European Heart Journal Advance Access originally published online on December 8, 2006
European Heart Journal 2007 28(8):996-1003; doi:10.1093/eurheartj/ehl364
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Antithrombotic therapy in elderly patients with atrial fibrillation: effects and bleeding complications: a stratified analysis of the NASPEAF randomized trial
1 Section of Cardiology, Instituto Cardiovascular, Hospital Universitario San Carlos, Madrid, Spain
2 Anticoagulation Unit, Hospital Basurto, Bilbao, Spain
3 Department of Cardiology, Hospital Galdakao, Bilbao, Spain
4 Department of Cardiology, Hospital de Navarra, Pamplona, Spain
5 Department of Cardiology, Hospital Dr. Peset, Valencia, Spain
6 Department of Cardiology, Hospital La Fe, Valencia, Spain
7 Section of Cardiology, Clínica Universitaria, Pamplona, Spain
8 Anticoagulation Unit, Hospital San Carlos, Madrid, Spain
9 Anticoagulation Unit, Hospital San Carlos, Madrid, Spain
10 Anticoagulation Unit, Centro Medico, Avenida Portugal, Madrid, Spain
11 Department of Medicine, Hospital San Agustín, Avilés, Spain
12 Instituto Cardiovascular, Hospital San Carlos, Madrid, Spain
13 Epidemiological and Research Unit, Hospital San Carlos, Madrid, Spain
Received 28 June 2006; revised 9 October 2006; accepted 19 October 2006; online publish-ahead-of-print 8 December 2006.
* Corresponding author. Tel: +34 91 3303149; fax: +34 91 3303142. E-mail address: fperezg.hcsc{at}salud.madrid.org
See page 926 for the editorial comment on this article (doi:10.1093/eurheartj/ehm077)
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Abstract |
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Aims: Atrial fibrillation patients with prior embolism have a high risk of vascular events in spite of anticoagulant therapy and elderly patients carry an additional risk. We analysed and compared vascular events-rate between older and younger than 75 years atrial fibrillation patients randomized to anticoagulant-alone or combined antiplatelet plus moderate-level anticoagulant therapy.
Methods and results: A total of 967 patients stratified by age and the history of prior embolism were randomized to therapeutic doses of anticoagulant-alone or combined antithrombotic therapy. Primary events were fatal and non-fatal ischaemic or haemorrhagic stroke/transient ischaemic attack, systemic embolism and myocardial infarction, sudden death and death from bleeding. The elderly, compared with the younger patients, had higher event-rate [hazard ratio 2.31 (95% confidence interval 1.37–3.90), P < 0.003]. The elderly suffered higher severe bleeding event-rate during anticoagulant therapy. The combined, compared with the anticoagulant therapy, reduced the vascular events-rate in the elderly (P = 0.012) and caused less intracranial haemorrhages and less bleeding mortality, although more non-fatal gastric bleeding.
Conclusion: The elderly with AF had a higher event-rate than the younger patients. A higher severe bleeding event-rate was also registered in elderly patients receiving anticoagulant therapy. Combined, compared with anticoagulant therapy, significantly reduced vascular events and bleeding mortality in elderly patients.
Key Words: Atrial fibrillation • Stroke • Haemorrhages • Elderly • Anticoagulation • Antiplatelets
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Introduction |
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Age is an important predictive risk factor for atrial fibrillation (AF) in the general population and also for stroke in AF patients.1 Adjusted-dose oral anticoagulation for an international normalized ratio (INR) of 2.0–3.0 has been the most effective treatment for stroke prevention in patients with AF.2 Nevertheless, this therapy was found to favour the risk of intracranial haemorrhage, especially in the elderly.3–5 This was the reason why international guidelines for stroke prevention in AF patients, published in 2001, proposed a lower than standard anticoagulant intensity in the elderly patients (INR of 1.6–2.5), even when these patients have a higher risk of vascular events.6 The recently published guidelines, in the absence of new publications, recommended an INR level of 2.0–3.0, limiting the 1.6–2.5 range to cases with increased risk of bleeding.7
Our recent articles showed that combined antiplatelet plus moderate anticoagulant therapy (combined therapy), compared with anticoagulant-alone therapy, significantly reduced the events-rate in patients of the National Study for Prevention of Embolism in AF (NASPEAF).8,9 This benefit was obtained without increasing the risk of severe bleeding. It was the intention of this analysis to evaluate and compare the effects and bleeding risk of these two antithrombotic therapies in our randomized cohort of patients stratified into two age groups: older and younger than 75 years.
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Study population and randomized treatments
The study design, inclusion and exclusion criteria, statistical analysis and general results, have been given in a previous publication.8 More detailed results on mitral stenosis patients have also been reported.9 We included in this analysis all valvular and non-valvular patients randomized to anticoagulant-alone or combined therapy, who were previously divided into two groups according to diagnostic criteria and the prevalence of baseline risk factors. The high risk group included patients with non-valvular AF and prior embolism or mitral stenosis with or without prior embolism. These patients were randomized to anti-vitamin K anticoagulant therapy (target INR of 2.0–3.0) or to combined therapy (600 mg of the antiplatelet agent triflusal and a moderate anticoagulation intensity for an INR range from 1.4 to 2.4) (the mean INR was 2.17). Non-valvular AF patients with risk factors, but no prior embolism, were included in the intermediate risk group. These patients were also randomized to anticoagulant therapy alone for an INR range of 2.0–3.0 or to the combined therapy for an INR range of 1.25–2.0, although the resultant mean value was 1.97.8 Patients randomized to antiplatelet therapy alone were not included in this analysis. The planned length of follow-up was 4 years and the patients were controlled every 6 months.
The antiplatelet agent used was triflusal, an anti-COX drug structurally related to acetylsalicylic acid,10 for which clinical trials have shown that 600 mg/day have both a biological effect and a similar clinical efficacy to aspirin 300 mg/day, but with fewer bleeding complications.11,12
Randomization was balanced by the study centre and also by the three subgroups of patients included in the high-risk group (mitral stenosis with or without prior embolism and non-valvular AF patients with prior embolism). All valvular and non-valvular patients, previously stratified by the history of prior embolism, were randomized to anticoagulant-alone or combined therapy. Each of these four groups was again divided into two new groups according to their baseline age: the older group was composed of patients 75 years of age or older and the younger group by patients younger than 75 years (Figure 1).
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The parameters used for this analysis were the prevalence of the baseline risk factors and their predictive value for vascular events, the anticoagulation control data, the primary events, and the severe bleeding events. The study outcome was a composite of those events which could be related to the failure or harms of the antithrombotic therapy: systemic embolism, ischaemic or haemorrhagic stroke/transient ischaemic attack (TIA) or myocardial infarction, sudden death and death occurring within 30 days after a vascular or bleeding event, whichever occurred first. Definition of these events has been previously reported.8 Non-intracranial, non-fatal severe bleeding was considered secondary endpoint and was defined as such that required hospital admission, blood transfusion, or surgery. These events alone or in combination were also analysed. Primary events and severe bleeding were jointly analysed to evaluate the benefit-to-risk ratio.
Statistical analysis
Statistical analysis has been described in previous articles.8,9 The analyses have been performed according to the intention-to-treat (ITT) and ‘on treatment’ (OT) principles. Baseline comparisons were performed using the exact Fisher or 
2 tests for categorical data and analysis of variance test for continuous data. A Cox model was used to identify risk factors for vascular events among the following variables: prior embolism, age, diabetes, and hypertension (systolic blood pressure >160 mmHg). We used the Kaplan–Meier method to calculate the free-of-events survival curves until the first event occurred. The representation of these charts was cut at the median follow-up time. The estimated hazard regression was assessed and satisfied comparing estimated ln (–ln) survival curves resulting in parallel curves. The linearity assumption was assessed introducing log-transformed continuous variables in the model. The exact significance was calculated by Cox model. We used the hazard ratio (HR) and 95% confidence interval (CI) of a Cox regression model. All tests were carried out at 0.05 level of significance.
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Results |
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In this analysis, 967 patients have been included. Figure 1 shows their distribution: 688 had not had prior embolism (351 treated with anticoagulation alone and 337 received combined therapy) and 279 had prior embolism (145 and 134 treated, respectively, with anticoagulant and combined therapy); 219 patients were 75 years of age or older (older group) and 748 were younger than 75 (younger group). Of 311 mitral stenosis patients, 277 were younger and 34 older than 75 years. Patients were distributed in different subgroups according to the history of prior embolism and the allocated anticoagulant or combined treatment. A total of 4.5% were lost to follow-up after randomization. During follow-up, the reasons for withdrawal were the following: adverse events (8.7%) and general practitioner's or patient's decision (9.2%), without significant difference among groups.
The elderly, compared with the younger group, needed a significantly lower anticoagulant dose: 1.9 (0.8) vs. 2.1 (1.4) mg/day in the anticoagulant arm and 1.45 (0.6) vs. 1.7 (0.6) in the combined arm (P < 0.001) to maintain similar INR levels in both groups. Also, they remained a shorter proportion of time within the preset INR range (64.5 vs. 68.4% of the total time, P < 0.001), with occasional tendency to present over-range levels (Table 1).
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Outcomes
Considering all patients together, the event-rate, the composite of embolism–stroke–TIA, and the outcome plus severe bleeding rates were significantly greater in the elderly, compared with the younger group (P of 0.003, 0.006, and 0.001, respectively), and also the outcome survival curves showed a worse clinical prognosis in the elderly (Figure 2A). The greater event-rate in the elderly was mainly due to the differences registered in the anticoagulant arm (P = 0.001), whereas the differences during combined therapy were non-significant (P = 0.423) (Table 2 and Figure 3A).
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The elderly patients with prior embolism, during standard anticoagulant therapy, presented an excessively high events-rate, which was six times that registered in younger patients without prior embolism (11.1 vs. 1.8% patient/year). The same patients receiving combined therapy also presented six times higher event-rate than the younger without prior embolism (5.0 vs. 0.8% patient/year) (Table 2).
The outcome survival curves in elderly patients receiving combined therapy, compared with those receiving anticoagulant-alone therapy, showed a very significant benefit [HR 0.33 (95% CI 0.13–0.83), P = 0.012], and the composite of outcome plus severe bleeding events was also lower (P = 0.012). Nevertheless, the outcome difference in the younger group, although greater, was not significant [HR 0.59 (95% CI 0.29–1.17), P = 0.124] (Table 3 and Figures 3 and 4).
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The relative outcome rate reduction (RRR), during combined compared with anticoagulant therapy was higher in the elderly than in the younger group (67.1 vs. 40%). The difference was mainly due to a higher reduction of vascular death during combined therapy in the elderly, compared with the younger group (77.8 vs. 45.5%). The resulting RRR of primary events plus severe bleeding during combined vs. anticoagulant therapy was 59.2 and 19.4% in the elderly and younger groups, respectively.
Bleeding complications
Considering all cases together, the incidence of severe bleeding was not significantly higher in elderly patients, compared with the younger group [HR 0.42 (95% CI 0.13–1.36), P = 0.110]. Nevertheless, the elderly patients, receiving standard anticoagulation, suffered a higher bleeding rate (P = 0.024) (Table 2, Figure 3A). They also suffered a higher intacranial bleeding rate (3.1 vs. 0.2), HR 13.29 (95% CI 2.53–131.2), and higher bleeding mortality rates (2.1 vs. 0.3), HR 6.33 (95% CI 1.23–40.76). The mean registered INR was 2.5 in both groups and the mean percentage of time over the preset range was also the same (16.9 and 17.1%). During combined therapy, the incidence was very similar in both groups (rates of 1.3 vs. 1.1 and 2.5 vs. 2.5 in patients with and without prior embolism, respectively) (Table 2).
The combined, compared with the anticoagulant-alone treatment, showed a similar incidence of severe bleeding events in the younger group (P = 0.788) and the incidence was lower but not significant in the elderly (P = 0.132) (Table 3 and Figure 3B). Nevertheless, the geographical distribution and the severity of the bleeding events were significantly different during either therapy (P < 0.02). Nine of the 12 intracranial events were registered in the anticoagulant therapy arm (six of them died) and 11 of the 15 gastric bleedings were registered in the combined therapy arm (only one died). Gastric endoscopy was performed in three of the four patients with gastric bleeding during anticoagulant therapy and all had acute bleeding ulcers. It was also obtained in the 11 patients who suffered gastric bleeding during combined therapy and 10 of them had superficial erosions of the gastric mucosa. Seven of them also had hiatus hernia. If we exclude gastric bleeding, which eventually could be avoided with gastric protection therapy, the bleeding rate would be significantly greater in the anticoagulant, compared with the combined arms (20 vs. 7 events), [HR 2.65 (95% CI 1.13–6.23), P = 0.019].
The mean INR on admission to hospital for severe bleeding was 2.8 (ranging from 2.3 to 3.5) in the anticoagulant therapy group and 2.4 (ranging from 1.7 to 4.0) in those patients receiving combined therapy. The INR was lower than 2.0 in 58.1% of the latter group. Patients in the anticoagulant group admitted for intracranial bleeding had a mean INR of 3.25 and all cases maintained the therapy allocated at randomization. One of the three cases in the combined group admitted for intracranial haemorrhage was receiving anticoagulant treatment alone, after abandoning the antiplatelet therapy, and the INR was 3.6. This patient died, whereas the other two patients with INR of 2.02 and 1.9, respectively, recovered.
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Discussion |
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Our valvular and non-valvular patients, stratified by the history of prior embolism, had similar event-rates and survival curves during either anticoagulant or combined therapies.8,9 We have, therefore, joined both groups for this comparative analysis.
The prevention of vascular events in AF patients with standard oral anticoagulation was significantly better than with aspirin either given alone2 or combined with clopidogrel13 or associated with low-level anticoagulation.14,15 NASPEAF trial assessed the combination of a therapeutic dose of the anti-COX antiplatelet triflusal with moderate level of anticoagulation.
The first randomized trials on antithrombotic therapy in AF selected ischaemic stroke (TIA not included) and systemic embolism as primary events5,16–19 and based their conclusions on the incidence of these primary events. The European AF Trial (EAFT) added haemorrhagic stroke, myocardial infarction, and cardiovascular death (sudden death and death from heart failure, pulmonary embolism, myocardial infarction, or vascular events).4 Following a similar design, we included cardiovascular death as primary event, although we did not consider death from heart failure or pulmonary embolism.9 Also in support of our criterion came the CONSORT Statement, which aiming to improve the reports of all randomized trials, proposed a more strict and complete consideration of all severe and life-threatening adverse events in order to offer a better balance of the benefits–harms ratio.20
Outcome events
The Cox proportional hazard model identified prior embolism and age as predictive factors for vascular events.9 The present analysis confirms the great clinical influence of these two risk factors, since the elderly patients with prior embolism suffered, during equal therapy, six times more vascular events than younger patients without embolism.
The elderly patients, compared with the younger, suffered a higher event-rate, embolism–stroke rate, and higher outcome plus severe bleeding rate (P = 0.003–0.001). These figures came mainly from the significant differences registered during anticoagulant-alone therapy. During combined therapy, the older group suffered higher event-rates than the younger (2.3 vs. 1.5), but the difference was non-significant. Previous trials on AF included in the meta-analysis of van Walraven et al.2 showed a higher incidence of ischaemic events (systemic embolism and ischaemic stroke) in the elderly during anticoagulant therapy (3.7 vs. 1.3% patient/years). We also found similar figures but non-significant differences (2.5 vs. 1.3% patient/years).
The combined, compared with the anticoagulant-alone therapy, significantly reduced the event-rate and the composite of outcome plus severe bleeding events in elderly patients. However, the outcome was not significantly reduced in the younger group (P = 0.124). According to our data, combined therapy is effective and safe in AF elderly patients and may be specially indicated in these patients with prior embolism, in whom the event-rate is excessively high during anticoagulant-alone therapy. This group of patients represented the 8% of our cohort.
Bleeding complications
The severe bleeding rate in the elderly, compared with the younger group, was not significantly higher; however, elderly patients without prior embolism during anticoagulant therapy suffered greater bleeding rate (P = 0.024). In the presence of similar anticoagulation data in both groups, age seems to be the only factor to justify a higher outcome and bleeding rate in these patients.
The addition of aspirin to high-intensity anticoagulant therapy in valvular prosthetic patients significantly reduced the events-rate, at the expense of a higher incidence of severe bleeding complications.21 However, trials published after 1990, combining anticoagulation and aspirin at a dose of 75–100 mg/day, compared with anticoagulant-alone therapy, showed a similar level of bleeding events, and the events-rate reduction was maintained both during high22 and moderate levels of anticoagulation.23,24
In our experience, patients treated with standard anticoagulant therapy tended to suffer a greater number of intracranial bleeding complications, usually fatal, and those receiving combined therapy tended to suffer non-fatal upper gastrointestinal bleeding. Previous publications on AF patients, receiving combined therapy, have not emphasized the risk of gastric bleeding, probably because SPAF III14 and AFASAK II15 trials used a very low level of anticoagulation. Gastric endoscopy, in non-cardiovascular patients treated with aspirin, systematically showed superficial bleeding erosions of the gastric mucosa and increased blood loss in stools and gastric aspiration content.25–27 Salicylates usually cause direct mucosal injury, which is independent of the degree of prostaglandin inhibition and may be transient until the mucosa becomes accommodated.27,28 However, clinical gastric bleeding was not seen in our patients during aspirin-alone therapy,8 nor was it seen in 109 ischaemic patients reported by Younossi et al.29 after coronary angioplasty. On the contrary, these investigators registered upper gastrointestinal bleeding in 28 out of 138 patients, after coronary stent implantation, when aspirin was associated with standard anticoagulation (mean INR = 2.5). Gastric endoscopy, like in our study, showed superficial mucosal erosions in most of the bleeding patients.29 It has been recently shown by Chang et al.30 that patients with gastric bleeding caused by aspirin could continue the same treatment without further complications by simply protecting the gastric mucosa with proton-pump inhibitors. This policy may substantially reduce gastric bleeding complications and probably should always be used in patients receiving combined therapy. Provided that gastric bleeding could be avoided in our patients receiving combined therapy, the total bleeding events in this group would be significantly lower than in the anticoagulant group (P < 0.02).
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Conclusions |
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This randomized study shows a significant six-fold increased risk of vascular events in the elderly patients with AF and prior embolism, compared with younger patients without embolism. The older group, compared with the younger, had a higher incidence of primary events, embolism/stroke rate, and outcome plus severe bleeding events. The significant differences and a higher severe bleeding rate were mainly registered during standard anticoagulation therapy.
The combined antiplatelet plus moderate anticoagulant therapy, compared with anticoagulant-alone therapy, reduced outcome, intracranial bleeding rates, and bleeding mortality in the elderly. This therapy resulted more beneficial in AF elderly patients with a history of prior embolism.
Because of the relative small number of elderly AF patients, further studies with larger number of cases should be planned to establish the best therapy for these high-risk patients.
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Study participants and committees are listed in previous publication8
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The secretariat, data bank, statistical analysis, and the expenses for travelling and working meetings were supported by grants from the Spanish Society of Cardiology (Madrid) and Uriach Foundation (Barcelona).
Conflict of interest: none declared.
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References |
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