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doi:10.1182/blood-2011-05-357343Prepublished online September 2, 2011;2011 118: 4992-4999

Melton IIIJohn A. Heit, Brian D. Lahr, Tanya M. Petterson, Kent R. Bailey, Aneel A. Ashrani and L. Josephpopulation-based cohort studyrecurrence after deep vein thrombosis or pulmonary embolism: aHeparin and warfarin anticoagulation intensity as predictors of

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THROMBOSIS AND HEMOSTASIS

Heparin and warfarin anticoagulation intensity as predictors of recurrence afterdeep vein thrombosis or pulmonary embolism: a population-based cohort study

John A. Heit,1,2 Brian D. Lahr,3 Tanya M. Petterson,3 Kent R. Bailey,3 Aneel A. Ashrani,2 and L. Joseph Melton III4

1Division of Cardiovascular Diseases (Section of Vascular Diseases) and 2Division of Hematology (Section of Hematology Research), Department of Internal

Medicine, and3

Division of Biomedical Statistics and Informatics and4

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic,Rochester, MN

To test recommended anticoagulation

measures as predictors of 180-day ve-

nous thromboembolism (VTE) recurrence,

we identified all Olmsted County, MN resi-

dents with incident VTE over the 14-year

period of 1984-1997, and followed each

case (N 1166) forward in time for VTE

recurrence. We tested the activated par-

tial thromboplastin time (APTT), interna-

tional normalized ratio (INR), and other

measures of heparin and warfarin antico-agulation as predictors of VTE recurrence

while controlling for baseline and time-

dependent characteristics using Cox pro-

portional hazards modeling. Overall,

1026 (88%) and 989 (85%) patients re-

ceived heparin and warfarin, respectively,

and 85 (8%) developed VTE recurrence. In

multivariable analyses, increasing propor-

tions of time on heparin with an APTT

> 0.2 anti-Xa U/mL and on warfarin with

an INR> 2.0 were associated with signifi-

cant reductions in VTE recurrence, while

the hazard with active cancer was signifi-cantly increased. Time from VTE onset to

heparin start, duration of overlapping hep-

arin and warfarin, and inferior vena cava

(IVC) filter placement were not indepen-

dent predictors of recurrence. At a hepa-

rin dose> 30 000 U/d, the median propor-

tion of time with an APTT > 0.2 anti-Xa

U/mL was 92%, suggesting that routine

APTT monitoring and heparin dose adjust-

ment may be unnecessary. In summary,

lower-intensity heparin and standard-

intensity warfarin anticoagulation are ef-

fective in preventing VTE recurrence.(Blood. 2011;118(18):4992-4999)

Introduction

Heparin is recommended as the initial treatment for acute deep vein

thrombosis (DVT) and pulmonary embolism (PE)1 because such

therapy improves survival after PE,2 and reduces asymptomatic

DVT extension and possibly 3-month VTE recurrence.3 Activated

partial thromboplastin time (APTT) monitoring and heparin dose

adjustment to rapidly achieve and maintain an APTT therapeutic

range corresponding to a plasma heparin level of 0.3-0.7 anti-XaU/mL is also recommended.1,4 The College of American Patholo-

gists, the British Committee for Standards in Haematology, and theAmerican College of Chest Physicians (ACCP) have recommended

procedures to identify the laboratory-specific APTT therapeutic

range,1,4-6 and heparin therapy nomograms have been developed to

achieve this heparin level.7

Despite these recommendations, several important issues regard-

ing unfractionated heparin (UFH) therapy remain unresolved,

including the minimal time to achieve a therapeutic APTT after

starting heparin therapy,7-11 the optimal intensity of heparin

therapy,7,10,12,13 the required duration of heparin and warfarin

therapy overlap,14-16 and the effect of these anticoagulation

measures on VTE recurrence after controlling for other predictors

of recurrence.17,18 These issues remain clinically relevant because

UFH continues to be preferred over low-molecular-weight heparintherapy for patients with acute PE, high bleeding risk, or impaired

renal function.19,20 Moreover, the Joint Commission performance

measures on heparin anticoagulation management,21 based largely

on ACCP recommendations, prompted many hospitals to establish

time-consuming and costly pharmacy- and/or nurse-staffed ser-

vices solely devoted to heparin monitoring and dose adjustment.

Whereas a warfarin anticoagulation intensity international normal-

ized ratio (INR) 2.0-3.0 is superior to lower intensity(ie, INR 1.5-1.9) or no anticoagulation as secondary prophylaxis

for idiopathic VTE,22,23 only 2 small studies have addressed the

optimal intensity of warfarin anticoagulation for acute VTE therapy:

The first reported no INR,24 and the second was limited to idiopathic

VTE.25 Therefore, the most appropriate intensity of warfarin

anticoagulation for overall acute VTE therapy remains uncertain.To address these important gaps in knowledge, we performed a

large, population-based cohort study to test heparin anticoagulation

intensity4,12 as a predictor of 180-day VTE recurrence after

controlling for other baseline characteristics previously identified

as independent predictors of VTE recurrence.17 In addition, we

tested time from symptomatic VTE onset to start of heparin

therapy, rapid achievement of a therapeutic APTT, and the duration

of overlapping heparin and warfarin therapy as predictors of

recurrence. Finally, we explored the effect of a higher proportion of

time spent above several different therapeutic thresholds of

heparin and warfarin anticoagulation on VTE recurrence.

Methods

Study setting and design

Using the unique resources of the Rochester Epidemiology Project (REP),26

we identified the inception cohort of all Olmsted County, MN residents with

Submitted May 27, 2011; accepted August 22, 2011. Prepublished online as

BloodFirst Edition paper, September 2, 2011; DOI 10.1182/blood-2011-05-357343.

The online version of this article contains a data supplement.

The publication costs of this article were defrayed in part by page charge

payment. Therefore, and solely to indicate this fact, this article is hereby

marked advertisement in accordance with 18 USC section 1734.

2011 by The American Society of Hematology

4992 BLOOD, 3 NOVEMBER 2011 VOLUME 118, NUMBER 18

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incident DVT and PE over the 35-year period 1966-2000, as described

previously.27,28 The REP medical records linkage system affords access to

comprehensive details regarding all medical care provided to local residents

for their entire period of residence in the community. The REP exists

because: (1) Olmsted County is isolated from other urban centers, (2) unit

patient medical records that combine all inpatient and outpatient data for

each resident have been preserved since 1910, and (3) indexes to diagnoses,

surgical procedures, and test results have provided access to the patients of

interest since 1935. The result is linkage of individual level medical datafrom all sources of medical care available to and used by the population of

Olmsted County, thus ensuring complete ascertainment of all clinically

recognized VTE events and outcomes.

For this study, we restricted our analyses to residents with incident VTE

over the 14-year period 1984-1997 who lived at least 1 day after the

incident VTE event (N 1166). We started the study time period in

1984 because laboratory data were retrievable electronically beginning in

1983. We ended the time period in 1997 because standard heparin was

solely used as initial VTE therapy until 1998 (when low-molecular-weight

heparin therapy became available) and our study aim was to address the

effect of UFH therapy. We followed each patient from the onset of incident

VTE symptoms or signs forward in time using their complete (inpatient and

outpatient) medical records in the community for first DVT or PE

recurrence as defined previously.17,28 Recurrent VTE was defined as venous

thrombosis of a site that was either previously uninvolved or had interval

documentation of incident DVT or PE resolution. For deceased patients, all

death certificates and autopsy reports were reviewed regardless of the

location at death. The study was approved by the Mayo Clinic and the

Olmsted Medical Center institutional review boards.

Measurements

Using explicit criteria, trained and experienced nurse abstractors reviewed

all medical records in the community for consenting cases from date first

seen by an REP health-care provider until the earliest of death, date of last

medical record follow-up, or 2000 as performed previously.29,30 Data were

collectedon date andtype of incident VTE, baseline characteristics, dates of

heparin and warfarin initiation and completion, total daily heparin dose,

inferior vena cava (IVC) filter placement, date and type of first VTErecurrence, bleeding events, and vital status at last clinical contact, as

described in detail elsewhere.17,29,30 Baseline characteristics included

hospitalization for surgery (general, orthopedic or gynecologic surgery,

neurosurgery) requiring anesthesia (general or neuraxial); hospitalization

for acute medical illness; nursing home confinement; trauma and/or fracture

requiring hospital admission (major fracture or severe soft tissue injury);

active cancer (excluding nonmelanoma skin cancer) with or without

chemotherapy (cytotoxic or immunosuppressive therapy for malignancy,

excluding tamoxifen); serious neurologic disease (stroke or other disease

affecting the nervous system with associated extremity paresis or acute

stroke with extremity paresis requiring hospitalization within the previous

3 months); for women only: pregnancy or postpartum (within 3 months of

delivery) at the time of the incident event, oral contraceptive use, and

hormone therapy (estrogen or progesterone); congestive heart failure;

chronic lung disease (chronic obstructive pulmonary disease, emphysema,chronic bronchitis, bronchiectasis, interstitial lung disease, pulmonary

hypertension, and asthma included only if documented evidence of fixed

airflow obstruction); chronic liver disease (including active hepatitis within

the previous 3 months); and chronic renal disease (physicians diagnosis

and creatinine 175 mol/L [2 mg/dL] for at least 3 months, or nephrotic

syndrome). The characteristics related to hospitalization for surgery or

acute medical illness, nursing home confinement, trauma/fracture, pregnancy/

postpartum state, and oral contraceptive or hormone therapy were recorded

as present only if documented within the 3 months before the VTE event.

Active cancer had to be documented in the 3 months before or after the

incident VTE event. All other characteristics were recorded as present if

documented any time before the incident VTE event. Major bleeding was

defined as CNS, intraocular, mediastinal, pericardial, or retroperitoneal

bleeding or visible bleeding with a 20 g/L hemoglobin decrement or

2 blood product units transfusion. We also retrieved all complete blood

count (CBC), APTT, and prothrombin time (PT)/INR values from the Mayo

Clinic Laboratory Information System.

Over the course of the 14-year study period, the 2 successive APTT

reagent and coagulometer instrument combinations used were highly

correlated (r2 0.949), as were APTT reagent lot-to-lot comparisons. The

target APTT was derived by comparison with chromogenic anti-Xa levels,

as recommended previously.4-6 An APTT threshold of 58 seconds

(corresponding to a plasma heparin level 0.3 anti-Xa U/mL) was used in

the primary analysis of heparin therapy on VTE recurrence, and thresholdsof 40, 70 or 90 seconds (corresponding to plasma heparin levels

0.2, 0.5, or 0.9 anti-Xa U/mL, respectively) were tested in secondary

analyses.

Analyses

Descriptive statistics were used to summarize the demographic and clinical

characteristics of the cohort, including counts and percentages for categori-

cal data and Kaplan-Meier rates for survival outcomes (cumulative

incidence) such as VTE recurrence and major bleeding. For continuous

data, means and standard deviations and/or medians along with ranges or

interquartile ranges are reported. For formal comparisons of 2 or more

groups, such as subjects who did versus did not receive any heparin during

their 180-day follow-up, ANOVA methods (t test if only 2 groups) and

2

tests were used for continuous and categorical variables, respectively.Using Cox proportional hazards (PH) modeling, we tested demo-

graphic, baseline, and time-dependent characteristics as potential predictors

of the rate of VTE recurrence from 1-180 days. Demographic and baseline

characteristics included patient age and body mass index (BMI) at the

incident VTE event and sex, active cancer, neurologic disease with leg

paresis, and neurosurgery within 3 months before the incident VTE event.17

In addition, we created a baseline characteristic termed idiopathic VTE,

as defined previously.30

A time-dependent structure of the data was used to account for variables

that changed over time, including hemoglobin, platelet count, APTT, PT,

and INR. For hemoglobin and platelet count, the daily average was used if

assayed more than once per day. In addition, the presence or absence of

heparin or warfarin therapy were assessed as time-dependent covariates, as

were time from onset of VTE symptoms to start of heparin therapy and

duration of overlapping therapy with heparin and warfarin. Using all dailymeasurements, we calculated the cumulative proportions of time spent with

an APTT 58, 40, 70, and 90 seconds during heparin treatment,

and the cumulative proportions of time spent with an INR 1.5 and

2.0 during warfarin treatment. A complete description of the time

dependent variables is provided in the supplementalAppendix (available on

the BloodWeb site; see the Supplemental Materials link at the top of the

online article).

All variables were initially tested for an association with rate of VTE

recurrence in univariate Cox PH models. Those variables demonstrating a

univariate association with at least marginal significance (P .10) were

included in a multivariable model, with the exception of idiopathic VTE

because of collinearity with other covariates included in the idiopathic VTE

definition.

Absolute risk reduction was estimated by comparing: (1) the recurrence

risk (number of events or rate) derived from applying the fitted Cox PHregression model to the observed data, with (2) the recurrence risk derived

from applying the same fitted model to a hypothetical dataset reflecting the

assumption that continual APTT monitoring and heparin dose adjustment

would lead to a proportion of time in the therapeutic APTT range (APTT

40 or 58 seconds) that was no less than the median proportion of time

in therapeutic APTT range observed in our cohort. The hypothetical

estimates for the rate and number of recurrences under this simulated

scenario were derived and then subtracted from the original set of estimates

to provide the absolute risk reduction. We calculated the number needed to

treat (NNT) to prevent one additional VTE recurrence as the inverse of the

absolute risk reduction. Similar analyses were performed for the duration of

overlapping heparin and warfarin therapy (in days). Technical details of the

analyses are provided in the supplemental Appendix.

Finally, we used Cox PH regression to determine whether the time-

dependent measures of heparin and warfarin anticoagulation intensity were

HEPARIN/WARFARIN INTENSITYAND VTE RECURRENCE 4993BLOOD, 3 NOVEMBER 2011 VOLUME 118, NUMBER 18



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associated with major bleeding from 1-180 days. However, because of the

low number of major bleeding events, these analyses were limited to

univariate modeling and were considered exploratory.

All analyses were performed using SAS Version 8.2 (SAS Institute).

P .05 was considered statistically significant.

Results

Over the 14-year period 1984-1997, 1353 Olmsted County resi-

dents developed an incident DVT and/or PE, 1166 of whom lived

for at least 1 day after their incident VTE onset and were included

in the analyses. The demographic and baseline characteristics

(including laboratory data) of these 1166 patients are shown in

Table 1. Of these 1166 patients, 1023 (88%) were objectively

diagnosed, whereas 1025 (88%) and 987 (85%), respectively,

received heparin therapy (subcutaneous heparin, n 16) and

warfarin therapy. The proportion of patients on heparin and/or

warfarin therapy by day from the incident VTE event is shown in

Figure 1. The 141 patients not receiving heparin were more likely

to have neurologic disease, congestive heart failure, or recent

neurosurgery and were less likely to have received warfarin. Of

these 141 patients, 31 received an IVC filter. Of the entire cohort,

1159 (99%) completed follow-up to 180 days; only 7 patients were

lost to follow-up before 180 days.

The median duration of heparin therapy was 6 days, and 76% ofpatients received 5 days of heparin therapy (Table 2). The

median duration of heparin therapy with an APTT 58 seconds

was nearly 4 days, and 33% of patients received heparin therapy

with an APTT 58 seconds for at least 5 days; heparin durations

with an APTT 40, 70 and 90 seconds are shown in Table 2.

The median time from VTE onset to start of heparin therapy was

1.4 days (range 0-30 days), and of overlapping heparin and

warfarin was 4.0 days (mean SD 4.0 3.0; range: 0-14 days;interquartile range: 2-6 days). Both the time interval from start of

heparin to start of warfarin and the total duration of heparin

decreased in later calendar years (Spearman correlation coeffi-

cients 0.23 and 0.13, respectively; P .001 for both).Over 5461 person-years of follow-up, 254 (22%) patients

developed recurrent VTE; 85 (8%) events occurred within 180 daysand served as outcomes in this analysis. The 14-, 90-, 180- and 14-

to 180-day cumulative incidence rates of VTE recurrence are

shown in Figure 2A. Of the VTE recurrences, 31 were PE DVT,

53 were DVT alone, and 1 was chronic thromboembolic pulmonary

hypertension. The 2-week case fatality rates for recurrent DVT

alone and recurrent PE DVT were 2% and 11%, respectively.In univariate analyses, the duration of time from VTE symptom

or sign onset to start of heparin therapy, as well as the time-

dependent variable having started heparin therapy, were not

associated with recurrence (Table 3). However, rapidly achieving

an APTT 58 or 40 seconds and increasing proportions of time

on heparin with an APTT 58 seconds or 40 seconds were

associated with significantly reduced hazards of recurrence. Amongpatients with available heparin dose data, the mean initial heparin

Table 1. Baseline patient characteristics and laboratory test dataamong Olmsted County, MN residents with incident DVT or PE in

1984-1997

Baseline characteristic and

laboratory test data Results (N 1166)

Patient age at incident DVT or PE, y,

mean SD (range)

63.2 19.4 (0-100)

Female, n (%) 637 (55)

BMI, kg/m2, mean SD (range) 27.6 6.7 (6.2-72.3)

Major VTE risk factors, n (%)*

Hospitalization for surgery 350 (30)

Hospitalization for acute medical illness 251 (22)

Nursing home confinement 110 (9)

Trauma/fracture 163 (14)

Active cancer 263 (23)

Neurologic disease with leg paresis 75 (6)

Pregnancy or postpartum (n 635) 35 (6)

Oral contraceptive or hormone therapy

among women

136 (12)

Idiopathic 302 (26)

Congestive heart failure 209 (18)

Chronic lung disease 206 (18)

Chronic liver disease 11 (1)

Chronic renal disease 31 (3)

Baseline laboratory test data,

mean SD (range)

Hemoglobin, g/L 12.1 1.9 (5.5-17.0)

Platelet count, 109/L 264.3 111.3 (36.0-626.0)

APTT, s 29.3 10.9 (19.1-97.0)

PT, s/INR 12.2 2.0/1.3 0.4

(9.0-22.8/0.9-3.9)

Serum creatinine, mol/L 102.8 48.1 (26.5, 424.3)

*Hospitalization for surgery or for acute medical illness, nursing home confine-

ment,trauma/fracture,pregnancy/postpartum,and oral contraceptive/hormone therapy

had to be documented as present in the 3 months prior to the incident VTE date.

Active cancer had to be documented in the 3 months before or after the incident VTE

event.

Neurologic disease with leg paresis, congestive heart failure, and chronic lung,

liver or renal disease had to be documented as present at any time prior to the

incident VTE date.

Baseline laboratory data were based on a subset of the cohort with at least one

measurement available (first value used) within the time window between onset of

VTE symptoms and start of therapy (median inter quartile range time window 2

0-6 days); this included n 280 patients having at least 1 among the 6 laboratory

parameters measured, and ranged from n 151 who had INR data to n 260 who

had hemoglobin data in this time window.

Figure 1. Percentage of patients on heparin therapy and on warfarin therapy by

day from symptomatic incident VTE onset.

Table 2. Total duration (in days) of heparin therapy and durations ofheparin therapy with APTT exceeding 4 different therapeutic

thresholds among Olmsted County, MN residents with a first-lifetime VTE diagnosed in 1984-1997

Statistic Total duration

APTT, s

> 40* > 58 > 70 > 90

Median 6.00 4.80 3.84 2.09 0.76

Mean 6.60 5.24 4.14 2.37 1.13

SD 2.99 3.08 2.67 2.23 1.37

5 d 76.4% 45.6% 33.3% 11.1% 1.9%

*APTT values of 40, 58, 70, and 90 s correspond to plasma heparin levels of 0.2,

0.3, 0.5, and 0.9 anti-Xa IU/mL, respectively.

4994 HEIT et al BLOOD, 3 NOVEMBER 2011 VOLUME 118, NUMBER 18



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dose was significantly greater among those with VTE recurrence

within 14 days (n 14) compared with a random sample of thosewithout ear ly r ecur rence ( n 8 4; 33 39 0 7529 vs

26 083 10 859 U/d; P .02), and not significantly differentfrom the calculated dose (n 14; 35 705 8855; P .48 from

paired t test) using a weight-based heparin dosing nomogram.7

Whereas the duration of heparin and warfarin overlap was not

associated with recurrence, the proportions of time on warfarin

with an INR either 1.5 or 2.0 as well as the time-dependent

variable of being on warfarin therapy were all significantly

associated with reduced hazards of recurrence. In contrast, IVC

filter placement was associated with a significantly increasedhazard of recurrence. Of the 17 patients with recurrent VTE after

IVC filter placement, 5 (29%) had recurrent PE DVT.In multivariable analyses including all variables that were at

least marginally significant (P .10) in univariate analyses, rap-idly achieving an APTT 58 seconds was associated with a

reduced hazard of recurrence, but the proportion of time on heparin

with an APTT 58 seconds (per 10% increase) was not associated

with recurrence (Table 4). Conversely, in a separate multivariable

analysis using a lower APTT threshold, rapidly achieving an APTT

40 seconds was not associated with recurrence, but the propor-

tion of time on heparin with an APTT 40 seconds (per 10%

increase) was associated with a reduced hazard of recurrence

(Table 4). A higher proportion of time on warfarin therapy with an

INR 2.0 significantly reduced the hazard of recurrence, whereas

the proportion of time on warfarin with 1.5 INR 2.0 was not

associated with recurrence; IVC filter placement nonsignificantly

increased the hazard of VTE recurrence (Table 4).

In univariate analyses of previously identified predictors of

VTE recurrence,17 the hazards of 180-day VTE recurrence were

significantly increased for active cancer, neurologic disease with

leg paresis, and recent neurosurgery (and correspondingly reduced

for idiopathic VTE), and were marginally decreased for low BMI(Table 3); patient age and sex were not predictors of recurrence in

this updated inception cohort. The 180-day cumulative incidence of

recurrent VTE after idiopathic incident VTE was 4% (n 13)

compared with 16% (n 32) after active cancer-related incidentVTE. Adjusting for warfarin therapy did not account for the

reduced hazard of recurrence associated with idiopathic VTE

(compared with VTE associated with active cancer, neurologic

disease, or other causes), nor did adjusting for rapidly achieving a

therapeutic APTT (data not shown). In univariate analysis, a higher

daily mean hemoglobin level was significantly associated (hazard

ratio [HR] 0.87 per g/L; P .02) with a lower recurrence rate.

Adjusting for warfarin therapy slightly attenuated this effect

(HR 0.90; P .09). In the multivariable analysis that incorpo-

rated anticoagulation variables, active cancer was the only one of

these baseline characteristics that was independently associated

with an increased hazard of 180-day VTE recurrence (Table 4);

BMI, leg paresis, and neurosurgery were not significant predictors

of recurrence after controlling for measures of heparin and warfarin

Table 3. Univariate Cox proportional hazards analyses of predictors

of 1- to 180-d VTE recurrence among Olmsted County, MN residentswith a first-lifetime VTE diagnosed in 1984-1997

Variable HR (95%CI) P

Age, y (per decade increase) 1.03 (0.92, 1.15) .59

Female sex 1.25 (0.81, 1.93) .32

BMI, kg/m2 per 10 kg/m2 increase 1.11 (0.82, 1.51) .50

BMI, kg/m2

.07

20 0.15 (0.02, 1.12)

20, 25 Referent

25, 30 1.00 (0.60, 1.69)

30 0.86 (0.49, 1.51)

Active cancer 2.63 (1.69, 4.08) .01

N eu rol ogi c d ise as e wi th l eg pa res is 2. 65 (1 .4 4, 4. 88 ) .01

Recent neurosurgery 2.61 (1.14, 5.99) .02

D ai ly me an APTT, s pe r 1 0- s i nc re as e 0. 96 (0 .8 9, 1. 03 ) .24

Daily mean PT, s 0.98 (0.95, 1.02) .30

INR 1.02 (0.92, 1.13) .70

Daily mean platelet count, 109/L

per 20 109/L increase

0.99 (0.95, 1.02) .52

Daily mean hemoglobin, g/L 0.87 (0.77, 0.98) .02

Time from VTE onset to start of heparin, d 0.99 (0.95, 1.04) .82

Started heparin therapy 0.85 (0.46, 1.57) .61APTT 58 s within 24 4 h of starting heparin 0.40 (0.24, 0.65) .01

APTT 40 s within 24 4 h of starting heparin 0.44 (0.22, 0.89) .02

Proportion of time on heparin with APTT 58 s

per 10% increase*

0.92 (0.86, 0.99) .02

Proportion of time on heparin with APTT 40 s

per 10% increase

0.87 (0.82, 0.93) .001

Warfarin 0.30 (0.19, 0.47) .01

Duration of heparin/warfarin overlap, d 0.97 (0.91, 1.04) .43

Proportion of time on warfarin with INR 1.5

per 10% increase

0.90 (0.84, 0.97) .01

Proportion of time on warfarin with INR 2.0

per 10% increase

0.89 (0.82, 0.96) .01

Inferior vena cava filter placement 3.98 (2.33, 6.77) .01

*Corresponding to plasma heparin level 0.3 anti-Xa U/mL

Corresponding to plasma heparin level 0.2 anti-Xa U/mL

Figure 2. Analysis of cumulative VTE recurrence and major bleeding by day

from incident VTE event. (A) Cumulative 180-day VTE recurrence. (B) Cumulative

180-day major bleeding.




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therapy. Analyses restricted to patients with objectively diagnosed

incident VTE yielded essentially the same results (data not shown).Thirty-one (3%) patients had a bleeding episode within 180 days

of the incident VTE event; of these, 12 (1%) were major bleeding

events (Figure 2B). The incidence of major bleeding was highest

within the first 14 days (16.2 per 100 person-years), and progres-

sively decreased to 4.4 and 2.5 per 100 person-years by 90 and 180

days, respectively. The 14- and 30-day case fatality rates after a

major bleeding event were 8% (95% confidence interval [CI]:

1%-49%) and 25% (95% CI: 9%-59%), respectively. In univariate

analyses, the hazard of major bleeding was not significantly

increased for proportion of time on heparin with an APTT

40 seconds; however, the hazards were marginally and signifi-

cantly increased for proportion of time on heparin with an APTT

58 seconds (per 10% increase, HR 1.18; 95% CI: 0.97, 1.45;

P .101) and 70 seconds (per 10% increase, HR 1.21; 95%CI: 1.01, 1.44; P .034), respectively. In similar analyses, thehazards of major bleeding were not significantly increased for the

proportions of time on warfarin with an INR 1.5 or 2.0,

respectively; however, the hazards were significantly increased for

a higher daily mean prothrombin time (HR 1.04; 95% CI: 1.00,1.08; P .036) and for a higher daily mean INR (HR 1.21; 95%

CI: 1.09, 1.35; P .001) while on warfarin.To further explore the potential effect of APTT monitoring and

heparin dose adjustment on VTE recurrence, we estimated the

absolute reduction in risk of recurrence that would be expected if

the proportion of time spent with an APTT at: (1) 40 seconds or

(2) 58 seconds was maintained, in each individual, at or above

the respective cohort medians for these parameters (92% for 40 seconds and 63% for 58 seconds). For the 40-second

threshold, using the estimated coefficient, the model predicted anabsolute risk reduction of 1.4% in the180-day VTE recurrence rate,

resulting in 12 fewer recurrent VTE events (NNT 71). If theupper and lower confidence limits on the coefficients are used,

then 4 or 22 fewer events, respectively, are predicted. For the same

calculation applied to the 58-second threshold, the predicted

reduction (which was not statistically significant) would have been

7 fewer events (point estimate; absolute risk reduction 0.7%;

NNT 141). If the upper and lower confidence limits on the

coefficients are used, then 9 additional or 19 fewer events,

respectively, are predicted. To further explore the potential effect of

duration of overlapping heparin and warfarin therapy on VTE

recurrence, we estimated the absolute reduction in risk of recur-

rence that would have occurred if the overlap duration was

maintained, in each individual, at or above the cohort median 5-dayduration. Using the estimated coefficient, the risk reduction in the

model-predicted 180-day VTE recurrence rate would be 0.1%,

resulting in 1 fewer recurrent VTE events (NNT 883). If the

upper and lower confidence limits on the coefficients are used,

then 4 fewer and 2 more events, respectively, are predicted.

Discussion

In this population-based inception cohort, in which all incident

VTE cases were included and the data on initial heparin and

subsequent warfarin therapy, laboratory data, and the outcomes of

VTE are complete, our observed VTE recurrence and bleedingrates were similar to a contemporary study of UFH and warfarin

therapy for acute VTE.31 Our most noteworthy findings, however,

were related to the effect of heparin anticoagulation measures on

VTE recurrence. Specifically, we found that a greater proportion of

time spent on heparin but with a lower intensity of anticoagulation

(ie, 0.2 anti-Xa U/mL) provided a significantly reduced hazard of

VTE recurrence. In contrast, the proportion of time spent above the

currently recommended intensity of heparin anticoagulation was

not significantly associated with fewer events. Moreover, achieving

a lower intensity of anticoagulation for the duration of heparin

therapy is feasible in practice, as reflected by the respective 92%

and 100% median and upper quartile proportions of time with an

APTT

40 seconds while on heparin among our cohort ofcommunity patients. Current recommendations for a therapeutic

APTT corresponding to a heparin level of 0.3-0.7 anti-Xa U/mLare

largely extrapolated from animal model data,32-34 and a single small

cohort study of 234 patients (162 patients with mainly clinically

diagnosed VTE) who were treated with IV UFH (5000 U IV bolus

followed by initial dose of 24 000 U/24 hours). 3,4,12 APTT monitor-

ing and UFH dose adjustment to maintain the APTT between

1.5 and 2.5 times that of the controls was recommended but not

enforced. VTE recurrence was clinically diagnosed in 5 patients

within 12 days of beginning UFH, but only 4 of these patients were

actually being treated for VTE. No information was provided about

whether these VTE patients were being treated for incident or

recurrent VTE, and the investigators did not control for other

characteristics that are predictors of VTE recurrence (eg, cancer).

Table 4. Multivariable Cox PH analyses of predictors of 1- to 180-d VTE recurrence among Olmsted County, MN residents with afirst-lifetime VTE diagnosed in 1984-1997, by APTT therapeutic threshold

Variable

HR (95%CI) P

APTT threshold > 40 s* APTT threshold > 58 s

BMI, kg/m2 .08 .14

20 0.17 (0.02, 1.27) 0.19 (0.02, 1.38)

20 25 Referent Referent

25 30 1.13 (0.65, 1.96) 1.04 (0.60, 1.81) 30 0.83 (0.44, 1.56) 0.82 (0.44, 1.54)

Active cancer 2.93 (1.82, 4.74) .001 2.82 (1.74, 4.55) .001

Neurologic disease with leg paresis 1.65 (0.69, 3.97) .26 1.67 (0.69, 4.08) .26

Neurosurgery 2.23 (0.73, 6.84) .16 2.05 (0.65, 6.42) .22

APTT indicated seconds within 24 4 h of starting heparin 0.87 (0.40, 1.91) .73 0.57 (0.34, 0.97) .04

Proportion of time on heparin with APTT i nd ic at ed s ec on ds pe r 10% i nc re as e 0 .90 ( 0. 83 , 0 .9 7) .01 0.96 (0.89, 1.04) .33

Proportion of time on warfarin with 1.5 INR 2.0 per 10% increase 0.98 (0.84, 1.14) .76 0.97 (0.83, 1.13) .71

Proportion of time on warfarin with INR 2.0 per 10% increase 0.83 (0.77, 0.90) .001 0.83 (0.77, 0.90) .001

Inferior vena cava filter placement 1.54 (0.76, 3.11) .23 1.66 (0.82, 3.37) .16

*Corresponding to plasma heparin level 0.2 anti-Xa U/mL.

Corresponding to plasma heparin level 0.3 anti-Xa U/mL.




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Rapidly achieving an APTT 0.3 anti-Xa U/mL significantly

protected against 180-day VTE recurrence. Whereas initial studies

found an association between an early subtherapeutic APTT and

VTE recurrence,8,10 2 meta-analyses of randomized trials failed to

support this observation.9,11 Given the often prolonged delay by

patients in seeking medical attention for symptoms of VTE, it

seems biologically implausible to suggest that achieving a certain

APTT level within the next 24 hours affects VTE recurrence.Indeed, we found no significant relationship between the time from

onset of VTE symptoms to start of heparin therapy and the hazard

of recurrence. Moreover, the failure to rapidly achieve a target

APTT did not appear to reflect heparin underdosing; the initial

heparin dose in a subset of patients with heparin dose information

available was significantly higher for those patients with (n 14)

compared with those without (n 84) early recurrence, and was

also not significantly different from a calculated dose using a

weight-based heparin dosing nomogram.7 Therefore, we believe

that these patients were relatively heparin resistant, possibly because of

high factor VIII activity,35,36 which is a predictor of VTE recurrence.37

The duration of overlapping heparin and warfarin therapy was

not a predictor of VTE recurrence. Given the narrow CIs around

our estimated HR of recurrence per day of overlap, it is unlikely

that a longer duration of heparin/warfarin overlap provides an

important reduction in VTE recurrence risk, and our simulated

analyses support this conclusion. The recommendation that heparin

and warfarin therapy be overlapped for at least 5 days and until the

INR is 2.0 for at least 24 hours1 is largely extrapolated from

animal model studies.38,39 Two small clinical trials showed that

5-7 and 10-14 days of IV heparin therapy were similarly effective

for acute proximal DVT,14,15 but no clinical trials tested the current

recommendation for a 4- to 5-day heparin/warfarin overlap. In a

large cohort study, the 6-month incidence of recurrent VTE did not

differ for lengths of initial hospitalization for acute DVT ranging

from 3-10 days.16

Our finding that a higher proportion of time on warfarin with anINR 2.0 was associated with a significantly reduced hazard of

VTE recurrence is consistent with studies of acute therapy for

idiopathic VTE23 and secondary prophylaxis against recurrent

VTE.25 Our finding of an increased hazard of recurrence associated

with IVC filter placement, although not statistically significant, is

supported by a previous study.40 Moreover, almost 1/3 of patients

with VTE recurrence after IVC filter placement had recurrent PE.

These findings suggest that IVC filter placement is inadequate VTE

therapy and that anticoagulation should be started as soon as the

bleeding risk is acceptable.

In an earlier analysis of the 1719 Olmsted County residents who

survived at least 1 day after an incident VTE over the 25-year

period 1966-1990, we identified increasing patient age and BMI,active cancer, neurologic disease with leg paresis, and recent

neurosurgery as independent predictors of VTE recurrence out to

10 years.17 However, we were unable to control for the intensity of

heparin and warfarin anticoagulation because APTT and INR data

were not easily retrievable. In this update of our Olmsted County

VTE inception cohort through 1997, we found that, after control-

ling for heparin and warfarin therapy, only active cancer was an

independent predictor of 180-day VTE recurrence, with an approxi-

mately 3-fold increased hazard of recurrence. These findings

corroborate studies showing a high rate of warfarin failure among

active cancer patients.41,42 Neither sex nor idiopathic VTE were

independent predictors of 180-day VTE recurrence. Sex was not an

independent predictor of recurrence in our previous study,17 a

finding that was recently confirmed,43 and idiopathic VTE was not

a predictor of recurrence during initial anticoagulation therapy in

previous studies.42,44

The number of major bleeding events (n 12) was too few

for meaningful multivariable analysis. However, our explor-

atory findings of: (1) no significant association of major bleed-

ing with the proportion of time on heparin with an APTT

40 seconds, (2) a marginally significant association with the

proportion of time with an APTT 58 seconds (heparin level0.3 anti-Xa U/mL), and (3) a significant association with the

proportion of time with APTT 70 seconds (heparin levels of

0.5 anti-Xa U/mL) lend further support to a lower intensity of heparin

anticoagulation as therapy for acute VTE. Moreover, whereas a higher

mean daily prothrombin time/INR on warfarin is associated with a

significantly increased hazard of major bleeding, the hazard is not

significantly increased for proportion of time on warfarin with an INR

2.0. We interpret this finding to suggest that the immediate daily

prothrombin time/INR is more relevant to a warfarin-associated bleed-

ing complication than the cumulative time on warfarin with an INR

2.0. We believe that this further supports a standard intensity of

warfarin anticoagulation as therapy for acute VTE. These exploratory

results require confirmation in future studies.

Our study has several important strengths. The population-based

study design insured that the entire spectrum of VTE disease occurring

in the community was included, so our results are generalizable to

populations of similar demography and baseline characteristics. We

accurately separated incident from recurrent VTE events, used an

unambiguous definition of VTE recurrence, and our cohort follow up to

6 months was virtually complete. Our sample size was relatively large

and the observed VTE recurrence rate was comparable to contemporary

studies. The APTT and PT/INR assays and assay instruments were

standardized across the entire study time frame, and we had access to all

laboratory results in the analyses. We controlled for all known baseline

and time-dependent characteristics that could potentially affect VTE

recurrence, and we used a carry-forward method for calculation of

proportion of time in therapeutic range that avoids the use of futureinformation to biaspresent data, as is the case with linear interpolation.45

However, our study also has important limitations. Because of our

observational cohort study design, we could not ensure equal and

random patient allocation to differing durations and intensities of

heparin and warfarin anticoagulation or to differing durations of

overlapping heparin and warfarin therapy. However, the frequency

distribution of these characteristics in the cohort was sufficiently broad

that we had adequate power to assess their potential effects on VTE

recurrence.

Our findings have several implications. First, if providers

choose to monitor and adjust the heparin dose according to the

APTT despite a heparin dose 30 000 U/d, a lower intensity of

heparin anticoagulation (

0.2 anti-Xa U/mL) may be adequate.However, as has been suggested by others1,18 and shown in one

clinical trial,31 with a heparin dose 30 000 U/d, routine APTT (or

anti-Xa46) monitoring and heparin dose adjustment may be unneces-

sary because the median proportion of time with an APTT

0.2 anti-Xa U/mL was 90%. Second, initiating heparin and

warfarin concurrently and stopping the heparin when the INR is

2.0 regardless of the duration of overlapping heparin and

warfarin therapy appears to be as effective as the recommended

4-5 days of heparin/warfarin overlap. If confirmed by focused

clinical trial results, these 2 practice changes have the potential to

result in important cost savings by reducing the duration of

hospitalization and avoiding the need for costly heparin monitoring

programs. Moreover, the duration of heparin exposure likely will be

shortened, reducing the risk of heparin-induced thrombocytopenia.47




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Finally, in accordance with current recommendations,1 VTE patients

with active cancer should remain on anticoagulation (preferably low-

molecular-weight heparin41) for at least 6 months, and probably as long

as the cancer remains active.

Acknowledgments

This study was funded in part by grants from the National Institutesof Health (HL66216 and AG034676), the US Public Health

Service, and the Mayo Foundation.

Authorship

Contribution: J.A.H. designed and performed the research, col-

lected the data, analyzed and interpreted the data, and wrote the

manuscript; B.D.L. performed the statistical analyses and contrib-

uted to writing the manuscript; T.M.P. designed and performed the

research, collected the data, performed the statistical analyses, and

contributed to writing the manuscript; K.R.B. directed the statisti-

cal analyses and contributed to writing the manuscript; A.A.A.

analyzed and interpreted the data and contributed to writing the

manuscript; and L.J.M. contributed to the research design, ana-

lyzed and interpreted the data, and contributed to writing themanuscript.

Conflict-of-interest disclosure: J.A.H. has served on advisory

boards for which he received honoraria. The remaining authors

declare no competing financial interests.

Correspondence: John A. Heit, MD, Stabile 6-Hematology

Research, Mayo Clinic, 200 First St SW, Rochester, MN 55905;

e-mail: [email protected].

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