Correlates and Consequences of Venous Thromboembolism: The Iowa Women's Health Study

Abstract

Objectives. We sought to document incidence, case-fatality, and recurrence rates of venous thromboembolism (VTE) in women and to explore the relationship of demographic, lifestyle, and anthropometric factors to VTE incidence.

Methods. Data from participants aged 55 to 69 years in the Iowa Women's Health Study were linked to Medicare data for 1986 through 2004 (n = 40 377) to identify hospitalized VTE patients.

Results. A total of 2137 women developed VTE, yielding an incidence rate of 4.04 per 1000 person-years. The 28-day case-fatality rate was 7.7%, and the 1-year recurrence rate was 3.4%. Educational attainment, physical activity, and age at menopause were inversely associated with VTE. Risk of secondary (particularly cancer-related) VTE was higher among smokers than among those who had never smoked. Body mass index, waist circumference, waist-to-hip ratio, height, and diabetes were positively associated with VTE risk. Hormone replacement therapy use was associated with increased risk of idiopathic VTE.

Conclusions. VTE is a significant source of morbidity and mortality in older women. Risk was elevated among women who were smokers, physically inactive, overweight, and diabetic, indicating that lifestyle contributes to VTE risk.

Deep vein thrombosis and pulmonary embolism, collectively referred to as venous thromboembolism (VTE), are major sources of morbidity and mortality.¹ Definition of the public health burden of this condition remains incomplete because VTE incidence, case-fatality, and recurrence rates have not been fully documented. Furthermore, few studies have prospectively evaluated risk factors for VTE.

Data from 41 836 participants enrolled in the Iowa Women's Health Study (IWHS), who have been followed for nearly 20 years, were recently linked to Medicare enrollment and claims data. This linkage allowed us to examine VTE incidence, case-fatality, and recurrence rates among elderly women and to explore the prospective association between demographic and lifestyle factors and VTE incidence. We hypothesized that VTE risk would be elevated among women who were older, less well-educated, obese, taller, and physically inactive, as well as among those who used hormone replacement therapy, were older at menopause, were of higher parity, or had diabetes. We predicted that no association would be observed with cigarette smoking. In addition, we hypothesized that risk factors would differ according to whether VTE was idiopathic (unprovoked) or secondary (associated with a comorbid clinical condition known to cause VTE).

METHODS

In January 1986, a demographic and health questionnaire was mailed to 99 826 Iowa women aged 55 to 69 years who were randomly sampled from the Iowa driver's license list. The 41 836 women who responded to this initial questionnaire made up the IWHS cohort. Nonresponse bias appeared to be small given the similar cancer and mortality rates among respondents and nonrespondents.²

A method employed previously³ was used to link the IWHS data to Centers for Medicare and Medicaid Services (CMS) enrollment and health care utilization data from 1986 through 2004. Medicare covers all or part of the health care expenses of most US residents 65 years or older,^4,5 and Medicare billing information is now used widely as a population-based data source for clinical events.⁶ Information about inpatient services, including discharge diagnosis codes, has been available since 1986. Of the IWHS cohort members surviving to the age of 65 years, 99% (40 668 of 40 997) were successfully linked to CMS data.

Sample

Medicare beneficiary enrollment information from the denominator file was used to determine eligibility for inclusion in our analytic sample. We included only participants who, since 1986, had been enrolled in at least 1 month of fee-for-service part A and part B Medicare coverage after reaching 65 years of age. People enrolling in Medicare at younger ages as a result of disability or end-stage renal disease were included in our analyses only after age 65 years. Person-years were excluded when participants were enrolled in managed care plans and when participants had only part A coverage, because these 2 groups were unlikely to have complete claims histories. After these restrictions, our analytic data set included 40 377 IWHS participants.

Baseline Exposure Assessment

The baseline questionnaire collected information on women's age, educational attainment, physical activity, smoking habits, height, weight, exogenous hormone use, reproductive history, and diabetes status. Women were categorized as current, former, or never smokers. Pack-years of smoking were calculated as average number of packs smoked per day multiplied by number of years smoked. Women reported their frequency of moderate (e.g., golf, long walks) and vigorous (e.g., swimming, aerobics) physical activities. Their responses to these questions were combined into a 3-level index of total physical activity (low, moderate, high).⁷ Women reporting use of estrogen or other female hormones (not including birth control) were classified as current or former hormone replacement therapy users, as appropriate. Only women reporting natural menopause were included in age-at-menopause analyses.

Waist and hip circumferences were calculated as the mean of 2 measurements taken by the participant's spouse or friend using a paper tape measure that was included in the questionnaire.⁸ Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared, and waist-to-hip ratio was calculated as waist circumference over hip circumference, both in centimeters.

Venous Thromboemolism Ascertainment

Previous work comparing VTE International Classification of Diseases (ICD) codes with medical records has shown that ICD codes are reasonably valid indicators of VTE hospitalization.^9–13 IWHS participants were considered to have had a VTE if any of the following VTE ICD-9 codes were included in their Medicare hospitalization discharge diagnosis records: 415.1x, 451.1x, 451.2, 451.81, 451.9, 453.0, 453.1, 453.2, 453.3, 453.4x, 453.8, and 453.9 (for code descriptions, see Supplemental Table 1, available as a supplement to the online version of this article at http://www.ajph.org).¹⁴ Information from Medicare outpatient or carrier records was not included.

Venous Thromboemolism Incidence, Case Fatality, and Recurrence

VTE incidence, defined as rate of initial VTE events after our Medicare enrollment inclusion criteria had been met, was computed using the number of participants with VTE as the numerator and using person-years at risk of VTE as the denominator. Person-years accumulated from the date participants met the enrollment criteria until the occurrence of VTE, death, fee-for-service part A or B disenrollment, or the end of December 2004. We did not have information on VTE history at baseline, and thus we were unable to exclude women with such a history from our analyses. We defined 28-day and 1-year case-fatality rates as the number of deaths from any cause within 28 days and 1 year, respectively, of VTE hospitalization divided by the number of incident VTE cases.

A recurrent event is one that occurs subsequent to, and is independent of, the incident event. We had no specific information about independence of events. Therefore, to distinguish index VTE events from recurrent VTE events, we required a 6-month lag period between the discharge date of the initial event and the admission date of the subsequent event. Cumulative recurrence (as a percentage) of VTE was calculated using the number of people with recurrences as the numerator and using the number of people with incident events as the denominator. In the case of recurrence rates, the numerator was the number of people with recurrences, and the denominator was person-years accrued since the incident event.

Idiopathic Versus Secondary Venous Thromboemolism

We used a methodology similar to that employed previously in an administrative data set to classify VTE cases as idiopathic or secondary.¹⁵ VTE was considered secondary if VTE hospitalization data indicated malignancy at the time of discharge (ICD-9 codes 140–209, with the exception of 173), surgery in the 3 months preceding a VTE diagnosis (surgery diagnosis-related group code), hospitalization of 4 or more days or trauma (ICD-9 codes 800–904.9) in the 2 months before the VTE, or a serious medical disease at the time of hospital discharge (e.g., heart failure, stroke, pneumonia). All remaining cases were classified as idiopathic.

Statistical Analysis

We calculated VTE incidence, case-fatality, and recurrence rates. Five-year age-specific incidence rates were calculated according to ages when events and person-years accrued (range: 65–88 years). Also, we used life-table methods to illustrate the recurrence of VTE across time.

We conducted Cox proportional hazards regression analyses to estimate VTE hazard ratios (HRs) and 95% confidence intervals (CIs) according to the level of each potential risk factor. Model 1 adjusted for age. Model 2 sought to determine whether associations were independent of BMI as well as age, educational attainment, smoking status, and physical activity. Hazard ratios were also estimated for incident idiopathic and secondary VTE. We tested the proportional hazards assumption by graphing log[−log(survival)] versus log(time). We assessed interactions of BMI and age with other risk factors using cross-product terms. SAS version 9.2 (SAS Institute Inc, Cary, NC) was used in conducting all analyses.

RESULTS

At baseline, the mean age of respondents was 61.8 years, and most respondents were White (99%) and married (77%). Women were, on average, aged 65.9 years when they met our Medicare enrollment inclusion criteria and began contributing person-years.

Incidence, Case-Fatality, and Recurrence Rates

Through 19 years of follow-up (median: 13 years), 2137 incident VTE events involving hospitalization occurred over 529 360 person-years (Table 1). The VTE incidence rate was 4.04 per 1000 person-years. Rates were 2.93 per 1000 person-years among women aged 65 to 69 years and 5.82 per 1000 person-years among those 85 years or older.

TABLE 1.

Venous Thromboembolism (VTE) Incidence Rates Over 19 Years of Follow-Up: Iowa Women's Health Study, 1986–2004

	No. of VTE Events	No. of Participants	No. of Person-Years	Rate per 1000 Person-Years
Overall	2137	40 377	529 360	4.04
Age group,a y
65–69	474	39 825	161 622	2.93
70–74	684	37 906	179 364	3.81
75–79	612	32 182	122 927	4.98
80–84	309	17 295	55 479	5.57
≥ 85	58	5 577	9 968	5.82
VTE categoryb
Pulmonary embolism	824	39 064	518 344	1.59
Deep vein thrombosis	1559	39 779	524.353	2.97
VTE type
Idiopathic	463	38 703	514 897	0.90
Secondary (all)	1674	39 914	525 562	3.19
Cancer-related	444	38 684	514 682	0.86
Non–cancer-related	1230	39 470	521 979	2.37

^aStratified according to ages when events and person-years accrued (not baseline age).

^bPulmonary embolism and deep vein thrombosis were concurrent in 246 women.

Among incident VTE cases, 21.7% (n = 463) were classified as idiopathic and 78.3% (n = 1674) as secondary. Approximately 76% of participants with secondary VTE underwent a surgical procedure within the 3 months preceding their VTE, 34.8% were hospitalized 4 days or longer and 7.9% experienced trauma within the 2 months preceding their VTE, and 26.5% had cancer at the time of their VTE hospital discharge. Of the remainder, 12.3% were classified as having secondary VTE as a result of the presence of other serious medical conditions. The percentage of cases categorized as idiopathic decreased linearly with increasing participant age, from 23.0% between the ages of 65 and 69 years to 17.2% after the age of 85 years (data not shown).

The 28-day case-fatality rate after a VTE was 7.7%, whereas the 1-year rate was 22.3% (Table 2). Women experiencing cancer-related VTE had the highest case-fatality rates, those with a secondary non-cancer-related VTE had intermediate rates, and those with idiopathic VTE had the lowest rates. In a Cox model, idiopathic VTE (as a time-dependent covariate) was associated with a 72% (95% CI = 63%, 81%) increased mortality rate. Case fatality increased linearly with age. Among women aged 65 to 69 years, 28-day and 1-year case-fatality rates were 5.5% and 19.4%, respectively; the corresponding rates among women aged 85 years or older were 13.7% and 27.6% (data not shown).

TABLE 2.

Venous Thromboembolism (VTE) Case-Fatality Rates Among Women Experiencing an Incident VTE Event, by VTE Category and Type: Iowa Women's Health Study, 1986–2004

	No. of Deaths	No. of VTE Events	Case-Fatality Rate, %
VTE category
Overall
28 d	164	2137	7.7
1 y	477	2137	22.3
Pulmonary embolism
28 d	99	824	12.0
1 y	217	824	26.3
Deep vein thrombosisa
28 d	65	1313	5.0
1 y	260	1313	19.8
VTE type
Idiopathic
28 d	5	463	1.1
1 y	17	463	3.7
Secondary (all)
28 d	159	1674	9.5
1 y	460	1674	27.4
Secondary VTE type (all)
Cancer-related
28 d	71	444	16.0
1 y	241	444	54.3
Non–cancer-related
28 d	88	1230	7.2
1 y	219	1230	17.8

^aDeep vein thrombosis only; women with both deep vein thrombosis and pulmonary embolism were grouped in the pulmonary embolism category.

In the 6 to 12 months after the incident event, the cumulative VTE recurrence rate was 3.4% (Table 3). Recurrence rates were 3.3% among women initially presenting with idiopathic VTE, 5.7% among those with secondary cancer-related VTE, and 2.8% among those with secondary non-cancer-related VTE. As depicted in Figure 1, the 15-year cumulative risk of recurrence also varied according to VTE type, but differences narrowed over time since VTE.

TABLE 3.

Cumulative Venous Thromboembolism (VTE) Recurrence Among Women Experiencing an Incident VTE Event, by VTE Type: Iowa Women's Health Study, 1986–2004

Recurrenceb	No. of Recurrent VTE Events	No. of VTE Eventsa	Cumulative IR, %
VTE type
All VTE types, y
1	58	1691	3.4
2	119	1691	7.0
Idiopathic, y
1	16	430	3.7
2	30	430	7.0
Secondary, y
1	42	1261	3.3
2	89	1261	7.1
Secondary VTE type (all)
Cancer-related, y
1	14	244	5.7
2	30	244	12.3
Non–cancer related, y
1	28	1017	2.8
2	59	1017	5.8

Note. IR = incidence rate.

^aGiven the 6-month lag period required to define recurrence, only VTE patients not censored within the first 6 months after their incident event were eligible to have experienced a recurrent event (446 patients were censored, 366 who died and 80 who were no longer enrolled).

^bA 6-month lag period was required between the discharge date of the incident event and the admission date of the subsequent event to distinguish index events from recurrent events.

FIGURE 1.

Cumulative incidence of recurrent venous thromboembolism (VTE) during 15 years of follow-up, by type of VTE: Iowa Women's Health Study, 1986–2004.

Note. For log rank test: χ² = 13.0; P = .002. A 6-month lag period was required between the discharge date of the incident event and the admission date of the subsequent event to distinguish index from recurrent events. After 7.5 years of follow-up, there was no recurrent VTE among the 31 surviving women with cancer-associated VTE.

Exposure Analyses

Adjusted HRs for risk of incident VTE, by selected characteristics, are shown in Table 4. After multivariate adjustment, participants who had at least a high school education were at 15% lower risk of VTE than their counterparts without a high school education.

TABLE 4.

Hazard Ratios for Incident Venous Thromboembolism (VTE) Among Women Aged 65 Years or Older (n = 40 377), by Demographic, Lifestyle, and Physiological Characteristics: Iowa Women's Health Study, 1986–2004

			HR (95% CI)
	No. of VTE Events (n = 2137)	No. of Person-Years	Model 1	Model 2
Demographic and lifestyle characteristics
Education
< High school (Ref)	507	103 648	1.00	1.00
High school	846	219 164	0.80 (0.71, 0.89)	0.84 (0.75, 0.94)
> High school	779	205 061	0.78 (0.70, 0.87)	0.87 (0.77, 0.97)
Smoking status
Never smoker (Ref)	1389	355 358	1.00	1.00
Former smoker	446	99 330	1.17 (1.05, 1.30)	1.18 (1.06, 1.31)
Current smoker	267	66 457	1.08 (0.94, 1.23)	1.19 (1.04, 1.36)
Pack-years of smokinga
0 (Ref)	1389	355 358	1.00	1.00
1–19	279	68 607	1.06 (0.93, 1.21)	1.10 (0.97, 1.26)
20–39	234	53 446	1.16 (1.01, 1.33)	1.24 (1.08, 1.42)
≥ 40	184	39 564	1.24 (1.06, 1.44)	1.27 (1.08, 1.48)
Physical activity level
Low (Ref)	1045	237 247	1.00	1.00
Moderate	552	146 975	0.84 (0.76, 0.93)	0.91 (0.82, 1.01)
High	483	133 842	0.81 (0.72, 0.90)	0.91 (0.82, 1.02)
Anthropometric factors
BMI, kg/m2
< 25 (Ref)	589	209 358	1.00	…
25–29	821	198 585	1.46 (1.32, 1.63)	…
≥ 30	727	121 416	2.14 (1.92, 2.38)	…
Waist circumference, cm
Lowest tertile (Ref)	459	173 578	1.00	1.00
Middle tertile	676	181 895	1.39 (1.24, 1.57)	1.22 (1.08, 1.39)
Highest tertile	993	172 091	2.18 (1.95, 2.43)	1.53 (1.31, 1.78)
Waist-to-hip ratio
Lowest tertile (Ref)	547	174 876	1.00	1.00
Middle tertile	715	177 456	1.28 (1.14, 1.43)	1.10 (0.98, 1.23)
Highest tertile	866	174 946	1.57 (1.41, 1.75)	1.14 (1.01, 1.28)
Hip circumference, cm
Lowest tertile (Ref)	451	180 612	1.00	1.00
Middle tertile	671	171 794	1.56 (1.38, 1.76)	1.41 (1.24, 1.60)
Highest tertile	1007	175 018	2.31 (2.07, 2.58)	1.73 (1.48, 2.02)
Height, in
≤ 62 (Ref)	462	144 438	1.00	1.00
63–65	1465	344 550	1.34 (1.21, 1.49)	1.42 (1.27, 1.58)
≥ 66	210	40 371	1.66 (1.41, 1.96)	1.82 (1.54, 2.16)
HRT use and reproductive history
HRT use
Never (Ref)	1264	321 016	1.00	1.00
Former	641	150 122	1.07 (0.97, 1.18)	1.09 (0.99, 1.20)
Current	224	55 659	1.04 (0.90, 1.20)	1.16 (1.00, 1.34)
Parity
Nulliparous (Ref)	219	49 180	1.00	1.00
1–2	694	175 705	0.89 (0.76, 1.04)	0.90 (0.77, 1.05)
3–4	798	205 724	0.89 (0.76, 1.03)	0.86 (0.74, 1.00)
≥ 5	412	95 245	1.00 (0.85, 1.18)	0.90 (0.76, 1.07)
Age at menopause,b y
< 45 (Ref)	141	30 285	1.00	1.00
45–49	296	77 519	0.82 (0.67, 1.00)	0.84 (0.68, 1.03)
50–54	576	150 139	0.82 (0.69, 0.99)	0.83 (0.69, 1.01)
≥ 55	169	47 308	0.76 (0.60, 0.94)	0.74 (0.59, 0.93)
Self-reported diabetes
No (Ref)	1961	499 594	1.00	1.00
Yes	176	29 766	1.54 (1.32, 1.79)	1.22 (1.04, 1.44)

Note. BMI = body mass index; CI = confidence interval; HR = hazard ratio; HRT = hormone replacement therapy. Model 1 adjusted for age. Model 2 adjusted for age, education, smoking status, physical activity, and BMI (continuous).

^aNot adjusted for smoking status.

^bWomen reporting natural menopause only.

As compared with never smokers at baseline, current and former smokers had a nearly 20% increased risk of VTE. The association was restricted to those with secondary VTE (Supplemental Table 2, available as a supplement to the online version of this article at http://www.ajph.org), and secondary cancer-related VTE drove the association. Hazard ratios for cancer-related VTE were 1.27 (95% CI = 0.96, 1.67) among current smokers and 1.30 (95% CI = 1.02, 1.66) among former smokers. Corresponding HRs among those with secondary non-cancer-related VTE were 1.16 (95% CI = 0.97, 1.40) and 1.00 (95% CI = 0.87, 1.17). Likewise, increasing numbers of pack-years of smoking were associated with an increased risk of secondary VTE, a finding largely explained by cancer-related VTE.

As can be seen in Table 4, physical activity level was inversely related to VTE risk after adjustment for age. Adjustment for BMI in model 2 attenuated the inverse association between physical activity and VTE.

Anthropometric factors were strongly related to VTE risk (Table 4). Relative to women with a normal BMI (below 25 kg/m²), HRs were 1.46 (95% CI = 1.32, 1.63) for overweight women (a BMI of 25–30 kg/m²) and 2.14 (95% CI = 1.92, 2.38) for obese women (a BMI of 30 kg/m² or above). Independent of BMI (after model 2 adjustments), waist circumference, waist-to-hip ratio, and hip circumference were all positively and monotonically associated with VTE risk. Greater height was also positively associated with incident VTE. Anthropometric HRs were similar for idiopathic and secondary VTE (data not shown).

Hormone replacement therapy use at baseline was associated with an increased risk of idiopathic VTE (HR = 1.62; 95% CI = 1.22, 2.14), whereas no relationship was observed with secondary VTE (Supplemental Table 2). A modest inverse relationship was observed between age at menopause and incident VTE. Former hormone replacement therapy use and parity were not related to VTE risk.

Self-reported diabetes was positively related to VTE incidence (Table 4). The HR was 1.54 (95% CI = 1.32, 1.79) before adjustment for BMI. Additional adjustment for BMI, however, attenuated the association (HR = 1.22; 95% CI = 1.04, 1.44). No interactions of BMI or age with demographic, lifestyle, and anthropometric factors were observed.

In additional analyses, we restricted our sample to women aged 65 to 69 years at baseline, whose exposure information was collected when they were eligible to enroll in Medicare and thus begin contributing person-years. Results were similar to those of the entire cohort.

DISCUSSION

In this prospective study of older White women, the incidence rate (IR) of VTE was approximately 4 per 1000 person-years; 28-day and 1-year (all-cause) case-fatality rates were 7.7% and 22.3%, respectively. VTE risk was elevated among women who were older, taller, diabetic, as well as those with higher BMIs, waist circumferences, waist-to-hip ratios, and hip circumferences. Use of hormone replacement therapy was associated with an increased risk of idiopathic VTE, and smoking was associated with a higher risk of secondary cancer-related VTE. Higher educational attainment and physical activity levels and older age at menopause were associated with lower VTE risk, whereas parity was not related to VTE risk.

The VTE incidence rate we observed and the doubling of VTE risk between the ages of 65 and 85 years are consistent with previous findings.^9,12,16–20 Both coagulation factor levels²¹ and the prevalence of acquired risk factors (e.g., surgery, cancer) typically increase with age.²² In the IWHS, 22% of incident VTE cases were classified as idiopathic, a percentage similar to that found in a study conducted in Olmsted County, Minnesota (26%).²³ It is, however, lower than that observed in the Longitudinal Investigation of Thromboembolism Etiology (48%),⁹ which reviewed individual medical records to determine whether provoking factors were present. Our method of classifying VTE cases as idiopathic was conservative, and some misclassification certainly occurred in the absence of medical record reviews, which may explain the relatively lower proportion of idiopathic VTE in this study.

We observed substantial all-cause case-fatality rates of 8% at 28 days and 22% at 1 year. Rates were highest among women with cancer-related VTE, with 28-day and 1-year case-fatality rates of 16% and 54%, respectively. Other studies have identified cancer patients with VTE to be at an exceptionally elevated risk of mortality.^9,24–27 These individuals may be immobile as a result of their cancer or may have a thrombotic diathesis owing to the cancer or its treatment.

In the 6 months to 1 year after their incident VTE, 3.4% of participants experienced a recurrent event. This probability was further elevated (5.7%) among women with cancer-related VTE, as has been observed previously.^25,28,29 Although this rate may appear small, the cumulative risk of recurrence during 15 years of follow-up was 34%, similar to previously published cumulative risk estimates of long-term VTE recurrence.^28,30 These results indicate that VTE recurs frequently and continues to recur long after the incident event.

Level of educational attainment appeared to be predictive of VTE, with a threshold relationship in which participants who had earned a high school diploma or completed a higher level of education appeared to be at lower risk of VTE. Educational attainment serves as a surrogate for socioeconomic status, may reflect increased health knowledge and comprehension,³¹ and is inversely related to levels of physical activity and risk of obesity.³² Adjustment for physical activity and obesity, however, did not greatly attenuate the association between education and VTE.

IWHS participants who were current or former smokers at baseline were at increased risk of developing secondary VTE, a result driven by those with cancer-related VTE. Previous literature on the topic of smoking and VTE is inconclusive. Two prospective studies^33,34 and one case–control study³⁵ showed that smoking is a VTE risk factor, whereas numerous other case–control^36–38 and prospective^39,40 studies have revealed no associations. It is possible that prior studies may have had inadequate power to detect an association of this modest magnitude. Etiologically, one would expect smoking to elevate VTE risk given that smoking increases blood coagulability and impairs endothelial function and fibrinolysis.⁴¹ Our finding that the association between smoking and VTE was driven by cancer-related VTE is novel. One possible explanation for this result is that smoking increases cancer risk, which in turn increases VTE risk by activating the coagulation system.^42,43

Physical activity level was inversely related to VTE, but not after adjustment for BMI. Because it is likely that BMI resides on the causal pathway between physical activity and VTE, the observed attenuation by BMI is not surprising. Previous research on the relationship between physical activity and VTE is inconclusive, with 2 studies reporting a positive association,^36,44 1 reporting an inverse association,⁴⁵ and another reporting no association.³⁹

Consistent with earlier research,^39,46 BMI was positively and monotonically associated with VTE risk. Women categorized as obese were at a 2-fold higher risk of VTE than those with normal BMIs. Abdominal obesity, assessed via waist circumference or waist-to-hip ratio, was positively associated with VTE risk after control for BMI. Because it is associated with venous stasis, venous damage and varicosity,³⁹ and a prothrombogenic profile,⁴⁷ obesity may increase VTE risk. Height was positively associated with VTE, as has been observed elsewhere³⁶; it may be that taller individuals are at greater risk of VTE because they have longer veins and thus more area where a thrombosis could occur.

Hormone replacement therapy use at baseline was associated with a 62% increased risk of idiopathic VTE but was not related to secondary VTE. Researchers in both the Women's Health Initiative and the Heart and Estrogen/Progestin Replacement Study trials concluded that hormone replacement therapy use is associated with elevated VTE risk.^48,49 Our findings corroborate those of the Women's Health Initiative, in that most of the excess risk associated with hormone replacement therapy was due to a greater risk of idiopathic VTE.⁴⁸

Our data failed to replicate the results of a recent case–control study that identified older age at menopause and higher parity as risk factors for VTE.⁵⁰ In the IWHS, age at menopause was inversely associated with VTE risk, whereas parity was unrelated. The age at menopause finding was unexpected given that increased lifetime exposure to endogenous estrogen is hypothesized to increase VTE risk.⁵⁰

In this study, self-reported diabetes was associated with a 54% increased risk of VTE after basic adjustments. Adjustment for BMI attenuated the association, although it remained significant, suggesting that some of the association might have been due to a greater prevalence of obesity among participants with diabetes. Given that diabetes is associated with a hypercoagulable state, it would be expected to increase VTE risk.^51,52 However, previous findings are ambiguous, with some studies identifying diabetes as a relatively strong risk factor^36,39,53 and others reporting no association.^20,33,37

Study Limitations and Strengths

Several limitations of our study should be noted. First, the generalizability of our findings is limited because only older White women were included in the study. Second, the baseline questionnaire did not ask about past VTE history; thus, it was not possible to exclude women with prior VTE from our incidence rate data. Third, up to 10 years passed between when baseline exposure information was collected from the youngest IWHS participants and when they were eligible to enroll in Medicare and begin contributing person-years to our analyses. Restricting the analyses to women aged 65–69 years at baseline, however, yielded similar results.

Akin to virtually all other studies focusing on VTE, including those in which medical records have been reviewed, our case-finding strategy identified cases of clinically apparent VTE that were detected through the medical care system but did not identify any other cases. Over most of the follow-up period (1986–2004), VTE was treated in inpatient settings⁵⁴ and would therefore be captured in hospitalization file discharge diagnosis ICD-9 codes, which we used to define VTE. Previous work comparing VTE ICD-9 diagnosis codes derived from administrative data with medical records has shown that codes from administrative data are reasonably valid indicators of VTE hospitalizations.^9–13 Furthermore, our age-specific incidence rates were similar to those observed previously,^9,12,16–20 suggesting that our VTE definition is legitimate. However, some drawbacks of not reviewing individual medical records do exist, including potential misclassification between idiopathic and secondary VTE and an inability to clearly define recurrences.

Strengths of this study are the prospective design, large sample size, and successful CMS linkage. Most previous studies exploring the relationship of the exposures studied here to VTE have been case–control investigations, which are prone to recall bias. Those that have been prospective have often had limited power to detect effects. In these IWHS data 2137 incident VTE events accrued, granting us power not only to assess the relationship of exposures to VTE overall but also to explore the effects of exposures on VTE subtypes. The study's long follow-up also allowed us to document long-term risk of VTE recurrence, adding to the limited literature on that topic. Last, linkage to the CMS data allowed us to efficiently follow virtually all IWHS participants for VTE events.

Conclusions

We found that, in a reasonably healthy, older female population, the VTE incidence rate was more than 4 per 1000 person-years, the 28-day case-fatality rate was 7.7%, and the 15-year cumulative risk of recurrence was 34%. Our data thus highlight the significant morbidity and mortality associated with VTE in older persons. Although much VTE risk is perceived to be the consequence of nonmodifiable risk factors,⁵⁵ these data provide a spotlight on several modifiable VTE risk factors that might be potential intervention targets. Specifically, our results suggest that the burden of VTE may be reduced through participation in a healthful lifestyle, one that includes being physically active, avoiding overweight, and not smoking.