Oral anticoagulation and risk of death: a medical record linkage study

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http://bmj.com/cgi/content/full/325/7372/1073

Oral anticoagulation and risk of death: a medical record linkage study

Anders Odén, consulting statistician a, Martin Fahlén, associate professor of

medicine b.

a Valler 190, S-442 92 Romelanda, Sweden, b Department of Medicine, Hospital of

Kungälv, Sweden

Correspondence to: A Odén anders.oden

 

Abstract

Objective: To study how mortality varies with different degrees of

anticoagulation reflected by the international normalised ratio (INR).

Design: Record linkage analysis with death hazard estimated as a continuous

function of INR.

Data sources: 46 anticoagulation clinics in Sweden with computerised medical

records.

Subjects: Records for 42 451 patients, 3533 deaths, and 1.25 million INR

measurements.

Main outcome measures: Mortality from all causes and from intracranial

haemorrhage.

Results: Mortality from all causes of death was strongly related to level of

INR. Minimum risk of death was attained at 2.2 INR for all patients and 2.3 INR

for patients with mechanical heart valve prostheses. A high INR was associated

with an excess mortality: with an increase of 1 unit of INR above 2.5, the risks

of death from cerebral bleeding (149 deaths) and from any cause were about

doubled. Among patients with an INR of = "

src= " http://bmj.com/math/12pt/normal/ges.gif " align=bottom>3.0, 1069 deaths

occurred within 7 weeks; if the risk coincided with that with an INR of 2.9, the

expected number of deaths would have been 569. Thus at least 500 deaths were

associated with a high INR value, but not necessarily caused by the treatment.

Conclusions: The excess mortality associated with high INR values supports the

use of less intensive treatment and a small therapeutic window, with INR close

to 2.2-2.3 irrespective of the indication for anticoagulant treatment. More

preventive actions should be taken to avoid episodes of high INR.

 

 

What is already known on this topic

The optimal degree of anticoagulation (expressed as the international normalised

ratio (INR)) for different indications is still unclear, but the increased risk

of death due to bleeding at high INR values is well known

 

What this study adds

This large study of medical records from anticoagulation clinics in Sweden

confirmed the substantial excess mortality at high INR values and indicated

optimal treatment to be in a small therapeutic window with INR close to 2.2-2.3,

irrespective of the indication for anticoagulant treatment

 

 

 

 

Introduction

 

Treatment with oral anticoagulants requires a constant balancing between

undertreatment and overtreatment. The intensity of coagulation is monitored

within narrow therapeutic margins. The effect of the daily dose has to be

checked regularly because of the influence of disease, food, and other drugs on

coagulation. It has been difficult to estimate the optimal degree of

anticoagulation and how much it depends on the indication for treatment.

Routines vary, but in recent years there has been a shift towards lower

therapeutic ranges.1

 

The degree of anticoagulation is calculated from the prothrombin time and

expressed as the international normalised ratio (INR). Different targets of INR

for different conditions have been proposed,2 with more intense treatment at an

INR of 2.5-3.5 (reference value for untreated patient is 1.0) recommended for

patients with a mechanical heart valve prosthesis in the mitral position.3

Others find no reason to differentiate and suggest a target INR of 2.0-3.0 for

all conditions. In order to minimise complications, a combination treatment of

dipyridamole, aspirin, and a fixed low daily dose of warfarin has been suggested

for patients with a heart valve prosthesis. 4 5 Furthermore, the beneficial

effect of anticoagulation after fitting a biological replacement for an aortic

valve has been questioned.6

 

With the introduction of computerised records at anticoagulation clinics it is

possible to obtain data from much larger populations than have been used in

clinical trials to improve our understanding of how to optimise treatment. We

therefore analysed the medical records from about half of all anticoagulation

clinics in Sweden.

 

 

Methods

Since 1985 the hospital based and centralised anticoagulation clinics in Sweden,

where qualified nurses monitor anticoagulant treatment for outpatients with all

types of conditions, have gradually become computerised. Using software made by

Journalia, we analysed the records of 42 451 patients (42% women) who attended

46 clinics during 1990-7, most of them towards the end of the period. Their mean

age at the start of anticoagulation treatment was 70.5 years (SD 9.1 years). The

main indications for anticoagulation were atrial fibrillation (58%), venous

thrombosis and pulmonary embolism (25%), stroke and transient ischaemic attacks

(22%), valve prosthesis (18%), and myocardial infarction (3%). We identified

patients' deaths from the registry of causes of death maintained by the Swedish

National Board of Health and Welfare. This register includes more than 99% of

all deaths in Sweden, and 3553 deaths contributed to our base analysis. The

number of patient years was 60 668, and the number of INR measurements and

anticoagulant doses used was 1.25 million. After one year of treatment, the mean

interval between measurements was 18 days.

 

Our study was approved by the Ethics Committee for Medical Research at the

University of Göteborg.

 

Data analysis

In our base analysis each patient was followed from one INR measurement to the

next one or to death if either occurred within seven weeks. After this time,

which is a common maximum interval between anticoagulant doses, we censored the

patient data until a new INR measurement was performed, which was then used as a

starting value for another period of surveillance. Thus, a large number of INR

measurements were used as current INR values for estimating the death hazard

function depending on age, sex, and INR. The hazard function was estimated by a

Poisson model7 and was continuous as a function of age and INR. The death hazard

was exp(0+1×x1+1/4), where 0, 1, etc, were constants and x1, x2, etc, were the

values of the variables. The logarithm of the hazard function was linear for INR

values <1.8, quadratic between 1.8 and 2.5, and linear for higher values. The

corresponding values and their standard errors could be used to investigate the

shape of the curve and to assess changes with INR. We performed separate

analyses for the major indications for anticoagulation and analysed cerebral

bleeding separately as a cause of death.

 

 

 

 

Results

 

The table shows the mortality associated with different INR values for all

causes of death and for deaths where bleeding was a main or contributing cause.

Poisson regression analysis allowed us to include age and sex as well as INR.

There was a marked decrease in mortality from all causes with increasing INR in

the interval 1-1.8 but also a substantial increase in mortality for INR values

>2.5 (see figure). The death hazard function was lowest at an INR of 2.15.

Eighteen per cent of INR values were = "

src= " http://bmj.com/math/12pt/normal/ges.gif " align=bottom>3.0. For patients

with mechanical heart valve prostheses (401 deaths), risk of death was lowest at

an INR of 2.33. For other major indications for anticoagulation, the risk was

lowest at INR 2.2. The risk increase per unit increase in INR above 2.5 was 2.2

(95% confidence interval 2.1 to 2.2) for all indications, 2.1 for atrial

fibrillation, 2.3 for venous thrombosis and pulmonary embolism, 2.3 for stroke

and transient ischaemic attacks, and 2.1 for valve prosthesis.

 

 

View this table:

[in this window]

[in a new window]

 

Mortality from all causes and from bleeding as a main or contributing cause

among outpatients of Swedish anticoagulation clinics by level of anticoagulation

(measured as international normalised ratio (INR))

 

 

 

View larger version (14K):

[in this window]

[in a new window]

Risk of death associated with different levels of anticoagulation. The curve

was calculated from the results of the Poisson model and shows, as an example,

the risk for women aged 72: mean risk was 47.6 per 1000 patient years, attained

roughly at INR values of 1.6 or 2.9

 

 

 

We also calculated the risk of death from cerebral bleeding (ICD-9 codes 430,

431, and 432 and ICD-10 codes I60, I61, and I62). The risk significantly

decreased with increasing INR in the INR interval 1-1.5 (P=0.002) and

significantly increased at INR values of = "

src= " http://bmj.com/math/12pt/normal/ges.gif " align=bottom>1.5 (P<0.001).

However, at values of = " src= " http://bmj.com/math/12pt/normal/ges.gif "

align=bottom>3.0 the increased risk of dying from cerebral bleeding per unit

increase of INR was not higher than the corresponding figure calculated for

death from all causes. The risk of death was significantly higher for patients

who reached INR levels of = " src= " http://bmj.com/math/12pt/normal/ges.gif "

align=bottom>3.0 after an increase in anticoagulant dose compared with those who

reached the same level spontaneously (P=0.047).

 

The target INR depended largely on the type of indication for anticoagulation

rather than the individual patient's state of health. In some clinics the target

value was the same for all patients. The target value made no significant

difference to the risk of death associated with the actual INR.

 

There were 1069 deaths observed within seven weeks after an INR measurement of =

" src= " http://bmj.com/math/12pt/normal/ges.gif " align=bottom>3.0. Using the

Poisson model, we calculated the expected number of deaths to be 569 provided

that the risk was put equal to that of an INR of 2.9. Thus, at least 500 deaths

in our study were associated with, but not necessarily caused by, a high INR

value. Rough estimates of the number of patients treated with oral

anticoagulation in Sweden suggest that there were 65 deaths associated with high

INR values per million inhabitants annually.

 

 

Discussion

Our results show that mortality among patients treated with oral anticoagulants

was lowest at an INR value of 2.2-2.3 and that it increased substantially at

higher INR levels. Thus, we confirm the beneficial effects of anticoagulants on

thromboembolism when the INR is increased from 1.0 to 2.3 and confirm reports of

therapeutic effects with INR values lower than 2.0.8

 

The association between risk of bleeding and intensity of treatment is well

known, as is the need for vigilance to avoid occurrence of high INR values.9-13

Our findings indicate that preventive measures must also be taken when a high

INR has occurred. Hylek et al found that patients without symptoms at time of

measurement of an INR above 6.0 faced a substantial risk of major haemorrhage in

the next 14 days.14 Studies on the use of vitamin K after high INR values will

be of interest.

 

As the frequency of autopsies was low in our study, we could not accurately

determine the number of deaths due to bleeding even though we could accurately

measure the increase in mortality with increasing INR. We expected that bleeding

should be the only cause of death that increased with increasing INR, but our

analysis of deaths from cerebral bleeding suggests that other causes dominated.

As well as an indicator of high risk of bleeding, a high INR has been reported

to be an indicator of a final stage of disease, and several factors are known to

influence INR, including malnutrition,15 diarrhoea,16 malignancy,17 serious

comorbid diseases, 17 18 and interaction of warfarin with other drugs. Another

possible explanation is some synergistic disturbance in regulation of

coagulation before a high INR. Jansson et al have found an increased mortality19

and increased frequency of bleeding 20 associated with high levels of

thrombomodulin during long term anticoagulation treatment. It is also possible

that warfarin may have toxic effects: death from the rare side effect of skin

necrosis has been reported.21

 

As a spontaneous increase of INR is often seen in moribund patients, it might be

expected that patients with this phenomenon had the highest risk of death for a

certain level of INR compared with others who reached the same level after an

increased dose of anticoagulant. However, our study indicates that the risk of

death was significantly higher among patients whose high INR followed an

increased drug dose. This finding indicates that preventive actions can be

taken. In order to avoid high INR values and risky elevations of doses there is

a need for more careful treatment with oral anticoagulants. We propose the use

of lower target values of INR and a smaller therapeutic window compared with

what is used today. An INR of 2.2-2.3 seems to be associated with the lowest

risk of death for all indications.

 

Acknowledgments

We thank Jan Ramebäck and Knut Fahlén for programming and organisation necessary

for the data collection.

 

Contributors: MF performed the literature research and AO planned and made the

statistical analyses. Both authors initiated the project and contributed to the

writing, and both are guarantors for the study.

Footnotes

Competing interests: None declared.

 

References

1. Turpie AG. Safer anticoagulant therapy after heart valve replacement.

Recommendations for less intense regimens. Postgrad Med 1997; 101: 85-86, 89-90,

93-4. 2. Hirsh J. Optimal intensity and monitoring warfarin. Am J Cardiol 1995;

75: 39-42B. 3. Stein PD, Alpert JS, Bussey HI, Dalen JE, Turpie AG.

Antithrombotic therapy in patients with mechanical and biological prosthetic

heart valves. Chest 2001; 119: 220-27S. 4. Katircioglu SF, Yamak B, Ulus AT,

Iscan HZ, Mavitas B, Tasdemir O. Aortic valve replacement with the St. Jude

Medical prosthesis and fixed dose anticoagulation. J Card Surg 1997; 12:

363-370[iSI][Medline]. 5. Katircioglu SF, Yamak B, Ulus AT, Tasdemir O, Bayazit

K. Mitral valve replacement with St. Jude Medical prosthesis and low-dose

anticoagulation in patients aged over 50 years [see comments]. J Heart Valve Dis

1998; 7: 455-459[iSI][Medline]. 6. Moinuddeen K, Quin J, Shaw R, Dewar M,

Tellides G, Kopf G, et al. Anticoagulation is unnecessary after biological

aortic valve replacement. Circulation 1998; 98: II95-8[iSI][Medline]. 7. Breslow

NE, Day NE. Statistical methods in cancer research , Vol 2 Lyon: IARC, 1987. 8.

Levine M, Hirsh J, Gent M, Arnold A, Warr D, Falanga A, et al. Double-blind

randomised trial of a very-low-dose warfarin for prevention of thromboembolism

in stage IV breast cancer. Lancet 1994; 343: 886-889[iSI][Medline]. 9. Acar J,

Iung B, Boissel JP, Samama MM, Michel PL, Teppe JP, et al. AREVA: multicenter

randomized comparison of low-dose versus standard-dose anticoagulation in

patients with mechanical prosthetic heart valves [see comments]. Circulation

1996; 94: 2107-2112[Abstract/Free Full Text]. 10. Altman R, Rouvier J, Gurfinkel

E, D'Ortencio O, Manzanel R, de La FL, et al. Comparison of two levels of

anticoagulant therapy in patients with substitute heart valves. J Thorac

Cardiovasc Surg 1991; 101: 427-431[Abstract]. 11. Saour JN, Sieck JO, Mamo LA,

Gallus AS. Trial of different intensities of anticoagulation in patients with

prosthetic heart valves. N Engl J Med 1990; 322: 428-432[Abstract]. 12.

Tientadakul P, Opartkiattikul N, Sangtawesin W, Sakiyalak P. Effect of different

oral anticoagulant intensities on prothrombin fragment 1 + 2 in Thai patients

with mechanical heart valve prostheses. J Med Assoc Thai 1997; 80:

81-86[Medline]. 13. Turpie AG, Gunstensen J, Hirsh J, Nelson H, Gent M.

Randomised comparison of two intensities of oral anticoagulant therapy after

tissue heart valve replacement. Lancet 1988; i: 1242-1245. 14. Hylek EM, Chang

YC, Skates SJ, Hughes RA, Singer DE. Prospective study of the outcomes of

ambulatory patients with excessive warfarin anticoagulation. Arch Intern Med

2000; 160: 1612-1617[iSI][Medline]. 15. Lehmann AB. Vulnerability to warfarin:

could undernutrition be a predictor? Arch Intern Med 1997; 157: 1385. 16. Smith

JK, Aljazairi A, Fuller SH. INR elevation associated with diarrhea in a patient

receiving warfarin. Ann Pharmacother 1999; 33: 301-304[iSI][Medline]. 17. Chan

A, Woodruff RK. Complications and failure of anticoagulation therapy in the

treatment of venous thromboembolism in patients with disseminated malignancy.

Aust N Z J Med 1992; 22: 119-122[iSI][Medline]. 18. Landefeld CS, Beyth RJ.

Anticoagulant-related bleeding: clinical epidemiology, prediction, and

prevention. Am J Med 1993; 95: 315-328[iSI][Medline]. 19. Jansson JH, Boman K,

Brannstrom M, Nilsson TK. Increased levels of plasma thrombomodulin are

associated with vascular and all-cause mortality in patients on long-term

anticoagulant treatment. Eur Heart J 1996; 17: 1503-1505[iSI][Medline]. 20.

Jansson JH, Boman K, Brannstrom M, Nilsson TK. High concentration of

thrombomodulin in plasma is associated with hemorrhage: a prospective study in

patients receiving long-term anticoagulant treatment. Circulation 1997; 96:

2938-2943[Abstract/Free Full Text]. 21. DeFranzo AJ, Marasco P, Argenta LC.

Warfarin-induced necrosis of the skin. Ann Plast Surg 1995; 34:

203-208[iSI][Medline].

 

 

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