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Keywords:

  • anticoagulants;
  • atrial fibrillation;
  • epidemiology;
  • stroke

Abstract.

  1. Top of page
  2. Abstract.
  3. Background
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. References

Objectives.  Anticoagulation therapy is recommended in patients with atrial fibrillation (AF) and risk factors for stroke. We studied the temporal trends in the prescription of vitamin K antagonists (VKA) in patients with a first hospital diagnosis of AF in Denmark, 1995–2002.

Design.  The Danish National Hospital Registry was used to identify subjects with a first hospital diagnosis of AF and the Danish Register of Medical Products Statistics to determine the proportion of these patients who claimed a prescription of VKA within 3 months from discharge.

Results.  Amongst 68 546 patients aged 50–99 years with a diagnosis of AF who survived 3 months following discharge, 24 991 (36%) patients claimed a prescription of VKA within 3 months. In both men and women a gradual increase in the use of VKA with time was observed, the relative increase being largest amongst the 80- to 99-year olds. In all age groups, the prescription of VKA was lower in women than in men, including patients with a prior or concurrent stroke.

Conclusions.  From 1995 to 2002 the proportion of AF patients receiving VKA therapy increased significantly but the use of VKA therapy amongst women was lagging behind that of men. Even in patients with AF and prior stroke, the use of VKA seems to be less than optimal.


Background

  1. Top of page
  2. Abstract.
  3. Background
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. References

Atrial fibrillation (AF) is associated with an increased risk of stroke and systemic embolic events [1–6]. There is ample evidence that treatment with vitamin K antagonist (VKA) reduces the risk of stroke in patients with AF [7]. The use of dose-adjusted VKA with International Normalized Ratio levels of 2.0 to 3.0 is recommended in patients with AF and additional risk factors for stroke [8]. Despite the firm evidence that VKA reduces the risk of stroke in patients with AF, a considerable underutilization of VKA has been reported, especially amongst the elderly [9–19]. Little is known about the recent development in the prescription of VKA in patients with AF. The aim of our study was to determine the proportion of patients with a hospital diagnosis of AF who was treated with VKA from 1995 to 2002.

Materials and methods

  1. Top of page
  2. Abstract.
  3. Background
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. References

The Danish National Hospital Register contains administrative data for all hospitalizations in the country. We used the register to identify all cases of first hospitalization for AF as primary or secondary diagnosis [International Classification of Diseases 10th revision (ICD-10), code I48] between January 1995 and July 2002. Patients aged 50–99 years were included. Subjects with a prior hospital diagnosis of AF were excluded.

We also identified patients with first hospitalization for AF who had a previous or concurrent discharge diagnosis of nonhaemorrhagic stroke (ICD-8 codes 432–438 and ICD-10 codes I63–66, I69.3, I69.4 and G65) within 7 years of the index hospitalization. This subpopulation was of special interest, as it represents patients with higher risk of thromboembolic stroke and a definite indication for VKA treatment.

In Denmark, all prescription-based dispensing from pharmacies has been systematically registered on the individual level since 1995 in the Register of Medical Product Statistics. The register contains data on all prescription transactions from all Danish pharmacies, which are obliged through Danish legislation to provide this information. Data on prescriptions are registered at the individual level via a unique personal civil registration number. Each prescription record holds date of the prescription claim and detailed information on the dispensed drug: anatomical therapeutic classification system name, package size, quantity and formulation. Indication for treatment and prescribed daily dose are not registered.

By cross-linkage of the two registers via the civil registration number, we identified patients with a first hospital diagnosis of AF and the proportion of those who were treated with VKA (in Denmark warfarin or phenprocoumon) during the period January 1995 to July 2002. Patients were defined as VKA users if at least one VKA prescription was claimed within 3 months after discharge. Only patients alive 3 months after discharge were included in the analyses. Therefore, we also determined the temporal changes in 3-month mortality in patients with a first hospital diagnosis of AF. Information on patient's vital status was obtained through Statistics Denmark.

Statistical analyses

Temporal changes in the number of first hospital admissions for AF, in 3-month mortality and in the proportion of AF patients who claimed a prescription of VKA within 3 months of discharge were estimated by multiple logistic regression analyses. Tests for trends were performed by entering calendar year as a continuous variable. The 5% level of significance was used.

Results

  1. Top of page
  2. Abstract.
  3. Background
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. References

From 1995 to 2002 there was a total of 81 971 first hospitalizations for AF. Figure 1 shows the number of first hospitalizations per 1000 population by different age groups from 1995 to 2002. In men and women, the number of first hospitalizations for AF increased steadily throughout the period. The relative increase was equal across age groups.

image

Figure 1. Number of first hospital admissions for atrial fibrillation per 1000 population by age group.

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Of the 81 971 first hospitalizations for AF, data concerning 3-month survival following discharge was available for 78 749 patients (for 3222 patients discharged from hospital after July 2003, vital status was not yet available). Overall, 10 203 (13%) died within 3 months after discharge. Figure 2 shows the proportion of patients who died within 3 months after discharge by sex, calendar year and age group. In men, the 3-month mortality was constant over time in all age groups (test for trend, P = 0.83). In women, the 3-month mortality was constant over time in the 50- to 69-year olds, but in age groups 70–79 and 80–89, a slight increase in mortality over time was observed (test for trend, P < 0.001).

image

Figure 2. Three-month mortality following first hospital admission for atrial fibrillation.

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Amongst the 68 546 patients who survived the initial 3 months following hospital discharge, a total of 24 991 (36%) patients claimed a prescription of VKA within 3 months from discharge. Figure 3 shows the proportion of VKA users by sex, calendar year and age group. A gradual increase in the proportion of VKA users from 1995 to 2001 was observed in both sexes. Table 1 shows the results of multivariate regression models for VKA treatment. Overall, men used VKA more frequently than women (OR = 1.4, 95% CI = 1.3–1.4, adjusted for age). In both men and women, the largest relative increase in VKA users was observed in the two higher age groups (interaction between age group and calendar year, P < 0.001).

image

Figure 3. Proportion of vitamin K antagonist users following first hospital admission for atrial fibrillation.

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Table 1.  Multivariate models for vitamin K antagonist treatment
 Odds ratio (95% CI)
WomenMen
50–69 years (n = 7030)70–79 years (n = 11 712)80–99 years (n = 14 045)50–69 years (n = 14 658)70–79 years (n = 12 803)80–99 years (n = 8298)
  1. *Overall significance of variable. **P > 0.05.

Calendar yearP < 0.001*P < 0.001*P < 0.001*P < 0.001*P < 0.001*P < 0.001*
 19951.0 (Reference category)1.0 (Reference category)
 19961.4 (1.1–1.8)1.1 (1.0–1.4)**1.0 (0.8–1.3)**1.1 (0.9–1.3)**1.3 (1.1–1.5)1.2 (0.9–1.6)**
 19971.4 (1.1–1.7)1.5 (1.3–1.7)1.2 (1.0–1.5)**1.2 (1.1–1.4)1.5 (1.3–1.8)1.9 (1.4–2.4)
 19981.5 (1.2–1.9)1.6 (1.3–1.8)1.4 (1.1–1.7)1.4 (1.2–1.6)1.6 (1.4–1.9)1.7 (1.3–2.2)
 19991.6 (1.3–2,0)1.6 (1.4–1.9)1.9 (1.6–2.4)1.4 (1.3–1.7)1.6 (1.4–1.9)2.3 (1.8–3.0)
 20001.6 (1.3–2.01.7 (1.4–2.0)1.9 (1.6–2.3)1.4 (1.2–1.6)1.7 (1.5–2.0)2.4 (1.8–3.0)
 20011.7 (1.4–2.1)1.8 (1.6–2.1)2.4 (2.0–2.9)1.5 (1.3–1.7)1.9 (1.6–2.1)2.9 (2.3–3.7)
 20021.6 (1.3–2.0)2.2 (1.8–2.5)2.0 (1.7–2.5)1.4 (1.2–1.6)1.8 (1.5–2.1)2.6 (2.0–3.3)
Prior stroke2.1 (1.8–2.5)1.2 (1.1–1.4)1.2 (1.1–1.4)1.4 (1.3–1.6)1.2 (1.1–1.3)1.2 (1.1–1.4)

Amongst the 68 546 patients admitted for AF and surviving 3 months after discharge, 10 250 patients (5043 women and 5207 men) had a previous or concurrent diagnosis of ischaemic (nonhaemorrhagic) stroke. Figure 4 shows the proportion of VKA users in this subpopulation, stratified by sex and age. The proportion of VKA users increased significantly with calendar year in age groups 70–79 and 80–99 years (test for trend, P < 0.01), but was constant in the 50- to 69-year olds. Patients with a prior ischaemic stroke were more likely to receive VKA treatment than patients without a previous stroke (Table 1). The impact of a previous stroke diagnosis on the prescription of VKA therapy was significantly greater in women than in men (P = 0.02) and also greater in younger compared with older patients (P < 0.001). Still, male patients with a prior stroke were more likely to receive VKA therapy than female patients (OR = 1.2, 95% CI = 1.1–1.3, adjusted for age). By 2002, however, men and women with a prior stroke were equally likely to receive VKA therapy.

image

Figure 4. Proportion of vitamin K antagonist users following first hospital admission for atrial fibrillation. Subpopulation with prior or concurrent stroke.

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Discussion

  1. Top of page
  2. Abstract.
  3. Background
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. References

From 1995 to 2002, a considerable increase in the prescription of VKA therapy to patients with a hospital discharge diagnosis of AF was observed. This was particularly true for patients aged 80 years or more in whom the proportion increased from 13% in 1995 to 23% in 2002. In all age groups the prescription of VKA therapy was lower amongst women than amongst men. A prior or concomitant diagnosis of ischaemic stroke was associated with a higher proportion of VKA usage, although of modest extent. The increase in VKA use should be viewed against the increase in the number of first hospital admissions for AF that occurred during the study period. Whether this was a result of an increase in the incidence or prevalence of AF in the Danish population or whether it reflected a change in admission threshold or coding practice is unknown. If the latter was the case, this may have caused a change in the pool of risk factors for stroke in patients admitted with AF. However, the 3-month mortality of AF patients was largely constant throughout the study period indicating that the population of patients with an AF diagnosis has not changed substantially with time.

The VKA therapy is recommended to patients with AF, who have additional risk factors for stroke [8]. It is difficult to determine the optimal proportion of patients with AF in whom VKA therapy is indicated. Contraindications include high risk of haemorrhage and poor compliance and the optimal rate of VKA therapy is evidently below 100%. In our nationwide sample of patients with a discharge diagnosis of AF, we had no detailed information that could establish definite contraindications against VKA therapy. However, in a review of previous publications on warfarin use in AF patients from 2000, Bungard et al. [16] reported that in patients with AF who had no contraindications to warfarin therapy, only 15–44% were actually prescribed the drug. It seems likely, that we have not yet reached an optimal rate of VKA users.

Even though we found the highest relative increase in the use of VKA amongst the 80- to 99-year olds, the use of VKA in the very elderly remained lower than amongst patients <80 years of age. This finding is in accordance with previous studies [9, 12, 19]. The risk of stroke in subjects with AF rises steeply with increasing age [4] and an underutilization of VKA therapy in elderly AF patients is especially worrying. Even in patients with a prior or concomitant diagnosis of ischaemic stroke we found the use of VKA therapy surprisingly low, particularly amongst the >80-year olds. A perceived increased risk of haemorrhage imposed by VKA therapy in elderly patients [20] is likely to restrain many clinicians from prescribing warfarin and instead prescribe aspirin to this category of patients, although there is little evidence to support this approach. In a retrospective study, Coplan et al. [21] found that in an outpatient anticoagulation clinic, patient with AF and age >75 years had a comparative anticoagulation control and equal risk of haemorrhage compared with younger AF patients. Although the selection of elderly patients for warfarin therapy may have been biased, the results indicate that a large proportion of elderly AF patients can be treated with VKA therapy without excess risk of haemorrhage compared with younger patients.

In our study, women with AF were significantly less likely to receive VKA treatment than men, regardless of age group. This apparent, relative underutilization of VKA therapy in women compared with men has been observed in a number of previous studies [11, 22, 23], whereas other studies have not identified gender-specific difference in the use of VKA therapy [19, 24]. Notably, female gender has been identified as an independent risk factor for stroke in subjects with AF [25–27]. Hence, in our study, the group of patients with the perceived highest risk of stroke, i.e. the elderly women, had the lowest proportion of VKA users. In AF patients with a prior or concomitant diagnosis of ischaemic stroke, men and women were equally likely to receive VKA therapy by 2002.

The main limitation of our study is that we could not establish whether individuals with a hospital diagnosis of AF had definite indications or contraindications for VKA therapy. This was not possible, as we did not have full information on comorbidity. Furthermore, we had no knowledge of the duration of the qualifying episode of AF, which may have been a single episode following acute illness or surgery that would not indicate the initiation of VKA therapy.

The VKA therapy is considered troublesome by many patients and physicians [16]. It requires close follow-up, a high degree of compliance and has a narrow therapeutic index. The development of new anticoagulants for the use in AF patients that are simple to administer and have efficacy and safety profiles that are equivalent to or even superior to that of dose-adjusted VKA may possibly be the opening towards an optimal use of anticoagulants in the setting of AF. Until such treatment is available, the focus should be on securing the use of VKA therapy, especially in patients with the highest risk of thromboembolic complications, i.e. the elderly and patients with previous ischaemic stroke.

References

  1. Top of page
  2. Abstract.
  3. Background
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conflict of interest statement
  8. References
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