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European Heart Journal Advance Access originally published online on December 5, 2005
European Heart Journal 2006 27(8):960-967; doi:10.1093/eurheartj/ehi667
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Effect of antithrombotic therapy in patients with mitral stenosis and atrial fibrillation: a sub-analysis of NASPEAF randomized trial

Francisco Pérez-Gómez1,*, Antonio Salvador2, Javier Zumalde3, Jose A. Iriarte4, Jesús Berjón5, Eduardo Alegría6, Carlos Almería1, Ramón Bover1, Dionisio Herrera7, Cristina Fernández1 for the National Study for Prevention of Embolism in Atrial Fibrillation Investigators{dagger}

1Servicio de Cardiología, Hospital Clinico San Carlos, Prof. Martín Lagos s/n., 28040 Madrid, Spain
2Hospital Dr Peset, Valencia, Spain
3Hospital Galdakao, Bilbao, Spain
4Hospital Basurto, Bilbao, Spain
5Hospital de Navarra, Pamplona, Spain
6Clinica Universitaria de Navarra, Pamplona, Spain
7Centro Medico Avenida Portugal, Madrid, Spain

Received 16 May 2005; revised 23 September 2005; accepted 3 November 2005; online publish-ahead-of-print 5 December 2005.

* Corresponding author. Tel: +34 91 330 31 43; fax: +34 91 330 31 42. E-mail address: fperezg.hcsc{at}salud.madrid.org


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Aims The randomized NASPEAF study included non-valvular with prior embolism and mitral stenosis patients in the same group. This is a sub-study to specially focus on the antithrombotic therapy in mitral stenosis.

Methods and results We analysed 311 patients with mitral stenosis, compared with 175 non-valvular atrial fibrillation patients with prior embolism, stratified by a history of previous embolism and assigned to anticoagulant therapy [target international normalized ratio (INR)=2.0–3.0] or combined antiplatelet plus moderate intensity anticoagulant therapy. Median follow-up was 2.9 years. Outcomes were fatal and non-fatal embolism, stroke and myocardial infarction, sudden death, and death from bleeding. Combined therapy in mitral stenosis patients, compared with anticoagulant alone therapy, reduced the risk of vascular events by 58.3%. During equal therapy, the outcome annual rates were essentially the same in non-valvular and valvular patients [hazard ratio 0.90 (95% confidence interval 0.37–2.16), P=0.81]. During anticoagulant alone therapy, the annual event rate in mitral stenosis patients without prior embolism was low (2.5%) and it was very high in patients with prior embolism (6.6%).

Conclusion Combined therapy was effective in mitral stenosis patients. Prior embolism patients are not efficiently protected with anticoagulant alone therapy for an INR of 2.0–3.0.

Key Words: Atrial fibrillation • Stroke • Mitral stenosis • Anticoagulants • Antiplatelets • Severe bleeding


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Anticoagulation in rheumatic mitral stenosis patients associated with atrial fibrillation (AF) has not been compared with any other therapies in a randomized trial, although it has been generally accepted, after several retrospective studies, that long-term oral anticoagulant therapy is effective in preventing thrombo-embolism.1–3 The effect of the antithrombotic therapy has been largely investigated in non-valvular patients, but it has not been compared between valvular and non-valvular AF patients and between patients with and without prior embolism.

The incidence of embolism in rheumatic AF patients ranged from rates of 1.5 to 4.7 in six retrospective reports collected by Deverall et al.4 in 1968. There are reasons to believe that long-term anticoagulant therapy has altered the natural history of these patients and that the incidence of embolism is decreasing. However, it has been reasonably accepted that >20% of patients with rheumatic mitral stenosis have a chance of suffering a systemic embolism during the course of the disease and that recurrent emboli occur in ~50% of those patients with a history of a prior embolism.5

Guidelines did not agree on the appropriate intensity of anticoagulation in mitral stenosis patients with AF. In 1995, a group of European experts proposed an international normalized ratio (INR) range of 3.0–4.5,6 and the joint guidelines of the American College, the American Heart, and the European Societies of Cardiology in 2001 proposed an INR target of 2.5–3.5.7 The British Society of Haematology8 and the joint consensus of the American Colleges of Cardiology and of the Chest Physicians in 20019 and also in 200410 recommended an INR target of 2.0–3.0. Recently, Pengo et al.11 randomized 103 of these patients and showed that low intensities of anticoagulation (target INR of 2) were as effective as higher intensities (INR range of 2.5–3.5).

The multi-centre randomized National Study for Prevention of Embolism in Atrial Fibrillation trial (NASPEAF), previously published,12 evaluated in the same study the antithrombotic therapy in patients with valvular and non-valvular AF, both stratified by the history of prior embolism. In the absence of previous convincing information, we included all mitral stenosis patients in a high-risk group jointly with non-valvular AF patients with a history of prior embolism. The aim of this article was to independently analyse the antithrombotic therapy in mitral stenosis patients and to establish comparisons among the different groups. It was also our intention to establish the adequate intensity of anticoagulation to prevent vascular events in mitral stenosis patients.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Study population and randomized treatments
The study design, inclusion and exclusion criteria, definition of outcomes, statistical analysis, and the results of NASPEAF study have been described in detail in a previous publication.12 Patients were divided into two groups according to the prevalence of risk factors, and different intensities of the antithrombotic therapy were assigned to each group. The high-risk group was composed of three sub-groups of patients: those with mitral stenosis with or without prior embolism and those with non-valvular AF patients plus previous embolism. All were randomized to antivitamin K anticoagulant therapy alone (target INR of 2.0–3.0) or to 600 mg/day of the antiplatelet agent triflusal and a moderate intensity anticoagulation for an INR range of 1.4–2.4 (combined therapy). Randomization was balanced by the study centre and also by each sub-group. Patients with stenotic mitral bioprosthesis (mitral valve area under 2 cm2) were included in the mitral stenosis group, and patients with mechanical valve prosthesis were excluded.

The antiplatelet agent used was triflusal, a cyclo-oxygenase inhibitor drug structurally related to acetylsalicylic acid,13 of which clinical trials have shown that 600 mg/day has both similar biological effect and clinical efficacy to aspirin 300 mg/day with fewer bleeding complications.14,15

Risk factors
Vascular risk factors (age, sex, smoking, diabetes, ischaemic heart disease, heart failure, hypertension, hyperlipidaemia, and peripheral vascular disease) have been analysed to determine their prevalence in non-valvular and valvular patients. We recorded by trans-thoracic echo (TTE) the left atrial antero-posterior diameter in para-sternal long axis view, left ventricular ejection fraction, and mitral valve area, calculated by the pressure half-time method during properly controlled heart rate. Trans-oesophageal echo (TEE) was performed during 1996–1999 in 52 non-selected valvular and non-valvular patients of the study to evaluate atherosclerotic plaques from the aorta, atrial thrombus, atrial spontaneous echo-contrast, and intraatrial flow waves. Atrial spontaneous echo-contrast was classified into three grades: grade 1 (slight) when it was not persistent throughout the cardiac cycle or it was difficult to see without amplification; grade 2 (moderate) when it was well identified without amplification; and grade 3 (severe) when it was associated with persistent smoke. Pulsed Doppler velocity profiles were recorded from the left atrial appendage outlet in horizontal view. Peak emptying and peak filling velocities (cm/s) were blindly measured offline by two independent observers and were averaged from at least three consecutive cardiac cycles.

Statistics
Statistical analysis has been described in previous article.12 For comparison between groups of patients, we analysed a new post hoc composite of events, theoretically related to antithrombotic therapy: fatal and non-fatal systemic embolism, stroke/TIA and myocardial infarction, sudden death, and death from bleeding. Death from an event was considered when it occurred within the following 30 days. These events alone or in combination were also compared. The composite of events and non-fatal severe bleeding were jointly analysed to evaluate the benefit-to-risk ratio. The analyses were performed according to the intention to treat (ITT) and ‘on-treatment’ principles. Baseline comparisons were performed using the {chi}2 test for categorical data and analysis of variance test for continuous data. We used the Kaplan–Meier method to calculate the 4-year cumulative rate of events until the first event occurred. The representation of these charts was cut at the median follow-up. The proportional hazard regression was assessed and satisfied comparing estimated Ln (–Ln) survival curves resulting in parallel curves. The linearity assumption was assessed introducing in the model log-transformed continuous variables. We used the hazard ratio (HR) and 95% confidence interval (CI) of a Cox regression model. Student's t-test was applied for TEE comparative analysis after using Levene's test for the homogeneity of variance. A Cox model was used to identify independent risk factors for vascular events among the following variables: prior embolism, age (per year increment or >65 years), diabetes, hypertension (systolic blood pressure >160 mmHg), and left atrial size (mm). The first four variables were also analysed in non-valvular patients and prior embolism, age, and left atrial size or median mitral valve area in patients with mitral stenosis. All tests were carried out at a 0.05 level of significance.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Acknowledgements
 References
 
Figure 1 and Table 1 show the distribution of the high-risk group patients. Three hundred and eleven had mitral stenosis with or without prior embolism, and 184 had non-valvular AF with prior embolism. After randomization, 25 were lost to follow-up. The remaining ITT follow-up valvular population was composed of 207 patients without prior embolism (109 assigned to anticoagulation and 98 to combined therapy) and 88 cases with prior embolism (47 and 41 assigned to anticoagulation and combined therapy, respectively). The non-valvular follow-up population was composed of 175 cases (91 and 84 assigned to anticoagulation and combined therapy, respectively). During follow-up, there was a 5% treatment withdrawal due to adverse events (2.75%) and to general practitioner's or patient's decision (2.25%).


Figure 6671
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  		Figure 1 Flow chart diagram of high-risk group AF patients. Loss of follow-up corresponds to those patients of whom no efficacy and safety data are available. IQRP25–P75=interquartile range. Anticoagulant therapy=INR range (2.0–3.0). Combined therapy=triflusal 600 mg/day plus anticoagulation for an INR of 1.4–2.4.

 

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  		Table 1 Comparative prevalence of baseline risk factors between therapeutic groups of patients and between valvular and non-valvular patients
 
Risk factors
Table 1 shows a balanced prevalence of risk factors in the different sub-groups. Non-valvular patients, compared with mitral stenosis patients, were older and had a significantly higher systolic blood pressure, higher prevalence of diabetes, hypertension, hyperlipidaemia, peripheral vascular disease, and ischaemic heart disease. In contrast, mitral stenosis patients who had a larger left atrium and higher ejection fraction were predominantly females and had significantly lower left atrial flow wave velocities and a tendency to a greater degree of spontaneous echo-contrast (Table 2).


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  		Table 2 Trans-oesophageal echo risk factors in valvular and non-valvular patients
 
The Cox proportional hazard model for all patients together identified prior embolism, age, and diabetes as independently predictive variables for vascular events, but hypertension and left atrial size did not achieve significantly predictive values (Table 3). Independently predictive risk factors in non-valvular patients were prior embolism and diabetes and in patients with mitral stenosis, the factors were prior embolism and age. In the latter group, however, left atrial size and median mitral valve area did not achieve significant value to predict vascular events.


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  		Table 3 Relative risk (95% CI) for vascular events among all patients and independently in non-valvular and valvular patients
 
Anticoagulation intensity
Anticoagulation control data are shown in Table 4. The combined, compared with the anticoagulant therapy arms, maintained a lower median INR and had a significantly lower number of INR tests over 3.5 and higher number of INR tests below 2 (P<0.001).


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  		Table 4 Anticoagulant values in different non-valvular and valvular groups
 
Outcomes
The combined antiplatelet plus anticoagulant therapy in the whole high-risk group, compared with the anticoagulant therapy alone, significantly reduced the number of vascular events (14 vs. 29 events) [HR 0.51 (95% CI 0.27–0.96), P=0.03] (Figure 2). The ‘on-treatment’ difference was highly significant (6 vs. 28 events) [HR 0.26 (95% CI 0.11–0.64), P=0.001], because from the 14 ITT events, in the combined therapy group, eight occurred after treatment withdrawal (five receiving anticoagulant therapy alone and three antiplatelet therapy alone). Separate survival curves of the three sub-groups showed that the combined, compared with the anticoagulant therapy, offered a consistent and homogeneous clinical benefit, and there was no interaction between treatment and mitral stenosis. The relative risk reduction in non-valvular patients with prior embolism was 42.3% [HR 0.58 (95% CI 0.24–1.40), P=0.22] (Figure 3A). It was 68.8% [HR 0.31 (95% CI 0.06–1.46), P=0.10] in mitral stenosis patients without prior embolism and 47.5% in patients with prior embolism [HR 0.55 (95% CI 0.16–1.82), P=0.31] (Figure 3B).


Figure 6672
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  		Figure 2 Survival curves free from vascular events (systemic embolism, stroke, myocardial infarction, sudden death, and death from bleeding) among high-risk group patients during combined antiplatelet plus anticoagulant or anticoagulant alone therapy. High risk=non-valvular with prior embolism and mitral stenosis with or without prior embolism patients. SE, standard error; n, number of cases at risk.

 

Figure 6673
Figure 6673
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  		Figure 3 Survival curves free from vascular events (systemic embolism, stroke, myocardial infarction, sudden death, and death from bleeding) in the three sub-groups of the high-risk group patients during combined or anticoagulant therapy: (A) non-valvular AF patients with prior embolism and (B) mitral stenosis patients with or without prior embolism. Emb, embolism; SE, standard error; n, number of patients at risk.

 
The survival curves also showed that absolute rates and the effect of treatment were essentially the same in both non-valvular and valvular patients with prior embolism (Table 5). The annual event rates during equal anticoagulant therapy were 6.74 or 6.59%, respectively, [HR 0.90 (95% CI 0.37–2.16), P=0.81] (Figure 4A). The survival curves were also similar during combined therapy in both groups [HR 0.92 (95% CI 0.28–3.06), P=0.89] (Figure 4B). In contrast, the registered curves in mitral stenosis patients without a history of prior embolism showed significantly better survival than in those with embolism. The difference was shown either during equal anticoagulant alone therapy [HR 0.28 (95% CI 0.13–0.60), P=0.001] (Figure 4A) or during combined therapy [HR 0.23 (95% CI 0.09–0.59), P=0.01] (Figure 4B).


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  		Table 5 Vascular events in valvular and non-valvular atrial fibrillation patients assigned to anticoagulant or combined therapy
 

Figure 6674
Figure 6674
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  		Figure 4 Survival curves free from vascular events (systemic embolism, stroke, myocardial infarction, sudden death, and death from bleeding) in non-valvular with prior embolism and valvular with/without prior embolism patients during anticoagulant or combined therapy: (A) during anticoagulant alone therapy and (B) during combined therapy. SE, standard error; n, number of patients at risk; Emb, embolism.

 
Bleeding complications
Severe bleeding in valvular and non-valvular AF patients receiving anticoagulant therapy tended to a preferential intracranial location (eight out of 12 events, five fatal) (Table 5). In contrast, patients assigned to the combined therapy presented a preferential gastric bleeding location, which was less likely to be fatal (11 out of 15 events, only one fatal).12


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Acknowledgements
 References
 
Outcome primary events
For this sub-analysis, we used a composite of events theoretically related to the efficacy and safety of the antithrombotic therapy: stroke or TIA (ischaemic or haemorrhagic), systemic embolism, myocardial infarction, death from severe bleeding or vascular events, and unexplained sudden death. In contrast to a previous NASPEAF publication,12 here we did not include death from heart failure as an outcome event and the comparison between therapies offered the same significant value. The recently published critical appraisal on antithrombotic therapy in AF meta-analysis incorporated vascular death hazard as a necessary function to evaluate the antithrombotic therapy.16

Anticoagulation intensity in mitral stenosis patients
The absence of multi-centre randomized studies in mitral stenosis patients probably explains why different committees and groups of experts could not agree on the intensity of anticoagulation in these patients, which varied from INR ranges of 3.0–4.56 to a target INR of 2.0.8–11 There is no reliable published evidence in the literature to support any of these therapeutic regimens, and some of the proposals might come from the extrapolation of non-valvular AF randomized trials.17

NASPEAF showed that it is mandatory to stratify the mitral stenosis AF patients by the history of prior embolism before settling the intensity of anticoagulation. A moderate intensity (INR of 2.0–3.0) or the combined therapy with antiplatelets and moderate anticoagulation (target INR of 2.17) offered a reliable protection in patients without prior embolism. The annual events rate was 2.50% in patients treated with anticoagulants and 0.78% in those receiving combined therapy and the embolism plus stroke rates were 1.43 and 0.78%, respectively.

The uncertainty continues when we are dealing with prior embolism patients, in whom anticoagulant therapy alone (INR from 2.0 to 3.0) was not sufficiently effective to prevent vascular events.18,19 SPAF III trial17 showed ischaemic stroke rates of 3.4% in non-valvular patients with prior embolism and 1.1% in those without embolism. Our annual stroke/TIA rates in patients with/without prior embolism were, respectively, 4.33 and 1.08% in non-valvular and 3.29 and 0.71% in those with mitral stenosis. The European Atrial Fibrillation Trial Investigators have proposed a higher intensity of anticoagulation in these patients (INR target of 3.0)19 at the risk of increasing bleeding events. Combined antiplatelet plus anticoagulant therapy significantly reduced the risk of vascular events in patients included in the high-risk group (P=0.03), without increasing the risk of bleeding.

Combined anticoagulant and antiplatelet therapy in mitral stenosis patients
Prior NASPEAF publication has reported that combined antiplatelet plus anticoagulant therapy was superior to anticoagulant therapy alone in the high-risk group AF patients (mitral stenosis with and without prior embolism and non-valvular AF patients with prior embolism)12 (P=0.03). A separate analysis of the three sub-groups was mandatory, and the combined therapy showed a consistent and homogeneous efficacy in each of them. The relative risk reduction varied from 42.3 to 68.8%, and there was no interaction between treatment and mitral stenosis in the appropriate Cox model. The difference did not achieve statistical significance in each sub-group probably because of the insufficient sample size, which had been previously calculated for all the patients included in the high-risk group.12

The INR range (1.4–2.4) for the combined therapy arm was chosen in 1995 before SPAF III trial17 published the failure of low anticoagulation intensities. However, our haematologists did not maintain low INR levels and the median INR was 2.17 from the beginning. Our findings showed that the risk of bleeding was low and laboratory control cannot be avoided, so we assume there may not be reasons to maintain an INR range below 1.9 nor over 2.5, with a target of about 2.2.

The benefit of an antiplatelet drug in combined therapy should depend on its effectiveness to interfere both platelet activity (acid phospholipid release inhibition) and platelet aggregation.20 The cyclo-oxygenase inhibitor drugs, aspirin and triflusal, have both effects and also have been shown to have similar clinical effects: aspirin has been recommended at a dose of 75–100 mg/day9 and we have used triflusal at a dose of 600 mg/day.

Events risk in mitral stenosis and non-valvular patients
In this study, the event-free survival curves were similar in mitral stenosis and non-valvular patients stratified by the history of prior embolism. All patients had a common factor: AF, and non-valvular patients had a greater prevalence of all classic risk factors (age, hypertension, diabetes, hyperlipidaemia, ischaemic heart disease, and peripheral vascular disease). In contrast, mitral stenosis patients had a larger left atrium with greater mechanical dysfunction and a tendency to a more severe degree of spontaneous echo-contrast. These last two TEE findings favour atrial thrombus formation21 and both are tightly connected because atrial dysfunction and increased concentrations of fibrinogen and red blood cells contribute to the appearance of spontaneous echo-contrast.22

Limitations
In our previous publication, mitral stenosis patients had been analysed within the high-risk group of AF patients (mitral stenosis with/without prior embolism and non-valvular with prior embolism), although each sub-group was independently randomized.12 Being the first large trial to include mitral stenosis patients, it was mandatory to independently analyse these patients, although the number included in each sub-group did not allow us to show significant differences between therapies. This article also incorporates TEE echo risk factors to clarify the comparison between mitral stenosis and non-valvular patients, which was not included in the previous article. The loss to follow-up was 5%, what represents some limitations to the study.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Acknowledgements
 References
 
NASPEAF study showed that combined antiplatelet plus moderate intensity anticoagulant therapy is effective in mitral stenosis patients. These patients had less prevalence of classic risk factors than non-valvular patients, but greater degree of other important factors like a larger, more static, and dysfunctional left atrium and more intense echo-contrast, so the risk for vascular events and their survival curves are equilibrated in both groups of patients.

The intensity of anticoagulation in mitral stenosis patients should be established according to the history of prior embolism. Although patients without embolism are reasonably protected with an intensity of anticoagulation for an INR of 2.0–3.0, those with prior embolism require higher intensities or better a combined therapy for a target INR of 2.2 and a range of about 1.9–2.5.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
References
 
We are grateful to Daniel Singer (Massachusetts General Hospital) for helpful comments on early drafts of the manuscript. The secretariat, data bank, statistical analysis, and expenses for working meetings were supported by grants from the Spanish Society of Cardiology (Madrid) and Uriach Foundation (Barcelona).

Conflict of interest: none declared.


   Footnotes
 
{dagger} The study participants and committees are listed in previous publication.12 Back


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 

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L. T. Cooper, K. L. Baughman, A. M. Feldman, A. Frustaci, M. Jessup, U. Kuhl, G. N. Levine, J. Narula, R. C. Starling, J. Towbin, et al.
The Role of Endomyocardial Biopsy in the Management of Cardiovascular Disease: A Scientific Statement From the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology
J. Am. Coll. Cardiol., November 6, 2007; 50(19): 1914 - 1931.
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 CirculationHome page
L. T. Cooper, K. L. Baughman, A. M. Feldman, A. Frustaci, M. Jessup, U. Kuhl, G. N. Levine, J. Narula, R. C. Starling, J. Towbin, et al.
The Role of Endomyocardial Biopsy in the Management of Cardiovascular Disease: A Scientific Statement From the American Heart Association, the American College of Cardiology, and the European Society of Cardiology
Circulation, November 6, 2007; 116(19): 2216 - 2233.
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 Eur Heart JHome page
F. Perez-Gomez, J. A. Iriarte, J. Zumalde, J. Berjon, A. Salvador, E. Alegria, M. P. Maluenda, S. Asenjo, R. Perez-Saldana, R. G. de la Torre, et al.
Antithrombotic therapy in elderly patients with atrial fibrillation: effects and bleeding complications: a stratified analysis of the NASPEAF randomized trial
Eur. Heart J., April 2, 2007; 28(8): 996 - 1003.
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 StrokeHome page
J. Borja, I. Izquierdo, and J. Garcia-Rafanell
Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack
Stroke, November 1, 2006; 37(11): 2653 - 2653.
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