Chronic kidney disease is a risk factor for cardiovascular events, but how it relates to the prognosis associated with clinical risk factors for thromboembolism in patients with nonvalvular atrial fibrillation (AF) is not well known. Estimated glomerular filtration rate (eGFR), score for congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and stroke/transient ischemic attack (CHADS 2 ), and clinical outcomes of cardiovascular events were determined in 387 patients with nonvalvular AF (mean age 66 years, 289 men, mean follow-up 5.6 ± 3.2 years). Decreased eGFR (<60 ml/min/1.73 m 2 ) combined with CHADS 2 score ≥2 was associated with higher all-cause (12.9% vs 1.4% per year, hazard ratio [HR] 6.9, p <0.001) and cardiovascular (6.5% vs 0.2% per year, HR 29.7, p <0.001) mortalities compared to preserved eGFR (≥60 ml/min/1.73 m 2 ) combined with CHADS 2 score <2. This was also true for rates of cardiac events (cardiac death, nonfatal myocardial infarction, or hospitalization for worsening of heart failure, 10.4% vs 1.3% per year, HR 8.9, p <0.001), ischemic stroke (3.6% vs 0.2% per year, HR 11.0, p <0.001), and cardiovascular events (cardiac events and ischemic stroke, 13.6% vs 1.5% per year, HR 8.3, p <0.001). On multivariate analysis, CHADS 2 score ≥2, decreased eGFR, and male gender independently predicted all-cause mortality. In conclusion, combined eGFR and CHADS 2 score could be an independent powerful predictor of cardiovascular events and mortality in patients with nonvalvular AF. Long-term mortality, cardiac events, and stroke risk were >8 times higher when decreased eGFR (<60 ml/min/1.73 m 2 ) was present with higher CHADS 2 score (≥2).
Atrial fibrillation (AF) is associated with an increased risk of thromboembolic events including stroke, and risk can vary with clinical characteristics of patients. The score for congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and stroke/transient ischemic attack (CHADS 2 ; 1 point each for congestive heart failure, hypertension, age ≥75 years, and diabetes mellitus and 2 points for previous stroke/transient ischemic attack) is a well-validated stroke risk stratification scheme for patients with nonvalvular AF. The CHADS 2 components, i.e., heart failure, hypertension, and diabetes mellitus, are risk factors for stroke, cardiovascular events, and mortality. Chronic kidney disease (CKD) is also a risk factor for cardiovascular events and mortality in community and high-risk patients. The CHADS 2 risk factors are well known to contribute to the progression of kidney disease. The present study examined the prognostic usefulness of estimated glomerular filtration rate (eGFR) as a marker of CKD in combination with CHADS 2 score to predict subsequent cardiovascular events in patients with nonvalvular AF.
Methods
From November 1994 through May 2007, 745 patients with AF underwent transesophageal echocardiography at Toyama University Hospital (Toyama, Japan). Of these 745, 526 patients with nonvalvular AF gave written informed consent to participate in the follow-up study. Three hundred eighty-seven patients with nonvalvular AF had determination of eGFR at time of transesophageal echocardiography (289 men, mean age 66 ± 11 years) and constituted the study group. Transesophageal echocardiography was performed to determine embolic risk levels in these patients. Patients in the acute phase of cardiovascular diseases including ischemic stroke or infection and those receiving kidney transplant or hemodialysis were excluded. Chronic AF was defined as AF documented electrocardiographically on ≥2 separate occasions (4 weeks apart). Baseline characteristics including CHADS 2 score for each patient were obtained from medical records. The eGFR was determined using the plasma creatinine level within 1 month after entry: eGFR (milliliters per minute per 1.73 m 2 ) = 194 × (serum creatinine [milligrams per deciliter]) −1.094 × age −0.287 × 0.739 (in women).
Patients were divided into groups by eGFR (≥60 and <60 ml/min/1.73 m 2 ), CHADS 2 score (<2 and ≥2), and their combination. The study was approved by the institutional ethics committee, and informed consent was obtained from each patient as indicated earlier.
Composite end points of death from any cause, ischemic stroke, and cardiac events (myocardial infarction or hospitalization for worsening of heart failure) were determined in October 2008. Stroke and cardiac events constituted cardiovascular events. Information on end points was collected from hospital databases and responses to questionnaires by patients or their relatives. Stroke was defined as a neurologic deficit of sudden onset, lasting >24 hours, and confirmed by brain computed tomography or magnetic resonance imaging. Myocardial infarction was defined as typical chest symptoms with electrocardiographic changes and increases in cardiac enzymes.
Data are expressed as mean ± SD. All analyses were performed using SPSS 11.0 J (SPSS, Inc., Chicago, Illinois). Mean values and proportions of variables were compared using unpaired Student’s t test, analysis of variance, and chi-square test, respectively. Outcomes were displayed with Kaplan–Meier survival curves and compared using log-rank test. Multivariate Cox proportional hazards regression was used to determine independent predictors of the end points. A p value <0.05 was considered statistically significant.
Results
Mean eGFR at entry to the study was 68 ± 21 ml/min/1.73 m 2 . Table 1 lists clinical characteristics according to baseline eGFR levels. Patients with decreased eGFR (<60 ml/min/1.73 m 2 ) were older and had higher CHADS 2 score compared to those with preserved eGFR (≥60 ml/min/1.73 m 2 ). Proportions of women and patients with chronic AF tended to be larger and those with previous heart failure and stroke/transient ischemic attack were larger in the decreased eGFR group than in the preserved eGFR group. Warfarin and antiplatelet administrations were similar for the 2 groups. Mean prothrombin time-international normalized ratio did not differ between the 2 groups ( Table 1 ). Mean eGFR significantly decreased with an increase in CHADS 2 score ( Table 2 ).
| Variable | Overall (n = 387) | eGFR (ml/min/1.73 m 2 ) | p Value ⁎ | |
|---|---|---|---|---|
| ≥60 (n = 258) | <60 (n = 129) | |||
| Mean estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 68 ± 21 | 79 ± 15 | 46 ± 13 | <0.001 |
| Age (years) | 66 ± 11 | 63 ± 11 | 72 ± 10 | <0.001 |
| Men | 289 (75%) | 200 (78%) | 89 (69%) | 0.07 |
| Chronic atrial fibrillation | 190 (49%) | 118 (46%) | 72 (56%) | 0.06 |
| Heart failure | 98 (25%) | 56 (22%) | 42 (33%) | <0.05 |
| Hypertension | 157 (41%) | 102 (40%) | 55 (43%) | 0.56 |
| Age ≥75 years | 96 (25%) | 37 (14%) | 59 (46%) | <0.001 |
| Diabetes mellitus | 64 (17%) | 40 (16%) | 24 (19%) | 0.44 |
| Previous stroke/transient ischemic attack | 107 (28%) | 63 (24%) | 44 (34%) | <0.05 |
| CHADS 2 score | 1.6 ± 1.4 | 1.4 ± 1.4 | 2.1 ± 1.3 | <0.001 |
| CHADS 2 score ≥2 | 177 (46%) | 103 (40%) | 74 (57%) | <0.01 |
| Antiplatelet drugs | 85 (22%) | 56 (22%) | 29 (22%) | 0.98 |
| Warfarin | 284 (73%) | 188 (73%) | 96 (74%) | 0.84 |
| Prothrombin time-international normalized ratio | 1.7 ± 1.2 | 1.8 ± 1.4 | 1.6 ± 0.7 | 0.38 |
⁎ For estimated glomerular filtration rate ≥60 versus <60 ml/min/1.73 m 2 .
| Variable | CHADS 2 Score | p Value | ||
|---|---|---|---|---|
| 0 | 1 | ≥2 | ||
| (n = 101) | (n = 109) | (n = 177) | ||
| Age (years) | 59 ± 11 | 66 ± 10 | 71 ± 10 | <0.001 |
| Men | 74 (73%) | 81 (74%) | 134 (76%) | 0.90 |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 77 ± 18 | 68 ± 22 | 64 ± 21 | <0.001 |
During a follow-up period of 5.6 ± 3.2 years, 95 patients (25%) died, 68 (18%) had cardiac events (11 with myocardial infarction and 57 with hospitalization for worsening of heart failure), 25 (6%) had ischemic stroke, and 5 (1%) had bleeding events (4 with cerebral bleeding and 1 with gastric bleeding). Table 3 lists causes of death. Long-term survival was significantly lower in patients with decreased eGFR than in those with preserved eGFR (60% vs 83%, p <0.001; Figure 1 ) and in patients with CHADS 2 score ≥2 than in those with CHADS 2 score <2 (64 vs 85%, p <0.001; Figure 2 ). In Cox proportional hazards analysis, decreased eGFR and higher CHADS 2 score (≥2) predicted all-cause mortality (hazard ratio [HR] 2.4, 95% confidence interval 1.4 to 4.1, p <0.01; and HR = 2.2, confidence interval 1.3 to 3.7, p <0.01, respectively, adjusted for age and gender).
| Overall | eGFR (ml/min/1.73 m 2 ) | ||
|---|---|---|---|
| ≥60 | <60 | ||
| Cardiovascular disease | 39 (41%) | 16 (37%) | 23 (44%) |
| Cardiac disease | 32 (34%) | 13 (30%) | 19 (37%) |
| Heart failure | 25 (26%) | 8 (19%) | 17 (33%) |
| Myocardial infarction | 7 (7%) | 5 (12%) | 2 (4%) |
| Stroke | 7 (7%) | 3 (7%) | 4 (8%) |
| Ischemic stroke | 5 (5%) | 1 (2%) | 4 (8%) |
| Hemorrhagic stroke | 2 (2%) | 2 (5%) | 0 (0%) |
| Infection | 11 (12%) | 7 (16%) | 4 (8%) |
| Malignancy | 22 (23%) | 11 (26%) | 11 (21%) |
| Miscellaneous | 23 (24%) | 9 (21%) | 14 (27%) |
Annual event rates according to combinations of eGFR and CHADS 2 score are presented in Table 4 . Compared to preserved eGFR and lower CHADS 2 score (<2), decreased eGFR and higher CHADS 2 score (≥2) was associated with higher rates of all-cause and cardiovascular mortalities, cardiac events, ischemic stroke, and cardiovascular events. Those with preserved eGFR and higher CHADS 2 score showed adjusted HRs for end points comparable to those with decreased eGFR and lower CHADS 2 score ( Table 4 ). In addition, warfarin use did not differ between patients with higher (≥2) and lower (<2) CHADS 2 scores in those with decreased eGFR (72 vs 78%, p = 0.42), although more patients with higher CHADS 2 score (≥2) received warfarin compared to those with lower CHADS 2 score (<2) of those with preserved eGFR (82 vs 68%, p <0.05). Prothrombin time-international normalized ratio in patients with decreased eGFR and CHADS 2 score ≥2 (1.7 ± 0.8) was not significantly different from that in those with decreased eGFR and CHADS 2 score <2 (1.4 ± 0.7). On Cox proportional hazards analysis, male gender, CHADS 2 score ≥2, and eGFR <60 ml/min/1.73 m 2 were independent predictors for all-cause mortality; chronic AF, CHADS 2 score ≥2, and eGFR <60 ml/min/1.73 m 2 were independent predictors for cardiovascular mortality ( Table 5 ). Decreased eGFR (<60 ml/min/1.73 m 2 ) and higher CHADS 2 score (≥2) were related to cardiovascular events with a sensitivity of 36% and specificity of 86%.
| Event (%/year) | Adjusted HR (95% CI) | p Value | |
|---|---|---|---|
| All-cause death | |||
| Estimated glomerular filtration rate ≥60 ml/min/1.73 m 2 , CHADS 2 score <2 | 1.4 | 1.0 | |
| Estimated glomerular filtration rate ≥60 ml/min/1.73 m 2 , CHADS 2 score ≥2 | 5.1 | 2.6 (1.3–4.9) | <0.01 |
| Estimated glomerular filtration rate <60 ml/min/1.73 m 2 , CHADS 2 score <2 | 5.5 | 2.8 (1.3–5.8) | <0.01 |
| Estimated glomerular filtration rate <60 ml/min/1.73 m 2 , CHADS 2 score ≥2 | 12.9 | 6.9 (3.5–13.5) | <0.001 |
| Cardiovascular death | |||
| Estimated glomerular filtration rate ≥60 ml/min/1.73 m 2 , CHADS 2 score <2 | 0.2 | 1.0 | |
| Estimated glomerular filtration rate ≥60 ml/min/1.73 m 2 , CHADS 2 score ≥2 | 2.5 | 11.3 (2.5–50.7) | <0.01 |
| Estimated glomerular filtration rate <60 ml/min/1.73 m 2 , CHADS 2 score <2 | 1.7 | 7.7 (1.5–41.0) | <0.05 |
| Estimated glomerular filtration rate <60 ml/min/1.73 m 2 , CHADS 2 score ≥2 | 6.5 | 29.7 (6.5–136.5) | <0.001 |
| Cardiac events | |||
| Estimated glomerular filtration rate ≥60 ml/min/1.73 m 2 , CHADS 2 score <2 | 1.3 | 1.0 | |
| Estimated glomerular filtration rate ≥60 ml/min/1.73 m 2 , CHADS 2 score ≥2 | 3.6 | 2.7 (1.3–5.6) | <0.01 |
| Estimated glomerular filtration rate <60 ml/min/1.73 m 2 , CHADS 2 score <2 | 3.9 | 3.3 (1.4–7.6) | <0.01 |
| Estimated glomerular filtration rate <60 ml/min/1.73 m 2 , CHADS 2 score ≥2 | 10.4 | 8.9 (4.1–19.0) | <0.001 |
| Ischemic stroke | |||
| Estimated glomerular filtration rate ≥60 ml/min/1.73 m 2 , CHADS 2 score <2 | 0.2 | 1.0 | |
| Estimated glomerular filtration rate ≥60 ml/min/1.73 m 2 , CHADS 2 score ≥2 | 1.5 | 5.4 (1.1–26.2) | <0.05 |
| Estimated glomerular filtration rate <60 ml/min/1.73 m 2 , CHADS 2 score <2 | 1.8 | 5.9 (1.1–31.5) | <0.05 |
| Estimated glomerular filtration rate <60 ml/min/1.73 m 2 , CHADS 2 score ≥2 | 3.6 | 11.0 (2.2–55.7) | <0.01 |
| Cardiovascular events | |||
| Estimated glomerular filtration rate ≥60 ml/min/1.73 m 2 , CHADS 2 score <2 | 1.5 | 1.0 | |
| Estimated glomerular filtration rate ≥60 ml/min/1.73 m 2 , CHADS 2 score ≥2 | 5.2 | 3.1 (1.6–6.0) | <0.001 |
| Estimated glomerular filtration rate <60 ml/min/1.73 m 2 , CHADS 2 score <2 | 5.3 | 3.4 (1.6–7.3) | <0.01 |
| Estimated glomerular filtration rate <60 ml/min/1.73 m 2 , CHADS 2 score ≥2 | 13.6 | 8.3 (4.2–16.7) | <0.001 |
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