Author + information
- Received March 13, 2009
- Revision received May 6, 2009
- Accepted May 25, 2009
- Published online September 8, 2009.
- Daniela Poli, MD⁎,†,⁎ (, )
- Emilia Antonucci, MS⁎,†,
- Elisa Grifoni, MD⁎,†,
- Rosanna Abbate, MD⁎,†,
- Gian Franco Gensini, MD⁎,†,‡ and
- Domenico Prisco, MD⁎,†
- ↵⁎Reprint requests and correspondence:
Dr. Daniela Poli, Centro di Riferimento Regionale per la Trombosi, Azienda Ospedaliera Universitaria Careggi, V.le Morgagni 85-50134 Firenze, Italy
Objectives We sought to evaluate the rate of bleeding in relation to age (<80 and ≥80 years), the quality of anticoagulation (expressed as time spent in international normalized ratio therapeutic range), and factors associated with bleeding events.
Background Stroke prevention in patients with atrial fibrillation (AF) is an increasingly crucial public health target, particularly in patients ages ≥80 years.
Methods We conducted a prospective observational study on 783 patients with AF on oral anticoagulant treatment (OAT).
Results Patients spent a median 14%, 71%, and 15% of time below, within, and above the intended therapeutic range, respectively. No difference in OAT quality was found between patients age <80 and ≥80 years. During follow-up, 94 patients experienced bleeding complications (rate 3.7 × 100 patient/years), 37 major (rate 1.4 × 100 patient/years), and 57 minor (rate 2.2 × 100 patient/years). Different rates of major hemorrhage were observed between patients age <80 and ≥80 years (0.9 vs. 1.9 × 100 patient/years; p = 0.004). Bleeding risk also was greater in patients with a history of previous cerebral ischemic event (odds ratio [OR]: 2.5; 95% confidence interval: 1.3 to 4.8; p = 0.007). A Cox regression analysis confirmed age ≥80 years associated with bleeding risk (OR: 2.0).
Conclusions These results indicate that the rate of major bleeding complications may be kept acceptably low also in very elderly AF patients on OAT, provided a careful management of anticoagulation is obtained.
The prevalence of atrial fibrillation (AF) increases with age, and increasing numbers of elderly patients are candidates for and could benefit from the use of anticoagulants. This trend is expected to increase in the future (1); therefore, there is a need for reliable information on the bleeding risk of elderly patients. The quantification of bleeding risk and the identification of modifiable factors are crucial for management decisions. The bleeding risk of elderly patients administered oral anticoagulant treatment (OAT) was studied by several authors (1–4). However, data remain scarce on very old patients (i.e., those age ≥80 years). We conducted a prospective observational study on patients with AF receiving OAT that were followed by our anticoagulation clinic to evaluate the following: 1) the rate of bleeding in relation to age <80 and ≥80 years; 2) the quality of anticoagulation; and 3) factors associated with bleeding events.
From June 1998 to December 2007, we prospectively investigated 783 consecutive nonvalvular AF patients referred for OAT management to our anticoagulation clinic. All were outpatients and were enrolled at the beginning of OAT, mainly after hospital discharge and after giving informed consent. All patients were treated with warfarin, and the international normalized ratio (INR) was maintained at the intended therapeutic range of 2 to 3. At each follow-up visit, OAT was monitored by pro-thrombin time expressed as INR, which was determined by the use of a capillary blood test (Thrombotest, Nycomed Pharma AS, Oslo, Norway).
Dose adjustment was performed by a physician by the use of a computer-assisted prescription system (PARMA Instrumentation Laboratory SPA, Milan, Italy) (5). Date of starting OAT and dates of all visits were recorded. We calculated patient/years by our patient database. Time of observation was calculated on consecutive periods of observation. When a patient left the center for >2 months, this interval was excluded from the analysis, and adverse events that eventually occurred during this period were not included in the analysis. For the calculation of time in range, the Rosendaal method was used (6).
Patients' demographic and clinical data were collected. The presence of traditional cardiovascular risk factors and other characteristics associated with ischemic complications in AF were assessed on the basis of patients' interview, echocardiography results, and hospital records. Patients were classified as hypertensive if they had a history of hypertension and were taking antihypertensive treatment. Diabetes was defined according to American Diabetes Association criteria (7). Coronary artery disease was defined on the basis of a history of myocardial infarction or stable and unstable angina. Left ventricular dysfunction was defined as a recent diagnosis of congestive heart failure or a fractional shortening <25% by transthoracic echocardiography (8). History of previous gastrointestinal or cerebral bleeding events, thrombocytopenia, and malignancy was recorded.
Follow-up visits were scheduled every 2 to 4 weeks for INR monitoring. Hospital admissions, concomitant therapies, intercurrent illnesses, bleeding, and thrombotic events during follow-up were recorded. Patients who missed check-ups for >2 months were contacted (personally or through their family or general practitioner) and the reason for interrupting treatment monitoring was recorded. In the case of death, further information about its cause was requested. When this information was lacking, national register of causes of death and autopsy results (if available) were consulted. The use of aspirin in association to OAT was limited to patients with a recent episode of acute coronary syndrome or when they had recurrent episodes. Patients were instructed to avoid the use of aspirin and were routinely asked for occasional or chronic use of aspirin and recorded on electronic files.
Data were censored after the occurrence of transient ischemic attack (TIA) or stroke, major bleeding, after the cessation of OAT or when the patient stopped being monitored by our center. Stroke, TIA, and bleeding events were defined as previously described (9). When an ischemic or bleeding event occurred, the INR related to the event was recorded. The INR was defined as temporally related to the adverse event when it was obtained at the time of the event or during the preceding 8 days. No patient was receiving hormone-replacement therapy. We classified our patients for stroke risk by CHADS2(congestive heart failure, age, diabetes, previous stroke score) (10).
Incidence rates for ischemic and bleeding events were calculated as the number of events per 100 patient/years of observation. The SPSS statistical software package (software for Windows, version 11.5, Statistical Package for Social Sciences, Chicago, Illinois) was used for data processing. Data are expressed as median and range as the result of to their skewed distribution. Preliminary statistics was performed by the use of the Wilcoxon signed rank test. Statistical analysis was performed by use of the Fisher exact test (categorical data), and a p value <0.05 was chosen for statistical significance.
A univariate analysis and a Cox regression analysis were used to ascertain which factors were significantly associated with the risk of bleeding during follow-up. All odds ratios (ORs) are given with their 95% confidence intervals (CIs), and a 2-sided value of p < 0.05 was chosen for statistical significance.
We performed a prospective study on 783 AF patients (507 men) for a total follow-up period of 2,567 patient/years. The characteristics of patients are listed in Table 1.At enrollment the patients' median age was 75 years (range 37 to 94 years) and 180 patients were age ≥80 years. During follow-up, 147 patients became age >80 years. The overall exposure to warfarin for each patient was calculated in relation to aging, before and after his/her 80th birthday.
During follow-up, 83 patients died (3.2 × 100 patient/years), 9 of them for hemorrhagic complications (0.35 × 100 patient/years). Among these, 45 were age ≥80 years (13.8%), and 38 were age <80 years (8.3%). Ninety-four patients had bleeding complications (3.7 × 100 patient/years): 37 were major (1.4 × 100 patient/years) and 57 were minor (2.2 × 100 patient/years). The INR value related to major bleeding events was <3 in 25 (67.5%) of 37 patients, between 3 and 4 in 7 (19%) of 37 patients, and >4 in 5 (13.5%) of 37 patients. Major bleeding occurred at a median time of 36 months (range 3 to 124 months) after the beginning of OAT; in particular, 9 (24%) of 37 events occurred in the first year. The rates of hemorrhage in patients <80 and ≥80 years are reported in Table 2.
Overall, patients spent a median of 14%, 71%, and 15% of time below, within, and above the intended therapeutic range, respectively. No difference was found between patients age <80 and ≥80 years (data not shown). Mean dosage of warfarin was 27.2 mg/week for patients age <80 years and 21.1 mg/week for patients age ≥80 years (p < 0.001). No difference was found in relation to time spent below, within, and above the intended therapeutic range between patients with bleeding complications and those without, both in patients age <80 and ≥80 years. Twenty-seven patients (3.5%) also were treated with aspirin; no difference in the rate of bleeding events was found between patients treated or not treated with aspirin. Bleeding risk was similar between sexes.
Univariate analysis showed that age ≥80 years, a history of previous ischemic event, and CHADS2score were associated with bleeding risk. Instead, bleeding was not associated with hypertension and history of previous hemorrhage (Table 3).However, among the 8 patients who had a history of cerebral hemorrhage before beginning warfarin, one had a recurrent cerebral hemorrhage. These patients showed a greater risk for developing a recurrent cerebral hemorrhage than those without a previous cerebral bleeding (4.2 × 100 patient/years vs. 0.75 × 100 patient/years), even if not statistically significant (relative risk: 5.4; 95% CI: 0.1 to 34.4; p = 0.2). Cox regression analysis confirmed that age ≥80 years is associated with bleeding (OR: 2.0; 95% CI: 1.1 to 4.0; p = 0.05).
Rate of bleeding events by age
In this large prospective observational study on patients with AF administered warfarin we found that, even if greater than in younger patients, the absolute rate of major bleeding of patients ages ≥80 years is acceptably low (rate 2.5 × 100 patient/years). Conversely, Hylek et al. (11), when studying elderly AF patients, found a rate of major bleeding more than 5 times greater than that observed in our study. In the Hylek et al. study (11), 35% of patients experienced coronary artery disease instead of 20% of our cohort, and the concomitant use of aspirin was 40% in those patients and limited to 3.5% in ours. This point could help to explain the lower rate of bleeding recorded in our experience.
In our cohort, all patients were followed from the beginning of OAT; therefore, all events, even the early ones, were recorded. No patient was lost at follow-up, and we actively looked for all bleeding events. We cannot exclude underreporting for minor bleeding because we recorded clinically relevant events. However, we enrolled consecutive outpatients with a good life expectancy to justify warfarin prophylaxis. More frail patients are unlikely to be referred to an outpatient service, which could in part explain the low bleeding rate recorded.
Quality of anticoagulation control
Our study was conducted on patients managed by a devoted agency, providing the best quality of OAT (12). In our patients, the time spent in range was 71%, similar to that recorded in patients analyzed by the European ISCOAT (Italian Study on Complications of Oral Anticoagulant Therapy) and EAA (European Action on Anticoagulation) studies (5,13) but greater than that reported in the cohort followed up by Hylek et al. (11). The use of computer-assisted systems for dose adjustment has been demonstrated to be useful in OAT management (5), which could explain the low bleeding rate in our study.
Factors associated with bleeding
It is increasingly recognized that in patients with AF many risk factors for warfarin related bleeding are also indications for warfarin use (14). In particular a history of TIA/stroke is strongly associated with bleeding risk (15–17). Accordingly, in our study a history of previous ischemic event was associated with a high OR for bleeding during OAT. Instead, hypertension seemed not to be associated with bleeding, probably because all hypertensive patients were receiving therapy with a good blood pressure control. In our series history of previous bleeding event was not correlated with an increased bleeding risk. However, considering only patients who had had a cerebral bleeding before starting OAT, the rate of recurrent cerebral bleeding was particularly high. The small number of these patients limits the statistical significance of these data; nevertheless, it suggests the need for a careful evaluation of the risk/benefit ratio of OAT in patients with a previous cerebral bleeding.
Our study shows that in elderly patients with AF administered warfarin, the risk of bleeding is acceptably low. This finding suggests that patients ≥80 years of age could receive benefit from warfarin prophylaxis when a good quality of anticoagulation is obtained.
- Abbreviations and Acronyms
- atrial fibrillation
- congestive heart failure, age, diabetes, previous stroke
- confidence interval
- international normalized ratio
- oral anticoagulant treatment
- odds ratio
- transient ischemic attack
- Received March 13, 2009.
- Revision received May 6, 2009.
- Accepted May 25, 2009.
- American College of Cardiology Foundation
- ↵(2002) Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 26:S5–S20.
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