Recurrence of syncope is a common event, but the influence of recurrent syncope on the risk of death has not previously been investigated on a large scale. We examined the prognostic impact of recurrent syncope in a nationwide cohort of patients with syncope. All patients (n = 70,819) hospitalized from 2001 to 2009 in Denmark with a first-time diagnosis of syncope aged from 15 to 90 years were identified from national registries. Recurrence of syncope was incorporated as a time-dependent variable in multivariable-adjusted Cox models on the outcomes of 30-day, 1-year, and long-term all-cause mortality and cardiovascular death. During a mean follow-up of 3.9 ± 2.6 years, a total of 11,621 patients (16.4%) had at least 1 hospitalization for recurrent syncope, with a median time to recurrence of 251 days (33 to 364). A total of 14,270 patients died, and 3,204 deaths were preceded by a hospitalization for recurrent syncope. The long-term risk of all-cause death was significantly associated with recurrent syncope (hazard ratio 2.64, 95% confidence interval 2.54 to 2.75) compared with those with no recurrence. On 1-year mortality, recurrent syncope was associated with a 3.2-fold increase in risk and on 30-day mortality associated with a threefold increase. The increased mortality risk was consistent over age groups 15 to 39, 40 to 59, and 60 to 89 years, and a similar pattern of increase in both long-term and short-term risk of cardiovascular death was evident. In conclusion, recurrent syncope is independently associated with all-cause and cardiovascular mortality across all age groups exhibiting a high prognostic influence. Increased awareness on high short- and long-term risk of adverse events in subjects with recurrent syncope is warranted for future risk stratification.
Syncope is a common symptom in the general population and a frequent cause of hospitalization and emergency department visit. Many patients experience recurrence, and it has recently been shown that in patients aged >50 years, at least 20% are rehospitalized for recurrent syncope within 3.5 years, while studies with implantable loop recorders in patients with multiple recurrences have shown even higher frequencies and short-term risk of recurrences. Recurrences have been associated with increased risk of fractures, low quality of life, and greater chance of subsequent recurrent syncope, but it is unknown if recurrence in itself is a cause for concern as a marker for increased risk of mortality and should be acknowledged in risk stratification. Naturally, the prognosis of syncope is determined by the underlying cause and/or co-morbidity. However, recent hospitalization for first syncope was associated with adverse prognosis even in otherwise healthy subjects suggesting that either syncope could be the first sign of unrecognized cardiovascular disease or that syncope per se (maybe due to recurrences, fractures, or traumatic accidents) was responsible for the increased risk. Studies on specific cardiac conditions such as Brugada syndrome and long QT syndrome have shown that the number of recurrences is directly correlated with increased risk of death, but the impact of recurrent syncope in an unselected cohort of patients hospitalized for syncope has never been examined. We aimed to investigate the overall prognosis of syncope and the incidence and effect of recurrent syncope in a large cohort of unselected patients hospitalized for first-time syncope.
Methods
In Denmark, all residents have a unique and permanent civil registration number that enables linkage on an individual level among nationwide administrative registries. We identified all patients aged 15 to 90 years who had a first-time diagnosis of syncope (International Classification of Diseases, tenth revision [ICD-10] discharge diagnosis R55.9) from all public hospitals and emergency departments in the period 2001 to 2009. The patients were censored at the end of follow-up (December 31, 2009) or on the date of turning 90 years. Validation of the syncope diagnosis (R55.9) carried out in 2012 revealed a positive predictive value of 95% and a sensitivity of 63%. Validation and chart review also showed that the syncope discharge diagnosis contained most common forms of etiological causes of syncope, such as reflex syncope, orthostatic hypotension syncope, and cardiac syncope, and that approximately 50% are of unknown or undetermined etiology at the end of follow-up. Etiological data are not available in the registries on the individual level, because they are not registered as such in the ICD-10 system.
Information on previous hospitalizations and co-morbidities were gathered from the Danish National Patient Register in a 5-year period before first-time hospitalization for syncope. The diagnoses were based on primary or secondary discharge diagnoses according to the ICD-10 system. Cardiovascular disease was categorized as presence of one of the following co-morbidities: hypertension, previous stroke, ischemic heart disease or previous myocardial infarction, heart failure, atrial fibrillation, previous atrioventricular block, peripheral vascular disease, or a previous implantation with implantable cardioverter-defibrillator or pacemaker.
Baseline medications were obtained from the Register of Medicinal Products Statistics in a 180-day period up to first-time hospitalization for syncope. This register holds information on all dispensed prescriptions from all Danish pharmacies and is based on the Anatomical Therapeutic Chemical system. Cause and date of death, date of birth, and vital status were obtained from the Danish Register of Causes of Death and the Central Personal Registry.
Recurrent syncope was defined as a discharge diagnosis of syncope (ICD-10 R55.9) from either an admission or visit to an emergency department (hospital contact) at any time after discharge of initial first-time syncope until end of follow-up or until time of censoring. Outpatient or ambulatory diagnoses were not considered as events. Primary outcome was all-cause mortality, and deaths defined as cardiovascular deaths were considered secondary outcomes. Tertiary outcomes were all-cause mortality and cardiovascular mortality within 1 year, 30 days, and 1 week. The study was accepted by the Danish Data Protection Agency (ref. 2007-58-0015, int.ref. GEH-2010-001).
Comparison of categorical variables between patients with syncope with recurrence and without recurrence was performed using chi-square test, whereas age was compared using Kruskal-Wallis test. For trend test analysis among categorical age groups and recurrent syncope, we used the method of Cochran-Armitage. Cumulative probabilities of all-cause death are shown by method of Kaplan-Meier.
Cox proportional hazards regression models were used to identify predictors of all-cause mortality by a stepwise selection of variables from the pool of available covariates in the data set as previously identified and defined. The limit of significance for entry in the model was set at 0.05. Thirteen covariates were selected for the final fitted model, including age, gender, cancer, heart failure, liver disease, chronic obstructive pulmonary disease, previous stroke, renal disease, peripheral vascular disease, dementia, atrial fibrillation, and year of inclusion. We adjusted for these predictive covariates in the adjusted models. Relative risks are presented as hazard ratios with 95% confidence intervals. Recurrent syncope was then entered into the fitted models as a time-dependent variable taking into account the date of recurrence, and thus the contributing risk time of the covariate is incorporated in the analysis. We tested interactions of age as a continuous variable and gender, because these were a priori expected to influence the time-dependent recurrent syncope covariate. Interaction was considered significant in univariate and multivariate models at the 0.05 level. Significant interactions were found between age and time-dependent recurrent syncope and gender and time-dependent recurrent syncope on the end point of all-cause mortality. Therefore, the presented models are also stratified by gender and age intervals into 3 groups (15 to 39, 40 to 59, and 60 to 89 years). An overall 2-sided p value was considered statistically significant if <0.05. Analyses were performed in SAS (version 9.2; SAS Institute, Cary, North Carolina).
Results
We identified a cohort of 70,819 patients with syncope discharged after admission (49%) or discharged directly from emergency department (51%) for first-time syncope. The mean age was 60 ± 20 years, 51% were men, and 38% had a cardiovascular co-morbidity at inclusion in the study ( Table 1 ). During an average follow-up of 3.9 ± 2.6 years, 14,270 patients (20%) with syncope died from all causes, and 7,681 (54%) of these deaths were due to cardiovascular causes. The overall 1-year mortality for first-syncope patients aged 15 to 39 years was 0.4% (48 of 13,161), 2.7% (468 of 17,053) in the age group of 40 to 59, and 10.6% (4,299 of 40,605) for patients aged 60 to 89 years. The 4-year cumulative probability of all-cause mortality for the whole population was 19%, whereas Kaplan-Meier graphs stratified by presence of cardiovascular disease and the age groups show an expected influence on all-cause mortality ( Figure 1 ).
| Variable | Total Patients (n = 70,819) | Recurrent Syncope | |
|---|---|---|---|
| Yes (n = 11,621 [16.4%]) | No (n = 59,198 [83.6%]) | ||
| Men | 34,692 (49.0) | 5,982 (51.5) | 28,710 (48.5) ∗ |
| Women | 36,127 (51.0) | 5,639 (48.5) | 30,488 (51.5) ∗ |
| Age, yrs (mean ± SD) | 60.4 ± 19.7 | 63.7 ± 18.5 | 59.7 ± 19.9 ∗ |
| 15–39 | 13,161 (18.6) | 1,592 (13.7) | 11,569 (19.5) ∗ |
| 40–59 | 17,053 (24.1) | 2,333 (20.1) | 14,270 (24.9) ∗ |
| 60–89 | 40,605 (57.3) | 7,696 (66.2) | 32,909 (55.6) ∗ |
| <60 | 30,214 (42.7) | 3,925 (33.8) | 26,289 (44.4) |
| ED as first syncope contact | 36,268 (51.2) | 4,983 (42.9) | 31,285 (52.9) ∗ |
| Admitted at first syncope | 34,551 (48.8) | 6,638 (57.1) | 27,913 (47.2) ∗ |
| Cardiovascular disease | 27,117 (38.4) | 5,427 (46.7) | 21,750 (36.7) ∗ |
| Hypertension | 19,075 (26.9) | 3,772 (32.5) | 15,303 (25.9) ∗ |
| Coronary heart disease | 7,565 (10.7) | 1,696 (14.6) | 5,869 (9.9) ∗ |
| Myocardial infarction | 2.638 (3.7) | 537 (4.6) | 2,101 (3.6) ∗ |
| Heart failure | 4,430 (6.3) | 904 (7.8) | 3,526 (6.0) ∗ |
| Cerebral vascular disease | 5,502 (7.8) | 1,045 (9.0) | 4,457 (7.5) ∗ |
| Peripheral artery disease | 948 (1.3) | 209 (1.8) | 739 (1.3) |
| Atrioventricular block | 1,378 (1.9) | 318 (2.7) | 1,060 (1.8) ∗ |
| Atrial fibrillation | 5,273 (7.5) | 1,119 (9.6) | 4,154 (7.0) ∗ |
| Diabetes mellitus | 5,679 (8.0) | 1,106 (9.5) | 4,573 (7.7) ∗ |
| Renal disease | 961 (1.4) | 216 (1.9) | 745 (1.3) ∗ |
| Liver disease | 657 (0.9) | 115 (1.0) | 542 (0.9) |
| Chronic obstructive pulmonary disorder | 6,970 (9.9) | 1,265 (10.9) | 5,714 (9.7) ∗ |
| Cancer | 2,264 (3.2) | 389 (3.4) | 1,875 (3.2) |
| Implanted pacemaker | 725 (1.0) | 139 (1.2) | 586 (1.0) |
| Implanted cardioverter-defibrillator | 201 (0.3) | 41 (0.4) | 160 (0.3) |
| Concomitant pharmacotherapy | |||
| β Blockers | 12,329 (17.4) | 2,450 (21.1) | 9,979 (16.7) ∗ |
| ACEi/ARB | 16,931 (23.9) | 3,375 (29.0) | 13,556 (22.9) ∗ |
| Loop diuretics | 8,718 (12.3) | 1,802 (15.5) | 6,916 (11.7) ∗ |
| Thiazide | 9,642 (13.6) | 1,874 (16.1) | 7,768 (13.1) ∗ |
| Nitrates | 4,871 (6.9) | 1,131 (9.7) | 3,740 (6.3) ∗ |
| Antipsychotics | 3,582 (5.1) | 590 (5.1) | 2,992 (5.1) |
| Anxiolytics | 16,561 (23.4) | 3,090 (26.6) | 13,471 (22.8) ∗ |
A total of 11,621 patients (16%) experienced at least 1 episode of syncopal recurrence requiring hospital contact. There was an increasing proportion of hospitalization for recurrent syncope with increasing age, with 12%, 14%, and 19% for ages 15 to 39, 40 to 59, and 60 to 89 years (p for trend test <0.001), respectively. This is despite the competing risk of death of the elderly, leaving them with less follow-up time for recurrent events than the younger patients. Comparing those with recurrent syncope versus those with first-time syncope only ( Table 1 ) shows some differences, most importantly higher mean age and an overall higher frequency of cardiovascular as well as noncardiovascular diseases in patients with recurrent syncope. The mean time from first-time syncope to recurrent syncope was 1.1 ± 0.6 years, and 50% of the patients experienced the recurrence within 251 days (33 to 364).
The mean time from recurrence of syncope to death was 3.2 ± 2.6 years. The influence of recurrent syncope on risk of all-cause death ( Table 2 ) showed a significant, more than twofold, increase in risk of death compared with those who did not experience recurrent syncope. The risk of all-cause death was significantly associated with recurrent syncope in all the age groups from 15 to 39, 40 to 59, and 60 to 89 years ( Table 3 ). Looking specifically in the youngest age group (15 to 39 years) 185 patients died during follow-up, and 31 of those (16.8%) were preceded by recurrent syncope. The relative risk of all-cause death in those with recurrence for this age group was 74% higher than in those without recurrence ( Table 3 ).
| Variable | Hazard Ratio | 95% Confidence Interval | p Value |
|---|---|---|---|
| Recurrent syncope requiring hospitalization | 2.64 | 2.54–2.75 | <0.001 |
| Age (/yr increase) | 1.07 | 1.07–1.07 | <0.001 |
| Cancer | 3.07 | 2.90–3.24 | <0.001 |
| Heart failure | 1.76 | 1.68–1.85 | <0.001 |
| Male sex | 1.52 | 1.47–1.57 | <0.001 |
| Liver disease | 3.51 | 3.13–3.93 | <0.001 |
| Chronic obstructive pulmonary disease | 1.53 | 1.46–1.60 | <0.001 |
| Renal disease | 1.98 | 1.81–2.16 | <0.001 |
| Previous stroke | 1.39 | 1.33–1.45 | <0.001 |
| Diabetes mellitus | 1.45 | 1.37–1.54 | <0.001 |
| Peripheral vascular disease | 1.67 | 1.53–1.82 | <0.001 |
| Dementia | 2.97 | 2.42–3.64 | <0.001 |
| Atrial fibrillation | 1.21 | 1.15–1.27 | <0.001 |
| Year of inclusion (/yr) | 0.97 | 0.96–0.97 | <0.001 |
| Total Number of Deaths/Recurrences | Recurrence and Death | Hazard Ratio Recurrence:No Recurrence | 95% Confidence Interval | p Value | |
|---|---|---|---|---|---|
| Long-term ACM | |||||
| Age 15–39 | 185/1,592 | 31 | 1.74 | 1.18–2.56 | 0.005 |
| Age 40–59 | 1,501/2,333 | 283 | 1.72 | 1.51–1.96 | <0.001 |
| Age 60–89 | 12,584/7,696 | 2,890 | 1.69 | 1.60–1.74 | <0.001 |
| Women | 6,151/5,639 | 1,315 | 2.41 | 2.27–2.56 | <0.001 |
| Men | 8,119/5,982 | 1,889 | 2.83 | 2.69–2.99 | <0.001 |
| 1-yr ACM | |||||
| Age 15–39 | 48/1,194 | 6 | 1.96 | 0.83–4.62 | 0.123 |
| Age 40–59 | 468/1,778 | 56 | 1.95 | 1.48–2.58 | <0.001 |
| Age 60–89 | 4,299/6,013 | 630 | 3.12 | 2.86–3.40 | <0.001 |
| Women | 2,044/4,255 | 267 | 2.87 | 2.52–3.27 | <0.001 |
| Men | 2,811/4,730 | 425 | 3.49 | 3.14–3.87 | <0.001 |
| 30-Day ACM | |||||
| Age 15–39 | 6/537 | 2 | 17.34 | 3.18–94.72 | 0.001 |
| Age 40–59 | 66/740 | 2 | 1.09 | 0.27–4.44 | 0.908 |
| Age 60–89 | 691/1,538 | 46 | 2.96 | 2.18–4.01 | <0.001 |
| Women | 312/1,434 | 20 | 2.91 | 1.84–4.60 | <0.001 |
| Men | 451/1,381 | 30 | 3.24 | 2.22–4.72 | <0.001 |
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