In-Hospital Mortality with Deep Venous Thrombosis

Accepted Manuscript In-hospital Mortality with Deep Venous Thrombosis Paul D. Stein, MD, Fadi Matta, MD, Mary J. Hughes, DO PII:

S0002-9343(16)31207-4

DOI:

10.1016/j.amjmed.2016.10.030

Reference:

AJM 13793

To appear in:

The American Journal of Medicine

Received Date: 25 October 2016 Accepted Date: 25 October 2016

Please cite this article as: Stein PD, Matta F, Hughes MJ, In-hospital Mortality with Deep Venous Thrombosis, The American Journal of Medicine (2016), doi: 10.1016/j.amjmed.2016.10.030. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

In-hospital Mortality with Deep Venous Thrombosis Paul D. Stein, MD, Fadi Matta, MD, Mary J. Hughes, DO

RUNNING HEAD: Mortality with Deep Venous Thrombosis

Abstract: 250 Text: 1290 (excluding abstract, references, tables and legends)

SC

WORD COUNT:

RI PT

Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan

Support: None Conflict of interest: None

M AN U

Key words: pulmonary embolism, deep venous thrombosis, mortality, case fatality rate

FOR REPLIES:

TE D

Participation: All authors had access to the data and participated in preparation of the manuscript.

AC C

EP

Paul D. Stein, MD Michigan State University College of Osteopathic Medicine 909 Fee Road, Department of Osteopathic Medical Specialties East Lansing, MI 48824 Tel 248/701 7210 E-mail: [email protected]

1

ACCEPTED MANUSCRIPT

ABSTRACT BACKGROUND: Little is known about the in-hospital mortality of deep venous

RI PT

thrombosis in recent years. This investigation was undertaken to determine trends in inhospital mortality in patients with deep venous thrombosis and mortality according to age.

METHODS: Administrative data was analyzed from the National (Nationwide) Inpatient

SC

Sample (NIS), 2003-2012. We determined in-hospital all-cause mortality according to

M AN U

year and to age among patients with a primary (first–listed) diagnosis of deep venous thrombosis. We analyzed all such patients and we analyzed those who had none of the comorbid conditions listed in the Charlson Comorbidity Index.

RESULTS: From 2003-2012, 1,603,690 hospitalized patients had a primary diagnosis of deep venous thrombosis. All-cause in-hospital mortality decreased from 1.25% in

TE D

2003 to 0.6% in 2012. Mortality increased with age from 0.1% in those aged 18-20 years to 1.5% in those over aged 80 years. All-cause in-hospital mortality in those with no comorbid conditions according to the Charlson Comorbidity Index (1,094,184

EP

patients) decreased from 1.1% in 2003 to 0.5% in 2012. Presumably these deaths were

AC C

from pulmonary embolism. All-cause mortality in those with no comorbid conditions increased with age from 0.1% in those aged 18-20 years to 1.4% in those over aged 80 years.

CONCLUSION: All-cause death and death due to pulmonary embolism in patients hospitalized with a primary diagnosis of deep venous thrombosis decreased from 20032012. The death rate increased with age. The decreased mortality over the period of

2

ACCEPTED MANUSCRIPT

investigation may have resulted from a shift toward use of low-molecular–weight

AC C

EP

TE D

M AN U

SC

RI PT

heparins and newer anticoagulants.

3

ACCEPTED MANUSCRIPT

It has been known for 150 years that deep venous thrombosis is potentially fatal because of pulmonary embolism.1 Little is known about the in-hospital mortality of deep venous thrombosis in recent years. In 1985-1986, in-hospital all-cause mortality (case

RI PT

fatality rate) was 5% among 274 patients with a first episode of deep venous thrombosis in the Worcester DVT Study.2 Mortality increased with age.2 It was 2% in patients

younger than aged 40 years and 16% in patients aged 80 years or older.2 Among 8923

M AN U

through 1989, in-hospital mortality was 3%.3

SC

patients with deep venous thrombosis who received Medicare (aged 65 or older) 1986

In the Prévention du Risque d'Embolie Pulmonaire par Interruption Cave (PREPIC) investigation, among hospitalized patients with proximal deep venous thrombosis with or without concomitant pulmonary embolism, September 1991-

TE D

February 1995, (200 with a vena cava filter plus anticoagulants and 200 with anticoagulants alone), all-cause mortality in the first 12 days, in 372 patients who were evaluated was 2.7%.4 One percent died from pulmonary embolism.4 Among 432

EP

patients with proximal deep venous thrombosis (14% with pulmonary embolism in addition) treated with low-molecular-weight heparin or unfractionated heparin followed

AC C

by warfarin, all-cause death within 2 weeks occurred in 9 (2.1%) and death from pulmonary embolism or possible pulmonary embolism occurred in 0.9%.5 Among 198 patients with proximal deep venous thrombosis and no suspected pulmonary embolism treated in-hospital with unfractionated heparin, none died.6 These investigations were randomized controlled trials designed to compare the effectiveness of low-molecular– weight-heparin with unfractionated heparin5,6 or anticoagulants with vena cava filters in

4

ACCEPTED MANUSCRIPT

addition. 4 Limited numbers of included patients prevented analysis of in-hospital mortality according to age. Analysis of trends in mortality according to year was not

RI PT

possible. This investigation was undertaken to determine such information.

METHODS

Administrative data was analyzed from the National (Nationwide) Inpatient

SC

Sample (NIS), Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality, 2003-2012.7 The NIS provides information on approximately 8 million

M AN U

inpatient stays yearly from about 1,000 hospitals. The NIS is designed to approximate a 20-percent sample of United States non-Federal, short-term, general, and other specialty hospitals.7

Beginning with data from 2012, the NIS was redesigned to improve national

TE D

estimates. To highlight the design change, beginning with 2012 data, the database was renamed from the "Nationwide Inpatient Sample" to the "National Inpatient Sample." The NIS is now a sample of discharge records from all Healthcare Cost and

EP

Utilization Project-participating hospitals, rather than a sample of hospitals from which

AC C

all discharges were retained.7

We determined the in-hospital all-cause mortality according to age and

according to year among patients with a primary (first–listed) diagnosis of deep venous thrombosis. We assume that patients with a first-listed diagnosis were admitted to the hospital because of deep venous thrombosis.

5

ACCEPTED MANUSCRIPT

We analyzed all such patients and we analyzed those who had none of the comorbid conditions listed in the Charlson Comorbidity Index.8

RI PT

Included patients were adults (> aged 18 years) of both genders and all races hospitalized in short-stay hospitals from all regions of the United States.

The International Classification of Diseases-9-Clinical Modification (ICD-9-CM)

SC

Codes for deep venous thrombosis were 451.1, 451.2, 451.8, 451.9, 453.2, 453.4, 453.8, 453.9, 671.3, and 671.4.

M AN U

Comorbid conditions listed in the Charlson Comorbidity Index6 as well as the ICD-9-CM codes used to identify these comorbid conditions are shown in Table 1. we assume that mortality was due to pulmonary embolism in patients with primary

Statistical Methods:

TE D

diagnosis of DVT, and no comorbid conditions.

Descriptive statistics were used. Differences of categorical variables were

EP

calculated by Fisher’s two-tailed exact test using GraphPad Software (San Diego, CA). Continuous variables were expressed as means and 95% confidence intervals (CI) and

AC C

were calculated using Graphpad Quickcalcs (Graphpad, San Diego, California). Linear regression analyses were performed using SPSS Version 22 for Windows (SPSS Inc., Chicago, IL).

RESULTS All patients with a primary diagnosis of deep venous thrombosis.

6

ACCEPTED MANUSCRIPT

From 2003 through 2012, 5,279,743 patients throughout United States were discharged with a diagnosis of deep venous thrombosis. Among these 1,603,690 (30.4%) had a primary diagnosis of deep venous thrombosis. Females were 54.7%

RI PT

(P<0.0001) of those with a primary diagnosis of deep venous thrombosis. Whites were 73.4% and blacks 15.5%. In-hospital all-cause mortality 2003-2012 was 0.9% in

females and 0.8% in males (P<0.0001). Mortality 2003-2012 in whites and blacks was

SC

the same, 0.9%.

M AN U

All-cause in-hospital mortality in all patients with a primary diagnosis of deep venous thrombosis decreased from 1.3% in 2003 to 0.6% in 2012 (Table 2, Figure 1).

All-cause in-hospital mortality in all patients with a primary diagnosis of deep

TE D

venous thrombosis increased with age from 0.1% in those aged 18-20 years to 1.5% in those over aged 80 years (Table 2, Figure 2).

conditions.

EP

Patients with a primary diagnosis of deep venous thrombosis and no comorbid

AC C

There were 1,094,184 patients with a primary diagnosis of deep venous

thrombosis and no comorbid conditions according to the Charlson Comorbidity Index. Females were 55.7% (P<0.0001). In-hospital all-cause mortality, 2003-2012, was 0.9% in females and 0.7% in males (P<0.0001). Whites were 75.3% and blacks 14.2%. Mortality 2003-2012 was the same in whites and blacks, 0.8%.

7

ACCEPTED MANUSCRIPT

All-cause in-hospital mortality in those with no comorbid conditions decreased from 1.1% in 2003 to 0.5% in 2012 (Table 3, Figure 1).

RI PT

All-cause in-hospital mortality in those with no comorbid conditions increased with age from 0.1% in those aged 18-20 years to 1.4% in those over aged 80 years

SC

(Table 3, Figure 2).

DISCUSSION

M AN U

All–cause mortality in all patients with a primary diagnosis of deep venous thrombosis as well as those with no comorbid conditions according to the Charlson Comorbidity Index decreased from 2003-2012. In both groups, mortality increased with

TE D

age.

Death in patients with none of the comorbid conditions listed in the Charlson Comorbidity Index probably occurred from pulmonary embolism. In rare instances, it is

EP

possible that death may have occurred from causes not listed in the Charlson Index,

AC C

such as bleeding from anticoagulants.

All-cause mortality from deep venous thrombosis decreased from 5% in 1985-

19862 to 0.6% in 2012 based on data in the current study. Death from pulmonary embolism decreased from 1% in 1991-19954 to 0.5% in 2012 based on data in the current study. The decreased mortality probably occurred because of increased use of low–molecular–weight heparin and other newer anticoagulants. Between 1999 and

8

ACCEPTED MANUSCRIPT

2009, based on data from the Worcester, Massachusetts metropolitan statistical area, treatment of venous thromboembolism shifted from warfarin and unfractionated heparin toward use of low-molecular–weight heparins and newer anticoagulants.9 During this

RI PT

time, all-cause mortality decreased.9 Meta-analysis showed that fixed dose low-

molecular–weight heparins compared with adjusted dose subcutaneous or intravenous unfractionated heparin in patients with venous thromboembolism was associated with

SC

fewer deaths (odds ratio 0.76).10

M AN U

Presumably the patients did not have clinically apparent pulmonary embolism on admission. If pulmonary embolism was clinically apparent, it is remote that the primary diagnosis would have been deep venous thrombosis.

TE D

Strength of this investigation is the huge number of patients which permitted assessment of trends in mortality over time, and the relation of mortality to age. Adults

EP

of all ages, both genders, all races, and from all regions of United States were included.

A weakness is that we have no information about whether deep venous

AC C

thrombosis was proximal or distal. This may be important because silent pulmonary embolism occurs in 31% of patients with deep venous thrombosis11 and 13% of patients with distal deep venous thrombosis.11, 12 Silent pulmonary embolism appeared to increase the risk of recurrent pulmonary embolism.11 We have no information about fatal recurrent pulmonary embolism in patients with silent pulmonary embolism.

9

ACCEPTED MANUSCRIPT

In conclusion, all-cause mortality in patients hospitalized with a primary diagnosis of deep venous thrombosis, as well as, mortality due to pulmonary embolism decreased from 2003-2012. All-cause mortality and mortality from pulmonary embolism increased

AC C

EP

TE D

M AN U

SC

RI PT

with age.

10

ACCEPTED MANUSCRIPT

REFERENCES 1. Phlegmatia alba dolens. In: Trousseau A. Clinique médicale de l’HôtelDieu de Paris. 3rd ed. Vol. 3. Paris: J.B. Baillière, 1868:652-95 quoted by Decousus H1, Leizorovicz

RI PT

A, Parent F et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group. N Engl J

M AN U

SC

Med. 1998;338:409-415.

2. Anderson FA Jr, Wheeler HB, Goldberg RJ et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med. 1991;151:933-938.

TE D

3. Kniffin WD Jr, Baron JA, Barrett J, et al. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med.

EP

1994;154:861-866.

4. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the

AC C

prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998; 12;338:409-415.

11

ACCEPTED MANUSCRIPT

5. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein

RI PT

thrombosis. N Engl J Med. 1992;326:975-982.

6. Koopman MM, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with

SC

subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med. 1996;334:682-687. Erratum in: N Engl J Med

M AN U

1997;337:1251.

7. HCUP Databases. Healthcare Cost and Utilization Project (HCUP). February 2016. Agency for Healthcare Research and Quality, Rockville, MD. www.hcup-

TE D

us.ahrq.gov/nisoverview.jsp. Accessed July 23, 2016.

8. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying

EP

prognostic comorbidity in longitudinal studies: development and validation. J Chronic

AC C

Dis. 1987;40:373-383.

9. Huang W, Goldberg RJ, Cohen AT, et al. Declining long-term risk of adverse events after first-time community-presenting venous thromboembolism: The populationbased Worcester VTE study (1999 to 2009). Thromb Res. 2015;135:1100-1106.

12

ACCEPTED MANUSCRIPT

10. Erkens PM, Prins MH. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism.

RI PT

Cochrane Database Syst Rev. 2010:CD001100.

11. Stein PD, Matta F, Musani MH, Diaczok B. Silent pulmonary embolism in patients with deep venous thrombosis: A systematic review. Am J Med. 2010;123:426-431.

SC

12. Hughes MJ, Stein PD, Matta F. Silent pulmonary embolism in patients with distal

M AN U

deep venous thrombosis: Systematic Review. Thrombosis Research.

AC C

EP

TE D

2014;134:1182-1185.

13

ACCEPTED MANUSCRIPT

LEGENDS

Figure 1.

RI PT

All-cause in-hospital mortality in patients with primary diagnosis of deep venous thrombosis (Primary DVT) and such patients with no comorbid conditions (No

Comorbid) shown according to year. Among all patients with primary DVT, r = 0.9541,

SC

P<0.0001. Among patients with primary DVT and no comorbid conditions, r = 0.8989,

M AN U

P=0.0004.

Figure 2.

All-cause in-hospital mortality in patients with primary diagnosis of deep venous

TE D

thrombosis (Primary DVT) and such patients with no comorbid conditions (No Comorbid) shown according to age. Among all patients with primary DVT, r = 0.9683, P<0.0001. Among patients with primary DVT and no comorbid conditions, r = 0.9682,

AC C

EP

P=0.0001.

14

ACCEPTED MANUSCRIPT

Table 1. International Classification of Diseases, 9th Edition, Clinical Modification Comorbid Conditions Included in the Charlson Index8 Comorbid Condition

RI PT

ICD-9-CM Codes Used

410 428 440.2, 443.9 430-438 290 490-496 710.0, 710.1, 710.4, 714.0, 714.1, 714.2, 714.8 531-534 570, 571 250.0-250.3 342.0-342.9 344.1 580-586, 588 250.4-250.6 140-195, 200-208 196-199 042

TE D

M AN U

SC

Comorbid Conditions Included in the Charlson Index Acute myocardial infarction Heart failure Peripheral vascular disease Cerebrovascular disease Dementia Chronic obstructive pulmonary disease Rheumatologic disease Ulcer disease Acute or chronic liver disease Diabetes mellitus Hemiplegia and hemiparesis Paraplegia Moderate or severe renal disease Diabetes with chronic complications Any neoplasms, leukemia, lymphoma Metastatic cancer HIV and AIDS

AC C

EP

HIV = human immunodeficiency virus AIDS = Acquired immune deficiency syndrome

1

ACCEPTED MANUSCRIPT

Table 2. Mortality according to year and age in all patients with a primary diagnosis of deep venous thrombosis

Mortality (n)

Year

RI PT

95% CI

All primary DVT (n)

Mortality (%)

160,915

1,945

1.2

1.2-1.3

2004

152,012

1,635

1.1

1.0-1.1

2005

155,873

1,653

1.1

1.0-1.1

2006

157,884

1,521

1.0

0.9-1.0

2007

156,991

1,252

0.8

0.8-0.8

2008

168,781

1,492

0.9

0.8-0.9

2009

167,360

1,435

0.9

0.8-0.9

2010

165,373

1,229

0.7

0.7-0.8

2011

165,961

1,166

0.7

0.7-0.7

2012

152,540

975

0.6

0.6-0.7

All years

1,603,690

14,304

0.9

0.9-0.9

10,602

15

0.1

0.1-0.2

72,349

81

0.1

0.1-0.1

124,558

204

0.2

0.1-0.2

207,849

792

0.4

0.4-0.4

254,328

1,863

0.7

0.7-0.8

61-70

274,650

2,547

0.9

0.9-1.0

71-80

321,733

3,784

1.2

1.1-1.2

> 80

337,620

5,018

1.5

1.4-1.5

All ages

1,603,690

14,304

0.9

0.9-0.9

21-30 31-40 41-50

M AN U

AC C

EP

51-60

TE D

Age (years) 18-20

SC

2003

DVT, deep venous thrombosis; CI, confidence interval.

2

ACCEPTED MANUSCRIPT

Table 3. Mortality according to year and age in patients with a primary diagnosis of deep venous thrombosis no comorbid conditions Mortality (n)

Mortality (%)

95% CI

1.0-1.1

Year

RI PT

Primary DVT No Comorbidity (n) 2003

114,862

1,236

1.1

2004

107,224

988

0.9

2005

111,007

1,030

2006

111,008

963

2007

104,819

695

2008

113,566

885

0.8

0.7-0.8

2009

111,906

851

0.8

0.7-0.8

2010

110,248

717

0.7

0.6-0.7

2011

110,064

730

0.7

0.6-0.7

2012

99,480

495

0.5

0.5-0.5

All years

1,094,184

8,589

0.8

0.8-0.8

10,049

15

0.1

0.1-0.2

66,080

67

0.1

0.1-0.1

105,178

167

0.2

0.1-0.2

160,610

549

0.3

0.3-0.4

173,042

1,117

0.6

0.6-0.7

61-70

167,030

1,429

0.9

0.8-0.9

71-80

190,094

2,097

1.1

1.1-1.1

> 80

222,100

3,148

1.4

1.4-1.5

1,094,184

8,589

0.8

0.8-0.8

18-20 21-30 31-40 41-50

All ages

SC 0.9

0.9-1.0

0.9

0.8-0.9

0.7

0.6-0.7

M AN U

AC C

EP

51-60

TE D

Age (years)

0.9-1.0

DVT, deep venous thrombosis; CI, confidence interval.

3

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Figure 1

1

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Figure 2

2