Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC G8c7c5ZvVR4Qs5JfsPptRmK S0066-782X2017000400290 10.5935/abc.20170052 Original Articles Cardiac Arrhythmia SAMe-TT2R2 Score in the Outpatient Anticoagulation Clinic to Predict Time in Therapeutic Range and Adverse Events Pivatto Fernando Júnior Scheffel Rafael Selbach Ries Lucas Wolkind Ricardo Roitman Marobin Roberta Barkan Sabrina Sigal Amon Luís Carlos Biolo Andréia Hospital de Clínicas de Porto Alegre Porto Alegre RS Brazil Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS - Brazil Mailing Address: Fernando Pivatto Júnior, Rua Ramiro Barcelos, 2.350, sala 700. Postal Code 90.035-903, Porto Alegre - RS, Brazil. E-mail: fpivatto@gmail.com

Author contributions

Conception and design of the research, Analysis and interpretation of the data and Critical revision of the manuscript for intellectual content: Pivatto Júnior F, Scheffel RS, Amon LC, Biolo A; Acquisition of data: Ries L, Wolkind RR, Marobin R, Barkan SS; Statistical analysis: Pivatto Júnior F, Scheffel RS; Writing of the manuscript: Pivatto Júnior F, Scheffel RS, Ries L, Wolkind RR, Marobin R, Barkan SS, Amon LC, Biolo A.

Potential Conflict of Interest

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

 04 2017 108 4 290 296 23 08 2016 30 11 2016 13 12 2016 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background:

The SAMe-TT2R2 score was developed to predict which patients on oral anticoagulation with vitamin K antagonists (VKAs) will reach an adequate time in therapeutic range (TTR) (> 65%-70%). Studies have reported a relationship between this score and the occurrence of adverse events.

 Objective:

To describe the TTR according to the score, in addition to relating the score obtained with the occurrence of adverse events in patients with nonvalvular atrial fibrillation (AF) on oral anticoagulation with VKAs.

 Methods:

Retrospective cohort study including patients with nonvalvular AF attending an outpatient anticoagulation clinic of a tertiary hospital. Visits to the outpatient clinic and emergency, as well as hospital admissions to the institution, during 2014 were evaluated. The TTR was calculated through the Rosendaal´s method.

 Results:

We analyzed 263 patients (median TTR, 62.5%). The low-risk group (score 0-1) had a better median TTR as compared with the high-risk group (score ≥ 2): 69.2% vs. 56.3%, p = 0.002. Similarly, the percentage of patients with TTR ≥ 60%, 65% or 70% was higher in the low-risk group (p < 0.001, p = 0.001 and p = 0.003, respectively). The high-risk group had a higher percentage of adverse events (11.2% vs. 7.2%), although not significant (p = 0.369).

 Conclusions:

The SAMe-TT2R2 score proved to be effective to predict patients with a better TTR, but was not associated with adverse events.

Keywords: Atrial Fibrillation Anticoagulants / adverse effects Decision Support Techniques Warfarin Phenprocoumon Vitamin K Introduction

Vitamin K antagonists (VKAs) reduce the risk for ischemic stroke in patients with atrial fibrillation (AF) by approximately 60%.1 The efficacy of the treatment with VKAs is directly related to the time in therapeutic range (TTR), that is, percent time with prothrombin time/international normalized ratio (PT/INR) between 2.0 and 3.0.2 A previous study3 has suggested that the target TTR would be 58%-65%, below which there appears to be little benefit of oral anticoagulation with VKAs over dual antiplatelet therapy. Additional evidence has emphasized that stroke prevention with the use of VKAs is effective when individual mean TTR is high (> 70%).4

Predicting which patients are good candidates for anticoagulation therapy would be very useful. Scores are currently used to assess the risk for thromboembolic events (CHADS2 and CHA2DS2-VASc),5,6 as well as the risk for the major adverse effect from that therapy, bleeding (HAS-BLED).7 Those scores allow us to assess the indication for that therapy and its risk; however, they provide no information on how the patient will respond to treatment, that is, whether the patient will maintain the target TTR. An easy prediction of which AF patients are likely to reach the target TTR by using VKAs could guide decision making in the strategy of anticoagulation with VKAs or new oral anticoagulants (NOACs).8 Recently, Apostolakis et al.9 have proposed and validated the SAMe-TT2R2 score. Those authors have reported the possibility of identifying AF patients on VKAs who reached the target TTR (score 0-1), as well as those who required additional interventions to reach the target TTR, achieving a low TTR with the use of VKAs (score ≥ 2), being thus likely candidates for the use of NOACs. Later studies have validated that score for the prediction of both TTR8,10-17 and adverse events.8,10-12,16,17 Others, however, have shown that the score cannot do that.18-20

In a previous study,21 we have described our experience in an outpatient anticoagulation clinic of a Brazilian tertiary hospital, with a mean TTR of 64.8%. This study aimed at describing the TTR according to the SAMe-TT2R2 score, in addition to relating the score obtained with the occurrence of adverse events in patients with nonvalvular AF on anticoagulation with VKAs.

 Methods

This is a retrospective cohort including patients on oral anticoagulation with VKAs being followed up at the Outpatient Anticoagulation Clinic of the Internal Medicine Service of the Hospital de Clínicas de Porto Alegre (HCPA), a university-affiliated hospital for tertiary care in the Southern region of Brazil. Decisions regarding anticoagulation management were based on the protocol by Kim et al.22 All patients attending consultations from January to March 2014 were screened, and those with nonvalvular AF were included in this study. Valvular AF was considered when moderate to severe mitral stenosis or prosthetic heart valve coexisted.4

The risk for ischemic stroke was estimated based on the CHADS2 and CHA2DS2-VASc scores, while the risk for bleeding was estimated based on the HAS-BLED score.5-7 To analyze the SAMe-TT2R2 score (0-8 points), the following variables were assessed: female sex (1 point), age < 60 years (1 point), presence of > 2 comorbidities (1 point), use of amiodarone to control heart rhythm (1 point), smoking within 2 years (2 points), and non-Caucasian race (2 points). The following were considered comorbidities: previous stroke, diabetes, peripheral artery disease, coronary artery disease, liver disease, lung disease, kidney disease, hypertension, and heart failure. Patients were categorized based on the SAMe-TT2R2 score into two groups: low risk (0-1 point) and high risk (≥ 2 points).9

Demographic and clinical data and results from complementary tests were obtained via retrospective assessment to electronic medical records, outpatient clinic consultations, visits to the emergency unit and admissions to the HCPA from January to December 2014. Patients lost to follow-up, those who died or whose anticoagulation with VKAs was suspended were also included in the analysis, and the TTR was analyzed up to the last available PT/INR test. Patients were assessed regarding anticoagulation control (via PT/INR tests) and occurrence of adverse events [major bleeding, stroke, transient ischemic attack (TIA), systemic embolism or death]. The TTR was estimated by use of the Rosendaal´s linear interpolation method.23

The laboratory tests, left ventricular ejection fraction (preferably assessed on echocardiogram) and number of drugs used were recorded based on the information available on the date closest to the beginning of follow-up. Anemia was considered when hemoglobin (Hb) < 13.0 g/dL for men or < 12 g/dL for women.24 Uncontrolled hypertension was defined as systolic blood pressure > 160 mm Hg at the outpatient clinic visit closest to the beginning of follow-up.7 Major bleeding was characterized as an event requiring hospitalization or transfusion of red blood cell concentrate, or Hb drop ≥ 2 g/dL.7 Kidney disease was considered in the presence of kidney transplantation, chronic dialysis, or serum creatinine ≥ 2.26 mg/dL.7 Liver disease was considered in the presence of chronic liver disease (ex.: cirrhosis) or biochemical evidence of significant liver damage (ex.: bilirubin > 2x the upper limit of normality, associated with aspartate aminotranferase, alanine aminotranferase or alkaline phosphatase levels > 3x the normal limit).7

Statistical analysis

Data were analyzed with the Statistical Package for Social Sciences (SPSS) software, version 21.0. Descriptive analysis was performed based on the distribution of absolute and relative frequency for qualitative variables, and based on mean ± standard deviation and median for quantitative variables with symmetrical and asymmetrical distribution, respectively. The median 25-75% percentiles were presented when deemed suitable. The groups were compared by using non-paired Student t test for symmetrical quantitative variables, Mann-Whitney U test for asymmetrical quantitative variables, and chi-square test for categorical variables. In low-frequency situations, Fisher exact test was used. The normality of the distribution of each variable was assessed by using Shapiro-Wilk test. Area under the Receiver Operating Characteristic (ROC) curve was calculated to assess the ability of the SAMe-TT2R2 score to predict the outcome 'TTR ≥ 65%' and the occurrence of adverse events, the best cutoff point of the score being considered that with the highest sensitivity x specificity product. Event-free survival was assessed by using Kaplan-Meier curves with the Log-Rank test. The significance level adopted for all tests was 5%. This study was submitted to the Committee on Ethics and Research from the HCPA, and approved.

 Results

This study assessed 263 patients on oral anticoagulation with VKAs due to nonvalvular AF, corresponding to 38.5% of those being followed up at the Outpatient Anticoagulation Clinic of the HCPA. Of those, 205 patients (77.9%) completed the follow-up (Figure 1). Table 1 shows the demographic characteristics of the sample.

Study diagram. DVT: deep venous thrombosis; PTE: pulmonary embolism; AF: atrial fibrillation; LV: left ventricular; OAC: oral anticoagulation.

Demographic characteristics of the sample
Variable n = 263
Female sex 113 (43.0)
Age (years) 71.2 (64.1-78.5)
Use of warfarin 256 (97.3)
Labile PT/INR (TTR < 60%) 124 (47.1)
Hypertension 231 (87.8)
Uncontrolled hypertension 22 (8.4)
HF/LVEF < 40% 149 (56.7)
Diabetes 108 (41.1)
Previous stroke/TIA 96 (36.5)
Coronary artery disease 76 (28.9)
Use of antiplatelet drugs/NSAIDs 64 (24.3)
Anemia 67 (25.5)
Pulmonary disease 36 (13.7)
Previous major bleeding 24 (9.1)
Peripheral artery disease 25 (9.5)
Kidney disease 7 (2.7)
Liver disease 2 (0.8)
Number of medications 7 (6-9)
CHADS2 3 (2-4)
CHA2DS2-VASc 4 (3-5)
HAS-BLED 2 (1-3)

PT/INR: prothrombin time / international normalized ratio; TTR: time in therapeutic range; HF: heart failure; LVEF: left ventricular ejection fraction; TIA: transient ischemic attack; NSAIDs: non-steroidal anti-inflammatory drugs. Categorical variables are shown as n (%), and continuous variables, as median (25%-75%).

During follow-up, 2,754 PT/INR tests (median: 10 tests/patient) were performed, and 1,270 (46.1%) resulted between 2.0 and 3.0. Median TTR was 62.5% (P25-75 44.2%-79.5%). The median of subtherapeutic PT/INR time (< 2.0) was 18.9%, and that of supratherapeutic PT/INR time (> 3.0), 9.6%.

Regarding the SAMe-TT2R2 score, 138 patients (52.5%) had it 0-1 (low risk), while 125 (47.5%) had it ≥ 2 (high risk), the median being 1 (1-2). When assessing the SAMe-TT2R2 score criteria individually (Table 2), the criterion "medical history" (presence of > 2 comorbidities) was the most prevalent (57.0%). Low-risk (score 0-1) patients had a significantly higher median TTR as compared to high-risk (score ≥ 2) ones: 69.2% vs. 56.3% (p = 0.002). Likewise, the percentage of patients with TTR ≥ 60%, 65% or 70% was higher among low-risk patients for all cutoff points analyzed (Figure 2).

Prevalence of the SAMe-TT<sub>2</sub>R<sub>2</sub> score components
Score Component n (%)
S Sex (female) 113 (43.0)
A Age (< 60 years) 41 (15.6)
Me Medical history (> 2 comorbidities*) 150 (57.0)
T Treatment (amiodarone) 26 (9.9)
T2 Tobacco use (within 2 years) 37 (14.1)
R2 Race (non-Caucasian) 22 (8.4)

Previous stroke, diabetes, peripheral artery disease, coronary artery disease, liver disease, lung disease, kidney disease, hypertension, and heart failure.

Percentage of patients with TTR ≥ 60%, 65% and 70% according to the points obtained in the SAMe-TT<sub>2</sub>R<sub>2</sub> score (p < 0.001, 0.001 and 0.003, respectively).

When assessing the ability of the SAMe-TT2R2 score to predict the outcome 'TTR ≥ 65%' by using the ROC curve (Figure 3), the cutoff point ≥ 2 showed the best combination of sensitivity and specificity (63.8% and 58.1%, respectively). The area under the curve was 0.612 (95%CI: 0.544 - 0.681; p = 0.002).

ROC curve for the outcome 'TTR ≥ 65%'.

During follow-up, there were 24 (9.1%) adverse events, whose complete description is shown in Table 3. Neither TIA nor systemic embolism occurred during the period studied. High-risk patients (score ≥ 2) had more events, but with no statistically significant difference (11.2% vs. 7.2%; p = 0.369). The area under the ROC curve of the score for the occurrence of adverse events was 0.566 (95%CI: 0.449 - 0.682; p = 0.289), ≥ 2 being again the best cutoff point, with sensitivity and specificity of 58.3% and 53.6%, respectively. Figure 4 shows the event-free survival curves.

Adverse events in total follow-up and according to the points obtained in the SAMe TT<sub>2</sub>R<sub>2</sub> score.
Adverse Events n = 263 SAMe-TT2R2 p
0-1 point ≥ 2 points
Major bleeding 15 (5.7) 6 (4.3) 9 (7.2) 0.465
Stroke 4 (1.5) 1 (0.7) 3 (2.4) 0.349
Death 12 (4.6) 5 (3.6) 7 (5.6) 0.637
TOTAL 24 (9.1) 10 (7.2) 14 (11.2) 0.369

Data shown as n (%).

Event-free survival curve according to the points obtained in the SAMe-TT<sub>2</sub>R<sub>2</sub> score (p = 0.224).

Discussion

The use of anticoagulation in patients with AF to prevent thromboembolic events is known to be effective and TTR-dependent. Predicting which patients on VKAs are more likely to reach the target TTR is important, especially currently when new drugs that do not require PT/INR monitoring are available. In this study with a Brazilian sample, the SAMe-TT2R2 score proved to be a good predictor of TTR for nonvalvular AF patients on oral anticoagulation with VKAs. That score can be useful in the initial assessment of patients with indication for anticoagulation. Median TTR, as well as the percentage of patients with TTR ≥ 60%, 65% and 70%, were higher among patients with a low SAMe-TT2R2 score (0-1 point) as compared to the group whose score was ≥ 2.

The usefulness of that score in other populations and clinical settings has been reported. Ruiz-Ortiz et al.,15 in a prospective analysis of Spanish cardiology outpatients, have reported a progressive decrease in mean TTR according to the score obtained. In their study, patients who scored 0 had a mean TTR of 67.5% ± 24.6%, while those who scored ≥ 4 had a mean TTR of 52.7% ± 28.7% (p < 0.01), with an area under the ROC curve for the outcome 'TTR ≥ 65%' of 0.57 (95%CI: 0.53 - 0.60; p < 0.0005). Roldán et al.,14 assessing 459 patients of an outpatient anticoagulation clinic, have reported that those with a score of 0-1 had a mean TTR of 67% ± 18%, while those with a score ≥ 2 had a mean TTR of 61% ± 16% (p < 0.001). In their study, the odds ratio for reaching a TTR < 65% was 2.10 (95%CI: 1.44 - 3.06; p < 0.001) in patients with a score ≥ 2. In a retrospective study including 4,468 patients selected from a registry of primary care units in the United Kingdom, Martinez et al.17 have reported that the proportion of patients with TTR ≥ 60% was 44.1% among those with a score of 0-1, and 37.1% among those with a score ≥ 2 (p < 0.01).

The association of the points obtained in the score with the occurrence of anticoagulation adverse events (major bleeding, stroke, systemic embolism and/or death) has been described in other studies8,10-12,16,17 after the original study,9 always relating the quality of anticoagulation, assessed via TTR, with the occurrence of those outcomes. Only the study by Poli et al.13 has not observed that relationship. In a retrospective study including 4,468 AF patients on VKAs with a 3-year follow-up, Martinez et al.17 have reported a higher risk for stroke in patients with score ≥ 2 as compared to those with score of 0-1 (log rank p < 0.01). Lip et al.,12 in a retrospective study with 8,120 patients (mean follow-up, 1,016 ± 1,108 days), have reported that the SAMe-TT2R2 score predicted stroke/thromboembolism, severe bleeding and death, reflecting a suboptimum TTR in patients with score ≥ 2. In the present study, the lack of association between the score and the occurrence of adverse events, specifically stroke, can be attributed to the low incidence of that complication.

Several studies have proposed the inclusion of the SAMe-TT2R2 score in the flowchart for strategic decision-making about which anticoagulant should be used for patients recently diagnosed with AF.14,25-28 Based on the score obtained, for patients with ≥ 2 points, the use of NOACs should begin immediately, while those with a score of 0-1 should begin their treatment with VKAs, which should be changed to NOACs if target TTR (> 70%) was not achieved during follow-up. Current guidelines for AF management, however, have not included that strategy.4,29,30

Our study has some limitations. Its retrospective design has inherent limitations, which can affect the quality of the data analyzed. Nevertheless, we believe that there was no great loss of data necessary for this study, because at our institution patients undergo systematic care, by use of protocols and structured outpatient clinic visits. Thus, most data necessary for the study was systematically collected during outpatient visits. Another limitation is that the medical record review identified only in-hospital adverse events or events reported by patients during their visits to the outpatient clinic, and some events, especially the adverse ones, might have been missed. Finally, the single-center characteristic of this study ensures the uniform follow-up of the patients described in this cohort, but might have decreased its external validity.

 Conclusion

Based on our findings, the SAMe-TT2R2 score proved to be effective to predict TTR for AF patients on anticoagulation with VKAs. Thus, the association of that score with the scores to assess the indication of anticoagulation (CHADS2 and/or CHA2DS2-VASc), as well as the risk for bleeding (HAS-BLED), will provide a high-quality assessment of the treatment. For patients with a high SAMe-TT2R2 score (≥ 2), anticoagulation with VKAs is more likely to be less effective, and, thus, the use of NOACs should be considered. Low-risk patients (score 0-1), however, respond better to VKAs. Therefore, an intervention based on patients' risk allows the use of new technologies (in our case, NOACs), usually more expensive and less available, to be directed to a group of patients with a more specific indication.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the thesis of master submitted by Fernando Pivatto Júnior, from Universidade Federal do Rio Grande do Sul.

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SAMeTT2R2 does not predict time in therapeutic range of the international normalized ratio in patients attending a high-quality anticoagulation clinic. Chest. 2014;145(1):187-8. Skov J Bladbjerg E Bor MV Gram J SAMeTT2R2 does not predict time in therapeutic range of the international normalized ratio in patients attending a high-quality anticoagulation clinic Chest 2014 145 1 187 188 21 Pivatto Jr F, da Silva AL, Simionato BM, Fuzinatto F, Oliveira JC, Pires LM, et al. Management of anticoagulation with vitamin K antagonists in a tertiary hospital outpatient clinic. Clin Biomed Res. 2014;34(2):139-44. Pivatto F Jr da Silva AL Simionato BM Fuzinatto F Oliveira JC Pires LM Management of anticoagulation with vitamin K antagonists in a tertiary hospital outpatient clinic Clin Biomed Res 2014 34 2 139 144 22 Kim YK, Nieuwlaat R, Connolly SJ, Schulman S, Meijer K, Raju N, et al. Effect of a simple two-step warfarin dosing algorithm on anticoagulant control as measured by time in therapeutic range: a pilot study. J Thromb Haemost. 2010;8(1):101-6. Kim YK Nieuwlaat R Connolly SJ Schulman S Meijer K Raju N Effect of a simple two-step warfarin dosing algorithm on anticoagulant control as measured by time in therapeutic range: a pilot study J Thromb Haemost 2010 8 1 101 106 23 Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993;69(3):236-9. Rosendaal FR Cannegieter SC van der Meer FJ Briet E A method to determine the optimal intensity of oral anticoagulant therapy Thromb Haemost 1993 69 3 236 239 24 World Health Organization. (WHO). Department of Nutrition for Health and Development. Iron deficiency anaemia: assessment, prevention and control: a guide for programme managers. Geneva; 2001. World Health Organization Department of Nutrition for Health and Development Iron deficiency anaemia: assessment, prevention and control: a guide for programme managers Geneva 2001 25 Fauchier L, Angoulvant D, Lip GY. The SAMe-TT2R2 score and quality of anticoagulation in atrial fibrillation: a simple aid to decision-making on who is suitable (or not) for vitamin K antagonists. Europace. 2015;17(5):671-3. Fauchier L Angoulvant D Lip GY The SAMe-TT2R2 score and quality of anticoagulation in atrial fibrillation: a simple aid to decision-making on who is suitable (or not) for vitamin K antagonists Europace 2015 17 5 671 673 26 Fauchier L, Poli D, Olshansky B. The SAMe-TT2R2 score and quality of anticoagulation in AF: Can we predict which patient benefits from anticoagulation? Thromb Haemost. 2015;114(4):657-9. Fauchier L Poli D Olshansky B The SAMe-TT2R2 score and quality of anticoagulation in AF: Can we predict which patient benefits from anticoagulation? Thromb Haemost 2015 114 4 657 659 27 Voukalis C, Lip GY, Shantsila E. Emerging tools for stroke prevention in atrial fibrillation. EBioMedicine. 2016;4:26-39. Voukalis C Lip GY Shantsila E Emerging tools for stroke prevention in atrial fibrillation EBioMedicine 2016 4 26 39 28 Esteve-Pastor MA, Roldán V, Valdés M, Lip GY, Marín F. The SAMe-TT2R2 score and decision-making between a vitamin K antagonist or a non-vitamin K antagonist oral anticoagulant in patients with atrial fibrillation. Expert Rev Cardiovasc Ther. 2016;14(2):177-87. Esteve-Pastor MA Roldán V Valdés M Lip GY Marín F The SAMe-TT2R2 score and decision-making between a vitamin K antagonist or a non-vitamin K antagonist oral anticoagulant in patients with atrial fibrillation Expert Rev Cardiovasc Ther 2016 14 2 177 187 29 January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64(21):e1-76. January CT Wann LS Alpert JS Calkins H Cigarroa JE Cleveland JC Jr 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society J Am Coll Cardiol 2014 64 21 e1 76 30 Magalhães LP, Figueiredo MJ, Cintra FD, Saad EB, Kuniyishi RR, Teixeira RA, et al; Sociedade Brasileira de Cardiologia. II Diretrizes brasileiras de fibrilação atrial. Arq Bras Cardiol. 2016;106(4 Supl. 2):1-22. Magalhães LP Figueiredo MJ Cintra FD Saad EB Kuniyishi RR Teixeira RA Sociedade Brasileira de Cardiologia II Diretrizes brasileiras de fibrilação atrial Arq Bras Cardiol 2016 106 4 Supl. 2 1 22 Artigos Originais Arritmia Cardíaca Uso do Escore SAMe-TT2R2 em Ambulatório de Anticoagulação para Predição de Tempo na Faixa Terapêutica e de Eventos Adversos Pivatto Fernando Júnior Scheffel Rafael Selbach Ries Lucas Wolkind Ricardo Roitman Marobin Roberta Barkan Sabrina Sigal Amon Luís Carlos Biolo Andréia Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS - Brasil Correspondência: Fernando Pivatto Júnior, Rua Ramiro Barcelos, 2.350, sala 700. CEP 90.035-903, Porto Alegre - RS, Brasil. E-mail: fpivatto@gmail.com

Contribuição dos autores

Concepção e desenho da pesquisa, Análise e interpretação dos dados e Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Pivatto Júnior F, Scheffel RS, Amon LC, Biolo A; Obtenção de dados: Ries L, Wolkind RR, Marobin R, Barkan SS; Análise estatística: Pivatto Júnior F, Scheffel RS; Redação do manuscrito: Pivatto Júnior F, Scheffel RS, Ries L, Wolkind RR, Marobin R, Barkan SS, Amon LC, Biolo A.

Potencial conflito de interesse

Declaro não haver conflito de interesses pertinentes.

 Resumo Fundamento:

O escore SAMe-TT2R2 foi desenvolvido visando predizer quais pacientes em anticoagulação oral com antagonistas da vitamina K (AVKs) atingirão um tempo na faixa terapêutica (TFT) adequado (> 65%-70%) no seguimento. Estudos também o relacionaram com a ocorrência de eventos adversos.

 Objetivos:

Descrever o TFT de acordo com o escore, além de relacionar a pontuação obtida com a ocorrência de eventos adversos adversos em pacientes com fibrilação atrial (FA) não valvar em anticoagulação oral com AVKs.

 Métodos:

Estudo de coorte retrospectivo incluindo pacientes com FA não valvar em acompanhamento em ambulatório de anticoagulação de um hospital terciário. Foi realizada uma avaliação retrospectiva de consultas ambulatoriais, visitas a emergência e internações hospitalares na instituição no período de janeiro-dezembro/2014. O TFT foi calculado aplicando-se o método de Rosendaal.

 Resultados:

Foram analisados 263 pacientes com TFT mediano de 62,5%. O grupo de baixo risco (0-1 ponto) obteve um TFT mediano maior em comparação com o grupo de alto risco (≥ 2 pontos): 69,2% vs. 56,3%, p = 0,002. Da mesma forma, o percentual de pacientes com TFT ≥ 60%, 65% ou 70% foi superior nos pacientes de baixo risco (p < 0,001, p = 0,001 e p = 0,003, respectivamente). Os pacientes de alto risco tiveram um percentual maior de eventos adversos (11,2% vs. 7,2%), embora não significativo (p = 0,369).

 Conclusões:

O escore SAMe-TT2R2 foi uma ferramenta eficaz na predição do TFT em pacientes com FA em uso de AVKs para anticoagulação, porém não se associou à ocorrência de eventos adversos.

Palavras-chave: Fibrilação Atrial Anticoagulantes / efeitos adversos Técnicas de Apoio para a Decisão Varfarina Femprocumona Vitamina K Introdução

Os antagonistas da vitamina K (AVKs) reduzem o risco de acidente vascular cerebral (AVC) isquêmico em pacientes com fibrilação atrial (FA) em aproximadamente 60%.1 A eficácia do tratamento com os AVKs está diretamente relacionada com o tempo na faixa terapêutica (TFT), ou seja, percentual do tempo com tempo de protrombina/razão normalizada internacional (TP/RNI) entre 2,0-3,0.2 Estudo prévio3 sugeriu que um TFT adequado seria entre 58-65%, abaixo do qual o benefício da anticoagulação oral com AVKs seria pequeno sobre a dupla terapia antiplaquetária. Evidências adicionais enfatizam que a prevenção do AVC com o uso de AVKs é eficaz quando o TFT médio individual é elevado, isto é, > 70%.4

A predição de quais pacientes serão bons candidatos à terapia com anticoagulantes seria de grande utilidade. Atualmente, utilizam-se escores que avaliam o risco de o paciente sofrer eventos tromboembólicos (CHADS2 e CHA2DS2-VASc),5,6 bem como de apresentar o principal efeito adverso dessa terapêutica, ou seja, sangramento (HAS-BLED).7 Com esses escores consegue-se avaliar a indicação e o risco da terapia, porém eles não trazem consigo a informação de como o paciente responderá ao tratamento, ou seja, se manterá um TFT adequado. A predição de maneira fácil de quais pacientes com FA são prováveis de atingir um TFT adequado com o uso dos AVKs poderia guiar a tomada de decisão da estratégia de anticoagulação com AVKs ou novos anticoagulantes (NOACs).8 Recentemente, Apostolakis et al.9 propuseram e validaram o escore SAMe-TT2R2, tendo observado ser possível identificar os pacientes com FA que atingirão TFT adequado em uso de AVKs (pontuação 0-1), bem como os que necessitarão de intervenções adicionais para conseguir um TFT adequado, atingindo um baixo TFT em vigência do uso de AVKs (pontuação ≥ 2), sendo esses possíveis candidatos para o uso dos NOACs. Estudos posteriores já validaram esse escore tanto para predição de TFT8,10-17 como de eventos adversos.8,10-12,16,17 Alguns, entretanto, mostraram incapacidade do escore para tal.18-20

Em estudo previamente publicado,21 descrevemos nossa experiência em um ambulatório de anticoagulação de um hospital terciário brasileiro, sendo o TFT médio de 64,8%. Neste estudo, temos como objetivo descrever o TFT de acordo com o escore SAMe-TT2R2, além de relacionar a pontuação obtida com a ocorrência de eventos adversos em pacientes com FA não valvar em anticoagulação com AVKs.

 Métodos

Estudo de coorte retrospectivo incluindo pacientes em anticoagulação oral com AVKs em acompanhamento no Ambulatório de Anticoagulação do Serviço de Medicina Interna do Hospital de Clínicas de Porto Alegre (HCPA), hospital universitário de atenção terciária localizado no sul do Brasil. As decisões relativas ao manejo da anticoagulação foram baseadas em protocolo publicado por Kim et al.22 Todos os pacientes que consultaram durante os meses de janeiro a março de 2014 foram triados para inclusão no estudo, sendo incluídos no estudo aqueles com FA não valvar. Considerou-se FA valvar a coexistência de estenose mitral moderada a grave ou válvula cardíaca protética.4

O risco para ocorrência de AVC isquêmico foi estimado com base nos escores CHADS2 e CHA2DS2-VASc, enquanto o risco de sangramento foi estimado a partir do escore HAS-BLED.5-7 Para análise do escore SAMe-TT2R2 (0-8 pontos), foram analisadas as variáveis sexo feminino (1 ponto), idade < 60 anos (1 ponto), presença de > 2 comorbidades (1 ponto), uso de amiodarona para controle do ritmo cardíaco (1 ponto), tabagismo nos últimos 2 anos (2 pontos) e raça não branca (2 pontos). Foram consideradas como comorbidades AVC prévio, diabetes, doença arterial periférica, coronariana, hepática, pulmonar, renal, hipertensão arterial e insuficiência cardíaca. Os pacientes foram divididos a partir do escore SAMe-TT2R2 em dois grupos: baixo risco (0-1 ponto) e alto risco (≥ 2 pontos).9

Os dados demográficos, clínicos e de exames complementares foram obtidos por avaliação retrospectiva, através do prontuário eletrônico, consultas ambulatoriais, visitas à emergência e internações hospitalares na instituição durante o período compreendido entre janeiro e dezembro de 2014. Pacientes que perderam seguimento, morreram ou tiveram anticoagulação com AVKs suspensa foram incluídos igualmente na análise, sendo o TFT analisado até o último exame de TP/RNI disponível. Os pacientes foram avaliados quanto ao controle da anticoagulação (por meio dos exames de TP/RNI) e ocorrência de eventos adversos [sangramento maior, AVC, ataque isquêmico transitório (AIT), embolização sistêmica ou óbito]. O TFT foi estimado através do método de interpolação linear de Rosendaal.23

Os exames laboratoriais, fração de ejeção do ventrículo esquerdo (preferencialmente avaliada por ecocardiograma) e número de medicações em uso foram registrados conforme as informações disponíveis mais próximas da data do início do seguimento. Anemia foi considerada como hemoglobina (Hb) < 13,0 g/dL em homens ou < 12 g/dL em mulheres.24 Hipertensão não controlada foi definida como pressão arterial sistólica > 160 mmHg na consulta ambulatorial mais próxima do início do seguimento.7 Sangramento maior foi caracterizado como evento com necessidade de hospitalização, transfusão de concentrado de hemácias ou queda da Hb ≥ 2 g/dL.7 Doença renal foi assinalada na presença de transplante renal, terapia dialítica crônica ou creatinina sérica ≥ 2,26 mg/dL.7 Doença hepática foi considerada na existência de doença hepática crônica (ex.: cirrose) ou evidências bioquímicas de dano hepático significativo (ex.: bilirrubina > 2x limite superior da normalidade, em associação com TGO, TGP ou fosfatase alcalina > 3x limite normal).7

Análise estatística

Os dados foram inseridos e analisados no software Statistical Package for Social Sciences (SPSS) versão 21.0. A análise descritiva foi realizada a partir da distribuição de frequência absoluta e relativa, para as variáveis qualitativas, e através da média ± desvio-padrão e mediana, para as quantitativas com distribuição simétrica e assimétrica, respectivamente. Os percentis 25-75% das medianas foram apresentados quando se julgou adequado. A comparação dos grupos foi realizada pelo teste t de Student não pareado para as variáveis quantitativas simétricas, teste U de Mann-Whitney para as variáveis quantitativas assimétricas e teste do qui-quadrado para as variáveis categóricas. Em situações de baixa frequência, foi utilizado o teste exato de Fisher. A normalidade da distribuição de cada variável foi avaliada por meio do teste de Shapiro-Wilk. Área sob a curva Receiver Operating Characteristic (ROC) foi calculada para avaliar a capacidade de o escore SAMe-TT2R2 predizer o desfecho TFT ≥ 65% e a ocorrência de eventos adversos, sendo considerado o melhor ponto de corte do escore a partir do valor com o maior produto sensibilidade x especificidade. A comparação da sobrevida livre de eventos adversos foi realizada através de curvas de Kaplan-Meier com o teste de Log-Rank. O nível de significância adotado em todos os testes foi de 5%. O estudo foi submetido ao Comitê de Ética em Pesquisa do HCPA e aprovado.

 Resultados

Foram estudados 263 pacientes em anticoagulação oral com AVKs por FA não valvar, correspondendo a 38,5% dos indivíduos em acompanhamento no Ambulatório de Anticoagulação do HCPA. Do total, 205 (77,9%) completaram o seguimento (Figura 1). As características demográficas da amostra estão descritas na Tabela 1.

Diagrama do estudo. TVP: trombose venosa profunda; TEP: tromboembolismo pulmonar; FA: fibrilação atrial; VE: ventrículo esquerdo; ACO: anticoagulação oral.

Características demográficas da amostra
Variável n = 263
Sexo feminino 113 (43,0)
Idade (anos) 71,2 (64,1-78,5)
Uso de varfarina 256 (97,3)
TP/RNI lábil (TFT < 60%) 124 (47,1)
Hipertensão 231 (87,8)
Hipertensão não controlada 22 (8,4)
IC / FEVE < 40% 149 (56,7)
Diabetes 108 (41,1)
AVC / AIT prévios 96 (36,5)
Doença coronariana 76 (28,9)
Uso de antiplaquetários / AINE 64 (24,3)
Anemia 67 (25,5)
Doença pulmonar 36 (13,7)
Sangramento maior prévio 24 (9,1)
Doença arterial periférica 25 (9,5)
Doença renal 7 (2,7)
Doença hepática 2 (0,8)
Número de medicações 7 (6-9)
CHADS2 3 (2-4)
CHA2DS2-VASc 4 (3-5)
HAS-BLED 2 (1-3)

TP/RNI: tempo de protrombina/razão normalizada internacional; TFT: tempo na faixa terapêutica; IC: insuficiência cardíaca; FEVE: fração de ejeção do ventrículo esquerdo; AVC: acidente vascular cerebral; AIT: ataque isquêmico transitório; AINE: anti-inflamatórios não esteroides. As variáveis categóricas estão apresentadas como n (%) e as variáveis contínuas como mediana (25%-75%).

Durante o acompanhamento, foram realizados 2.754 exames de TP/RNI (mediana 10 exames/paciente), sendo 1.270 (46,1%) com valores entre 2,0 e 3,0. O TFT mediano foi de 62,5% (P25-75 44,2%-79,5%). A mediana do tempo de TP/RNI subterapêutico (< 2,0) foi de 18,9% e supraterapêutico (> 3,0) de 9,6%.

Em relação ao escore SAMe-TT2R2, 138 pacientes (52,5%) obtiveram pontuação 0-1 (baixo risco), enquanto que 125 (47,5%), pontuação ≥ 2 (alto risco), sendo a mediana 1 ponto (1-2). Quando avaliados os critérios do escore SAMe-TT2R2 de forma individual (Tabela 2), o critério "História Médica" (presença de > 2 comorbidades) foi o mais prevalente (57,0%). Os pacientes de baixo risco (escore 0-1) obtiveram um TFT mediano significativamente maior quando comparados com os de alto risco (pontuação ≥ 2): 69,2% vs. 56,3% (p = 0,002). Da mesma forma, o percentual de pacientes com TFT ≥ 60%, 65% ou 70% também se mostrou superior nos pacientes de baixo risco em todos os pontos de corte analisados (Figura 2).

Prevalência dos componentes do escore SAMe-TT<sub>2</sub>R<sub>2</sub>
Componente Escore n (%)
S Sexo Feminino 113 (43,0)
A Abaixo de 60 anos 41 (15,6)
Me História Médica (> 2 comorbidades*) 150 (57,0)
T Tratamento com amiodarona 26 (9,9)
T2 Tabagismo 37 (14,1)
R2 Raça não-branca 22 (8,4)

Acidente vascular cerebral prévio; diabetes; doença arterial periférica, coronariana, hepática, pulmonar, renal; hipertensão arterial e insuficiência cardíaca. Adaptado de Sex, Age, Medical history, Treatment, Tobacco use, Race.

Percentual de pacientes com TFT ≥ 60%, 65% e 70% de acordo com a pontuação no escore SAMe-TT<sub>2</sub>R<sub>2</sub> (p < 0,001, 0,001 e 0,003, respectivamente).

Na avaliação do escore SAMe-TT2R2 pela curva ROC para predição de TFT ≥ 65% (Figura 3), o ponto de corte de 2 pontos foi aquele que apresentou melhor combinação sensibilidade e especificidade (63,8% e 58,1%, respectivamente). A área sob a curva foi de 0,612 (IC95%: 0,544 - 0,681; p = 0,002).

Curva ROC para o desfecho TFT ≥ 65%<italic>.</italic>

Durante o seguimento, ocorreram 24 (9,1%) eventos adversos, estando a descrição completa na Tabela 3. Não houve casos de AIT ou embolização sistêmica durante o período analisado. Os pacientes de alto risco (escore ≥ 2) tiveram um percentual maior, porém sem diferença estatisticamente significativa, de eventos (11,2% vs. 7,2%; p = 0,369). A área sob a curva ROC do escore para a ocorrência de eventos adversos foi de 0,566 (IC95%: 0,449 - 0,682; p = 0,289), sendo novamente 2 o melhor ponto de corte, com sensibilidade e especificidade de 58,3% e 53,6%, respectivamente. As curvas de sobrevida livre de eventos adversos estão demonstradas na Figura 4.

Eventos adversos no seguimento total e de acordo com a pontuação no escore SAMe TT<sub>2</sub>R<sub>2</sub>
Eventos Adversos n = 263 SAMe-TT2R2 p
0-1 ponto ≥ 2 pontos
Sangramento maior 15 (5,7) 6 (4,3) 9 (7,2) 0,465
AVC 4 (1,5) 1 (0,7) 3 (2,4) 0,349
Óbito 12 (4,6) 5 (3,6) 7 (5,6) 0,637
TOTAL 24 (9,1) 10 (7,2) 14 (11,2) 0,369

AVC: acidente vascular cerebral. Dados apresentados como n (%).

Curva de sobrevida livre de eventos adversos de acordo com a pontuação no escore SAMe-TT<sub>2</sub>R<sub>2</sub> (p = 0,224).

Discussão

O uso da anticoagulação em pacientes com FA para prevenção de eventos tromboembólicos é uma estratégia com eficácia conhecida e dependente do TFT. A predição daqueles pacientes que terão maior chance de atingir um TFT adequado com AVKs é um aspecto importante na avaliação desses pacientes, especialmente no cenário atual em que novos medicamentos estão disponíveis para o tratamento desses pacientes (sem necessitar da monitorização do TP/RNI). Neste estudo, observamos que o escore SAMe-TT2R2 foi um bom preditor do TFT em pacientes recebendo anticoagulação oral com AVKs por FA não valvar em uma amostra brasileira, podendo ser uma ferramenta importante na avaliação inicial dos pacientes com indicação de anticoagulação. A mediana do TFT, assim como o percentual de pacientes com TFT ≥ 60%, 65% e 70%, foram superiores nos pacientes com baixa pontuação no escore SAMe-TT2R2 (0-1 ponto) quando comparados com o grupo de pacientes com pontuação ≥ 2.

A utilidade da aplicação deste escore já foi observada em outras populações e cenários clínicos. Ruiz-Ortiz et al.,15 analisando prospectivamente pacientes de ambulatórios de cardiologia espanhóis, observaram um declínio progressivo da média do TFT de acordo com a pontuação obtida no escore. Nesse estudo, os pacientes com pontuação 0 tiveram um TFT médio de 67,5% ± 24,6%, enquanto que, nos pacientes com pontuação ≥ 4, a média do TFT foi de 52,7% ± 28,7% (p < 0,01), sendo a área sob a curva ROC para o desfecho TFT ≥ 65% de 0,57 (IC95%: 0,53-0,60; p < 0,0005). Roldán et al.,14 analisando 459 pacientes de um ambulatório de anticoagulação, observaram que pacientes com pontuação 0-1 tinham um TFT médio de 67% ± 18%, enquanto que, nos pacientes com pontuação ≥ 2 pontos, esse valor era de 61% ± 16% (p < 0,001). Nesse estudo, o odds ratio de atingir um TFT < 65% foi de 2,10 (IC95%: 1,44 - 3,06; p < 0,001) nos pacientes com escore ≥ 2. Em estudo retrospectivo incluindo 4.468 pacientes selecionados a partir de registro das unidades de atenção primária do Reino Unido, Martinez et al.17 descreveram que a proporção de pacientes com TFT ≥60% foi de 44,1% nos pacientes com escore 0-1, e de 37,1% nos com escore ≥ 2 (p < 0,01).

A associação da pontuação do escore com a ocorrência de eventos adversos da anticoagulação (sangramento maior, AVC, embolização sistêmica e/ou óbito) foi descrita em estudos posteriores8,10-12,16,17 ao estudo original,9 relacionando sempre a qualidade da anticoagulação, avaliada pelo TFT, com a ocorrência desses desfechos. Isoladamente, apenas o estudo de Poli et al.13 não observou essa relação. Em estudo retrospectivo incluindo 4.468 pacientes com FA em uso de AVKs durante seguimento de 3 anos, Martinez et al.17 observaram um risco de AVC superior nos pacientes com escore ≥ 2 em comparação à pontuação 0-1, ao longo do acompanhamento (log rank p < 0,01). Lip et al.,12 em estudo retrospectivo com 8.120 pacientes (seguimento médio, 1.016 ± 1.108 dias), descreveram que o escore SAMe-TT2R2 foi preditivo de AVC/tromboembolismo, sangramento grave e morte, refletindo o TFT subótimo nos pacientes com escore ≥ 2. No presente estudo, atribui-se a não associação do escore com a ocorrência do total de eventos adversos, especificamente AVC, à baixa incidência dessa complicação.

Diversos estudos têm proposto a inclusão do escore SAMe-TT2R2 no fluxograma de decisão sobre qual anticoagulante ser usado em pacientes com FA recém-diagnosticada.14,25-28 A partir da pontuação obtida, pacientes com ≥ 2 pontos iniciariam direto o uso de NOACs, ao passo que aqueles com pontuação 0-1 iniciariam o uso de AVKs, sendo esse trocado por NOACs se o TFT não fosse adequado no seguimento (> 70%). As diretrizes atuais para o manejo da FA, entretanto, ainda não incluíram essa estratégia.4,29,30

Nosso estudo apresenta algumas limitações. Inicialmente o desenho retrospectivo carrega consigo limitações inerentes a ele, podendo influenciar a qualidade dos dados analisados. Apesar disso, acreditamos que os dados necessários para a realização desse estudo não tiveram grande perda, uma vez que o atendimento a esses pacientes na nossa instituição é feito de maneira sistematizada através de protocolo e consulta ambulatorial estruturada. Dessa forma, a grande maioria dos dados necessários para estudo foi coletada de forma sistemática durante a consulta assistencial. Uma segunda limitação é que a revisão de prontuários identificou apenas eventos adversos que ocorreram nas dependências do hospital ou que foram relatados pelos pacientes em consultas ambulatoriais, podendo haver alguns eventos que não tenham sido identificados (especialmente eventos adversos). Por fim, o fato de o estudo ser unicêntrico garante a uniformidade do acompanhamento dos pacientes descritos nesta coorte, porém pode diminuir a sua validade externa.

 Conclusão

Com base nos nossos dados, podemos afirmar que o escore SAMe-TT2R2 é uma ferramenta eficaz na predição do TFT em pacientes com FA em uso de AVKs para anticoagulação. Dessa forma, a aplicação desse escore em conjunto com os escores para avaliação da indicação de anticoagulação (CHADS2 e/ou CHA2DS2-VASc) e do risco de sangramento (HAS-BLED) permitirá também a obtenção de uma avaliação da qualidade desse tratamento. Naqueles pacientes com escore SAMe-TT2R2 elevado (pontuação ≥ 2), existe uma maior probabilidade de baixa efetividade da anticoagulação com AVKs, podendo então ser considerado o uso de NOACs. Por outro lado, os pacientes de baixo risco (escore 0-1) perfazem um grupo com melhor resposta aos AVKs e podem ser tratados com os mesmos. Com esse tipo de seleção, realizando-se uma intervenção baseada no risco do paciente, será possível que novas tecnologias (no caso, os NOACs), normalmente mais caras e menos disponíveis, sejam direcionadas para um grupo de pacientes com indicação mais precisa.

Fontes de financiamento

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Vinculação acadêmica

Este artigo é parte de Dissertação de Mestrado de Fernando Pivatto Júnior pela Universidade Federal do Rio Grande do Sul.