Trend in Mortality after Stroke with Atrial Fibrillation
Article Outline
Abstract
Purpose
To evaluate trend in mortality in stroke associated with atrial fibrillation, we examined mortality trend after stroke with atrial fibrillation by calendar year period (1980-1984, 1985-1989, 1990-1994, 1995-1999, and 2000-2002). We estimated trends separately for each sex in unadjusted analyses. We also adjusted for age, comorbid conditions, and general trend in mortality in the background population.
Methods
We identified all individuals, aged 40-89 years, with an incident diagnosis of stroke of any nature (ischemic or hemorrhagic) and no history of heart valve disease and a previous or concomitant diagnosis of atrial fibrillation or flutter in the Danish National Registry of Patients. Subjects were followed in the Danish Civil Registration System for emigration and vital status. We used multivariate Cox proportional hazards regression analysis to estimate trend in mortality.
Results
Incident stroke with a previous or concomitant diagnosis of nonvalvular atrial fibrillation or flutter was diagnosed in 24,470 subjects (11,554 men and 12,916 women). During 34,405 years of observation, 9237 men died, and during 35,381 years of observation, 10,827 women died. The hazard ratio for mortality after stroke in the last 3-year period compared with the first 5-year period was .65 (95% confidence interval [CI], .61-.71) in men and .69 (95% CI, .64-.74) in women.
Conclusions
We observed a substantially better survival in men and women after stroke associated with atrial fibrillation or flutter in Denmark during the years 1980 to 2002. However, we could not control for changes in admission practice, diagnostic performance, or treatment.
Keywords: Arrhythmia, Cohort study, Epidemiology, Mortality
Stroke is the third leading cause of death in developed countries such as the United States and many European countries.1 Reports from the United States and Europe have indicated that stroke-associated mortality has decreased during the period from 1970 to 2000 in developed countries.2
Atrial fibrillation is an important cause of stroke, especially in elderly subjects.3 The outcome (ie, disability and mortality) in stroke with atrial fibrillation is worse than in stroke without atrial fibrillation.4, 5, 6 Embolization from the heart, in particular from the left atrium in patients with atrial fibrillation, accounts for 17%-27% of all strokes.2 Approximately 17% of all deaths among stroke victims are attributable to atrial fibrillation.6
We do not have much information on trend in mortality in stroke with atrial fibrillation, but investigators from the Mayo Clinic recently reported that survival after stroke with atrial fibrillation in Olmsted County, Minnesota, United States, has remained unchanged over time in the period from 1980 to 2000 in men and women.7 However, the study from Olmsted County was based on 363 deaths during follow-up in 446 subjects with incident stroke and may, therefore, have been statistically underpowered due to the relatively low number of outcomes.
We examined national trends in mortality by calendar year period of stroke in patients with atrial fibrillation in Denmark (1980-1984, 1985-1989, 1990-1994, 1995-1999, and 2000-2002). We estimated trends separately for each sex in unadjusted analyses. We also adjusted for age, stroke severity, comorbid conditions, and general mortality in the background population.
Methods
Study Period and Study Population
The study was conducted in Denmark from January 1, 1980 to December 31, 2002 (identification of incident stroke with previous or concomitant nonvalvular atrial fibrillation or flutter), and to September 10, 2004 (follow-up on vital status) in Denmark. During the study period the total population increased from about 5.1 million to 5.4 million, and the population of interest for the present study, namely subjects aged 40-89 years, increased from 2.1 to 2.5 million. The general health and hospital care systems in Denmark are no charge and nonprofit systems that are financed through taxes.
Identification of Patients with an Incident Stroke Diagnosis Associated with a Diagnosis of Atrial Fibrillation
We identified all patients in Denmark, aged 40-89, with a first hospital diagnosis of stroke of any nature (ischemic or hemorrhagic) in the Danish National Registry of Patients from January 1, 1977 through December 31, 2002, or with an outpatient hospital clinic diagnosis of stroke during the period from January 1, 1994 through December 31, 2002. A primary, as well as a secondary diagnosis of stroke was included. Among those, we included patients with a diagnosis of nonvalvular atrial fibrillation that occurred before or at the time of a diagnosis of stroke for the survival analysis. The date of the first stroke diagnosis (date of admission) was defined as the baseline date and was noted, together with information about sex, age at stroke diagnosis, and comorbid conditions, before or at baseline. To reduce the risk of including patients with prevalent stroke diagnosis, we excluded patients who had a diagnosis of stroke during the period from 1977 to 1979. Patients with a diagnosis of heart valve disease before or at baseline also were excluded.
The Danish National Registry of Patients was established in 1977 and records 99.4% of all nonpsychiatric hospital contacts in Denmark.8 Data include the civil registry number, dates of admission and discharge, surgical procedures performed, and one or several diagnoses per discharge. The Danish version of the International Classification of Diseases, 8th Revision (ICD-8) was used until 1993, and thereafter the national version of ICD-10 was used. The physician who discharged a patient coded all diagnoses for that patient. A change in ICD coding from ICD-8 to ICD-10 occurred in Denmark in the beginning of 1994: Atrial fibrillation and atrial flutter were coded separately in ICD-8 (codes 427.93 and 427.94), but in ICD-10, atrial fibrillation and flutter have the same ICD code (I48). Therefore, we had to include atrial flutter in our study. Relevant ICD-8 and ICD-10 codes are listed in the Appendix.
Comorbidity
We obtained data on previous or simultaneous—if any—diagnoses of hyperthyroidism, diabetes and cardiovascular diseases (hypertension, ischemic heart disease, congestive heart failure, and heart valve disease) from the Danish National Registry of Patients from 1977 to the end of 2002.
Validation of Diagnoses of Atrial Fibrillation, Atrial Flutter and Stroke
To validate the diagnoses, we studied 2 random samples of 200 patients from the county of Aarhus, Denmark who had a diagnosis of atrial fibrillation or flutter or a diagnosis of stroke that occurred after a diagnosis of atrial fibrillation or flutter in the Danish National Registry of Patients during the study period from 1980 to 2002. (Aarhus, Denmark has approximately 500,000 inhabitants and 11 hospitals including 1 university hospital.) For atrial fibrillation or flutter, we could retrieve 174 of 200 medical records (index hospitalizations). In 172 of 174 patients, we found documentation for atrial fibrillation in an electrocardiogram, a printout from telemetry, a Holter recording, or an event recorder; this corresponds to a verification rate of 99%.
For a diagnosis of stroke after a diagnosis of atrial fibrillation or flutter, we could retrieve 164 of 200 medical records (index hospitalizations). Among those, 159 patients (97%) had a clinical diagnosis of stroke, defined according to the World Health Organization’s definition of stroke (ie, an acute disturbance of focal or global cerebral function with symptoms lasting more than 24 hours or leading to death of presumed vascular origin).9 The mean modified Rankin scale stroke severity score (scale from 0 to 5) was 3.5 among 151 subjects that could be scored during the validation process, and the mean Rankin scale score (score from 0 to 5) was 3.9 (calendar years 1980-1984), 3.9 (calendar years 1985-1989), 4.0 (calendar years 1990-1994), 3.2 (calendar years 1995-1999), and 3.3 (calendar years 2000-2002). The subjects that were erroneously coded as having stroke had transient ischemic attack (4 patients), and one patient had a pituitary gland tumor. Thus, the verification rate of stroke was 97%. Among those, 96% were admitted to the hospital within 30 days of the occurrence of symptoms of stroke; the vast majority were admitted within 24 hours from onset of symptoms. Eighty-three of 164 patients with a diagnosis of stroke had a computed tomography cerebral scan or a magnetic resonance cerebral scan. Among those, 92% could be classified as having ischemic stroke and 8% as having hemorrhagic stroke. Ischemic stroke with a hemorrhagic transformation was categorized as stroke of ischemic nature.
Follow-up and Outcome
Patients were followed in the Danish Civil Registration System until September 10, 2004 (emigration and vital status). This Civil Registration System has electronic records of all changes in status for the Danish population since 1968, including change in address, date of emigration, and date of death. The outcome of interest in this study was time to death after stroke.
We linked records from the different registries by using the civil registration number, a unique 10-digit code given to each individual having or having had an address in Denmark since April 1968.
Statistical Analysis
We used a multivariate Cox regression model separately in men and women with forced entry of age (10-year age group), history of diabetes (no, yes), history of hyperthyroidism (no, yes), history of hypertension (no, yes), history of ischemic heart disease (no, yes), history of congestive heart failure (no, yes), and calendar period of diagnosis of stroke. (Categories of calendar year intervals were: 1980-1984, 1985-1989, 1990-1994, 1995-1999, and 2000-2002.) We performed supplementary analyses by adding product terms, which included age and sex, and age and comorbid conditions, to test for interaction. We also assessed effect modification by stratified analyses (stratification by age 40-74 years vs age 75-89 years, and by conditions of comorbidity). The relevance of a variable in the model was further assessed by the change-in-estimate method.10 To adjust for the general mortality in the Danish population, we introduced a transformed version of observation time into Cox regression analysis, namely, the patients’ expected normal risk of dying during the time of observation, computed from the observed mortality in the general Danish population by sex, age and calendar period.11 To try to adjust for trend in severity of stroke, we assigned the mean modified Rankin scale score found in the validation series in each of the calendar year periods to all individuals within the same calendar year period. The proportional hazards assumption in the Cox models was evaluated using graphical assessment and was found appropriate in all models. We calculated 95% confidence intervals (CI) throughout the analyses. Trends in age and comorbidity by calendar period were evaluated by using Spearman nonparametric correlation analysis. All reported P values are 2-sided. We used SPSS statistical software version 11.5 (SPSS Inc., Chicago, Ill), and STATA statistical software version 7 (Stata Corp, College Station, Tex). Our study was approved by the Danish Data Protection Agency.
Results
During the study period from 1980 to 2002, we identified 24,470 subjects, aged 40-89 years, with an incident hospital diagnosis of stroke and a previous or concomitant diagnosis of nonvalvular atrial fibrillation or flutter; 11,554 were men and 12,916 were women. The age distribution and the proportion of men and women with a previous or a concomitant diagnosis of an endocrine or cardiovascular disease at baseline are shown in Table 1.
Table 1. Demographic and Clinical Data for 24,470 Men and Women with an Incident Hospital Diagnosis of Stroke and a Previous or Concomitant Diagnosis of Nonvalvular Atrial Fibrillation or Flutter in Denmark, 1980-2002
| Characteristic | Men (n = 11,554) | Women (n = 12,916) |
|---|---|---|
| Age (% of total) | ||
 40-49 | 1.1 | 0.3 |
| 50-59 | 5.7 | 1.6 |
| 60-69 | 19.3 | 9.5 |
| 70-79 | 43.2 | 37.6 |
| 80-89 | 30.7 | 51.0 |
| Condition of comorbidity (% of total) | ||
| Diabetes | 15.3 | 16.2 |
| Hyperthyroidism | 2.4 | 9.3 |
| Hypertension | 25.1 | 28.2 |
| Ischemic heart disease | 50.6 | 47.3 |
| Congestive heart failure | 30.3 | 29.9 |
Trend in Age and Diagnosed Comorbidity
Table 2 shows trends in age and comorbid conditions in patients with incident stroke by calendar year period. The number of patients diagnosed with stroke and atrial fibrillation increased over the study period. The mean age at time of stroke increased by 0.3 years from 73.9 years to 74.2 years in men, and by 2.0 years from 77.1 years to 79.1 years in women. Among subjects with stroke, the proportion diagnosed with diabetes decreased in women, but not in men. More patients had a diagnosis of hypertension, but fewer men and women had a diagnosis of ischemic heart disease and congestive heart failure during the study period.
Table 2. Trends in Age and Diagnosed Comorbidity by Calendar Period in 11,554 Men and 12,916 Women with an Incident Hospital Diagnosis of Stroke and a Previous or Concomitant Hospital Diagnosis of Nonvalvular Atrial Fibrillation or Flutter in Denmark, 1980-2002
| Characteristic | Calendar Year Period | |||||
|---|---|---|---|---|---|---|
| 1980-1984 | 1985-1989 | 1990-1994 | 1995-1999 | 2000-2002 | P Value for Correlation⁎ | |
| Men | ||||||
| Number of subjects | 1469 | 1923 | 2518 | 3149 | 2495 | |
| Age (mean ± SD) | 73.9±8.5 | 74.1±8.6 | 74.4±8.4 | 74.6±8.9 | 74.2±9.5 | <.001 |
| History and/or presence of (% of total) | ||||||
| Diabetes | 14.0 | 15.4 | 14.1 | 15.6 | 16.6 | .12 |
| Hyperthyroidism | 2.2 | 2.3 | 2.6 | 2.4 | 2.5 | .55 |
| Hypertension | 18.7 | 25.3 | 24.3 | 24.4 | 30.6 | <.001 |
| Ischemic heart disease | 68.5 | 61.5 | 49.6 | 43.4 | 41.9 | <.001 |
| Congestive heart failure | 29.3 | 35.7 | 32.8 | 28.6 | 26.1 | <.001 |
| Women | ||||||
| Number of subjects | 1810 | 2227 | 2837 | 3439 | 2603 | |
| Age (mean ± SD) | 77.1±7.3 | 78.2±7.1 | 78.5±7.1 | 79.0±7.3 | 79.1±7.3 | <.001 |
| History and/or presence of (% of total) | ||||||
| Diabetes | 18.4 | 18.6 | 16.0 | 14.4 | 15.3 | <.001 |
| Hyperthyroidism | 6.9 | 9.2 | 10.0 | 9.6 | 10.1 | .003 |
| Hypertension | 26.1 | 27.8 | 25.7 | 27.0 | 34.2 | <.001 |
| Ischemic heart disease | 66.0 | 58.9 | 47.0 | 39.3 | 35.3 | <.001 |
| Congestive heart failure | 29.4 | 32.7 | 32.3 | 29.2 | 25.9 | <.001 |
⁎Spearman nonparametric correlation. |
Trend in All-Cause Mortality
During 34,405 years of observation (mean 3.0 years), 9237 men died, and during 35,381 years of observation (mean 2.7 years), 10,827 women died. The age-adjusted cumulative survival (Kaplan-Meier estimate) improved by calendar period in both men and women (Figure 1). We observed a modest excess in risk of mortality in men relative to women, adjusted hazard ratio 1.07 (95% CI, 1.04-1.10) (adjusted by 10-year age group and conditions of comorbidity), but when we adjusted for mortality trend in the general population, we observed that the excess risk of mortality was reduced among men relative to women, adjusted hazard ratio 0.87 (95% CI, 0.82-0.87).
Figure 1.
Cumulative survival (Kaplan-Meier estimate) adjusted to age 75 years in men and women with stroke associated with nonvalvular atrial fibrillation by calendar period of diagnosis of stroke.
The relative magnitude of the improvement in survival by calendar period was estimated by Cox regression analyses, and the results appear in Table 3, Table 4. The adjusted hazard ratio for mortality decreased by 35% (95% CI, 29%-39%) in men and 31% (95% CI, 26%-36%) in women during the study period (Table 4). Adjustment for assigned mean Rankin stroke scale score within the calendar year periods did not change the estimated hazard ratio by calendar year period.
Table 3. Effect of Calendar Period of Stroke on Risk of Dying in 24,470 Men and Women with an Incident Hospital Diagnosis of Stroke and a Previous or Concomitant Hospital Diagnosis of Nonvalvular Atrial Fibrillation or Flutter in Denmark, 1980–2002
| Men (n = 11,554) Hazard Ratio (95% CI) | Women (n = 12,916) Hazard Ratio (95% CI) | |
|---|---|---|
| Model 1.Unadjusted estimates | ||
| 1980-1984 (reference) | 1.00 | 1.00 |
| 1985-1989 | 0.92(0.85-0.99) | 0.98(0.92-1.04) |
| 1990-1994 | 0.85(0.79-0.91) | 0.91(0.85-0.97) |
| 1995-1999 | 0.73(0.68-0.78) | 0.82(0.77-0.87) |
| 2000-2002 | 0.63(0.58-0.68) | 0.73(0.68-0.79) |
| P value for trend <.001 | P value for trend <.001 | |
| Model 2.Adjustment for 10-year age group and conditions of comorbidity⁎ | ||
| 1980-1984 (reference) | 1.00 | 1.00 |
| 1985-1989 | 0.91(0.85-0.97) | 0.94(0.88-1.00) |
| 1990-1994 | 0.83(0.77-0.88) | 0.87(0.82-0.92) |
| 1995-1999 | 0.72(0.67-0.77) | 0.78(0.73-0.83) |
| 2000-2002 | 0.62(0.57-0.67) | 0.70(0.65-0.75) |
| P value for trend <.001 | P value for trend <.001 | |
⁎Adjusted for 10-year age group, hypertension, diabetes, hyperthyroidism, ischemic heart disease, and congestive heart failure. |
Table 4. Effect of Calendar Period of Stroke on Risk of Dying in 24,470 Men and Women with an Incident Hospital Diagnosis of Stroke and a Previous or Concomitant Hospital Diagnosis of Nonvalvular Atrial Fibrillation or Flutter in Denmark, 1980–2002 with Adjustment for Mortality trend in the Danish Population
| Men (n = 11,554) Hazard Ratio (95% CI) | Women (n = 12,916) Hazard Ratio (95% CI) | |
|---|---|---|
| Model 3. Adjustment for 10-year age group, conditions of comorbidity and general mortality in the Danish population⁎ | ||
| 1980-1984 (reference) | 1.00 | 1.00 |
| 1985-1989 | 0.93(0.87-1.00) | 0.93(0.88-0.99) |
| 1990-1994 | 0.86(0.80-0.92) | 0.87(0.82-0.92) |
| 1995-1999 | 0.76(0.71-0.81) | 0.78(0.73-0.83) |
| 2000-2002 | 0.65(0.61-0.71) | 0.69(0.64-0.74) |
| P value for trend <.001 | P value for trend <.001 | |
⁎Adjusted for 10-year age group, hypertension, diabetes, hyperthyroidism, ischemic heart disease, congestive heart failure, and mortality trend in the Danish population. |
Discussion
We observed a marked advance in survival after stroke associated with nonvalvular atrial fibrillation or flutter. Several improvements have been introduced in medical treatment during the study period, such as oral anticoagulation, potent lipid lowering drugs, more intensive treatment of hypertension and heart failure, together with the establishment of facilities for thrombolysis, and stroke rehabilitation units. On the other hand, equipment for cerebral computed tomography or magnetic resonance scan has been widely disseminated in our country during the study period, and this may have led to diagnosis of many minor strokes, which would not have been diagnosed during the early part of the study period. This would cause us to overestimate the improvement in survival by calendar period. However, controlling for stroke severity did not change the estimates of improvement in survival.
Consistency with Other Findings
We found that an increasing number of patients with stroke associated with atrial fibrillation were reported to the Danish National Registry of Patients during the study period. This is in accordance with findings in Oxfordshire, UK, where a population-based cohort study with ascertainment of incident strokes by referral of any patients with a suspected cerebrovascular event from general practice to the Oxford Vascular Study for clinical assessment showed that the proportion of patients with known previous atrial fibrillation among patients with incident stroke increased from 9.6% in the period from 1981-1984 to 16.8% in the period from 2002-2004.12 We do not know if this increase in the number (or proportion) of patients with stroke associated with atrial fibrillation reflects a true increase in the incidence of atrial fibrillation at the population level, or if it mirrors the increasing interest in atrial fibrillation among health professionals and lay persons.13
We observed a better survival after stroke with atrial fibrillation over time. This is in contrast to findings in Olmsted County, Minnesota, where a community-based cohort study, which ascertained information on atrial fibrillation and stroke from recordings in administrative databases in the Mayo Clinic, showed that the relative mortality hazard in those who sustained a stroke with atrial fibrillation did not change over time in the period from 1980-2000.7 However, the results found in Olmsted County may be affected by lack of statistical power, because the number of subjects with the outcome of interest determines the statistical power. The number of subjects with stroke followed by death in the Olmsted County study was 363, whereas the number of subjects with stroke followed by death exceeded 20,000 in our study.
We believe that progress in medical treatment and rehabilitation of patients with stroke should translate into a better chance of surviving a stroke. For example, the user rate of oral anticoagulant therapy has increased during the study period in our country,14, 15 and an observational study has shown that oral anticoagulation in patients with atrial fibrillation reduces not only the frequency of ischemic stroke but also its severity and the risk of death from stroke.16 However, such an observational study should be interpreted with caution due to risk of confounding by indication.
Patients with stroke associated with atrial fibrillation are at a substantially increased risk of another stroke, the risk of a second stroke being approximately 10% annually.17 Treatment with oral anticoagulation in patients with stroke associated with atrial fibrillation is very effective in the prevention of another stroke, and the user rate of oral anticoagulation after stroke with atrial fibrillation has increased in our country.15
Strengths and Limitations
The major advantages of our study derive from the population-based design, the uniformly organized health care system, the identification of incident cases, the validation of a random sample of diagnoses, completeness of follow-up, and the large number of outcomes. Limitations arise from possible errors in assigning stroke severity score and coding of diagnoses. We assigned a stroke severity score to the total study cohort based on a relatively small sample of patients, so this part of our study should be read with caution. Misclassification of comorbid conditions, especially hypertension, may have occurred,18 and we lacked clinical details such as smoking status and severity of comorbid conditions. An earlier study has, together with the internal validation of diagnoses in this study, documented a high validity (ie, a high predictive value) of a diagnosis of atrial fibrillation or flutter in the Danish National Registry of Patients.19 Furthermore, as stroke severity is more pronounced in patients with atrial fibrillation, we find it very likely that those with a diagnosis of stroke actually had a stroke, and this was documented by the internal validation of stroke diagnoses in our study. A priori, we decided not to exclude patients with hemorrhagic stroke, because many strokes are reported to the Danish National Hospital Registry as unspecified strokes. However, the nature of stroke in patients with atrial fibrillation is predominantly embolic.17, 20, 21, 22, 23, 24, 25
Future Perspective
The health authorities in our country have recently introduced standards for treatment of stroke and a database to which all patients with stroke have to be reported together with information on comorbid medical conditions, stroke severity score, and treatment. Hopefully, those standardizing and monitoring activities will lead to better treatment and improved survival in patients with stroke, but any assessment of the progress in survival in stroke victims caused by monitoring activities initiated by health authorities should take into account that improvements in survival in stroke victims are already being seen.
Acknowledgments
This work was supported in part by the Clinical Institute, Aarhus University, and Western Danish Research Forum for Health Sciences.
Appendix
World Health Organization International Disease Classification (ICD) Codes, ICD-8 and ICD-10 used in the present analysis.
Atrial fibrillation and atrial flutter
427.93, 427.94, I48
Hyperthyreoidism
242, E05
Hypertension
400-404, 410.09, 411.09, 412.09, 413.09, 414.09, 435.09, 437.00, 437.01, 437.08, 437.09, 438.09, I10-I15
Diabetes
249, 250, E10-E14
Ischemic heart disease
410-414, I20-I25
Congestive heart failure
425.99, 427.09, 427.10, 427.11, 427.19, 427.99, 428.99, I50
Mitral and/or aortic valve disease
394-396, I05, I06, I08, I34, I35
Stroke
430-434, 436, I60-I64
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PII: S0002-9343(06)00095-7
doi:10.1016/j.amjmed.2005.12.027
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