Based on different estimation methods, mortality attributable to atrial fibrillation (AF) has been demonstrated to increase over time in developed countries, reaching a share ranging from 1% to 5% of overall deaths. To assess the whole burden of AF-associated mortality, all diseases mentioned in death certificates of subjects aged ≥45 years resident in the Veneto Region (Northeastern Italy) were analyzed for the 2008 to 2013 period. The prevalence of common chronic co-morbidities was compared between deaths with mention of AF and a sample of age-matched deaths without reported AF. The disease was mentioned among conditions contributing to death in 25,834 subjects, corresponding to 9.8% of all regional deaths. Rates of AF-associated mortality were higher in men and increased steeply with age, being above 1 per 100 among residents aged ≥85 years. Compared with non–AF-associated deaths, the strongest associations were observed between AF and hypertensive diseases (prevalence ratio 1.62, 95% CI 1.57 to 1.67), cardiac valve disorders (2.43, 2.25 to 2.61), cardiomyopathies (1.93, 1.70 to 2.19), cerebrovascular diseases (1.55, 1.50 to 1.60), and chronic obstructive pulmonary disease (1.49, 1.42 to 1.57). AF-associated mortality resulted higher than previously reported, probably due to aging of the population with multiple predisposing diseases, an increased recognition of AF among the elderly, and a raised awareness of certifying physicians about the importance of AF. Analyses of all diseases mentioned in death certificates underscored the interaction of AF with several other circulatory and respiratory disorders in pathologic networks leading to an increased risk of death.
Atrial fibrillation (AF) is a well-established risk factor for stroke, peripheral vascular complications, and heart failure. Patients with AF have a fivefold and twofold higher risk of stroke and death, respectively. In population-based studies, patients with AF had a significantly increased risk of all-cause mortality compared with controls, even after adjustment for concomitant diseases. Mortality attributable to AF has been demonstrated to increase over time by studies adopting different methods, reaching in developed countries a share ranging from 1% to 5% of overall deaths. By analysis of multiple causes of death (MCOD) data, the aim of the study was to estimate the whole burden of AF-associated mortality in the Veneto Region (Northeastern Italy) and to investigate the main co-morbidities.
Methods
The Veneto region has about 4.9 million inhabitants. Life expectancy is about 80 and 85 years in men and women, respectively. A copy of death certificates of each resident in Veneto is routinely transmitted to the Regional Epidemiology Department for coding of the causes of death according to the International Classification of Diseases, Tenth Edition (ICD-10). Part I of the death certificate reports the causal sequence from the immediate cause of death, to intermediate cause(s), to a single underlying cause of death (UCOD), defined as the disease or injury which initiated the train of morbid events leading directly to death. Part II includes other significant conditions contributing to death. Standard mortality statistics are based on internationally adopted algorithms that identify the UCOD from all the conditions reported on a certificate. The UCOD generally corresponds to the underlying cause stated by the certifier, but it could also be another disease reported in Part I or II, or a derived condition. Since 2008, the regional mortality database includes not only the UCOD but all the diseases mentioned in the certificate (MCOD). The selection of the UCOD is performed using the Automated Classification of Medical Entities, which is a computer program developed by the US National Center for Health Statistics to standardize assignment of the underlying cause.
Mention of AF or flutter (ICD-10 code I48) was searched among MCOD records of all decedents aged ≥45 years in the period 2008 to 2013 to retrieve all AF-associated deaths. Proportional mortality (percentage of all registered deaths) and age- and gender-specific mortality rates were computed for AF selected as the UCOD, and for AF mentioned anywhere in the certificate; population data were downloaded from the National Institute for Statistics website ( http://demo.istat.it/ ).
The proportion of death certificates with mention of AF was determined for the most frequently selected UCOD among all deaths of residents in the Region. Among deaths with any mention of AF, the distribution of the UCOD according to major disease categories and the prevalence of common chronic co-morbidities reported in any position of death certificates were investigated. The latter figures were compared with a sample of frequency-matched deaths (matched by 5-year age classes) without reported AF. The probability of mention of selected co-morbidities was compared between AF-associated and non–AF-associated deaths by means of prevalence ratios with 95% CIs estimated through log-binomial regression.
Results
AF was selected as the UCOD in only 1.1% of all deaths among subjects aged ≥45 years but was mentioned in 9.8% of all death certificates ( Table 1 ). Both proportional mortality and population-based mortality rates increased steeply with age; AF-associated mortality rates were above 1 per 100 among residents aged ≥85 years. When AF was reported in the certificate, the probability of selection as the UCOD was higher among older age classes.
| Age | Atrial Fibrillation UCOD, n | Proportional mortality % | Rate x 100,000 | Atrial Fibrillation MCOD, n | Proportional mortality % | Rate x 100,000 | UCOD/MCOD ratio |
|---|---|---|---|---|---|---|---|
| 45-49 | 1 | 0.0% | 0.0 | 15 | 0.4% | 0.6 | 0.07 |
| 50-54 | 2 | 0.0% | 0.1 | 32 | 0.7% | 1.6 | 0.06 |
| 55-59 | 8 | 0.1% | 0.4 | 105 | 1.5% | 5.8 | 0.08 |
| 60-64 | 9 | 0.1% | 0.5 | 253 | 2.2% | 14.4 | 0.04 |
| 65-69 | 41 | 0.3% | 2.6 | 561 | 3.5% | 35.4 | 0.07 |
| 70-74 | 100 | 0.4% | 6.9 | 1351 | 5.6% | 93.6 | 0.07 |
| 75-79 | 242 | 0.7% | 20.9 | 2843 | 8.3% | 245.7 | 0.09 |
| 80-84 | 558 | 1.1% | 62.2 | 5652 | 11.4% | 630.4 | 0.10 |
| 85-89 | 845 | 1.5% | 155.6 | 7685 | 13.4% | 1414.9 | 0.11 |
| 90+ | 1,039 | 1.9% | 430.6 | 7337 | 13.3% | 3040.8 | 0.14 |
| Total 45+ | 2845 | 1.1% | 20.6 | 25834 | 9.8% | 187.1 | 0.11 |
Age-specific mortality rates were higher in men than in women ( Figure 1 ). In analyses restricted to the UCOD, death rates from AF tended to converge between genders among the very elderly; in MCOD analyses of all AF-associated deaths, rates remained higher in men across all age classes.
Table 2 lists the probability of mention of AF in regional deaths according to the selected UCOD. AF was reported in 16% of all deaths from circulatory diseases (especially cardiac valve disorders, hypertensive diseases, and cardiomyopathy) and in only 4.4% of deaths from cancer. AF was mentioned in a large proportion of deaths from respiratory diseases, both chronic (chronic obstructive pulmonary disease [COPD]) and acute (pneumonia).
| n | % with mention of atrial fibrillation | |
|---|---|---|
| All circulatory diseases (I00-I99) | 97,611 | 16.0% |
| Atrial fibrillation and flutter (I48) | 2,845 | 100.0% |
| Hypertensive diseases (I10-I15) | 12,957 | 19.7% |
| Ischemic heart diseases (I20-I25) | 35,351 | 13.6% |
| Cardiac valve disorders (I05-I08, I34-I38) | 3,965 | 23.3% |
| Cardiomyopathy (I42) | 2,076 | 18.4% |
| Cerebrovascular diseases (I60-I69) | 22,865 | 12.5% |
| All neoplasms (C00-D48) | 82,372 | 4.4% |
| Diabetes (E10-E14) | 7,904 | 8.4% |
| Dementia, Alzheimer (F01–F03, G30) | 14,537 | 6.5% |
| All respiratory diseases (J00-J98) | 18,379 | 11.0% |
| COPD (J40–J44, J47) | 7,068 | 12.3% |
| Influenza, pneumonia (J10-J18) | 5,696 | 11.1% |
| All other causes of death | 42,441 | 7.1% |
| All deaths | 263,244 | 9.8% |
The proportion of deaths from cerebrovascular diseases reporting AF resulted equal to 12.5%. However, AF and cerebrovascular diseases are competing causes for the selection as the UCOD: Figure 2 shows that in about 35% of deaths with AF selected as the UCOD, a cerebrovascular disease was mentioned in the certificate. Furthermore, in nearly 3,300 deaths, both AF and cerebrovascular diseases were reported, but another UCOD was selected.
Among all AF-associated deaths, the UCOD was a circulatory disease in 60% and a neoplasm in 14% of cases ( Table 3 ). When comparing all mentioned co-morbidities between AF-associated and non–AF-associated deaths, the strongest associations were observed between AF and hypertensive diseases, cardiac valve disorders, cardiomyopathies, cerebrovascular diseases, and COPD.
| AF-associated deaths (n=25,834) | Age-matched non-AF associated deaths (n=25,834) | Mention in AF compared to non-AF associated deaths | |||
|---|---|---|---|---|---|
| UCOD | MCOD | UCOD | MCOD | Prevalence ratio (95% Confidence Interval) | |
| All circulatory diseases (I00-I99) | 60.3% | 39.0% | |||
| Atrial fibrillation and flutter (I48) | 11.0% | 0.0% | |||
| Hypertensive diseases (I10-I15) | 9.9% | 32.3% | 5.3% | 19.8% | 1.62 (1.57 – 1.67) |
| Ischemic heart diseases (I20-I25) | 18.6% | 29.3% | 14.1% | 23.1% | 1.27 (1.33 – 1.31) |
| Cardiac valve disorders (I05-I08, I34-I38) | 3.6% | 8.5% | 1.3% | 3.5% | 2.43 (2.25 – 2.61) |
| Cardiomyopathy (I42) | 1.5% | 2.6% | 0.7% | 1.4% | 1.93 (1.70 – 2.19) |
| Cerebrovascular diseases (I60-I69) | 11.1% | 27.7% | 9.9% | 17.8% | 1.55 (1.50 – 1.60) |
| All neoplasms (C00-D48) | 14.0% | 21.2% | 26.4% | 31.4% | 0.67 (0.65 – 0.69) |
| Diabetes (E10-E14) | 2.6% | 16.6% | 3.1% | 12.5% | 1.34 (1.28 – 1.39) |
| Dementia, Alzheimer (F01–F03, G30) | 3.7% | 10.1% | 7.3% | 13.6% | 0.75 (0.71 – 0.78) |
| COPD (J40–J44, J47) | 3.4% | 12.6% | 3.1% | 8.5% | 1.49 (1.42 – 1.57) |
| Influenza, pneumonia (J10-J18) | 2.4% | 12.7% | 2.5% | 11.4% | 1.12 (1.07 – 1.17) |
| All other causes of death | 13.7% | 18.6% | |||
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