14] and others reporting no such effect.[15]
[16]
[17] Most previous studies focused exclusively on deep vein thrombosis and pulmonary
embolism.[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17] Studies on cerebral vein thrombosis seasonality have been small (<200 patients)
and inconclusive,[18]
[19]
[20] while, to the best of our knowledge, no previous study has investigated the seasonality
of splanchnic vein thrombosis and retinal vein thrombosis. As improved imaging modalities
lead to more accurate diagnoses, it may be time to revisit earlier findings.[7]
[15]
[16]
Several biological mechanisms could contribute to the seasonality of VTE.[6] Seasonal alterations in ambient temperature are considered pivotal, as exposure
to cold promotes acute and chronic physiological changes, including elevations in
both peripheral vasoconstriction, sympathetic nervous system activity, blood viscosity,
fibrinogen levels, and C-reactive protein levels—in turn, these changes may trigger
adverse cardiovascular events.[6]
[8] Acute infections, occurring most often in winter, also are associated with increased
risk of deep vein thrombosis and pulmonary embolism.[21] Moreover, the seasonal pattern likely depends on the susceptibility of individual
patients. Thus, deep vein thrombosis or pulmonary embolism in patients with a recent
immobilization due to a medical condition or surgery may follow a different seasonal
pattern than in those without such provoking factors.
To add to the understanding of the seasonal pattern of VTE, we undertook a nationwide
population-based study in Denmark, using data from 1977 to 2016.
Methods
Setting
This study was based on data obtained from Danish healthcare and administrative registries.
The Danish healthcare system is government-funded, ensuring free access to health
care for all legal residents.[22] The unique 10-digit identifier assigned to all residents at birth or upon immigration
by the Danish Civil Registration System (CRS) allows complete individual-level linkage
of all health and administrative registries.[23] The Danish National Patient Registry (DNPR) contains data on more than 99% of all
discharges from Danish hospitals.[24] Each hospital discharge (available from 1977) or outpatient visit (available from
1995) is recorded in the DNPR with one primary diagnosis and one or more secondary
diagnoses coded according to the Eighth Revision of the International Classification of Diseases (ICD) during 1977–1993 and according to the Tenth Revision thereafter.[24]
Patients with Venous Thromboembolism
We searched the DNPR and identified all inpatients and outpatients with a first-time
primary or secondary discharge diagnosis of deep vein thrombosis, pulmonary embolism,
splanchnic vein thrombosis (January 1, 1977, through December 31, 2016), cerebral
vein thrombosis, and retinal vein thrombosis (1 January 1994 through 31 December 2016)
based on ICD diagnosis codes.[24] Due to the paucity of cerebral vein thrombosis and retinal vein thrombosis events
before 1994 and the presumed low validity of ICD-8 diagnosis codes, we included only
patients with an ICD-10 diagnosis code for these conditions. If a patient had a simultaneous
diagnosis of pulmonary embolism and deep vein thrombosis, we used the pulmonary embolism
diagnosis, owing to its higher mortality rate.[3] Patients with a diagnosis of splanchnic vein thrombosis, cerebral vein thrombosis,
or retinal vein thrombosis and a concurrent diagnosis of any of the other conditions
under study were considered in both analyses.
We also categorized a VTE as provoked or unprovoked. Patients with a preexisting cancer
diagnosis as well as a fracture or trauma, surgery, pregnancy, or prolonged immobilization
due to hospitalization within 90 days before a deep vein thrombosis or pulmonary embolism
diagnosis were classified as having a provoked VTE, while those without these factors
were classified as having an unprovoked VTE.[25] We defined prolonged immobilization as an inpatient stay of at least 14 days from
the date of admission to discharge.[26] We considered an admission occurring on the same day as discharge from another admission
a transfer between hospital departments rather than two separate admissions.
Statistical Analysis
To assess seasonality, we summed monthly frequencies of each year in the study period.
To adjust for varying length of month, we multiplied each monthly frequency by 30
and divided the result by the length of the month. We then applied Edwards' model,
which assumes that the expected values for monthly frequencies follow a sine curve
with a single annual cycle.[27] Based on this model, we estimated the peak-to-trough ratio of the summarized monthly
frequencies using a sine curve fitted to the 12 adjusted monthly frequencies.[28] Edwards' model is sensitive to cyclic trends, and considerably more so than alternatives
that do not involve fitting a cyclic curve to the data, for example, comparisons of
discrete time periods.[27] The magnitude of the peak-to-trough ratio indicates the intensity of seasonality,
equivalent to a risk ratio that contrasts risks for the peak month versus the trough
month.[29] Unlike some other effect measures, the peak-to-trough ratio cannot take a value
less than 1.0.
Because occurrence of VTE and associated mortality may follow different seasonal patterns,
we searched the CRS to ascertain 90-day mortality counts following a diagnosis of
deep vein thrombosis and pulmonary embolism (separately for provoked and unprovoked
events), splanchnic vein thrombosis, cerebral vein thrombosis, and retinal vein thrombosis.
We then estimated the peak-to-trough ratio in mortality by summarizing these mortality
counts during the study period.
Bias Assessment
Because the peak-to-trough ratio is always 1.0 or greater, variability of monthly
frequencies even in the absence of any seasonality will produce estimates greater
than 1.0.[30] Thus, as a bias analysis, we performed a plasmode simulation to assess the effect
of randomness in the data.[31] We reassigned the summarized monthly frequencies at random and then estimated the
peak-to-trough ratio. We repeated this process 1,000 times and computed the average
of all simulations.
Additional Analyses
To explore whether any biological interactions or cohort effects were present, we
stratified the analysis of seasonality in occurrence of VTEs by sex, age group (0–29,
30–49, 50–69, and 70+ years), comorbidity based on Charlson Comorbidity Index scores
(0, 1, 2, 3 + ),[32] calendar period (1977–1993, 1994–2008, and 2009–2016), type of diagnosis (primary,
secondary), and department (inpatient, outpatient).
As a sensitivity analysis, we repeated the seasonal analysis of monthly frequencies
of occurrence using a log-linear Poisson periodic regression model that allowed inclusion
of covariates and secular trends in seasonality: log(disease occurrence) = seasonality + covariates + secular
trend.[29]
We used R, version 3.3.3, and SAS, version 9.4 (SAS Institute Inc., Cary, North Carolina)
to conduct the analyses. The ICD codes used in the study are listed in [Supplementary Tables S1] and [S2].
Table 1
Characteristics (no., %) of patients with deep vein thrombosis, pulmonary embolism,
provoked VTE, unprovoked VTE, and splanchnic vein thrombosis during 1977–2016, and
cerebral vein thrombosis and retinal vein thrombosis during 1994–2016
|
Deep venous thrombosis
|
Pulmonary embolism
|
Provoked VTE
|
Unprovoked VTE
|
Splanchnic venous thrombosis
|
Cerebral venous thrombosis
|
Retinal venous thrombosis
|
|
All patients
|
101,895
|
84,080
|
69,908
|
116,067
|
3,972
|
1,118
|
15,706
|
|
Women
|
52,517 (51.5)
|
44,853 (53.3)
|
38,411 (54.9)
|
58,959 (50.8)
|
1,919 (48.3)
|
679 (61.0)
|
7,973 (50.8)
|
|
Median age (25th–75th percentiles), y
|
65 (51–76)
|
71 (60–79)
|
70 (59–79)
|
68 (52–77)
|
66 (53–77)
|
45 (27–62)
|
71 (62–79)
|
|
Age groups, y
|
|
0–29
|
5,228 (5.1)
|
2,419 (2.9)
|
2,175 (3.1)
|
5,472 (4.7)
|
195 (4.9)
|
334 (29.9)
|
114 (0.7)
|
|
30–49
|
18,862 (18.5)
|
8,874 (10.6)
|
7,836 (11.2)
|
19,900 (17.1)
|
617 (15.5)
|
309 (27.6)
|
1,125 (7.2)
|
|
50–69
|
37,518 (36.8)
|
27,969 (33.3)
|
24,524 (35.1)
|
40,963 (35.3)
|
1,566 (39.4)
|
309 (27.6)
|
5,992 (38.2)
|
|
70+
|
40,287 (39.5)
|
44,818 (53.3)
|
35,373 (50.6)
|
49,732 (42.8)
|
1,594 (40.1)
|
166 (14.8)
|
8,475 (54.0)
|
|
Charlson Comorbidity Index score
|
|
0
|
59,949 (58.8)
|
42,300 (50.3)
|
24,021 (34.4)
|
78,228 (67.4)
|
1,568 (39.5)
|
701 (62.7)
|
8,752 (55.7)
|
|
1
|
16,022 (15.7)
|
14,397 (17.1)
|
8,685 (12.4)
|
21,734 (18.7)
|
733 (18.5)
|
216 (19.3)
|
2,867 (18.3)
|
|
2
|
13,325 (13.1)
|
13,070 (15.5)
|
17,254 (24.7)
|
9,141 (7.9)
|
582 (14.7)
|
104 (9.3)
|
2,096 (13.3)
|
|
3+
|
12,599 (12.4)
|
14,313 (17.0)
|
19,948 (28.5)
|
6,964 (6.0)
|
1,089 (27.4)
|
97 (8.7)
|
1,991 (12.7)
|
|
Calendar period
|
|
1977–1993
|
29,103 (28.6)
|
31,284 (37.2)
|
24,347 (34.8)
|
36,040 (31.1)
|
1,374 (34.6)
|
NA
|
NA
|
|
1994–2008
|
43,725 (42.9)
|
25,400 (30.2)
|
23,070 (33.0)
|
46,055 (39.7)
|
1,062 (26.7)
|
581 (52.0)
|
8,181 (52.1)
|
|
2009–2016
|
29,067 (28.5)
|
27,396 (32.6)
|
22,491 (32.2)
|
33,972 (29.3)
|
1,536 (38.7)
|
537 (48.0)
|
7,525 (47.9)
|
|
Type of diagnosis
|
|
Primary
|
79,529 (78.0)
|
56,353 (67.0)
|
45,504 (65.1)
|
90,378 (77.9)
|
2,320 (58.4)
|
886 (79.2)
|
12,385 (78.9)
|
|
Secondary
|
22,366 (22.0)
|
27,727 (33.0)
|
24,404 (34.9)
|
25,689 (22.1)
|
1,652 (41.6)
|
232 (20.8)
|
3,321 (21.1)
|
|
Department
|
|
Inpatient
|
86,920 (85.3)
|
79,370 (94.4)
|
63,691 (91.1)
|
102,599 (88.4)
|
3,551 (89.4)
|
976 (87.3)
|
590 (3.8)
|
|
Outpatient
|
14,975 (14.7)
|
4,710 (5.6)
|
6,217 (8.9)
|
13,468 (11.6)
|
421 (10.6)
|
142 (12.7)
|
15,116 (96.2)
|
Abbreviation: VTE, venous thromboembolism (deep venous thrombosis and pulmonary embolism).
Table 2
Peak-to-trough ratios (95% confidence intervals) of summarized monthly cases during
1977–2016 (deep vein thrombosis, pulmonary embolism, provoked VTE, unprovoked VTE,
and splanchnic vein thrombosis) and during 1994–2016 (cerebral vein thrombosis and
retinal vein thrombosis)
|
Deep venous thrombosis
|
Pulmonary embolism
|
Provoked VTE
|
Unprovoked VTE
|
Splanchnic venous thrombosis
|
Cerebral venous thrombosis
|
Retinal venous thrombosis
|
|
All patients
|
1.09 (1.07–1.11)
|
1.22 (1.19–1.24)
|
1.15 (1.13–1.18)
|
1.13 (1.11–1.15)
|
1.10 (1.01–1.20)
|
1.19 (1.00–1.40)
|
1.12 (1.07–1.17)
|
|
Women
|
1.06 (1.03–1.09)
|
1.23 (1.20–1.27)
|
1.15 (1.11–1.18)
|
1.11 (1.08–1.14)
|
1.30 (1.10–1.53)
|
1.11 (1.00–1.38)
|
1.08 (1.01–1.15)
|
|
Men
|
1.13 (1.10–1.16)
|
1.20 (1.17–1.23)
|
1.16 (1.12–1.19)
|
1.16 (1.13–1.19)
|
1.17 (1.00–1.35)
|
1.12 (1.00–1.47)
|
1.15 (1.08–1.23)
|
|
Age groups, y
|
|
0–29
|
1.05 (1.00–1.14)
|
1.25 (1.11–1.40)
|
1.08 (1.00–1.22)
|
1.11 (1.03–1.19)
|
1.09 (1.00–1.75)
|
1.23 (1.00–1.67)
|
1.06 (1.00–1.78)
|
|
30–49
|
1.05 (1.01–1.10)
|
1.06 (1.00–1.13)
|
1.09 (1.02–1.16)
|
1.08 (1.04–1.12)
|
1.24 (1.00–1.60)
|
1.09 (1.00–1.50)
|
1.20 (1.01–1.42)
|
|
50–69
|
1.10 (1.07–1.13)
|
1.23 (1.19–1.27)
|
1.16 (1.12–1.21)
|
1.14 (1.11–1.18)
|
1.30 (1.09–1.54)
|
1.10 (1.00–1.52)
|
1.12 (1.04–1.20)
|
|
70+
|
1.17 (1.13–1.20)
|
1.25 (1.22–1.29)
|
1.17 (1.13–1.20)
|
1.23 (1.20–1.26)
|
1.04 (1.00–1.26)
|
1.11 (1.00–1.71)
|
1.10 (1.03–1.17)
|
|
Charlson Comorbidity Index score
|
|
0
|
1.13 (1.11–1.16)
|
1.25 (1.21–1.28)
|
1.22 (1.18–1.27)
|
1.16 (1.14–1.18)
|
1.10 (1.00–1.32)
|
1.16 (1.00–1.44)
|
1.09 (1.03–1.16)
|
|
1
|
1.08 (1.03–1.13)
|
1.20 (1.14–1.26)
|
1.11 (1.04–1.18)
|
1.11 (1.07–1.15)
|
1.27 (1.00–1.67)
|
1.19 (1.00–1.74)
|
1.16 (1.05–1.29)
|
|
2
|
1.03 (1.00–1.08)
|
1.17 (1.11–1.23)
|
1.12 (1.08–1.17)
|
1.05 (1.00–1.12)
|
1.01 (1.00–1.34)
|
1.07 (1.00–1.85)
|
1.07 (1.00–1.21)
|
|
3+
|
1.01 (1.00–1.06)
|
1.19 (1.14–1.25)
|
1.11 (1.06–1.15)
|
1.06 (1.00–1.14)
|
1.34 (1.01–1.63)
|
1.03 (1.00–1.82)
|
1.17 (1.03–1.33)
|
|
Calendar period
|
|
1977–1993
|
1.17 (1.13–1.21)
|
1.23 (1.20–1.28)
|
1.18 (1.14–1.22)
|
1.22 (1.18–1.26)
|
1.04 (1.00–1.21)
|
NA
|
NA
|
|
1994–2008
|
1.07 (1.04–1.11)
|
1.19 (1.15–1.24)
|
1.13 (1.09–1.17)
|
1.10 (1.07–1.13)
|
1.15 (1.00–1.37)
|
1.08 (1.00–1.36)
|
1.07 (1.01–1.14)
|
|
2009–2016
|
1.04 (1.01–1.08)
|
1.22 (1.18–1.26)
|
1.14 (1.10–1.18)
|
1.09 (1.05–1.12)
|
1.20 (1.04–1.39)
|
1.29 (1.01–1.65)
|
1.16 (1.08–1.23)
|
|
Type of diagnosis
|
|
Primary
|
1.09 (1.07–1.11)
|
1.22 (1.20–1.25)
|
1.15 (1.12–1.18)
|
1.13 (1.11–1.15)
|
1.12 (1.00–1.26)
|
1.10 (1.00–1.32)
|
1.11 (1.06–1.17)
|
|
Secondary
|
1.10 (1.06–1.15)
|
1.20 (1.16–1.24)
|
1.15 (1.11–1.19)
|
1.15 (1.11–1.19)
|
1.03 (1.00–1.18)
|
1.09 (1.00–1.57)
|
1.12 (1.02–1.24)
|
|
Department
|
|
Inpatient
|
1.10 (1.08–1.12)
|
1.22 (1.19–1.24)
|
1.15 (1.13–1.18)
|
1.14 (1.12–1.26)
|
1.04 (1.00–1.15)
|
1.20 (1.00–1.43)
|
1.05 (1.00–1.33)
|
|
Outpatient
|
1.08 (1.03–1.13)
|
1.23 (1.13–1.33)
|
1.18 (1.10–1.27)
|
1.09 (1.04–1.15)
|
1.23 (1.00–1.62)
|
1.06 (1.00–1.70)
|
1.11 (1.06–1.16)
|
|
Plasmode simulation[a]
|
1.05 (1.03–1.07)
|
1.09 (1.07–1.11)
|
1.06 (1.04–1.09)
|
1.06 (1.05–1.09)
|
1.05 (1.00–1.14)
|
1.13 (1.00–1.31)
|
1.07 (1.03–1.12)
|
Abbreviations: NA, not applicable; VTE, venous thromboembolism (deep venous thrombosis
and pulmonary embolism).
a Mean peak-to-trough ratio from random reassignment of monthly cases 1000 times.
Ethics
According to Danish legislation, informed consent and approval from an ethics committee
are not required for registry-based studies. The study was approved by the Danish
Data Protection Agency (2015-57-0002).
Results
We identified 101,895 patients with a first-time diagnosis of deep vein thrombosis,
84,080 with pulmonary embolism (of which 6,798 [8.1%] also had a concurrent diagnosis
of deep vein thrombosis), 3,972 with splanchnic vein thrombosis, 1,118 with cerebral
vein thrombosis, and 15,706 with retinal vein thrombosis. Among patients with deep
vein thrombosis or pulmonary embolism, 116,067 (62%) events were unprovoked. The median
age of patients with pulmonary embolism and retinal vein thrombosis (71 years) was
higher than for those with deep vein thrombosis (65 years), splanchnic vein thrombosis
(66 years), and cerebral vein thrombosis (45 years). The majority of cerebral vein
thrombosis patients were women (61%; [Table 1], [Supplementary Table S3]).
Table 3
Peak-to-trough ratios (95% confidence intervals) of summarized monthly deaths during
1977–2016 (within 90 days following deep vein thrombosis, pulmonary embolism, provoked
VTE, unprovoked VTE, and splanchnic vein thrombosis) and during 1994–2016 (within
90 days following cerebral vein thrombosis and retinal vein thrombosis)
|
Deep venous thrombosis
|
Pulmonary embolism
|
Provoked VTE
|
Unprovoked VTE
|
Splanchnic venous thrombosis
|
Cerebral venous thrombosis
|
Retinal venous thrombosis
|
|
All patients
|
1.15 (1.07–1.23)
|
1.04 (1.01–1.08)
|
1.05 (1.01–1.09)
|
1.22 (1.17–1.28)
|
1.08 (1.00–1.24)
|
1.31 (1.00–2.52)
|
1.05 (1.00–1.74)
|
|
Plasmode simulation[a]
|
1.06 (1.00–1.13)
|
1.04 (1.01–1.08)
|
1.03 (1.00–1.07)
|
1.10 (1.06–1.14)
|
1.09 (1.00–1.23)
|
1.14 (1.00–2.01)
|
1.04 (1.00–1.68)
|
Abbreviation: VTE, venous thromboembolism (deep venous thrombosis and pulmonary embolism).
a Mean peak-to-trough ratio from random reassignment of monthly deaths 1,000 times.
Seasonality in Occurrence
[Fig. 1] shows summarized monthly frequencies of occurrence during the entire study period
with a fitted sine curve ([Supplementary Table S4]). Overall, there was evidence of modest seasonal fluctuations: The peak-to-trough
ratios of the summaries were 1.09 (95% confidence interval [CI]: 1.07–1.11) for deep
vein thrombosis, 1.22 (95% CI: 1.19–1.24) for pulmonary embolism, 1.15 (95% CI: 1.13–1.18)
for provoked VTE, 1.13 (95% CI: 1.11–1.15) for unprovoked VTE, 1.10 (95% CI: 1.01–1.20)
for splanchnic vein thrombosis, 1.19 (95% CI: 1.00–1.40) for cerebral vein thrombosis,
and 1.12 (95% CI: 1.07–1.17) for retinal vein thrombosis ([Table 2]). The estimated day of peak occurrence was February 5 for deep vein thrombosis,
January 2 for pulmonary embolism, January 9 for provoked VTE, January 17 for unprovoked
VTE, October 22 for splanchnic vein thrombosis, October 25 for cerebral vein thrombosis,
and December 11 for retinal vein thrombosis.
Fig. 1 Summarized cases within each calendar month during 1977–2016 (occurrence of deep
vein thrombosis, pulmonary embolism, provoked venous thromboembolism, unprovoked venous
thromboembolism, splanchnic vein thrombosis) and 1994–2016 (occurrence of cerebral
vein thrombosis and retinal vein thrombosis), adjusted for the length of month with
a fitted sine curve and 95% confidence band.
Seasonality in 90-Day Mortality
During the entire study period, we identified 6,560 deaths within 90 days following
a deep vein thrombosis, 28,560 deaths following a pulmonary embolism, 18,429 deaths
following a provoked VTE, 16,691 deaths following an unprovoked VTE, 1,695 deaths
following a splanchnic vein thrombosis, 75 deaths following a cerebral vein thrombosis,
and 123 deaths following a retinal vein thrombosis ([Supplementary Table S5]). [Fig. 2] displays these monthly frequencies ([Supplementary Table S6]). Again, the seasonal fluctuations in mortality were modest, although some were
stronger than the patterns for VTE occurrence. For deep vein thrombosis, the peak-to-trough
ratio was 1.15 (95% CI: 1.07–1.23); for pulmonary embolism, 1.04 (95% CI: 1.01–1.08);
for provoked VTE, 1.05 (95% CI: 1.01–1.09); for unprovoked VTE, 1.22 (95% CI: 1.17–1.28);
for splanchnic vein thrombosis, 1.08 (95% CI: 1.00–1.24); for cerebral vein thrombosis,
1.31 (95% CI: 1.00–2.52); and for retinal vein thrombosis, 1.05 (95% CI: 1.00–1.74)
([Table 3]). The time of peak mortality was January 4 for deep vein thrombosis, February 1
for pulmonary embolism, December 2 for provoked VTE, January 29 for unprovoked VTE,
June 10 for splanchnic vein thrombosis, March 23 for cerebral vein thrombosis, and
November 6 for retinal vein thrombosis.
Fig. 2 Summarized deaths within each calendar month during 1977–2016 (within 90 days following
deep vein thrombosis, pulmonary embolism, provoked venous thromboembolism, unprovoked
venous thromboembolism, and splanchnic vein thrombosis) and 1994–2016 (within 90 days
following cerebral vein thrombosis and retinal vein thrombosis), adjusted for the
length of month with a fitted sine curve and 95% confidence band.
Bias Assessment
After randomly reassigning the summarized monthly frequencies in VTE occurrence, the
simulated mean peak-to-trough ratio for the entire study period was 1.05 (95% CI:
1.03–1.17) for deep vein thrombosis, 1.09 (95% CI: 1.07–1.11) for pulmonary embolism,
1.06 (95% CI: 1.04–1.09) for provoked VTE, 1.06 (95% CI: 1.06–1.09) for unprovoked
VTE, 1.05 (95% CI: 1.00–1.14) for splanchnic vein thrombosis, 1.13 (95% CI: 1.00–1.31)
for cerebral vein thrombosis, and 1.07 (95% CI: 1.03–1.12) for retinal vein thrombosis
([Table 2]).
Similarly, we randomly reassigned summarized monthly mortality counts. The mean simulated
peak-to-trough ratio was 1.06 (95% CI: 1.00–1.13) for deep vein thrombosis, 1.04 (95%
CI: 1.01–1.08) for pulmonary embolism, 1.03 (95% CI: 1.00–1.07) for provoked VTE,
1.10 (95% CI: 1.06–1.14) for unprovoked VTE, 1.09 (95% CI: 1.00–1.23) for splanchnic
vein thrombosis, 1.14 (95% CI: 1.00–2.01) for cerebral vein thrombosis, and 1.04 (95%
CI: 1.00–1.68) for retinal vein thrombosis ([Table 3]).
Additional Analyses
In subgroups of patients with a VTE diagnosis, the peak-to-trough ratio was comparable
for men and women for all VTE types. For deep vein thrombosis, provoked VTE, and unprovoked
VTE, the peak-to-trough ratio largely increased with age while it decreased with higher
Charlson Comorbidity Index scores. Conversely, for pulmonary embolism, splanchnic
vein thrombosis, cerebral vein thrombosis, and retinal vein thrombosis, the peak-to-trough
ratio did not fluctuate in any clear direction in these subgroups. Between 1977–1993
and 2009–2016, the peak-to-trough ratio decreased for deep vein thrombosis, but remained
stable for pulmonary embolism. For splanchnic vein thrombosis, the peak-to-trough
ratio increased considerably between calendar periods. A similar increasing trend
was observed for cerebral vein thrombosis and retinal vein thrombosis between calendar
periods. The peak-to-trough ratios were largely similar between primary/secondary
and inpatient/outpatient diagnoses ([Table 2]).
When we repeated the seasonal analyses with a log-linear Poisson regression model,
peak-to-trough ratios were similar ([Supplementary Table S7]).
Discussion
Our summary data for the 1977–2016 period showed that occurrence of VTE follows a
gentle seasonal pattern with a peak during winter, but with substantially different
excess risks in winter for deep vein thrombosis (9%) and pulmonary embolism (22%).
Seasonal risks were similar for provoked and unprovoked VTE. For splanchnic vein thrombosis,
cerebral vein thrombosis, and retinal vein thrombosis, the excess winter risk was
negligible during the first part of the study period and then increased. Excess winter
risks in mortality were higher following deep vein thrombosis (15%) than following
pulmonary embolism (4%).
Our findings are consistent in part with those of a 2011 meta-analysis of 12 studies
including 23,469 patients with either deep vein thrombosis or pulmonary embolism.
The meta-analysis reported a higher occurrence of VTE during winter, with a relative
risk of 1.14 (99% CI: 1.14–1.15).[8] However, most patients (n = 19,245, 82%) came from an Italian study[9] that found excess risks in winter based on hospital admissions for pulmonary embolism
in the Emilia Romagna region. It did not include a large American study[16] that showed little seasonality over a 21-year summary period based on hospital discharges
in the National Hospital Discharge Survey. Most,[10]
[11]
[12]
[13]
[14] but not all,[17] subsequent studies found similar findings to those from the meta-analyses. Of note,
a Danish study of 152,548 patients above 20 years of age with a first-time discharge
diagnosis of deep vein thrombosis or pulmonary embolism in the DNPR during 1980–2010
estimated a peak-to-trough ratio of 1.19 with a peak during winter.[12]
Our results support previous research suggesting that seasonality of VTE increases
at older ages.[11]
[14] Elderly patients have enhanced susceptibility to VTE due to respiratory tract infections
and the associated inflammatory state.[14] However, this relation is inconsistent with our finding that the peak-to-trough
ratio increased more markedly with age for unprovoked VTE compared with provoked VTE.
Thus, the cause of the apparent age dependence is not known.
In contrast to previous studies, we conducted a simulation analysis allowing us to
assess the degree of a seasonal pattern that chance might produce. Since the peak-to-trough
ratio, a common estimator of seasonality, is biased upward,[30] earlier research using this estimator may have overestimated the seasonal intensity.[8]
[11]
[12] After taking into consideration the results from our simulation analysis, we conclude
that any excess winter risks of deep vein thrombosis, splanchnic vein thrombosis,
cerebral vein thrombosis, and retinal vein thrombosis occurrence are modest at best.
In contrast, the excess risks of pulmonary embolism and provoked/unprovoked VTE occurrence
were marked enough to persist even after subtracting the effect of the estimation
bias. Thus, our findings demonstrate that deep vein thrombosis and pulmonary embolism
occurrence follow distinct seasonal patterns. It is possible that presentation with
an acute respiratory tract infection increased the probability of pulmonary embolism
detection during the winter. We believe, however, that this is an insufficient explanation
for the divergent seasonal risks between deep vein thrombosis and pulmonary embolism.
Moreover, our findings indicate that the timing of peak pulmonary embolism occurrence
precedes that of deep vein thrombosis occurrence. However, considering the uncertainty
in estimating the timing of these peaks, both peaks should be interpreted more broadly
as winter peaks.
We found comparable peak-to-trough ratios for provoked and unprovoked VTE occurrence,
suggesting that none of the provoking factors plays a substantial seasonal role. Although
the summary peak-to-trough ratios of splanchnic vein thrombosis, cerebral vein thrombosis,
and retinal vein thrombosis were minimal after consideration of bias, we found a considerable
secular trend for these conditions. Considering temporal improvements in diagnostic
imaging, the estimated peak-to-trough ratios found in the later part of the study
period may depict more accurately the seasonal pattern of these conditions.
We also examined the seasonality of monthly mortality counts. Previous studies on
seasonality of VTE mortality have focused on pulmonary embolism, with most reporting
peaks in winter.[33] Unexpectedly, in our study, the seasonal risks for deep vein thrombosis and pulmonary
embolism mortality differed considerably, both between conditions and compared with
the seasonal risks in occurrence. Indeed, the seasonal risks found for pulmonary embolism
mortality was negligible when considering bias, in contrast to previous findings.[33] Similarly, we found a substantial difference in seasonality between provoked VTE
and unprovoked VTE mortality despite similar seasonal risks in occurrence.
Ambient environmental conditions largely drive the seasonality of cardiovascular disease,
including any observed seasonal pattern in occurrence of VTE and associated mortality.[6] However, the precise mechanisms underlying this driving force are multifactorial
and unclear. Our findings suggest that any acute and chronic physiological changes
in response to ambient temperature lead to a clear seasonal pattern in occurrence
of pulmonary embolism but not in occurrence of deep vein thrombosis. Respiratory tract
infections may be involved in the pathogenesis of VTE, particularly pulmonary embolism,
due to local impairment of the coagulation cascade and associated systemic inflammation.
Such infections may constitute a link to any seasonal pattern in occurrence.[21]
Our estimates of seasonality in VTE occurrence are contingent on the validity of diagnoses
in the DNPR. Of note, a validation study found positive predictive values of 86 and
90% for diagnoses of first-time deep vein thrombosis and pulmonary embolism.[34] The diagnosis of retinal vein thrombosis in the DNPR is assumed to have high validity
because almost all patients are diagnosed at ophthalmologic departments.[35] While the splanchnic vein thrombosis and cerebral vein thrombosis diagnoses in the
DNPR have not yet been validated, most splanchnic vein thrombosis diagnoses are based
on an ultrasound examination or a computed tomography scan,[36] and it is unlikely that the validity of the cerebral vein thrombosis diagnosis diverges
greatly from that of other VTE diagnoses.
In this population-based study covering 40 years, we found that VTE occurrence follows
a seasonal pattern with a peak during winter. However, excess winter risks were marked
for pulmonary embolism occurrence and less so for deep vein thrombosis occurrence.
In contrast, we found pronounced seasonal risks in mortality within 90 days of a deep
vein thrombosis but negligible risks following a pulmonary embolism. For splanchnic
vein thrombosis, cerebral vein thrombosis, and retinal vein thrombosis occurrence,
seasonal risks increased steadily over the study period.
