Warfarin or Aspirin in embolism prevention in patients with mitral valvulopathy and atrial fibrillation

Abstracts

FUNDAMENTO: A fibrilação atrial (FA) associada à doença valvar mitral reumatismal (DVMR) aumenta a incidência de tromboembolismo (TE), sendo a Varfarina a medicação padrão, apesar das dificuldades na adesão e no controle terapêutico. OBJETIVO: Comparar a eficácia da Aspirina contra a Varfarina na prevenção do TE em pacientes com FA e DVMR. MÉTODOS: Acompanhamos 229 pacientes (pts), portadores de FA e DVMR, em estudo prospectivo e randomizado. 110 pts receberam Aspirina 200 mg/dia, compondo o Grupo A (GA), e 119, a Varfarina, em doses ajustáveis individualmente, compondo o Grupo V (GV). RESULTADOS: Ocorreram 15 eventos embólicos no GA e 24 no GV (p = 0,187), dos quais 21 com o INR menor que 2,0. Assim, excluindo os pacientes com INR inadequado, houve maior número de eventos embólicos no GA (15 vs 3) (p < 0,0061). Houve menor adesão ao tratamento no GV (p = 0,001). Não houve sangramentos maiores em ambos os grupos. Pequenos sangramentos foram mais frequentes no GV (p < 0,01). O nível sérico de colesterol e triglicérides aumentados constituiu fator de risco para maior número de eventos tromboembólicos na população estudada, não havendo diferença entre os grupos. CONCLUSÃO: Na DVMR com FA há menos de um ano e sem embolia prévia, a Aspirina é uma opção pouco eficaz na prevenção do TE. Nos portadores de valvopatia mitral com menor risco (insuficiência mitral e prótese biológica mitral), sobretudo se houver contraindicação ou baixa aderência à Varfarina, a Aspirina pode ter algum benefício na prevenção do TE.

Tromboembolia; varfarina; valva mitral; fibrilação atrial

FUNDAMENTO: La fibrilación atrial (FA) asociada a la enfermedad valvar mitral reumática (DVMR) aumenta la incidencia de tromboembolismo (TE), siendo la Varfarina la medicación estándar, a pesar de las dificultades en la adhesión y en el control terapéutico. OBJETIVO: Comparar la eficacia de la Aspirina contra la Varfarina en la prevención del TE en pacientes con FA y DVMR. Métodos: Controlamos 229 pacientes (pts), portadores de FA y DVMR, en estudio prospectivo y randomizado. 110 pts recibieron Aspirina 200 mg/día, componiendo el Grupo A (GA), y 119, la Varfarina, en dosis ajustables individualmente, componiendo el Grupo V (GV). RESULTADOS: Ocurrieron 15 eventos embólicos en el GA y 24 en el GV (p = 0,187), de los cuales 21 con el INR menor que 2,0. Así, excluyendo los pacientes con INR inadecuado, hubo mayor número de eventos embólicos en el GA (15 vs. 3) (p < 0,0061). Hubo menor adhesión al tratamiento en el GV (p = 0,001). No hubo sangrados mayores en ambos grupos. Pequeños sangrados fueron más frecuentes en el GV (p < 0,01). El nivel sérico de colesterol y triglicéridos aumentados constituyó factor de riesgo para mayor número de eventos tromboembólicos en la población estudiada, no habiendo diferencia entre los grupos. CONCLUSIÓN: En la DVMR con FA hace menos de un año y sin embolia previa, la Aspirina es una opción poco eficaz en la prevención del TE. En los portadores de valvopatía mitral con menor riesgo (insuficiencia mitral y prótesis biológica mitral), sobre todo se hubiese contraindicación o baja adherencia a la Varfarina, la Aspirina puede tener algún beneficio en la prevención del TE.

Tromboembolia; Varfarina; valva mitral; fibrilación atrial

ORIGINAL ARTICLE

Instituto do Coração - HCFMUSP, São Paulo, SP - Brazil

Mailing address

ABSTRACT

BACKGROUND: Atrial fibrillation (AF) associated to rheumatic mitral valve disease (RMVD) increases the incidence of thromboembolism (TE), with warfarin being the standard therapy, in spite of difficulties in treatment adherence and therapeutic control.

OBJECTIVE: To compare the effectiveness of Aspirin vs. Warfarin in TE prevention in patients with AF and RMVD.

METHODS: A total of 229 patients (pts) with AF and RMVD were followed in a prospective and randomized study. The first group consisted of 110 pts receiving Aspirin - 200 mg/day (Group Aspirin - GA) and the second group consisted of 119 pts receiving Warfarin at individually-adjusted doses (Group Warfarin - GW).

RESULTS: There were 15 embolic events in GA and 24 in GW (p = 0.187), of which 21 presented INR < 2.0. Thus, after excluding patients with inadequate INR, there was a higher number of embolic events in GA than in GW (15 vs 3) (p < 0.0061). The GW showed lower treatment adherence (p = 0.001). Neither group presented episodes of major bleeding. Small bleeding episodes were more frequent in the GW (p < 0.01). Increased serum levels of cholesterol and triglycerides constituted a risk factor for a higher number of thromboembolic events in the studied population, with no difference between the groups.

CONCLUSION: In patients presenting RMVD with AF for less than a year and no previous embolism, Aspirin is little effective in preventing TE. Patients with lower-risk mitral valvulopathy (mitral regurgitation and mitral biological prosthesis), especially in cases presenting contraindication to or low adherence to Warfarin, Aspirin use can present some benefit in TE prevention.

Key words: Tromboembolism; warfarin; aspirin; mitral valve/physiopathology; atrial fibrillation.

Introduction

There is a higher incidence of thromboembolic events in patients with rheumatic mitral valve disease (RMVD) associated to atrial fibrillation (AF), when compared to those that maintain sinus rhythm^1,2.

The natural history of RMVD can be significantly modified after the occurrence of thromboembolism (TE), which unquestionably demonstrates the need for its prevention. Warfarin has become the drug of choice in TE prevention^3,4. For the "anti-vitamin K" drug to be effective, it is necessary that the patient follow complex treatment norms. In daily practice, it is not always possible to maintain the required treatment adherence in the long term, resulting in the loss of target INR-values. For patients whose INR control is difficult, Aspirin has been used as an alternative drug, especially due to its easier handling in TE prevention^5,6.

However, in spite of the better applicability of Aspirin as an anti-thrombotic in patients with RMVD with native valve or biological prosthesis associated to AF, this alternative is little explored, thus becoming a challenge⁷. The objective of the present study was to evaluate whether the Aspirin therapy can be used in patients with RMVD and AF as an effective alternative to Warfarin, in a population at risk for thromboembolic events presenting treatment adherence difficulties when submitted to Warfarin therapy.

Methods

Patients with a diagnosis of atrial fibrillation, of which onset had been up to 12 months before and a history of rheumatic disease or echocardiographic diagnosis of previous rheumatic disease associated to: 1) mitral valve stenosis, mild to important, according to the classification established by the American Society of Echocardiography (valve area > 1.5 cm² = mild, valve area < 1.5 cm² = moderate/important); (2) mitral valve regurgitation or mitral bioprosthesis (implanted for more than 6 months) with regurgitation, both quantified at the beginning of the study as of mild or mild/moderate degree, also according to the criteria established by the American Society of Echocardiography⁸. The study was approved by the Scientific and Ethics Committee in Research of our institution. All patients agreed to participate in the study and signed the Free and Informed Consent Form. The patients were followed at the Outpatient Clinic Unit of our Service.

The exclusion criteria were: age < 18 years, current antithrombotic drug use, previous episodes of embolism or hemorrhagic disease, coronary disease, arterial hypertension (defined as BP > 140 x 90 mmHg), functional class III or IV according to the New York Heart Association or presence of left ventricular dysfunction, defined as ejection fraction < 60% calculated by Teichholz method, or < 55%, calculated by Simpson's method⁸. Patients that went for more than eight days without medication (voluntary medication withdrawal), who voluntarily missed the ambulatory treatment, whose laboratory control was not possible or those who failed to maintain contact by telephone were also excluded from the study.

Initially, 339 patients with rheumatic mitral valve disease (RMVD) were randomly selected for the study from a randomization list that was especially prepared for this purpose. The patients that withdrew from treatment in up to 18 months were excluded from the assessment. The remaining 229 patients comprised the study sample. The end of the protocol was considered when: 1) there was an embolic event; 2) there was a hemorrhagic event; 3) the study period finished (> 18 months up to a maximum of 7 years).

The remaining 229 patients were then divided in two groups, as follows: 110 received 200 mg/day of Aspirin, comprising Group A (GA) and 119 patients received Warfarin at a variable dose, although it was sufficient to maintain an average INR of 2.5 (ranging from 2.0-3.0), comprising Group W (GW). All patients had equal chances of receiving the drug and none of the patients were allowed to choose the drug individually. The maximum follow-up period was 84 months (mean of 57 ± 18 months).

The diagnosis of the injury was attained by complete physical examination, in addition to a transthoracic echocardiogram carried out at study enrollment, which supported the clinical impression of the valve pathology. The transesophageal echocardiogram (TEE) was carried out in 203 patients during the first six months of study enrollment, in order to allow the identification of eventual thrombus in the left atrium, with no TE events occurring during this period. The other 26 patients underwent the transesophageal echocardiogram after six months of study enrollment, due to technical problems. As none of these patients submitted at a later date to the TEE had left atrial and auricular thrombus, the statistical analysis included all 229 patients. The 12-lead electrocardiogram (ECG) allowed the selection of those patients that presented atrial fibrillation (AF).

In both groups, the assessment of treatment adherence was carried out by a questionnaire applied and repeated every 30 days, on average, which sought to evaluate the adherence to the suggested prescription and the onset of side effects.

The patients from the GW had to keep control of the INR, which was assessed by a single examiner every 30 days at most, as well as diet adherence, when an unvaried menu was insisted upon, with the ingestion of a constant amount of vegetables (three tablespoons of cooked vegetables), preventing the fluctuation of plasma levels of vitamin K, the antidote for oral anticoagulants, in addition to taking fractionated doses of the drug. Furthermore, in this group, the contacts were anticipated when it was necessary to add a new drug to the pre-existing prescription. Thus, the following situations were considered to be non-adherence to treatment: (a) missing the appointment for INR control; (b) modified diets; (c) accidental or involuntary adherence failure or lack of adherence to the prescribed dose; (d) lack of information on the inclusion of new medications to the previously known regimen.

The information provided by the patients were entered into the database specifically created for this purpose and were obtained by telephone contact or during ambulatory return visits with the researcher.

The evaluation of the plasma levels of the drug (OAC) carried out by INR level control objectively showed whether the prescribed dose was effective. The correct ingestion of two daily acetylsalicylic acid (ASA) tablets were required for patients from the GA.

All patients were advised to contact the research center in case of onset of embolic or hemorrhagic events.

Other risk factors for TE events were assessed. The presence of diabetes mellitus⁹ (defined as fasting glycemia levels > 126 mg/dl), smoker status¹⁰ (defined as the habit of smoking more than ten cigarettes/day), dyslipidemia¹¹ (defined as plasma levels of low-density lipoprotein-cholesterol (LDL) > 130 mmol/dl or high-density lipoprotein-cholesterol (HDL) < 35 mg/dl) and hypertriglyceridemia (defined as plasma levels of triglycerides > 150 mg/dl) were evaluated. All these values were considered in the absence of specific medication.

The statistical analysis employed the Chi-square test to compare the GA and GW regarding the homogeneity of proportions or Fisher's exact test, when it was not possible to apply the Chi-square test. The Student's t test was used to carry out the quantitative comparison between the two groups. The Wilcoxon method was used to compare the groups from the beginning of treatment to the onset of embolic or hemorrhagic event. The uni- and multivariate analyses were carried out by the repeated-measurement analysis of variance, logistic regression and Pearson's coefficient of correlation.

Results

Thromboembolic events and risk factors

In the studied population, there was no difference regarding the distribution of patients between the GA and GW concerning sex, valve injury type, diabetes mellitus, smoking status, dyslipidemia or functional class (FC). Older patients (> 65 years) were more numerous among those receiving aspirin (p = 0.0319) (Table 1).

TE events, considering the two groups, occurred in 39 patients (17.03%) - 3.70% patient/year. When analyzing the two groups separately, there was no difference in the incidence of embolic events in the GW (24) when compared to GA (15) (p = 0.189) (Table 2). However, it is noteworthy the fact that among the 24 patients receiving Warfarin (GW), 21 presented INR< 2.0 and only 3 presented an INR between 2.0 and 2.2 at the moment of the TE event. Thus, if the patients with INR out of the therapeutic range were excluded, there would be three embolic episodes in the GW versus 15 in the GA (p < 0.0061) (Chart 1). Additionally, when the groups were analyzed separately, the brain thromboembolism events were observed in 10 (66.7%) patients from GA, com some type of sequela in 50% of them and in 19 (79.2%) of the patients from GW, with some type of sequela in 42.1% of them (Table 2). Peripheral thromboembolic events occurred in 5 patients from the GA and GW, with no sequelae. There was no statistical difference between them (Table 2).

In the studied population, the 39 patients that presented TE were distributed as follows in relation to the groups and valve pathology: in the GA, 11 (16.6%) of the 66 pts had Mitral stenosis (MS) and four (9.0%) of the 44 pts presented mild/moderate native valve regurgitation or bioprosthesis. In the GW, 17 (22.9%) of the 74 pts had MS and seven (15.5%) of the 45 pts presented mild/moderate native valve regurgitation or bioprosthesis (Table 3). The presence of spontaneous contrast was observed in all transesophageal echocardiograms carried out in the 229 patients and 39 (17.0%) of them presented thrombus in the left atrial appendage (Table 3).

The presence of left atrial or auricular thrombus was not a determinant of embolic event (Table 3) in the GW. However, there were more thromboembolic events in the group receiving aspirin, which presented intracavitary thrombus formation (p = 0.007) - Table 3.

Dyslipidemia and smoking, when considered in the entire study population, constituted an additional risk factor for thromboembolic events (Table 4). However, the univariate analysis showed that, when considering only patients with increased levels of cholesterol and triglycerides, as well as smokers, the incidence of TE events did not show statistical significance (p = 1.000 - 0.431 and 0.322 respectively).

At the univariate analysis, when considering only patients with increased cholesterol levels in the GA (10 pts), four presented TE (40.0%). In the GW, of the 14 pts with increased cholesterol levels, six (42.9%) pts presented TE (p = 1.000). Similarly, also at the univariate analysis, and considering the nine pts with increased levels of triglycerides in the GA, two (22.0%) pts presented TE. In the GW, of the 20 pts with hypertriglyceridemia, eight (40.0%) pts presented TE (p = 0.431).

Treatment adherence

Treatment adherence was observed in 72.7% of the patients from the GA and 42% from the GW (p = 0.001). Adherence was decreased in the GW when compared to the GA throughout the three study periods, with a significant difference in the third period (Table 5). The difference in behavior regarding the treatment norms in the GW resulted in higher percentages of INR assessments < 2.0 during the study and a higher incidence of TE events in this group (Chart 1).

During the study period, the GW presented 37.54% of the INR assessments < 2.0, 51.28% between 2.0 and 3.0 and 11.18% > 3.0 (Chart 2). The multivariate analysis showed that with every 1% of INR levels < 2.0, the probability of a TE event increased by 8.4%.

Hemorrhagic events

The hemorrhagic complications were more frequent in the GW - 7.9% patient/year - when compared to the GA- 4.09% patient/year (p = 0.007). There were no episodes of brain hemorrhage in either group.

The GW presented 44 hemorrhagic events (Table 2). Subclinical disease was identified in all 40 patients that presented hemorrhage with INR-target levels (2.0-3.0) or slightly higher levels. In the GA, of the 21 hemorrhagic events, only two (9.5%) did not have an associated disease that predisposed to bleeding. The difference in bleeding events between the groups was statistically significant (p = 0.0007) (Table 2).

Discussion

Patients with RMVD are systematically excluded from large studies assessing the consequences of AF^12,13. The present study focus on patients with AF and RMVD. All patients were randomized to receive either Aspirin or Warfarin as preventive therapy for TE events.

Warfarin is considered, in all large studies, as the most effective drug in TE prevention, due to its favorable pharmacological properties¹⁴. However, its action depends on the observance of strict norms, such as unvaried diets; regular visits to the laboratory and physician to establish INR adequacy; adherence to the fractionated and frequently modified doses of Warfarin; control of heart dynamics, especially in patients with heart failure and mandatory communication whenever it is necessary to add a new medication to the pre-existing regimen. These conditions are strenuous for patients in the long term, in addition to being little practical and very often the cause of the lack of adherence to treatment, resulting in a decrease of the expected - and desired - effectiveness of Warfarin therapy. The anti-thrombotic treatment with Aspirin is a simpler one, promoting treatment adherence. The difference in treatment adherence, perhaps due to the aforementioned matters of convenience and simplicity, helps to explain the observed outcomes¹⁵.

In our study, the incidence of embolic events among the 110 patients that received 200 mg/day of Aspirin (GA) was 2.9% patient/year, in comparison with the 4.3% patients/year that received Warfarin (GW) (p = 0.189). However, if one excludes patients whose INR was below the therapeutic value at the moment of the TE, a higher incidence of embolic episodes can be observed in patients who received Aspirin, as expected, as a matter of fact¹⁶.

The adequate treatment adherence, regardless of the chosen therapy, was associated with a lower number of thromboembolic events. In the present study, the better treatment adherence in the GA was noteworthy, when compared to the GW (Table 5). As the study progresses, a decrease in the adherence was observed in the GW, as well as an increase in embolic episodes. The decreased INR levels with desired values are a direct consequence of the difficulty in the adequacy of the treatment with the anti-vitamin K drug. There was a correlation between the inadequate INR levels, lower adherence to treatment and the incidence of TE (Chart 1 and Table 4), as previously identified¹⁷. It was also demonstrated that for every 1% of INR values < 2.0, there was an 8.4% increase in TE events.

New drugs, such as activated factor X-inhibitors administered orally or direct anti-thrombinic drugs seem to be promising as substitutes for the traditional dicumarinic therapy. Recent publication on a large multicentric study in patients with atrial fibrillation demonstrated the effectiveness of Dabigatran, a direct thrombin inhibitor, in comparison to Warfarin¹⁸. Dabigatran at a dose of 110 mg was associated with an equal number of brain and systemic TE episodes and a lower number of hemorrhagic complications¹⁸. Other anti-thrombinic drugs, such as Edoxaban, Apixaban, Rivaroxaban, are being developed and can be equally promising¹⁹.

Hypercholesterolemia and hypertriglyceridemia contributed to a higher incidence of TE events. Such findings showed that this population of patients with AF and RMVD must keep an adequate control of dyslipidemia for TE prevention.

Patients with mitral stenosis presented a higher number of embolic events, when compared to those that presented regurgitation, although there was no statistical significance. Mitral stenosis is a disease that poses a higher risk for TE than mitral regurgitation. Moreover, Yamamoto et al²⁰ demonstrated that plasma levels of markers of coagulation system activation, such as D-dimer, thrombin-antithrombin III complex and prothrombin fragments (F1+2), were lower in AF associated with mitral valve regurgitation, when compared to isolated AF, which can help in these findings.

We observed a higher number of hemorrhagic events in GW when compared to GA. It is noteworthy that most patients that presented bleeding with an INR value within the therapeutic range also had some type of predisposing pathology - as previously observed²¹.

Conclusion

TE prevention in patients with mitral valvulopathy is, unquestionably better with Warfarin than with Aspirin. Patients with mitral regurgitation and mitral biological prosthesis, due to the fact that they have a lower risk of TE, can somewhat benefit from the preventive use of Aspirin, especially if the administration of Warfarin is contraindicated or if treatment adherence is low.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the thesis of doctoral submitted by Paulo de Lara Lavitola, from Faculdade de Medicina da Universidade de São Paulo.

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Warfarin or Aspirin in embolism prevention in patients with mitral valvulopathy and atrial fibrillation

Paulo de Lara Lavitola; Roney Orismar Sampaio; Walter Amorim de Oliveira; Berta Napchan Bôer; Flavio Tarasoutchi; Guilherme Sobreira Spina; Max Grinberg

Publication Dates

• Publication in this collection
  22 Oct 2010
• Date of issue
  Dec 2010

History

• Received
  04 Nov 2009
• Accepted
  30 Apr 2010
• Reviewed
  22 Apr 2010