Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC 755ZHR96KWXmfKNLMz7dDKL S0066-782X2019000700111 10.5935/abc.20190128 Statement Statement on Antiplatelet Agents and Anticoagulants in Cardiology - 2019 0000-0002-9171-1224 Serrano Carlos V. Jr. 1 2 3 Soeiro Alexandre de M. 1 3 Leal Tatiana C. A. Torres 1 Godoy Lucas C. 1 Biselli Bruno 1 Hata Luiz Akira 1 Martins Eduardo B. 1 Abud-Manta Isabela C. K. 1 2 Tavares Caio A. M. 1 Cardozo Francisco Akira Malta 1 3 Oliveira Múcio Tavares de Jr. 1 Universidade de São Paulo Hospital das Clínicas Instituto do Coração São Paulo SP Brazil Instituto do Coração do Hospital das Clínicas da Universidade de São Paulo, São Paulo, SP - Brazil Hospital Israelita Albert Einstein São Paulo SP Brazil Hospital Israelita Albert Einstein, São Paulo, SP - Brazil Hospital Beneficência Portuguesa Mirante São Paulo SP Brazil Hospital Beneficência Portuguesa Mirante, São Paulo, SP - Brazil Correspondence: Sociedade Brasileira de Cardiologia - Av. Marechal Câmara, 360/330 - Centro - Rio de Janeiro - Postal Code: 20020-907. E-mail:sbc@cardiol.br.

Development: The Department of Clinical Cardiology of the Brazilian Society of Cardiology (Departamento de Cardiologia Clínica da Sociedade Brasileira da Cardiologia)

Norms and Guidelines Council: Fernando Bacal, Leandro Ioschpe Zimerman, Paulo Ricardo Avancini Caramori e Pedro A. Lemos

Norms and Guidelines Coordinator: Ludhmila Abrahão Hajjar

President of the Department of Clinical Cardiology: João Luiz Fernandes Petriz

Statement Coordinator: Carlos V. Serrano Jr.

 08 08 2019 07 2019 113 1 111 134 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
Declaration of potential conflict of interest of authors/collaborators of the Statement on Antiplatelet Agents and Anticoagulants in Cardiology - 2019
If the last three years the author/developer of the Statement:
Names Members of the Statement Participated in clinical studies and/or experimental trials supported by pharmaceutical or equipment related to the guideline in question Has spoken at events or activities sponsored by industry related to the guideline in question It was (is) advisory board member or director of a pharmaceutical or equipment Committees participated in completion of research sponsored by industry Personal or institutional aid received from industry Produced scientific papers in journals sponsored by industry It shares the industry
Alexandre de Matos Soeiro No Servier, Daiichi Sankyo No No Sanofi No No
Bruno Biselli No No No No No No No
Caio de Assis Moura Tavares No No No No No No No
Carlos Vicente Serrano Júnior No No No No No No No
Eduardo Bello Martins No No No No No No No
Francisco Akira Malta Cardozo No No No No No No No
Isabela C. K. Abud-Manta No No No No No No No
Lucas Colombo Godoy No No No No No No No
Luiz Akira Hata No No No No No No No
Múcio Tavares de Oliveira Júnior No Boehringer Ingelheim, EMS Sanofi Aventis, Boehringer Ingelheim, Roche Diagnostica, Philips Healthcare, Torrent Pharma Torrent Pharma Boehringer Ingelheim, Merck EMS, Novartis, Torrent Pharma No
Tatiana C. A. Torres Leal No No No No No No No
1. Introduction

In 2013, the Brazilian Cardiology Society published the “Brazilian Guidelines on Antiplatelet and Anticoagulant Agents in Cardiology.” Over the past years, new studies have been carried out, providing important information on the use of these medications, administered alone and in combination with other medications. It is, therefore, time to review our guidelines and update them with this new knowledge which has been produced.

We have carried out an extensive review of the literature, and for this update we have chosen to emphasize 6 major topics in clinical practice which have undergone innovation over the past years or which were not covered in the previous document. The themes of this update are:

Antithrombotic therapy in patients using oral anticoagulants and undergoing percutaneous coronary intervention (PCI);

Duration of dual antiplatelet therapy following PCI;

Reversal of new anticoagulants;

Pericardioversion anticoagulation in atrial fibrillation (AF);

Anticoagulation and antiplatelet therapy in patients with patent foramen ovale;

Antithrombotic therapy in oncology patients with thrombocytopenia.

In this update, grade of recommendations and level of evidence were applied in accordance with the following standards.

It is our hope that this document may be of benefit to all professionals who, in their daily practice, face dilemmas and doubts regarding the best manner to prescribe various options and doses of available anticoagulants and antiplatelet agents.

Grade of recommendation
Grade I Conditions for which there is conclusive evidence or, in the absence of conclusive evidence, general consensus that the procedure is safe and useful/effective
Grade IIa Conditions for which there are conflicting evidence and/or divergent opinions regarding the procedure's safety and usefulness/effectiveness. Weight or evidence/opinion in favor of the procedure. The majority of studies/experts approve.
Grade IIb Conditions for which there are conflicting evidence and/or divergent opinions regarding the procedure's safety and usefulness/effectiveness. Safety and usefulness/effectiveness less well established, with no prevailing opinions in favor.
Grade III Conditions for which there is evidence and/or consensus that the procedure is not useful/effective and may, in some cases, be potentially harmful
Level of evidence
Level A Data obtained from multiple concordant large randomized trials and/or robust meta-analysis of randomized clinical trials
Level B Data obtained from less robust meta-analysis, from a single randomized trial, or from non-randomized (observational) trials
Level C Data obtained through consensus of expert opinion
2. Antithrombotic Therapy in Patients Using Oral Anticoagulants and Undergoing Percutaneous Coronary Intervention 2.1. Introduction

Approximately 6% to 8% of patients undergoing PCI have a concomitant indication for long-term oral anticoagulant use, owing to various reasons such as AF, mechanical valves, or thromboembolism.1-4 It is, thus, fundamental to define the best way to treat these patients, especially regarding the combination of antiplatelet and anticoagulant medications.

For all patients who are receiving oral anticoagulants and who will undergo PCI, it is necessary to proceed to evaluating the need for maintaining anticoagulation and to calculate the risk of bleeding.

When AF is the reason for anticoagulation, the CHA2DS2-VASc score should be utilized, and maintenance should only be indicated when the score is ≥ 1 in men or ≥ 2 in women (Table 1). On the other hand, in patients with thromboembolic events or mechanical valve prostheses, anticoagulation should be maintained, regardless of any assessment.5-7

CHA<sub>2</sub>DS<sub>2</sub> VASc Criteria
Description Points
C Congestive heart failure 1
H Hypertension 1
A2 Age (≥ 75) 2
D Diabetes mellitus 1
S2 Prior TIA or stroke 2
V Vascular disease (prior AMI, PAD, or aortic plaque) 1
A Age (65-74) 1
Sc Sex (female) 1

AMI: acute myocardial infarction; PAD: peripheral arterial disease; TIA: transient ischemic attack.

Risk of bleeding should be assessed through the HAS-BLED score (Table 2). When it is ≥ 3, the patient is classified as at a high risk of bleeding. This should not contraindicate any form of treatment; however, it must be clear that the individual should be accompanied with more frequent consultations and that it is necessary to attempt to modify the risk factors present in the score in order to reduce the risk.6-8

HAS-BLED Criteria
Risk factor Points
H Arterial hypertension (SAP > 160 mmHg) 1
A Abnormal kidney function: CrCl ≤ 50 mL/min or creatinine ≥ 2.26 mg/dL or hemodialysis or kidney transplant 1
Abnormal liver function: bilirubin ≥ 2 × ULN or AST/ALT/AP ≥ 3 × ULN or hepatic cirrhosis 1
S Prior stroke 1
B Prior bleeding or predisposition to bleeding 1
L Labile INR or < 60% time within therapeutic range 1
E Age > 65 1
D Drug use (NSAID, antiplatelet) 1
Alcohol use (> 20 U per week) 1

ALT: alanine aminotransferase; AP: alkaline phosphatase; AST: aspartate aminotransferase; CrCl: creatinine clearance; INR: international normalized ratio; NSAID: nonsteroidal anti-inflammatory drugs; SAP: systolic arterial pressure; U: units; ULN: upper limit of normal.

 2.2. Management of Antithrombotic Agents and the Moment of Percutaneous Coronary Intervention

Interrupting oral anticoagulation (OAC) during the periprocedural period can increase both the rate of bleeding and the rate of thromboembolic events.

Although there is no consistent evidence, the introduction of parenteral anticoagulants in patients receiving warfarin should only be considered when the international normalized ratio (INR) is less than 2.5. PCI may be performed while using anticoagulants; however, it should be postponed, if possible, until the patient’s INR is < 1.5, unless there is an emergency situation, and it is necessary to take high ischemia risk (GRACE score > 140, TIMI score ≥ 5, recurrent angina, refractory angina, hemodynamic instability, or ventricular arrhythmias) into consideration.7,8

Furthermore, for patients receiving new oral anticoagulants (NOAC), there is also no evidence as to whether parenteral anticoagulation or PCI should be performed early or not. Once more, when the risk of ischemia is very high, PCI should be performed early, while still under the effect of the medication. The procedure should be postponed, however, whenever the risk of ischemia permits. For patients with creatinine clearance > 50 mL/min, the full effect of NOAC may be considered reversed 24 hours after the last dose. For patients with creatinine clearance, on the other hand, between 30 and 50 mL/min, 48 hours are necessary. Following this period, the patient may thus theoretically undergo PCI with a lower risk of bleeding. Parenteral anticoagulation may be performed in the event that PCI is early, regardless of when the last dose of NOAC was administered.7,8

In all OAC patients, priority vascular access should always be radial, and femoral access should only be performed in exceptional cases.

The use of pre-PCI dual antiplatelet therapy should be routinely avoided in this group of patients. Clopidogrel should only be used once coronary anatomy has been defined and coronary angioplasty with stent placement has been indicated. The use of prasugrel or ticagrelor is contraindicated in this situation, as there is insufficient evidence for their safety in this context. Acetylsalicylic acid (ASA) should always be used at a minimum dose, preferably less than 100 mg daily.7,8

The use of proton pump inhibitors as prophylaxis against stress ulcers in this group of patients should be the first choice considered due to the elevated risk of gastrointestinal bleeding.7,8

2.3. Choosing Stent Type for Percutaneous Coronary Intervention

The choice of stent type (between the newest generation of drug-eluting stents and conventional stents) in patients who require full anticoagulation continues to generate discussion.

Results of the Dual Antiplatelet Therapy (DAPT) study (see section 2.2) showed that the benefits of prolonged dual antiplatelet therapy do not depend on the type of stent used and that the risk of coronary events in patients who suspend therapy due to the need for non-cardiac surgery was the same with either drug-eluting or conventional stents.9-11

Furthermore, two randomized studies have demonstrated that second-generation drug-eluting stents are superior to conventional stents in patients with high bleeding risks who were not able to tolerate the use of prolonged dual antiplatelet therapy.12,13

In this manner, stent choice should be individualized based on coronary anatomy and bleeding risk. There are, however, no reasons to contraindicate the use of drug-eluting stents in this group of patients.

 2.4. Long-term Antithrombotic Therapy following Percutaneous Coronary Intervention

The first instances of evidence on this topic have begun to be published during the last five years, which means that the subject continues to be controversial and to produce doubts.

In 2012, data from the DANISH registry in patients with AF and acute myocardial infarction (AMI) showed that the 90-day risk of bleeding significantly increased with the use of triple therapy in comparison with anticoagulation combined with only one antiplatelet agent (hazard ratio [HR] = 1.47, 95% CI 1.04 to 2.08) with no differences in ischemic event rates (HR = 1.15, 95% CI 0.95 to 1.40). In this manner, analysis of this observational study would not recommend routine use of triple therapy.14,15

The What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (WOEST) study, with 573 patients, was the first randomized prospective study published on this topic. All patients were indicated for OAC (69% for AF) and PCI. Patients were divided into 2 groups: warfarin and clopidogrel; and warfarin, clopidogrel, and ASA 80 mg daily. This treatment regimen was maintained for 30 days for conventional stents and 12 months for drug-eluting stents. The primary outcome was any bleeding episode according to TIMI criteria. After 1 one year, they observed a significant reduction in bleeding in the dual therapy group (19.5% versus 44.9%; HR = 0.36, 95% CI 0.26 to 0.50, p < 0.001). There was no different in rates of major bleeding, AMI, stent thrombosis, or stroke. Lower mortality, however, was observed in the dual therapy group (2.5% versus 6.4%, p = 0.027).16

In 2015, the Triple Therapy in Patients on Oral Anticoagulation after Drug Eluting Stent Implantation (ISAR-TRIPLE) multicenter randomized study, with 614 patients, conducted in Germany and Denmark, evaluated whether shortening the duration of clopidogrel therapy from 6 months to 6 weeks after drug-eluting stent implantation would be associated with superior net clinical outcome in patients receiving aspirin and warfarin concomitantly. They included patients who had been receiving oral anticoagulants for AF for at least 12 months and who had received a drug-eluting stent for stable angina or acute coronary syndrome (ACS). The primary outcomes were death, AMI, stent thrombosis, stroke, and major bleeding in 9 months. No differences were observed in relation to the primary outcomes between the 2 groups (9.8% versus 8.8%; HR = 1.14, 95% CI 0.68 to 1.91; p = 0.63). On the other hand, the incidence of minor bleeding events was higher in the group that used clopidogrel for 6 months (10.9% versus 7.3%, p = 0.03).17

With respect to NOAC, the PIONEER AF-PCI randomized prospective study evaluated the best pharmacological treatment strategy using rivaroxaban in patients who required OAC due to AF and who were undergoing PCI. The study included 2,124 patients, divided into 3 groups: rivaroxaban (15 mg) + P2Y12 inhibitor for 12 months; rivaroxaban (2.5 mg twice daily) + ASA + P2Y12 inhibitor for 1, 6, and 12 months; and warfarin + ASA + P2Y12 inhibitor for 1, 6, and 12 months. Approximately 93% of patients used clopidogrel as the antiplatelet of choice, and 65% received drug-eluting stent implantation. Approximately 50% of cases had ACS. The primary outcome evaluated was clinically relevant bleeding according to TIMI criteria. They observed bleeding rates of 16.8%, 18.0%, and 26.7%, respectively between the groups (p < 0.001). The rates of mortality, stroke, and cardiovascular events did not show any significant differences. For patients with AF who need stent angioplasty, the authors concluded that dual therapy or triple therapy strategies with reduced doses of rivaroxaban were safer and that they reduced bleeding rates in comparison with conventional triple therapy.18

Similarly, in 2017, the Evaluation of Dual Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with AF that Undergo a PCI with Stenting (REDUAL-PCI) multicenter randomized prospective study included 2,725 patients with AF who underwent PCI, divided into triple therapy (warfarin + clopidogrel/ticagrelor + ASA) versus dabigatran + clopidogrel/ticagrelor. The primary outcome was major or clinically relevant bleeding. Furthermore, they tested the noninferiority of dual therapy in relation to thromboembolic events, death, and revascularization. The bleeding rate was 15.4% in the group that received 110 mg of dabigratan compared to 26.9% in the triple therapy group (p < 0.001 for noninferiority). In patients who received 150 mg of dabigratan, the bleeding rate was 20.2% compared to 25.7% in the triple therapy group (p < 0.001 for noninferiority). The combined events rates were 13.7% and 13.4% in the double and triple therapy groups, respectively (p = 0.005 for noninferiority). They mainly observed a reduced need for revascularization. The use of dual therapy with dabigatran was thus shown to be noninferior to triple therapy. As in the PIONEER AF-PCI study, the REDUAL-PCI study was not powered to show differences in coronary events or death. It was only possible to evaluate safety.19

Triple therapy should, thus, be considered only for patients with low hemorrhage risks during the shortest time possible (preferably 1 month, with the possibility of extending up to 6 months). After this period, anticoagulant use combined with just 1 antiplatelet agent should be maintained. However, when there is a high ischemia risk (Table 3) as well as a high hemorrhage risk, the recommendation is to use triple therapy for, at most, 1 month or to initiate dual therapy with an anticoagulant and clopidogrel directly (Table 4 and Figure 1).

Definition of high long-term ischemic risk
Prior history of stent thrombosis during adequate antiplatelet therapy
"Final" artery angioplasty
Multiarterial coronary disease, especially in patients with diabetes
Chronic renal insufficiency (ClCr < 60 mL/min)
At least 3 stents and/or 3 lesions treated
PCI in bifurcation, with at least 2 stents placed
Total stent length > 60 mm
Treatment for chronic coronary occlusion

CrCl: creatinine clearance.

 Recommendation for managing patients who require oral anticoagulation undergoing percutaneous coronary intervention
Indications Grade of recommendation Level of evidence
The CHA2DS2-VASc score should be used to evaluate the need for maintaining anticoagulation, and the HAS-BLED score should be used to calculate the risk of bleeding IIa C
During PCI, priority vascular access should always be radial, and femoral access should only be performed in exceptional cases. IIa C
Triple therapy should be considered for the shortest time possible, due to the high associated risk of hemorrhage. IIa C
Utilization of NOAC should be given preference over warfarin, due to the predictability of their effect. IIa C
When opting to use warfarin, INR should be maintained close to 2.0. IIa C
Clopidogrel should only be used once coronary anatomy has been defined and coronary angioplasty with stent placement has been indicated, and routine pre-PCI administration should be avoided. IIa C
The use of prasugrel or ticagrelor is contraindicated in this situation. III C
ASA should always be used at a minimum dose, preferably ≤ 100 mg daily. IIa C
The use of proton pump inhibitors as prophylaxis against stress ulcers in this group of patients should be the first choice considered, due to the elevated risk of gastrointestinal bleeding. IIa C
Triple therapy should be considered for patients with low hemorrhage risks during the shortest time possible (preferably 1 month, with the possibility of extending up to 6 months). After this period, anticoagulant use in combination with just one antiplatelet agent should be maintained. IIa B
When there is a high ischemia risk as well as a high hemorrhage risk, the recommendation is to use triple therapy for, at most, 1 month or to begin dual therapy with an anticoagulant and clopidogrel directly. IIa B
In patients with high risks of bleeding and low ischemia risks, dual therapy with an anticoagulant and clopidogrel should be initiated from the beginning. IIa A
When opting to use NOAC, the combination of dual therapy with clopidogrel 75 mg daily and rivaroxaban 15 mg daily or dabigatran 110 mg twice daily should be the first choice. IIb B
Discontinuation of antiplatelet therapy should be considered after 12 months. IIa B

ASA: acetylsalicylic acid; INR: international normalized ratio; NOAC: new oral anticoagulant; PCI: percutaneous coronary intervention.

Flowchart representing indications for antithrombotic therapy combinations in accordance with ischemic and hemorrhagic risk.

C: clopidogrel; OAC: oral anticoagulant; PCI: percutaneous coronary intervention.

On the other hand, in patients with high risks of bleeding and low ischemia risks, in accordance with the results of the main published studies, the current recommendation is to initiate dual therapy with an anticoagulant and clopidogrel from the beginning (Table 4 and Figure 1).

It is, preferably, recommended to use NOAC instead of warfarin, due to the predictability of their effect. Furthermore, the NOAC should be chosen in accordance with the medical knowledge already established in this context and at doses previously studied in scientific research. When opting to use warfarin, the INR should be maintained close to 2.0.

Suspension of the antiplatelet agent is recommended 12 months after the last coronary event. Evidence for this conduct is scarce; it is, however, based on studies that showed that, after 1 year, anticoagulation is superior to ASA and that the combination, in addition to increasing bleeding rate, has no additional benefits.20 Combined therapy with clopidogrel and OAC may be prolonged for more than 1 year in patients with high ischemia risk and mechanical valve prostheses.

 3. Duration of Dual Antiplatelet Therapy Following Percutaneous Coronary Intervention 3.1. Introduction

The combination of P2Y12 inhibitors with ASA monotherapy is known to be a great ally in the management of patients with coronary artery disease (CAD), be it acute or stable, and it reduces the risk of atherothrombotic phenomena, as well as stent thrombosis rates following PCI.21-23 This reduced ischemia risk is, however, indisputably associated with higher bleeding rates.22-25

The state of the art is to weigh the risks and benefits of dual therapy, as well as treatment duration, by contemplating clinical characteristics, the anatomical characteristics of the lesions addressed, and the type of stent used.

The risk of stent thrombosis in patients who have undergone PCI with conventional (metallic) stents is much more frequent during the first days and weeks following the procedure. In this manner, dual antiplatelet therapy is recommended for 1 month.26 With the advent of drug-eluting stents, conventional stents have been reserved, ideally, for patients with very high risks of bleeding who need shorter periods (at least 1 month) of dual antiplatelet therapy. In Brazil, however, conventional metallic stents continue to be used, especially in public health services.

Thrombosis in first-generation drug-eluting stents intensified perspectives on therapy duration in the past.27 Although the relative risk is still considerable, late or very late thrombosis in second-, third-, and fourth-generation drug-eluting stents has considerably reduced with modernization of the drugs eluted and the materials utilized. This has, thus, made it possible for dual therapy duration to be as short as possible, seeing that the risk of bleeding does not justify the small absolute benefit of reducing very late thrombosis. The use of first-generation drug-eluting stents is already infrequent in Brazil. For this reason, these guidelines do not include a discussion of treatment duration following percutaneous implantation of this type of stent.

The use of bioresorbable stents is already a reality in some centers. There are no studies to determine the ideal dual antiplatelet therapy duration specifically for this type of stent, although the recommendation for treatment duration is approximately 12 months. Some meta-analyses have suggested a lower rate of thrombosis in this type of stent in comparison with drug-eluting stents during the first 30 days following implantation. Use of the most potent P2Y12 inhibitors is thus indicated for this patient profile. There is still an increased risk of very late thrombosis, and longer treatment (more than 12 months) may consequently be considered for patients with low bleeding risks. Specific studies, however, are still lacking to reinforce this recommendation.28-31

3.2. Risk Scores

There are several known risk factors related to higher risks of ischemic events and bleeding episodes. Some of these factors are also related to both situations, which makes the medical decision even more complex.

Internationally implemented risk scores are currently available to aid in weighing treatment extension, taking the risk of bleeding and the benefit of reduced atherothrombotic risk into consideration.32,33 Based on studies, 2 scores have been elaborated: the DAPT score and the PRECISE-DAPT score.

The DAPT score (Table 5) was developed based on analysis of 11,648 patients included in the Dual Antiplatelet Therapy Study (DAPT) trial, and it has been validated in 8,136 patients who participated in the Patient Related Outcomes with Endeavor vs. Cypher Stenting (PROTECT) trial. Nine factors were identified: age, heart failure (HF) or reduced left ventricular ejection fraction (LVEF), saphenous vein graft stent implantation, AMI at initial presentation, prior AMI or prior PCI, paclitaxel-eluting stent, diabetes, stent diameter < 3 mm, and current tobacco use, resulting in a sum of points varying from −2 to +10. Patients with high DAPT scores (≥ 2) receive more benefits from prolonged dual antiplatelet therapy, as evaluated in cited study, over an average period of 30 months, given the reduction in AMI, stent thrombosis, and cardiovascular and cerebrovascular events, at the expense of a small increase in the risk of bleeding (NNT = 34 versus NNH = 272). On the other hand, patients with low DAPT scores (< 2) have an increased risk of events related to bleeding, with no reduction in the rate of cardiovascular and cerebrovascular events (NNH 64).32

Factors used to calculate DAPT score. Scores ≥ 2 are associated with favorable risk-benefit, whereas scores < 2 are associated with unfavorable risk-benefit
Age ≥ 75 Points
Age > 65 and < 75 -2
Age < 65 -1
Current tobacco use 0
Diabetes mellitus 1
AMI at initial presentation 1
Prior PCI or AMI 1
Stent diameter < 3 mm 1
Paclitaxel-eluting stent 1
HF or reduced LVEF 1
Saphenous vein graft PCI 2
ICP em enxerto de veia safena 2

AMI: acute myocardial infarction; HF: heart failure; LVEF: left ventricular ejection fraction; PCI: percutaneous coronary intervention.

The Predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) included 14,963 patients undergoing elective, urgent, or emergency PCI, randomized into long (12 to 24 months) or short (3 to 6 months) dual antiplatelet therapy durations, with relation to bleeding risk based on 5 factors: age, creatinine clearance, hemoglobin, white-blood-cell count, or prior spontaneous bleeding (calculator available at www.precisedaptscore.com). In patients with high PRECISE-DAPT scores (≥ 25), prolonged therapy was associated with higher bleeding rates and no ischemic benefits; in contrast, patients with low PRECISE-DAPT scores had low combined adverse ischemic events with no significant increase in risk of bleeding.33

Scientific evidence tested in randomized studies is lacking to evaluate the real value of these scores in improving long-term outcomes for patients receiving dual antiplatelet therapy and undergoing PCI. Nevertheless, their utilization may be considered when individualizing decisions and contemplating the risks and benefits of prolonging dual antiplatelet therapy.

 3.3. Dual Antiplatelet Therapy Duration following Percutaneous Coronary Intervention for Stable Coronary Artery Disease

Dual antiplatelet therapy in stable cases of CAD is not routinely indicated for patients receiving clinical treatment. It is only effectively necessary to indicate this following PCI, and the combination of ASA and clopidogrel is preferable.

There is no evidence from randomized studies on the use of prasugrel and ticagrelor as on option over clopidogrel for this patient profile. They are, however, options which may be considered for patients with high atherothrombotic risks if there is evidence that clopidogrel is not effective based on previous clinical outcomes or for patients who receive implantation of a bioresorbable stent.

Of the studies that evaluate dual antiplatelet therapy duration (ASA and clopidogrel) in stable patients, 3 are more recent, and they compare 6 months with 12 to 24 months of treatment. The Safety and Efficacy of 6 Months Dual Antiplatelet Therapy after Drug Eluting Stenting (ISAR-SAFE) study,34 which was the largest, randomized 4,005 patients and confirmed that there are no benefits and no reduction in ischemic events with the use of dual antiplatelet therapy for 12 months in comparison with 6 months. Similar results were also found in the Is There a Life for DES after Discontinuation of Clopidogrel? (ITALIC)35 and Second Generation Drug-eluting Stent Implantation followed by Six- versus Twelve-month Dual Antiplatelet Therapy (SECURITY) studies.36

Other meta-analyses37,38 have shown that 12 months of therapy did not add benefits in relation to reduced ischemic events in comparison with shorter therapy duration (< 6 months, including evaluation of studies that analyzed 3 months of therapy), which may be an option for patients with lower bleeding risks.

The DAPT trial and other meta-analyses37-39 have demonstrated that, in addition to reduced ischemic events, stent thrombosis, and infarction rates, as well as increased bleeding rates, therapy prolonged for more than 12 months showed a possible, albeit weak, relation to increased general mortality.

The recommendation of these guidelines is, thus, based on average dual antiplatelet therapy duration of 6 months following PCI in stable patients, with the possibility of considering a period of 3 months for patients with high bleeding risks. More prolonged use (> 12 months) is not routinely indicated and may be considered in accordance with the patient’s clinical and anatomical profile (Table 6).

Recommendations on duration of dual antiplatelet therapy following percutaneous coronary intervention in stable coronary artery disease
Indications Grade of recommendation Level of evidence
In patients with stable CAD undergoing PCI who need dual antiplatelet therapy, the preferred combination is clopidogrel (75 mg) and a dose of ASA (75 to 200 mg) I A
The use of drug-eluting stents is always preferable to conventional stents, regardless of dual antiplatelet therapy duration I A
In patients with stable CAD undergoing PCI with a drug-eluting stent, dual antiplatelet therapy should be maintained for a minimum period of 6 months, regardless of stent type I A
In patients with stable CAD undergoing PCI with a conventional stent, dual antiplatelet therapy may be maintained for a minimum period of 1 month when there is a high risk of bleeding I A
In patients with stable CAD undergoing PCI with a drug-eluting stent who have high bleeding risks, the suspension of dual antiplatelet therapy may be considered IIa B
In patients with stable CAD undergoing PCI with a drug-eluting stent who tolerate the routine dual antiplatelet therapy duration without bleeding episodes and who have low bleeding risks and high atherothrombotic risks (DAPT score ≥ 2 and PRECISE-DAPT < 25), it is possible to maintain antiplatelet therapy for > 12 months and ≤ 30 months IIb A

ASA: acetylsalicylic acid; CAD: coronary artery disease; PCI: percutaneous coronary intervention.

 3.4. Dual Antiplatelet Therapy Duration following Percutaneous Coronary Intervention for Acute Coronary Artery Disease

Ticagrelor and prasugrel are preferential P2Y12 inhibitors for patients undergoing PCI after ACS.

In patients who have ACS, the ischemia risk continues to be higher until approximately 1 year after the event, even after the culprit and non-culprit lesions have been treated.22,20,40,41 The main studies which affirm that ticagrelor and prasugrel have benefits over clopidogrel consider a reduction in events with an average treatment duration of 12 months.

A meta-analysis of 3 studies which compared 3, 6, and 12 months of dual therapy, including 11,473 patients, 4,758 of which had ACS, demonstrated that dual antiplatelet therapy for ≤ 6 months was associated with an increased risk of infarction, which was, however, not statistically significant. Considering the lower number of acute patients in comparison with studies that demonstrated the real benefits of intense dual antiplatelet therapy with ticagrelor and prasugrel (TRITON and PLATO), the discontinuation of dual antiplatelet therapy may be considered in patients with increased bleeding risks as early as 6 months after treatment initiation.42

The PEGASUS study evaluated patients who had had infarction 1 to 3 years prior to randomization. They studied the standard dose of ticagrelor (90 mg every 12 hours), a lower dose of ticagrelor (60 mg every 12 hours) and placebo. All patients received ASA and were followed for a median of 33 months. There was a significant reduction in the rates of infarction, cardiovascular death, and stroke, at the expense of an increase in events related to bleeding. The 60-mg dose of ticagrelor, however, demonstrated lower rates of bleeding in comparison with the 90-mg dose.43

In following with this, the recommendation of these guidelines is to administer dual antiplatelet therapy for at least 12 months to patients undergoing PCI after ACS, which may be modified to a minimum duration of 6 months in the event of increased risks of bleeding. In the same manner as in stable coronary disease, more prolonged use (> 12 months) is not routinely indicated and may be considered in accordance with patients’ clinical and anatomical profiles. When opting for this more prolonged treatment, a 60-mg dose of ticagrelor every 12 hours may be considered in combination with ASA (Table 7).

Recommendations on duration of dual antiplatelet therapy following percutaneous coronary intervention in acute coronary syndrome
Indications Grade of recommendation Level of evidence
In patients with ACS undergoing PCI, regardless of stent type, dual antiplatelet therapy should be maintained for a minimum period of 12 months I A
In patients with ACS undergoing PCI with increased risks of bleeding, it is possible to consider maintaining dual antiplatelet therapy for a minimum period of 6 months IIa B
In patients with ACS undergoing PCI with a drug-eluting stent who tolerate the routine dual antiplatelet therapy duration without bleeding episodes and who have low bleeding risks and high atherothrombotic risks (DAPT score ≥ 2 and PRECISE-DAPT < 25), it is possible to maintain antiplatelet therapy for > 12 months and ≤ 30 months IIb A

ACS: acute coronary syndrome; PCI: percutaneous coronary intervention.

 4. Reversal of New Anticoagulants 4.1. Introduction

At the same time that NOAC have been considered noninferior to vitamin K antagonists for ischemic stroke prevention in patients with AF and deep venous thrombosis treatment, they are related to lower risks of major bleeding, particularly hemorrhagic stroke.44

Furthermore, notwithstanding the current unavailability of antidotes for all NOAC, major bleeding episodes caused by these drugs do not seem to lead to worse clinical outcomes when compared to bleeding episodes in patients receiving vitamin K antagonists whose anticoagulant effects may be rapidly reversed.45

With the increased use of NOAC in clinical practice, the management of hemorrhagic events and the need to reverse anticoagulant effects in order to perform urgent procedures in patients receiving these medications have become common in emergency units.

In addition to general measures (Table 8), the utilization of antidotes, alternative therapies (e.g., prothrombin complex concentrates, factor VIIa, tranexamic acid) and the action of specialized teams (e.g., hematologists, endoscopists, neurologists, neurosurgeons, general surgeons, vascular surgeons, etc.) should be part of institutional protocols for reversing anticoagulation in the event of major bleeding episodes or urgent surgical procedures in patients receiving NOAC.46

General measures for controlling major bleeding events in patients receiving NOAC
Mechanical compression when possible
Determining last dose of NOAC
Exams (renal and hepatic function, hemogram, complete coagulogram, and factor anti-Xa)
Volume expansion and red cell concentrate, when necessary
Activated charcoal if NOAC was taken < 2 hours prior

NOAC: new oral anticoagulant.

 4.2. Antidotes

Three antidotes are in diverse developmental phases (Table 10). To date, only the monoclonal antibody idarucizumab has been approved for commercial use as an antidote for dabigratan. Andexanet alfa, an antidote for factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), has yet to be approved for commercial use in Brazil. Finally, ciraparantag, which is still in the early stages of development, is potentially capable of neutralizing the effects of both direct thrombin inhibitors and factor Xa inhibitors (Tables 9 and 10).

Reversal of NOAC anticoagulant effects8
NOAC Specific antidote Alternative therapeutic options
Dabigratan Idarucizumab 5 g IV (divided in 2 doses of 2.5 g) • PCC 50 IU/kg IV• RFVIIa 90 mcg/kg IV every 2 hours• Tranexamic acid 15 to 30 mg/kg IV• Hemodialysis
Rivaroxaban Anti-factor Xa (e.g., Andexanet alfa - not approved) • PCC 50 IU/kg IV• RFVIIa 90 mcg/kg IV every 2 hours• Tranexamic acid 15 to 30 mg/kg IV
Apixaban Anti-factor Xa (e.g., Andexanet alfa - not approved) • PCC 50 IU/kg IV• RFVIIa 90 mcg/kg IV every 2 hours• Tranexamic acid 15 to 30 mg/kg IV
Edoxaban Anti-factor Xa (e.g., Andexanet alfa - not approved) • PCC 50 IU/kg IV• RFVIIa 90 mcg/kg IV every 2 hours• Tranexamic acid 15 to 30mg/kg IV

IV: intravenous; NOAC: new oral anticoagulant; PCC: prothrombin complex concentrates; rFVIIa: recombinant activated factor VII.

 Recommendations on the use of NOAC antidotes
Indications Grade of recommendation Level of evidence
The use of idarucizumab in patients receiving dabigatran is indicated at a dose of 5 g intravenous, when emergency intervention or surgery are necessary in patients who cannot wait the time it takes to metabolize the anticoagulant or in the event of life-threatening or uncontrollable bleeding episodes IIa B
In the event of surgeries or procedures which are elective or for which it is possible to wait the NOAC clearance time, controlled bleeding events, or anticoagulant overdoses without bleeding, the use of antidotes should not be indicated III C

NOAC: new oral anticoagulant.

Potential indications for the use of antidotes for NOAC include:

A life-threatening bleeding episode (e.g. hemorrhagic stroke) or uncontrollable bleeding;

Persistent bleeding, notwithstanding hemostatic measures;

Risk of recurrent bleeding due to NOAC overdose or expected metabolism delay (e.g., renal insufficiency);

Bleeding in non-compressible locations or in vital organs (e.g., retroperitoneal, pericardial, or intraocular bleeding or intramuscular bleeding with compartment syndrome);

Need for emergency surgical intervention in patients with high risks of bleeding who cannot wait the time it takes to metabolize NOAC.

The use of antidotes does not seem to be necessary in patients who have received the last dose of NOAC more than 24 hours prior and who have creatinine clearance > 60 mL/min. In the event of elective surgeries or procedures, patients who may wait the time it takes to metabolize the NOAC, controlled bleeding, or anticoagulant overdose with no bleeding, antidote use does not need to be indicated.47

4.3. Idarucizumab

Idarucizumab is a monoclonal antibody fragment that neutralizes the anticoagulant effect of dabigatran by direct binding. Dabigatran, idarucizumab, and dabigatran-idarucizumab are eliminated by the kidneys.

The phase III Reversal Effects of Idarucizumab on Active Dabigatran (REVERSE-AD) study has shown that the intravenous use of 5 g of idarucizumab (2 consecutive doses of 2.5 g at 15-minute intervals) reverted the anticoagulant effect of dabigatran with normalization of thrombin time in more than 98% of patients, leading to early hemostasis in patients with major bleedings and low rates of hemorrhagic events in patients undergoing urgent surgery.48

4.3.1. Andexanet alfa

Andexanet alfa is a recombinant factor Xa protein that binds to direct and indirect factor Xa inhibitors, removing them from circulation.

Phase II studies in healthy elderly patients have demonstrated that this drug, administered via intravenous bolus with subsequent continuous 2-hour infusion, reverted more than 90% of rivaroxaban and apixaban’s anti-Xa factor activity.49 The phase III Ability of Andexanet Alfa to Reverse the Anticoagulant Activity-4 study, which is currently underway, will evaluate the efficacy and safety of andexanet in controlling hemostasis in patients receiving rivaroxaban, apixaban, and edoxaban who have major bleedings. Interim analysis of the study with 67 patients showed a reduction in anti-Xa factor activity in 89% and 93% of patients using rivaroxaban and apixaban, with 70% clinical hemostasis.50

4.4. Alternative Therapies

Fresh frozen plasma (FFP), prothrombin complex concentrates (PCC), recombinant activated factor VII, and tranexamic acid are suggested as alternative therapies for patients receiving NOAC who have life-threatening hemorrhagic events or who need to undergo urgent procedures in the absence of a specific antidote (Table 9).46

Animal model, in vitro, and case series studies have demonstrated improved laboratory parameters for coagulation in patients receiving rivaroxaban.51-53 On the other hand, new evidence has suggested the superiority of recombinant activated factor VII and partially activated prothrombin complex concentrate (FEIBA) in relation to PCC in patients receiving rivaroxaban.54,55 A randomized placebo-controlled study in healthy individuals receiving dabigatran failed to show benefits of PCC use in improving laboratory parameters of coagulation.56 Furthermore, case series studies have shown controversial results for the use of FFP, PCC, recombinant activated factor VII, and fibrinogen.57

The absence of evidence on clinical reversal of anticoagulant effects of NOAC through the utilization of these alternative homeostatic agents, as well as conflicting data in relation to effects and optimal dosages, make routine use of these medications controversial.

Finally, hemodialysis may remove approximately 49% to 57% of circulating dabigatran in up to 4 hours, seeing that only 35% of the drug is bound to plasma proteins. Patients with renal insufficiency and dabigatran overdose may benefit from hemodialysis in the context of major hemorrhagic events or the need for urgent procedures (Table 10). As rivaroxaban and apixaban are highly bound to plasma proteins, they are not removed by hemodialysis.46

5. Pericardioversion Anticoagulation in Atrial Fibrillation 5.1. Introduction

AF is the most common sustained arrhythmia in clinical practice. Its incidence and prevalence increase with age, with a prevalence of 8% in the population over age 80.58 Furthermore, some American studies have shown that this prevalence increases by about 0.3% per year and that it had an absolute growth of 4.5% between 1997 and 2007.58 The reason behind this increase, in addition to population aging, is related to the improvements in treatment of chronic heart diseases, which increases the number of susceptible individuals, in addition to improved diagnostic tools with greater documentation of this arrhythmia.59

AF is associated with increased risk of stroke, as well as heart failure and total mortality.60-64 At least 20% of stroke cases are caused by AF, and these cases of stroke are generally more severe and incapacitating than ischemic stroke.65-67 Some studies have also shown increased risks of cognitive impairment secondary to asymptomatic embolic events in this population.68

Antithrombotic therapy plays a fundamental role in the prevention of embolic events when these risk factors are present, making it one of the main pillar of treatment, regardless of the strategy adopted (sinus rhythm or heart rate control).69,70 Risk may be calculated using the CHA2DS2-VASc score71 (Table 11), with an indication for chronic anticoagulation if the score is greater than or equal to 2 points, as long as there are no contraindications and the bleeding risk is acceptable.

Recommendations on cardioversion anticoagulation in atrial fibrillation
Indications Grade of recommendation Level of evidence
Electrical cardioversion is recommended for patients with hemodynamic instability to reestablish cardiac output I B
Anticoagulation with heparin or a new oral anticoagulant should be initiated as soon as possible before any cardioversion for AF or flutter IIa B
In stable patients, with persistent AF, who are to undergo electrical or chemical cardioversion, OAC is recommended for at least 3 weeks before and 4 weeks after cardioversion within the therapeutic range (INR between 2 and 3). After 4 weeks, OAC maintenance should be in accordance with CHA2DS2VASc risk score I B
TEE is recommended to exclude thrombi as an alternative to periprocedural anticoagulation when early cardioversion is programmed I B
In the event that a thrombus is identified, anticoagulation should be maintained for 3 weeks I C
It is recommended to repeat TEE after 3 weeks of anticoagulation to ensure that the thrombus has been resolved before cardioversion IIa C
During the pericardioversion period, it is possible to opt for OAC with vitamin K antagonists or new anticoagulants, for the previously described duration IIa B
The use of OAC is indicated for patients with atrial flutter, with the same considerations as in AF I C
The preferred dose of rivaroxaban should be 20 mg daily, as long as there is a low risk of bleeding I B
The preferred dose of dabigatran should be 150 mg twice daily, as long as there is a low risk of bleeding I B
The preferred dose of apixaban should be 5 mg twice daily, as long as there is a low risk of bleeding I B
For patients undergoing electrical cardioversion guided by TEE without thrombi, UFH is recommended EV (bolus following by continuous infusion) before cardioversion and should be maintained until full OAC is reached I B
For patients with AF who need emergency electrical cardioversion, UFH is recommended EV (bolus following by continuous infusion) I C
For patients undergoing electrical cardioversion guided by TEE without thrombi, LMWH is recommended before cardioversion and should be maintained until full OAC is reached I B
For patients with AF who need emergency electrical cardioversion, a full dose of LMWH is recommended I C

AF: atrial fibrillation; EV: endovenous; INR: international normalized ratio; LMWH: low-molecular weight heparin; OAC: oral anticoagulation; TEE: transesophageal echocardiography; UFH: unfractionated heparin.

Warfarin is highly effective in preventing thromboembolic phenomena in AF, with a 64% reduction of risk in patients who receive adequate treatment.72-74 However, at least half of patients do not receive adequate treatment, for reasons that vary from difficulties in frequent INR monitoring to high risks of bleeding.72,73 Furthermore, patients receiving warfarin are not always within the appropriate therapeutic range (INR generally between 2 and 3), due to the occurrence of drug interactions (especially with antibiotic and anti-inflammatory drugs), food interactions, irregular medication use, and acute clinical intercurrences, among others.

With new anticoagulants becoming available over the past years, there have been improvements in relation to anticoagulation monitoring, given that they do not require INR monitoring, that they have few interactions with drugs and food, as well as elevated efficacy and safety, thus making it possible to increase treatment adherence and number of patients treated.75 The anticoagulants which have already been investigated are dabigatran, rivaroxaban, apixaban, and edoxaban. Dabigatran is a direct thrombin inhibitor, while the other 3 are factor Xa blockers, and they are used in clinical practice for patients with nonvalvular AF.

 5.2. Strategies for Pericardioversion Anticoagulation in Atrial Fibrillation

When AF is reversed to sinus rhythm, either spontaneously or intentionally (via chemical or electrical cardioversion), the short-term risk of thromboembolism increases even more, with the majority of events occurring during the first 10 days after rhythm reversal.76-81 The group with the highest risk is that of patients with AF lasting more than 48 hours (1% to 5% during the first month, in the absence of anticoagulation).82,83

Embolism is a consequence of thrombus dislocation from the left atrium after the return of synchronous contraction; there may also, however, be thrombus formation after cardioversion, and this is the reason for indicating anticoagulation for at least 4 months following cardioversion, even in low-risk patients.84-86

The risk of thromboembolism may be reduced to 0% to 0.9% with anticoagulation for at least 3 weeks before cardioversion and 1 month after the procedure.85-89 A further option, with less anticoagulation time, is to evaluate the presence of atrial thrombi via transesophageal echocardiography (TEE) and, in the absence of thrombi, proceed to cardioversion, initiating full anticoagulation at the moment of the procedure and maintaining it for at least 4 weeks.

Warfarin is the most studied anticoagulant in this scenario;90-99 there is, however, sufficient evidence to use NOAC when performing the procedure, and NOAC are, moreover, preferable in some cases, for instance, when the patient is already receiving an NOAC, in order to shorten the precardioversion anticoagulation period (With warfarin, average time to adjust to adequate INR for at least 3 weeks is 6-8 weeks), or when there are difficulties in INR management.

Regarding pericardioversion, rivaroxaban has been compared to vitamin K antagonists in the X-VeRT study, which randomized 1,504 patients with AF of more than 48 hours or unknown duration to receive 1 of the 2 anticoagulants. There were no significant differences in the primary outcome, which was a composite of transient ischemic attack, stroke, peripheral embolism, AMI, and cardiovascular death (0.51% versus 1.02%; risk ratio [RR] 0.5; 95% CI 0.15 to 1.73), or the safety outcome, which was major bleeding (0.6% versus 0.8%; RR 0.76; 95% CI 0.21 to 2.67). Time to cardioversion was shorter in the rivaroxaban group.79 Furthermore, post hoc analysis of the ROCKET-AF study also showed no difference in events between patients who underwent cardioversion using rivaroxaban or warfarin (HR 1.38; 95% CI 0.61 to 3.11).100

With relation to dabigatran, which is a direct thrombin inhibitor, post-hoc analysis of the RE-LY study observed that 1,983 cardioversions were performed with 1,270 patients (from the total of more than 18,000 patients randomized in the original study). The incidence of stroke or systemic embolism in up to 30 days after cardioversion was similar between the groups receiving pericardioversion anticoagulation with warfarin, dabigatran 110 mg twice daily, and dabigatran 150 mg twice daily (0.6%, 0.8%, and 0.3%, respectively; p > 0.05). In the same manner, there were no differences in bleeding rates between the groups (0.6%, 1.7%, and 0.6%, respectively; p > 0.05). The results were not altered by prior TEE.77 Moreover, an observational Danish study, which compared 456 patients with nonvalvular AF receiving dabigatran with 774 patients receiving warfarin, provided evidence that there was a reduced median time to first cardioversion (4.0 weeks, with interquartile interval [IQI] of 2.9 to 6.5 compared to 6.9 weeks, with IQI of 3.9 to 12.1, for dabigatran and warfarin, respectively). No differences were observed between the 2 drugs regarding efficacy and safety.101

With relation to apixaban, post-hoc analysis of the ARISTOTLE study compared patients who underwent cardioversion receiving apixaban or warfarin. A total of 743 cardioversions occurred in 540 patients, with 265 patients in the apixaban group and 275 in the warfarin group. Average age (67 years old) and LVEF (around 52%) were similar in both groups, and average CHADS2 score in the apixaban group was 1.8 (± 1.0) and 1.9 (± 1.1; p = 0.17) in the warfarin group. There were no (zero) strokes or embolic events over 30 days in either of the groups, and 1 major bleeding episode occurred in each group.78 These data were subsequently confirmed in the EMANATE trial, which was presented at the European Congress of Cardiology in 2017 (to be published). In this study, 1,500 patients were randomized to receive apixaban or heparin/warfarin (conventional treatment) within 48 hours after cardioversion. Average age in both groups was approximately 64, and average CHA2DS2-VASc scores were 2.4 in both treatments. No ischemic events were observed in the apixaban group, while 6 events occurred in the conventional treatment group (p = 0.016). Finally, edoxaban was evaluated during the pericardioversion period in 2,199 patients in the ENSURE-AF randomized prospective study, in comparison with enoxaparin and warfarin, with enoxaparin being suspended when INR > 2. There were no differences regarding the primary outcome composed of stroke, systemic embolism, myocardial infarction, or cardiovascular death (odds ratio 0.46; 95% CI 0.12 to 1.4) or in the safety outcome of bleeding (odds ratio 1.48; 95% CI 0.64 to 3.55) for a total period of 28 days of treatment, followed up for more than 30 days.80

In specific situations, for instance, for patients who are highly symptomatic or patients with high bleeding risks, cardioversion may be performed earlier, without 3 weeks of anticoagulation, as long as there are no thrombi in the atria or atrial appendices evaluated by TEE. Subsequently, anticoagulation is maintained for at least 4 weeks.71,102 If TEE indicates that thrombi are present, anticoagulation is maintained for 3 weeks, and, in the event that cardioversion is scheduled, TEE should be repeated before the procedure. If there are doubts regarding medical adherence, TEE is also indicated in order to rule out thrombus.78,103

This strategy was first evaluated in a randomized manner by the ACUTE study, which compared TEE and the conventional strategy (anticoagulation for 3 weeks before cardioversion). Patients randomized to TEE received heparin if they were hospitalized or warfarin for 5 days before TEE if they were not hospitalized, and cardioversion was performed if there were no thrombi. If they had thrombi (12% of patients), cardioversion was postponed for 3 weeks, with anticoagulation maintained during this period. There were no differences between the TEE and conventional groups regarding the incidence of ischemic stroke (0.6% versus 0.3%, respectively, RR 1.95, 95% CI 0.36 to 10.60) or embolic events in general (0.8% versus 0.5%, respectively, RR 1.62, 95% CI 0.39 to 6.76) during the 8-week period following cardioversion. The majority of events in the TEE group occurred in patients whose AF recurred or who were outside of the therapeutic range at the moment of the event, whereas, in the patients who were receiving warfarin, the events occurred in sinus rhythm and within the therapeutic range. It is also interesting to note that fewer bleeding episodes were observed in the TEE-guided group (2.9% versus 5.5%; p = 0.03). In this group, time to cardioversion was also shorter (3.0 ± 5.6 days versus 30.6 ± 10.6 days; p < 0.001), and the success rate of AF reversal was higher in comparison with the conventional strategy (71% versus 65.2%; p = 0.03), although there was no difference in the percentage of patients who remained in sinus rhythm for 8 weeks.104

In the event that AF lasts less than 48 hours, which is easily determined by inquiring about symptoms, and the patient is not at a high thromboembolism risk (valve disease, ventricular dysfunction, prosthesis, prior history of thromboembolism), the risk of thromboembolism is very low and cardioversion may be performed105,106 without prior full anticoagulation. Maintaining anticoagulation for 4 weeks after the procedure is controversial and there are no studies comparing different heparins or heparins and new anticoagulants for patients with AF lasting less than 48 hours.

In the event of AF lasting less than 48 hours in patients with moderate to high risks of thromboembolic events (CHA2DS2-VASc > 1), unfractionated or low-molecular weight heparin before cardioversion and long-term maintenance are recommended.86

In cases of AF with hemodynamic instability, urgent cardioversion should always be performed, with a pre-procedure heparin bolus.86

In relation to heparins, unfractionated heparin has given way to low-molecular weight heparins. Indications for using heparins are: (1) following chemical or electrical cardioversion in hospitalized patients, (2) in combination with oral anticoagulation during INR adjustment; (3) during provisory interruption of warfarin anticoagulation in order to perform diagnostic procedures or therapies with hemorrhage risks (a strategy commonly known as a “heparin bridge”). Although there are 3 types of low-molecular weight heparin (dalteparin, enoxaparin, and nadroparin), enoxaparin has been the most widely used in clinical practice.107

The flowchart in Figure 2 summarizes recommendations in relation to pericardioversion anticoagulation in atrial fibrillation.

Recommendations in relation to pericardioversion anticoagulation in atrial fibrillation.

AF: atrial fibrillation; INR: international normalized ratio; LMWH: low-molecular weight heparin; NOAC: new oral anticoagulant; TEE: transesophageal echocardiography; UFH: unfractionated heparin.

6. Anticoagulation and Antiplatelet Therapy in Patients with Patent Foramen Ovale 6.1. Introduction

Patent foramen ovale (PFO) is the most common congenital heart disease of fetal origin.108-110 It is present in 15% to 35% of the adult population (15% to 25% in studies whose diagnostic method was echocardiogram111,112 and 15% to 35% in autopsies).113-115 Several reports exist on the relation between PFO and diverse pathologies, with different strengths of association, including: platypnea-orthodeoxia syndrome,116 decompression syndrome,117,118 systemic and coronary embolism,119,120 obstructive sleep apnea-hypopnea syndrome (OSAHS),121 migraine with aura,122-125 and stroke.126

6.2. Relation between Patent Foramen Ovale and Cryptogenic Stroke

The causal relation between PFO and cryptogenic stroke, caused by paradoxical embolism of the right-left shunt, is dubious and much debated within the literature.112,127 Meta-analysis data128 have established a possible causal relation between PFO and cryptogenic stroke in patients < age 55. Another study129 evaluated the presence of PFO using TEE in stroke patients and identified a higher incidence of PFO in cryptogenic stroke patients in comparison with patients with stroke of known cause, both in patients < age 55 and in patients > age 55. A retrospective Brazilian study130 also identified the presence of PFO as a risk factor for cryptogenic stroke, with an odds ratio of 3.3 in patients with PFO compared to patients without PFO. In prospective population studies, on the other hand, the presence of PFO has not been related to increased stroke risk, either in patients who have already suffered a stroke131 (secondary prevention) or in asymptomatic patients (primary prevention).111,132,133

The conclusion is, thus, that diagnosis of PFO in a patient with cryptogenic stroke does not establish a causal relation between the two entities,134 given that the risk attributable to PFO decreases with age and in the presence of risk factors such as systemic arterial hypertension, diabetes mellitus, tobacco use, personal history of transient ischemic attack, or prior stroke.135 Based on data from a meta-analysis135 of 12 cohort studies which followed cryptogenic stroke patients, the Risk of Paradoxical Embolism (RoPE) score, which quantifies the risk of PFO-attributable stroke (Table 12), was developed. This study provided evidence that patients with higher scores (with increased risks attributable to PFO as a causal factor of stroke) also had lower risks of stroke recurrence during follow up. In conclusion, the causal relation between PFO and stroke continues to be uncertain, and, even in patients whose stroke mechanism is attributed to PFO/paradoxical embolism, the event recurrence rate is very low (1% to 3% over 2 years in patients with RoPE scores of 9 or 10).134,135

Risk of Paradoxical Embolism (RoPE) score. The higher the RoPE score, the higher the causality between patent foramen ovale and stroke
Characteristic Points
No PH or SAH 1
No PH of diabetes 1
No PH of stroke/TIA 1
Non-smoker 1
Cortical infarct on imaging exam 1
Age (in years):18 to 2930 to 3940 to 4950 to 5960 to 69≥ 70 543210

PH: personal history; SAH: systemic arterial hypertension; TIA: transient ischemic attack.

Some echocardiography characteristics of PFO may be related to greater risks of paradoxical embolism, such as: significant right-left shunt, spontaneous right-left shunt, greater PFO flap mobility, prominent Eustachian valve, presence of Chiari network, and atrial septal aneurysm.109,136-141 However, some of these characteristics have not been shown to be consistently related to higher rates of embolic events in other studies.111,132,142-145

6.3. Evidence for the Use of Antiplatelet Agents or Anticoagulants in Patients with Patent Foramen Ovale

Given the hypothesis that embolic events related to PFO occur either by paradoxical embolism or embolism of a thrombus formed in the left atrium, antiplatelet therapy or anticoagulation are justified in the following situations:

Primary prevention: no studies have evaluated primary prevention of embolic events in patients with PFO. Considering that the causal relation between PFO and systemic embolism is still uncertain, that the embolic event rate in patients with PFO alone is extremely low, and that the risks inherent in anticoagulant and antiplatelet therapy are not negligible, the use of antiplatelet agents or anticoagulation are not indicated as primary prevention of embolic events in patients with PFO.146

Secondary prevention: the best therapeutic strategy after an embolic event in the presence of PFO continues to be the focus of debate and controversy due to the dubious correlation which exists between the 2 phenomena. In 2002, the PICSS substudy of the WARSS study144 compared the use of warfarin to ASA (325 mg daily) in patients with stroke and PFO, in a subgroup of 265 patients with cryptogenic stroke. There were no statistically significant differences in the rate of recurrent embolic events between the warfarin and the ASA groups in this situation. Another study147 randomized 47 patients after cryptogenic stroke to ASA (240 mg daily) or warfarin (with an INR goal of 2 to 3), and the authors did not observe any difference between the risk of ischemic stroke or TIA between the groups. A meta-analysis148 with data from only 2 randomized studies did not identify differences in favor of warfarin in comparison with ASA in the presence of stroke. Another recent meta-analysis149 compared the use of antiplatelet agents with oral anticoagulation in patients with cryptogenic stroke, using individual data of 2,385 patients from 12 observational studies, and they did not observe any differences in the rates of recurrent stroke between patients receiving oral anticoagulation or antiplatelet agents. In 2017, the results of the CLOSE study were published, which compared percutaneous PFO closure to medical therapy with antiplatelet therapy or anticoagulation. Statistical analysis was not conducted between the clinical treatment groups, as the study did not recruit the target of 900 patients and the event rate was lower than expected. When evaluating the data in absolute values, however, it is possible to observe an incidence of 3 cases in the anticoagulation group and 7 in the antiplatelet therapy group, with an estimated probability of stroke over 5 years of 1.5% and 3%, respectively.45 Percutaneous or surgical PFO closure should also be considered in select cases; this discussion, however, lies beyond the scope of this paper.

There is, thus, insufficient evidence for recommending the preferential use of oral anticoagulation over antiplatelet agents, given the low rate of recurrent embolic events in young patients with cryptogenic stroke. The use of antiplatelet agents, thus, seems to be adequate due to the accumulated risk of hemorrhagic complications in these patients in the event that they receive oral anticoagulation and to the efficacy of antiplatelet agents in reducing the risk of embolic events in the general population, which has already been proven (Table 13). It is worth highlighting that the studies on secondary prevention on which these guidelines are based144,147,150 were not designed to demonstrate the superiority of oral anticoagulation over antiplatelet therapy, for which reason they are not statistically powered to provide evidence of any possible benefits of oral anticoagulation over antiplatelet therapy.

Recommendations for the use of antiplatelet agents and anticoagulants in primary and secondary prevention of cryptogenic stroke in patients with patent foramen ovale
Indications Grade of recommendation Level of evidence
Patients who are not indicated for anticoagulation for other reasons should be started on antiplatelet therapy as secondary prevention I B
Use of warfarin as a first choice following the first event IIb B
After a recurrent event while using antiplatelet agents, the use of warfarin with an INR goal between 2 and 3 should be considered IIa C
Use of Factor Xa inhibitors or thrombin inhibitors following the first event as an alternative to warfarin IIb C
Use of antiplatelet agents or anticoagulants as primary prevention III C

INR: international normalized ratio.

 7. Antithrombotic Therapy in Oncology Patients with Thrombocytopenia 7.1. Introduction

Cardiovascular diseases and cancer are the main causes of death in Brazil.151 Advances in treatment of neoplasm have increased survival in this population which has thus gone on to be more exposed to traditional risk factors for developing atherosclerotic disease.

On the other hand, oncology patients, as they are in a pro-inflammatory and pro-thrombotic state, may develop atherosclerosis more quickly, and they have a higher risk of developing ACS.152

Neoplasia treatment with radiotherapy and chemotherapy itself has deleterious collateral coronary effects, such as the occurrence of vasospasms and endothelial injuries.153

Finally, the presence of thrombocytopenia increases the risk of both bleeding and ischemic phenomena. A retrospective evaluation at the MD Anderson Hospital showed that 39% of patients with ACS had platelet counts of < 100,000 cells/mm3.154

7.2. Antithrombotic Therapy

There are no randomized studies on antithrombotic therapy in patients with thrombocytopenia, as this population is normally excluded from large clinical trials.

A retrospective study of 70 oncology patients with ACS showed lower 7-day mortality in patients with thrombocytopenia who received ASA.155

In a case series which evaluated patients with platelet counts > 50,000 cells/mm3 who underwent angioplasty, the use of antiplatelet agents and anticoagulants did not increase the incidence of bleeding events.156

On the other hand, in patients with platelet counts between 30,000 and 50,000 cells/mm3, the use of ASA and clopidogrel was safe; lower doses of unfractionated heparin (30 IU/kg to 50 IU/kg), however, were enough to reach the therapeutic goal in this population.156 In patients with platelet counts below 10,000, risks and benefits should be evaluated individually. Platelet transfusion and antiplatelet therapy are a therapeutic possibility (Table 14).156

Recommendations for use of antiplatelet agents and anticoagulants in oncology patients with thrombocytopenia
Indications Grade of recommendation Level of evidence
Use of acetylsalicylic acid in patients with coronary disease I A
Combined use of clopidogrel and acetylsalicylic acid in patients with high-risk acute coronary syndrome or after coronary angioplasty I A
Acetylsalicylic acid should always be used at a minimum dose, preferably ≤ 100 mg daily IIa C
Use of antiplatelet therapy and/or anticoagulant in acute coronary syndrome patients, even if they have thrombocytopenia IIa C
Use of a reduced dose of enoxaparin and unfractionated heparin in patients with platelet count < 50,000. Monitoring of therapeutic goal IIa C

There are no studies on new antiplatelet agents or non-vitamin K dependent anticoagulants in this population.

This statement shall be referred to as: Serrano Jr. CV, Soeiro AM, Leal TCAT, Godoy LC, Biselli B, Hata LA et al. Statement on Antiplatelet Agents and Anticoagulants in Cardiology - 2019. Arq Bras Cardiol. 2019; 113(1):111-134.

Note: These Guidelines are for information purposes and are not to replace the clinical judgment of a physician, who must ultimately determine the appropriate treatment for each patient.

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Wohrle J Kochs M Hombach V Merkle N Prevalence of myocardial scar in patients with cryptogenic cerebral ischemic events and patent foramen ovale JACC Cardiovasc Imaging 2010 3 8 833 839 120 Neisius U, Northridge DB, Cruden NL, Denvir MA. Myocardial infarction associated with patent foramen ovale and paradoxical embolism: case series. Int J Cardiol. 2015 Feb 1;180:34-7. Neisius U Northridge DB Cruden NL Denvir MA Myocardial infarction associated with patent foramen ovale and paradoxical embolism: case series Int J Cardiol 01 02 2015 180 34 37 121 Lau EM, Yee BJ, Grunstein RR, Celermajer DS. Patent foramen ovale and obstructive sleep apnea: a new association? Sleep Med Rev. 2010;14(6):391-5. Lau EM Yee BJ Grunstein RR Celermajer DS Patent foramen ovale and obstructive sleep apnea: a new association? Sleep Med Rev 2010 14 6 391 395 122 Sevgi EB, Erdener SE, Demirci M, Topcuoglu MA, Dalkara T. Paradoxical air microembolism induces cerebral bioelectrical abnormalities and occasionally headache in patent foramen ovale patients with migraine. J Am Heart Assoc. 2012;1(6):e001735. Sevgi EB Erdener SE Demirci M Topcuoglu MA Dalkara T Paradoxical air microembolism induces cerebral bioelectrical abnormalities and occasionally headache in patent foramen ovale patients with migraine J Am Heart Assoc 2012 1 6 e001735 123 Rundek T, Elkind MS, Di Tullio MR, Carrera E, Jin Z, Sacco RL, et al. Patent foramen ovale and migraine: a cross-sectional study from the Northern Manhattan Study (NOMAS). Circulation. 2008;118(14):1419-24. Erratum in: Circulation. 2008;118(18):e682. Rundek T Elkind MS Di Tullio MR Carrera E Jin Z Sacco RL Patent foramen ovale and migraine: a cross-sectional study from the Northern Manhattan Study (NOMAS) Circulation 2008 118 14 1419 1424 Erratum in: Circulation. 2008;118(18):e682 124 Lip PZ, Lip GY. Patent foramen ovale and migraine attacks: a systematic review. Am J Med. 2014;127(5):411-20. Lip PZ Lip GY Patent foramen ovale and migraine attacks: a systematic review Am J Med 2014 127 5 411 420 125 Dowson A, Mullen MJ, Peatfield R, Muir K, Khan AA, Wells C, et al. Migraine Intervention With STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation. 2008;117(11):1397-404. Erratum in: Circulation. 2009;120(9):e71-2. Dowson A Mullen MJ Peatfield R Muir K Khan AA Wells C Migraine Intervention With STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache Circulation 2008 117 11 1397 1404 Erratum in: Circulation. 2009;120(9):e71-2 126 Cohnheim JF. Vorlesungen Uber Allgemenie Pathologie. 2nd ed. Berlin: August Hirschwald; 1987. Cohnheim JF Vorlesungen Uber Allgemenie Pathologie 1987 2nd ed Berlin August Hirschwald 127 Rundek T. PFO in stroke: a direct association or coincidence? Eur J Neurol. 2008:15(9):887-8. Rundek T PFO in stroke: a direct association or coincidence? Eur J Neurol 2008 15 9 887 888 128 Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology. 2000;55(8):1172-9. Overell JR Bone I Lees KR Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies Neurology 2000 55 8 1172 1179 129 Handke M, Harloff A, Olschewski M. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med. 2007;357(22):2262-8. Handke M Harloff A Olschewski M Patent foramen ovale and cryptogenic stroke in older patients N Engl J Med 2007 357 22 2262 2268 130 Negrão EM, Brandi IV, Nunes SV, Távaro DG, Nakayama M, Beraldo PS. Patent foramen ovale and ischemic stroke in young people: statistical association or causal relation?. Arq Bras Cardiol. 2007;88(5):514-20. Negrão EM Brandi IV Nunes SV Távaro DG Nakayama M Beraldo PS Patent foramen ovale and ischemic stroke in young people: statistical association or causal relation? Arq Bras Cardiol 2007 88 5 514 520 131 Katsanos AH, Spence JD, Bogiatzi C, Parissis J, Giannopoulos S, Frogoudaki A, et al. Recurrent stroke and patent foramen ovale: a systematic review and meta-analysis. Stroke. 2014;45(11):3352-9. Katsanos AH Spence JD Bogiatzi C Parissis J Giannopoulos S Frogoudaki A Recurrent stroke and patent foramen ovale: a systematic review and meta-analysis Stroke 2014 45 11 3352 3359 132 Di Tullio MR, Sacco RL, Sciacca RR, Jin Z, Homma S. Patent foramen ovale and the risk of ischemic stroke in a multiethnic population. J Am Coll Cardiol. 2007;49(7):797-802. Di Tullio MR Sacco RL Sciacca RR Jin Z Homma S Patent foramen ovale and the risk of ischemic stroke in a multiethnic population J Am Coll Cardiol 2007 49 7 797 802 133 Di Tullio MR, Jin Z, Russo C, Elkind MS, Rundek T, Yoshita M, et al. Patent foramen ovale, subclinical cerebrovascular disease, and ischemic stroke in a population-based cohort. J Am Coll Cardiol. 2013;62(1):35-41. Di Tullio MR Jin Z Russo C Elkind MS Rundek T Yoshita M Patent foramen ovale, subclinical cerebrovascular disease, and ischemic stroke in a population-based cohort J Am Coll Cardiol 2013 62 1 35 41 134 Homma S, M Steven, Rundej T, Yee-Ping S, Franke J, Davidson K, et al. Patent foramen ovale. Nature Reviews Disease Primer. 2016 Jan;2:15087. Homma S Steven M Rundej T Yee-Ping S Franke J Davidson K Patent foramen ovale Nature Reviews Disease Primer 01 2016 2 15087 15087 135 Kent DM, Ruthazer R, Weimar C, Mas JL, Serena J, Homma S, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology. 2013;81(7):619-25. Kent DM Ruthazer R Weimar C Mas JL Serena J Homma S An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke Neurology 2013 81 7 619 625 136 Schuchlenz HW, Weihs W, Horner S, Quehenberger F. The association between the diameter of a patent foramen ovale and the risk of embolic cerebrovascular events. Am J Med. 2000;109(6):456-62. Schuchlenz HW Weihs W Horner S Quehenberger F The association between the diameter of a patent foramen ovale and the risk of embolic cerebrovascular events Am J Med 2000 109 6 456 462 137 Homma S, Di Tullio MR, Sacco RL, Mihalatos D, Li Mandri G, Mohr JP. Characteristics of patent foramen ovale associated with cryptogenic stroke. A biplane transesophageal echocardiographic study. Stroke. 1994;25(3):582-6. Homma S Di Tullio MR Sacco RL Mihalatos D Li Mandri G Mohr JP Characteristics of patent foramen ovale associated with cryptogenic stroke. A biplane transesophageal echocardiographic study Stroke 1994 25 3 582 586 138 De Castro S, Cartoni D, Fiorelli M, Rasura M, Anzini A, Zanette EM. Morphological and functional characteristics of patent foramen ovale and their embolic implications. Stroke. 2000;31(10):2407-13. De Castro S Cartoni D Fiorelli M Rasura M Anzini A Zanette EM Morphological and functional characteristics of patent foramen ovale and their embolic implications Stroke 2000 31 10 2407 2413 139 Stone DA, Godard J, Corretti MC, Kittner SJ, Sample C, Price TR. Patent foramen ovale: association between the degree of shunt by contrast transesophageal echocardiography and the risk of future ischemic neurologic events. Am Heart J. 1996;131(1):158-61. Stone DA Godard J Corretti MC Kittner SJ Sample C Price TR Patent foramen ovale: association between the degree of shunt by contrast transesophageal echocardiography and the risk of future ischemic neurologic events Am Heart J 1996 131 1 158 161 140 Hanna JP, Sun JP, Furlan AJ, Stewart WJ, Sila CA, Tan M. Patent foramen ovale and brain infarct. Echocardiographic predictors, recurrence, and prevention. Stroke. 1994;25(4):782-6. Hanna JP Sun JP Furlan AJ Stewart WJ Sila CA Tan M Patent foramen ovale and brain infarct: Echocardiographic predictors, recurrence, and prevention Stroke 1994 25 4 782 786 141 Rigatelli G, Dell'avvocata F, Braggion G, Giordan M, Chinaglia M, Cardaioli P. Persistent venous valves correlate with increased shunt and multiple preceding cryptogenic embolic events in patients with patent foramen ovale: an intracardiac echocardiographic study. Catheter Cardiovasc Interv. 2008;72(7):973-6. Rigatelli G Dell'avvocata F Braggion G Giordan M Chinaglia M Cardaioli P Persistent venous valves correlate with increased shunt and multiple preceding cryptogenic embolic events in patients with patent foramen ovale: an intracardiac echocardiographic study Catheter Cardiovasc Interv 2008 72 7 973 976 142 Serena J, Marti-Fàbregas J, Santamarina E, Rodríguez JJ, Perez-Ayuso MJ, Masjuan J, et al. Recurrent stroke and massive right-to-left shunt: results from the prospective Spanish multicenter (CODICIA) study. Stroke. 2008;39(12):3131-6. Serena J Marti-Fàbregas J Santamarina E Rodríguez JJ Perez-Ayuso MJ Masjuan J Recurrent stroke and massive right-to-left shunt: results from the prospective Spanish multicenter (CODICIA) study Stroke 2008 39 12 3131 3136 143 Mas JL, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med. 2001;345(24):1740-6. Mas JL Arquizan C Lamy C Zuber M Cabanes L Derumeaux G Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both N Engl J Med 2001 345 24 1740 1746 144 Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP; PFO in Cryptogenic Stroke Study (PICSS) Investigators. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation. 2002;105(22):2625-31. Homma S Sacco RL Di Tullio MR Sciacca RR Mohr JP PFO in Cryptogenic Stroke Study (PICSS) Investigators Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study Circulation 2002 105 22 2625 2631 145 Petty GW, Khandheria BK, Meissner I, Whisnant JP, Rocca WA, Christianson TJ, et al. Population-based study of the relationship between patent foramen ovale and cerebrovascular ischemic events. Mayo Clin Proc. 2006;81(5):602-8. Petty GW Khandheria BK Meissner I Whisnant JP Rocca WA Christianson TJ Population-based study of the relationship between patent foramen ovale and cerebrovascular ischemic events Mayo Clin Proc 2006 81 5 602 608 146 Meschia J, Bushnell C, Boden-Albala B, Braun LT, Bravata DM, Chaturvedi S, et al; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Functional Genomics and Translational Biology; Council on Hypertension. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014; 45(12):3754-832. Meschia J Bushnell C Boden-Albala B Braun LT Bravata DM Chaturvedi S American Heart Association Stroke Council Council on Cardiovascular and Stroke Nursing Council on Clinical Cardiology Council on Functional Genomics and Translational Biology Council on Hypertension Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke 2014 45 12 3754 3832 147 Shariat A, Yaghoubi E, Farazdaghi M, Aghasadeghi K, Borhani Haghighi A. Comparison of medical treatments in cryptogenic stroke patients with patent foramen ovale: a randomized clinical trial. J Res Med Sci. 2013;18(2):94-8. Shariat A Yaghoubi E Farazdaghi M Aghasadeghi K Borhani Haghighi A Comparison of medical treatments in cryptogenic stroke patients with patent foramen ovale: a randomized clinical trial J Res Med Sci 2013 18 2 94 98 148 Messé SR, Gronseth G, Kent DM, Kizer JR, Homma S, Rosterman L, et al. Practice advisory: Recurrent stroke with patent foramen ovale (update of practice parameter) Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016;87(8):815-21. Messé SR Gronseth G Kent DM Kizer JR Homma S Rosterman L Practice advisory: Recurrent stroke with patent foramen ovale (update of practice parameter) Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology Neurology 2016 87 8 815 821 149 Kent DM, Dahabreh IJ, Ruthazer R, Furlan AJ, Weimar C, Serena J, et al. Anticoagulant vs. antiplatelet therapy in patients with cryptogenic stroke and patent foramen ovale: an individual participant data meta-analysis. Eur Heart J. 2015;36(35):2381-9. Kent DM Dahabreh IJ Ruthazer R Furlan AJ Weimar C Serena J Anticoagulant vs. antiplatelet therapy in patients with cryptogenic stroke and patent foramen ovale: an individual participant data meta-analysis Eur Heart J 2015 36 35 2381 2389 150 Mas JL, Derumeaux G, Guillon B, Massardier E, Hosseini H, Mechtouff L, et al; CLOSE Investigators. Patent foramen ovale closure or anticoagulation vs antiplatelets after stroke. N Engl J Med. 2017;377(11):1011-21. Mas JL Derumeaux G Guillon B Massardier E Hosseini H Mechtouff L CLOSE Investigators Patent foramen ovale closure or anticoagulation vs antiplatelets after stroke N Engl J Med 2017 377 11 1011 1021 151 Brasil. Ministério da Saúde. DATASUS. [Internet]. Acesso em 2017 dez 1]. Disponível em: http://tabnet.datasus.gov.br/cgi/tabcgi.exe?sim/cnv/obt10uf.def Brasil Ministério da Saúde DATASUS. [Internet] 2017 dez 1 Disponível em: http://tabnet.datasus.gov.br/cgi/tabcgi.exe?sim/cnv/obt10uf.def 152 Chang HM, Moudgil R, Scarabelli T, Okwuosa TM, Yeh ET. Cardiovascular complications of cancer therapy best practices in diagnosis, prevention, and management: part 1. J Am Coll Cardiol. 2017;70(20):2536-51. Chang HM Moudgil R Scarabelli T Okwuosa TM Yeh ET Cardiovascular complications of cancer therapy best practices in diagnosis, prevention, and management: part 1 J Am Coll Cardiol 2017 70 20 2536 2551 153 Mosseri M, Fingert HJ, Varticovski L, Chokshi S, Isner JM. In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle. Cancer Res. 1993;53(13):3028-33. Mosseri M Fingert HJ Varticovski L Chokshi S Isner JM In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle Cancer Res 1993 53 13 3028 3033 154 Yusuf SW, Iliescu C, Bathina JD, Daher IN, Durand JB. Antiplatelet therapy and percutaneous coronary intervention in patients with acute coronary syndrome and thrombocytopenia. Tex Heart Inst J. 2010;37(3):336-40. Yusuf SW Iliescu C Bathina JD Daher IN Durand JB Antiplatelet therapy and percutaneous coronary intervention in patients with acute coronary syndrome and thrombocytopenia Tex Heart Inst J 2010 37 3 336 340 155 Sarkiss MG, Yusuf SW, Warneke CL, Botz G, Lakkis N, Hirch-Ginsburg C, et al. Impact of aspirin therapy in cancer patients with thrombocytopenia and acute coronary syndromes. Cancer. 2007;109(3):621-7. Sarkiss MG Yusuf SW Warneke CL Botz G Lakkis N Hirch-Ginsburg C Impact of aspirin therapy in cancer patients with thrombocytopenia and acute coronary syndromes Cancer 2007 109 3 621 627 156 Iliescu C, Durand J-B, Kroll M. Cardiovascular Interventions in thrombocytopenic cancer Patients. Tex Heart Inst J. 2011;38(3):259-60. Iliescu C Durand J-B Kroll M Cardiovascular Interventions in thrombocytopenic cancer Patients Tex Heart Inst J 2011 38 3 259 260 Posicionamento Posicionamento sobre Antiagregantes Plaquetários e Anticoagulantes em Cardiologia - 2019 0000-0002-9171-1224 Serrano Carlos V. Jr. 1 2 3 Soeiro Alexandre de M. 1 3 Leal Tatiana C. A. Torres 1 Godoy Lucas C. 1 Biselli Bruno 1 Hata Luiz Akira 1 Martins Eduardo B. 1 Abud-Manta Isabela C. K. 1 2 Tavares Caio A. M. 1 Cardozo Francisco Akira Malta 1 3 Oliveira Múcio Tavares de Jr. 1 Instituto do Coração do Hospital das Clínicas da Universidade de São Paulo, São Paulo, SP - Brasil Hospital Israelita Albert Einstein, São Paulo, SP - Brasil Hospital Beneficência Portuguesa Mirante, São Paulo, SP - Brasil Correspondência: Sociedade Brasileira de Cardiologia - Av. Marechal Câmara, 360/330 - Centro - Rio de Janeiro - CEP: 20020-907. E-mail:scb@cardiol.br

Realização: Departamento de Cardiologia Clínica da Sociedade Brasileira de Cardiologia

Conselho de Normatizações e Diretrizes: Fernando Bacal, Leandro Ioschpe Zimerman, Paulo Ricardo Avancini Caramori e Pedro A. Lemos

Coordenador de Normatizações e Diretrizes: Ludhmila Abrahão Hajjar

Presidente do Departamento de Cardiologia Clínica: João Luiz Fernandes Petriz

Coordenador do Posicionamento: Carlos V. Serrano Jr.
Declaração de potencial conflito de interesses dos autores/colaboradores do Posicionamento sobre Antiagregantes Plaquetários e Anticoagulantes em Cardiologia - 2019
Se nos últimos 3 anos o autor/colaborador das Diretrizes:
Nomes Integrantes do Posicionamento Participou de estudos clínicos e/ou experimentais subvencionados pela indústria farmacêutica ou de equipamentos relacionados à diretriz em questão Foi palestrante em eventos ou atividades patrocinadas pela indústria relacionados à diretriz em questão Foi (é) membro do conselho consultivo ou diretivo da indústria farmacêutica ou de equipamentos Participou de comitês normativos de estudos científicos patrocinados pela indústria Recebeu auxílio pessoal ou institucional da indústria Elaborou textos científicos em periódicos patrocinados pela indústria Tem ações da indústria
Alexandre de Matos Soeiro Não Servier, Daiichi Sankyo Não Não Sanofi Não Não
Bruno Biselli Não Não Não Não Não Não Não
Caio de Assis Moura Tavares Não Não Não Não Não Não Não
Carlos Vicente Serrano Júnior Não Não Não Não Não Não Não
Eduardo Bello Martins Não Não Não Não Não Não Não
Francisco Akira Malta Cardozo Não Não Não Não Não Não Não
Isabela C. K. Abud-Manta Não Não Não Não Não Não Não
Lucas Colombo Godoy Não Não Não Não Não Não Não
Luiz Akira Hata Não Não Não Não Não Não Não
Múcio Tavares de Oliveira Júnior Não Boehringer Ingelheim, EMS Sanofi Aventis, Boehringer Ingelheim, Roche Diagnostica, Philips Healthcare, Torrent Pharma Torrent Pharma Boehringer Ingelheim, Merck EMS, Novartis, Torrent Pharma Não
Tatiana C. A. Torres Leal Não Não Não Não Não Não Não
1. Introdução

Em 2013, a Sociedade Brasileira de Cardiologia publicou as “Diretrizes Brasileiras de Antiagregantes Plaquetários e Anticoagulantes em Cardiologia”. Ao longo dos últimos anos, novos estudos foram realizados, fornecendo informações importantes sobre o uso desses medicamentos, tanto de maneira isolada quanto em associações. É hora, portanto, de revermos as nossas diretrizes e atualizá-las com o novo conhecimento produzido.

Realizamos uma extensa revisão da literatura e optamos por enfatizar, nesta atualização, 6 grandes assuntos da prática clínica que sofreram inovações nos últimos anos ou que não tinham sido ainda abordados no documento anterior. Os temas desta atualização são:

Terapia antitrombótica em pacientes em uso de anticoagulantes orais submetidos à intervenção coronária percutânea (ICP);

Duração de dupla antiagregação plaquetária após ICP;

Reversão dos novos anticoagulantes;

Anticoagulação na pericardioversão de fibrilação atrial (FA);

Anticoagulação e antiagregação plaquetária em pacientes com forame oval patente;

Terapia antitrombótica em pacientes oncológicos com trombocitopenia.

As tabelas de classes de recomendação e níveis de evidência desta atualização foram realizadas conforme a padronização a seguir.

Esperamos que este documento seja de proveito para todos aqueles que, no seu dia a dia, enfrentam os dilemas e as dúvidas sobre qual a melhor forma de se prescrever as várias opções e posologias de anticoagulantes e antiagregantes plaquetários disponíveis.

Classes (graus) de recomendação
Classe I Condições para as quais há evidências conclusivas, ou, na sua falta, consenso geral de que o procedimento é seguro, e útil/eficaz
Classe IIa Condições para as quais há evidências conflitantes e/ou divergência de opinião sobre segurança, e utilidade/eficácia do procedimento. Peso ou evidência/opinião a favor do procedimento. A maioria dos estudos/especialistas aprova
Classe IIb Condições para as quais há evidências conflitantes e/ou divergência de opinião sobre segurança, e utilidade/eficácia do procedimento. Segurança e utilidade/eficácia menos bem estabelecida, não havendo predomínio de opiniões a favor
Classe III Condições para as quais há evidências e/ou consenso de que o procedimento não é útil/eficaz e, em alguns casos, pode ser prejudicial
Níveis de evidência
Nível A Dados obtidos a partir de múltiplos estudos randomizados de bom porte, concordantes e/ou de meta-análise robusta de estudos clínicos randomizados
Nível B Dados obtidos a partir de meta-análise menos robusta, a partir de um único estudo randomizado ou de estudos não randomizados (observacionais)
Nível C Dados obtidos de opiniões consensuais de especialistas
2. Terapia Antitrombótica em Pacientes em Uso de Anticoagulantes Orais Submetidos à Intervenção Coronária Percutânea 2.1. Introdução

Aproximadamente 6 a 8% dos pacientes submetidos à ICP têm indicação concomitante de utilização de anticoagulantes orais em longo prazo, devido a vários motivos como FA, valvas mecânicas ou tromboembolismo.1-4 Dessa forma, definir a melhor maneira de tratar esses pacientes torna-se fundamental, principalmente quanto à associação de medicamentos antiplaquetários e anticoagulantes.

Em todos os pacientes em uso de anticoagulantes orais que serão submetidos à ICP, é necessário que se proceda à avaliação da necessidade de manutenção da anticoagulação e ao cálculo do risco de sangramento.

Quando o motivo da anticoagulação for FA, o escore CHA2DS2-VASC deve ser utilizado e somente indicada sua manutenção quando ≥ 1 em homens ou ≥ 2 em mulheres (Tabela 1). Já em pacientes com eventos tromboembólicos ou próteses valvares mecânicas, a anticoagulação deve ser mantida independentemente de qualquer avaliação.5-7

Critérios de CHA<sub>2</sub>DS<sub>2</sub> VASc
Descrição Pontos
C Insuficiência cardíaca 1
H Hipertensão 1
A2 Idade (≥ 75 anos) 2
D Diabetes mellitus 1
S2 AIT ou AVE prévio 2
V Doença vascular (IAM prévio, DAP ou placa aórtica) 1
A Idade (65-74 anos) 1
Sc Sexo (se feminino) 1

AIT: ataque isquêmico transitório; AVE: acidente vascular encefálico; DAP: doença arterial periférica; IAM: infarto agudo do miocárdio

O risco de sangramento deve ser acessado através do escore HAS-BLED (Tabela 2). Quando ≥ 3, o paciente é classificado como de alto risco de sangramento. Isso não deve contraindicar qualquer forma de tratamento, no entanto, deixa claro que o indivíduo deve ser acompanhado com consultas mais frequentes e que é necessário tentar modificar os fatores de risco presentes dentro de escore para que seu risco seja reduzido.6-8

Critério de HAS-BLED
Fator de risco Pontos
H Hipertensão arterial (PAS > 160 mmHg) 1
A Disfunção renal = ClCr ≤ 50 mL/min ou creatinina ≥ 2,26 mg/dL ou hemodiálise ou transplante renal 1
Disfunção hepática = [bilirrubina ≥ 2x LSN + (AST ou ALT ou FALC ≥ 3 LSN)] ou cirrose hepática 1
S AVE prévio 1
B Sangramento prévio ou predisposição a sangramentos 1
L RNI lábil ou < 60% do tempo na faixa terapêutica 1
E Idade > 65 anos 1
D Fármacos (AINE/AINH, antiplaquetários) 1
Abuso de álcool (> 20 U por semana) 1

AINE/AINH: anti-inflamatório não esteroidal hormonal; ALT: alanina aminotransferase; AST: aspartato aminotransferase; AVE: acidente vascular encefálico; ClCr: clearance de creatinina; FALC: fosfatase alcalina; LSN: limite superior da normalidade; PAS: pressão arterial sistólica; RNI: relação normatizada internacional; U: unidades.

 2.2. Manejo dos Antitrombóticos e Momento da Intervenção Coronária Percutânea

A interrupção da anticoagulação oral (ACO) periprocedimento pode aumentar tanto a taxa de sangramento quanto a de eventos tromboembólicos.

Apesar de não haver evidências consistentes, a introdução de anticoagulantes parenterais em pacientes em uso de varfarina deve ser considerada apenas quando RNI (relação normatizada internacional) estiver menor que 2,5. A ICP pode ser realizada em uso do anticoagulante, no entanto, deve ser postergada, se possível, até que o paciente apresente RNI < 1,5, a menos que haja situações de emergência e levando-se em consideração o alto risco isquêmico do mesmo (GRACE escore > 140, TIMI escore ≥ 5, angina recorrente, angina refratária, instabilidade hemodinâmica ou presença de arritmias ventriculares).7,8

Já em pacientes em uso de novos anticoagulantes orais (NOACs) também não existem evidências se a anticoagulação parenteral ou a ICP podem ser realizadas precocemente ou não. Novamente, quando o risco isquêmico for muito elevado, a ICP deve ser realizada precocemente ainda sob efeito da medicação. No entanto, quando o risco isquêmico permitir, o procedimento deve ser postergado. Para aqueles com clearance de creatinina > 50 mL/min, o efeito pleno do NOAC pode ser considerado revertido após 24 horas da administração da última dose, ao passo que, naqueles com clearance de creatinina entre 30 e 50 mL/min, o prazo seria de 48 horas. Dessa forma, após esse período, o paciente teoricamente pode ser submetido à ICP sob menor risco de sangramento. Já a anticoagulação parenteral pode ser realizada caso a ICP seja precoce independentemente do horário da última dose administrada do NOAC.7,8

Em todos os pacientes com ACO, a prioridade de acesso vascular deve ser sempre radial, sendo realizado acesso femoral somente em caráter de exceção.

A utilização de dupla antiagregação plaquetária pré-ICP nesse grupo de pacientes deve ser evitada de rotina. O uso de clopidogrel deve ser realizado apenas após a definição da anatomia coronária e a indicação de angioplastia coronária com stent. Já o uso de prasugrel ou ticagrelor está contraindicado nessa situação por não haver evidências suficientes que confiram segurança nesse contexto. O ácido acetilsalicílico (AAS) deve ser usado sempre em dose mínima, preferencialmente abaixo de 100 mg ao dia.7,8

O uso de inibidores de bombas de prótons como profilaxia de úlcera de estresse nesse grupo de pacientes deve ser considerado como primeira escolha devido ao risco elevado de sangramento gastrintestinal.7,8

2.3. Escolha do Tipo de <italic>Stent</italic> na Intervenção Coronária Percutânea

A escolha do tipo de stent (stents farmacológicos de última geração ou stents convencionais) em pacientes que necessitam de anticoagulação plena ainda gera discussão.

Resultados do estudo DAPT (Dual Antiplatelet Therapy) (ver tópico 2.2) mostraram que o benefício do uso da dupla antiagregação plaquetária prolongado independe do tipo de stent utilizado e que o risco de eventos coronarianos em pacientes que suspenderam a terapia devido à necessidade de cirurgia não-cardíaca foi o mesmo com stent farmacológico ou convencional.9-11

Além disso, dois estudos randomizados demonstraram superioridade dos stents farmacológicos de segunda geração sobre os stents convencionais em pacientes com alto risco de sangramento, que não podem tolerar o uso de dupla terapia antiplaquetária por tempo prolongado.12,13

Dessa forma, a escolha do stent deve ser individual e baseada na anatomia coronária e no risco de sangramento. No entanto, não há motivos que contraindiquem o uso de stents farmacológicos nesse grupo de pacientes.

 2.4. Terapia Antitrombótica em Longo Prazo Após Intervenção Coronária Percutânea

As primeiras evidências sobre o assunto começaram a ser publicadas apenas nos últimos cinco anos, o que torna o assunto ainda controverso e duvidoso.

Em 2012, dados do registro DANISH em pacientes com FA e infarto agudo do miocárdio mostraram que em 90 dias o risco de sangramento aumentou significativamente com o uso da tripla terapia comparado com anticoagulação associada à apenas um antiplaquetário (hazard ratio, HR = 1,47, IC 95% 1,04 a 2,08) sem diferenças nas taxas de eventos isquêmicos (HR = 1,15, IC 95% 0,95 a 1,40). Dessa forma, a análise desse estudo observacional sugeria a não realização de tripla terapia de rotina.14,15

O estudo WOEST (What is the Optimal antiplatElet and anticoagulant therapy in patients with OAC and coronary STenting) foi o primeiro estudo prospectivo e randomizado com 573 pacientes publicado sobre o assunto. Todos os pacientes tinham indicação de ACO (69% por FA) e ICP. Os pacientes foram divididos em dois grupos: varfarina e clopidogrel e; varfarina, clopidogrel e AAS 80mg/dia. Esse esquema de tratamento foi mantido por 30 dias quando o stent era convencional e 12 meses quando era farmacológico. O desfecho primário foi qualquer sangramento por escore TIMI. Ao final de um ano, observou-se redução significativa de sangramentos no grupo de dupla terapia (19,5% versus 44,9%; HR = 0,36, IC 95% 0,26 a 0,50, p < 0,001). Não houve diferença nas taxas de sangramentos maiores, assim como de infarto agudo do miocárdio, trombose de stent ou acidente vascular encefálico (AVE). No entanto, observou-se menor mortalidade no grupo de dupla terapia (2,5% versus 6,4%, p = 0,027).16

Em 2015, o estudo ISAR-TRIPLE (Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation), multicêntrico e randomizado, com 614 pacientes, realizado na Alemanha e Dinamarca, avaliou se reduzir a duração da terapia clopidogrel de 6 meses para 6 semanas após a implante de stent farmacológico seria associado com um resultado clínico líquido superior em pacientes recebendo aspirina concomitante e varfarina. Foram incluídos pacientes em uso de anticoagulantes orais há, no mínimo, 12 meses por FA e que receberam stent farmacológico por angina estável ou síndrome coronária aguda (SCA). Os desfechos primários foram: morte, infarto agudo do miocárdio, trombose de stent, AVE e sangramento maior em 9 meses. Não se observaram diferenças em relação aos desfechos primários entre os dois grupos (9,8 % versus 8,8%; HR = 1,14, IC 95% 0,68 a 1,91; p = 0,63). No entanto, a incidência de sangramento menores foi maior no grupo que usou clopidogrel por 6 meses (10,9% versus 7,3%, p = 0,03).17

Em relação aos NOACs, o estudo PIONEER AF-PCI avaliou de forma prospectiva e randomizada qual a melhor estratégia de tratamento farmacológico utilizando rivaroxabana em pacientes submetidos à ICP com necessidade de ACO devido a FA. Foram incluídos 2124 pacientes e divididos em 3 grupos: rivaroxabana 15 mg + inibidor P2Y12 por 12 meses; rivaroxabana 2,5 mg 2 × ao dia + AAS + inibidor P2Y12 por 1, 6 e 12 meses e; varfarina + AAS + inibidor P2Y12 por 1, 6 e 12 meses. Cerca de 93% dos pacientes usaram clopidogrel como antiagregante de escolha e 65% implantaram stents farmacológicos. Aproximadamente 50% dos casos eram SCA. O desfecho primário avaliado foi sangramento clinicamente relevante pelo critério TIMI. Foram observadas taxas de sangramento de 16,8% × 18,0% × 26,7% respectivamente entre os grupos (p < 0,001). As taxas de mortalidade, AVE e eventos cardiovasculares não apresentaram diferenças significativas. Os autores concluíram que em pacientes com FA e necessidade de angioplastia com stent, as estratégias de dupla terapia ou tripla terapia com dose reduzida de rivaroxabana foram mais seguras e reduziram taxas de sangramento comparativamente à tripla terapia convencional.18

Seguindo a mesma linha, em 2017, o estudo REDUAL-PCI (The Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting) prospectivo, multicêntrico e randomizado incluindo 2.725 pacientes com FA submetidos à ICP, divididos entre tripla terapia (varfarina + clopidogrel/ticagrelor + AAS) versus dabigatrana + clopidogrel/ticagrelor. O desfecho primário foi sangramento maior ou clinicamente relevante. Além disso, foi testada não inferioridade na dupla terapia em relação a eventos tromboembólicos, morte e revascularização. A taxa de sangramento foi de 15,4% no grupo que usou 110mg de dabigratana × 26,9% no grupo tripla terapia (p < 0,001 para não inferioridade). Entre pacientes que usaram 150 mg de dabigratana, a taxa de sangramento foi de 20,2% × 25,7% no grupo tripla terapia (p < 0,001 para não inferioridade). A taxa de eventos combinados foi de 13,7% × 13,4% entre os grupos dupla e tripla terapia (p = 0,005 para não inferioridade). Observou-se, principalmente, redução de necessidade de revascularização. Dessa forma, o uso da dupla terapia com dabigatrana mostrou ser não inferior à tripla terapia. Assim como no estudo PIONEER AF-PCI, o estudo REDUAL-PCI não teve poder parar mostrar diferenças em eventos coronários ou morte, sendo somente possível a avaliação de segurança.19

Sendo assim, o uso de tripla terapia deve ser considerado somente em pacientes com baixo risco hemorrágico por menor tempo possível (preferencialmente 1 mês, podendo ser estendido até 6 meses), permanecendo após esse período o uso do anticoagulante associado a um antiplaquetário apenas. No entanto, quando houver alto risco isquêmico (Tabela 3) e também alto risco hemorrágico, recomenda-se que se use tripla terapia por, no máximo, 1 mês ou inicie-se diretamente dupla terapia com anticoagulante e clopidogrel (Tabela 4 e Figura 1).

Definição de alto risco isquêmico em longo prazo
História prévia de trombose de stent sob terapia antiplaquetária adequada
Angioplastia de artéria "derradeira"
Doença coronária multiarterial, principalmente em diabéticos
Insuficiência renal crônica (ClCr < 60 mL/min)
Pelo menos 3 stents e/ou 3 lesões tratadas
ICP em bifurcações, com pelo menos 2 stents colocados
Comprimento total da área coberta de stent > 60 mm
Tratamento de oclusão coronária crônica

ClCr: clearance de creatinina.

 Recomendações sobre o manejo de pacientes com necessidade de anticoagulação oral submetidos à intervenção coronária percutânea
Indicações Classe de recomendação Nível de evidência
A avaliação da necessidade de manutenção da anticoagulação e o cálculo do risco de sangramento devem ser realizados em todos os pacientes através dos escores de CHA2DS2-VASc e HAS-BLED, respectivamente IIa C
Durante a ICP, a prioridade de acesso vascular deve ser sempre radial, sendo realizado acesso femoral somente em caráter de exceção IIa C
O uso de tripla terapia deve ser considerado pelo menor tempo possível, devido ao alto risco hemorrágico associado IIa C
A utilização de NOACs deve ser preferida em relação à varfarina, devido sua previsibilidade de efeito IIa C
Quando optado pelo uso da varfarina, deve-se tentar manter o RNI próximo a 2,0 IIa C
O uso de clopidogrel deve ser realizado apenas após a definição da anatomia coronária e a indicação de angioplastia coronária com stent, evitando-se sua administração de rotina pré-ICP IIa C
O uso de prasugrel ou ticagrelor está contraindicado nessa situação III C
O AAS deve ser usado sempre em dose mínima, preferencialmente ≤ 100 mg ao dia IIa C
O uso de inibidores de bombas de prótons como profilaxia de úlcera de estresse nesse grupo de pacientes deve ser considerado como primeira escolha devido ao risco elevado de sangramento gastrintestinal IIa C
O uso de tripla terapia deve ser considerado em pacientes com baixo risco hemorrágico por menor tempo possível (preferencialmente um mês, podendo ser estendido até 6 meses), permanecendo após esse período o uso do anticoagulante associado a um antiplaquetário apenas IIa B
Quando houver alto risco isquêmico e também alto risco hemorrágico, recomenda-se que se use tripla terapia por, no máximo, um mês ou inicie-se diretamente dupla terapia com anticoagulante e clopidogrel IIa B
Nos pacientes com alto risco de sangramento e baixo risco isquêmico, deve-se introduzir diretamente dupla terapia com anticoagulante e clopidogrel desde o início IIa A
Quando se optar por uso de NOACs, a associação de dupla terapia entre clopidogrel 75 mg/dia e rivaroxabana 15 mg/dia ou dabigatrana 110 mg 2x ao dia devem ser a primeira escolha IIb B
A descontinuação do tratamento antiplaquetário deve ser considerada após 12 meses IIa B

AAS: ácido acetilsalicílico; ICP: intervenção coronária percutânea; NOAC: novo anticoagulante oral; RNI: relação normatizada internacional.

Já nos pacientes com alto risco de sangramento e baixo risco isquêmico, seguindo os resultados dos principais estudos publicados, a recomendação atual é que se comece diretamente dupla terapia com anticoagulante e clopidogrel desde o início (Tabela 4 e Figura 1).

Esquema representativo das indicações da associação de terapias antitrombóticas de acordo com o risco isquêmico e hemorrágico.

ACO: anticoagulante oral; ICP: intervenção coronária percutânea; C: clopidogrel.

Preferencialmente, recomenda-se que se usem NOACs em vez da varfarina, devido à sua previsibilidade de efeito. Além disso, o NOAC deve ser escolhido de acordo com o conhecimento médico já estabelecido nesse contexto e nas doses previamente estudadas em trabalhos científicos. Quando se opta pelo uso de varfarina, o RNI deve ser mantido próximo a 2,0.

Após 12 meses do último evento coronário, recomenda-se que o uso de antiplaquetários seja suspenso. As evidências para essa conduta são escassas, no entanto, baseiam-se em estudo que mostraram que o após um ano a anticoagulação é superior ao uso de AAS e sua combinação não traz benefício adicional, além de aumentar a taxa de sangramentos.20 Terapia associada entre clopidogrel e ACO pode ser prolongada além de um ano em pacientes com alto risco isquêmico e com próteses mecânicas valvares.

 3. Duração de Dupla Antiagregação Plaquetária Após Intervenção Coronária Percutânea 3.1. Introdução

O uso da associação dos inibidores P2Y12 à monoterapia com AAS é conhecida como grande aliada no manejo dos pacientes com doença arterial coronária (DAC), tanto aguda quanto estável, e reduz o risco de fenômenos aterotrombóticos assim como as taxas de trombose do stent após ICP.21-23 Entretanto, essa redução do risco isquêmico tem uma associação indiscutível com maiores taxas de sangramento.22-25

O estado da arte está em pesar o risco e benefício da dupla terapia, assim como a duração do tratamento através de ponderações em relação às características clínicas, características anatômicas das lesões abordadas e do tipo de stent utilizado.

O risco de trombose de stent em pacientes que foram submetidos à ICP com stents convencionais (metálicos) é muito mais frequente nos primeiros dias e semanas após o procedimento. Dessa forma, a dupla antiagregação plaquetária é recomendada por um mês.26 Com o advento dos stents farmacológicos, os stents convencionais foram reservados, idealmente, para os pacientes com risco muito alto de sangramento e que necessitam de um período mais curto (ao menos um mês) de dupla antiagregação. Entretanto, no Brasil, o stent convencional metálico ainda é utilizado principalmente em serviços públicos.

As tromboses em stents farmacológicos de primeira geração intensificaram a visão sobre a duração da terapia no passado.27 Apesar de um risco relativo ainda considerável, a trombose tardia ou muito tardia em stents farmacológicos de segunda, terceira e quarta geração reduziu-se consideravelmente com a modernização das drogas eluídas e do material utilizado. Dessa forma, permitiu-se que a duração da dupla terapia seja a mínima possível, visto que o risco de sangramento não justifica o benefício absoluto pequeno na redução nas tromboses muito tardias. O uso de stents farmacológicos de primeira geração já é infrequente no Brasil. Assim, as recomendações dessa diretriz excluem a discussão da duração do tratamento após o implante percutâneo desse tipo de stent.

O uso de stents absorvíveis em alguns centros já é uma realidade. Não há estudos específicos com esse tipo de stent para determinar o tempo ideal da dupla agregação plaquetária, apesar de existir uma recomendação para o tratamento durar em torno de 12 meses de tratamento. Algumas metanálises sugerem uma taxa maior de trombose nesse tipo de stent em comparação aos stents farmacológicos nos primeiros 30 dias após implante. Indica-se, portanto, o uso de inibidores P2Y12 mais potentes nesse perfil de pacientes. Há ainda um aumento do risco de trombose muito tardia e dessa forma, o tratamento mais longo (maior que 12 meses) pode ser considerado em pacientes com baixo risco de sangramento. Entretanto, ainda faltam estudos específicos para reforçar essa recomendação.28-31

3.2. Escores de Risco

Existem vários fatores de risco conhecidos relacionados a maiores taxas de eventos isquêmicos e episódios de sangramentos. Alguns desses fatores também estão relacionados a ambas situações, o que faz com que a decisão médica seja ainda mais complexa.

Atualmente dispomos de escores de risco implementados internacionalmente que auxiliam na ponderação sobre estender o tratamento, levando-se em consideração o risco de sangramento frente ao benefício da redução do risco aterotrombótico.32,33 A partir de estudos, foram elaborados 2 escores: DAPT escore e PRECISE-DAPT escore.

O DAPT escore (Tabela 5) foi desenvolvido a partir da análise de 11.648 pacientes incluídos no DAPT trial (Dual Antiplatelet Therapy Study) e validado em 8.136 pacientes que participaram do PROTECT trial (Patient related outcomes with Endeavor vs Cypher Stenting). Foram identificados 9 fatores: idade, insuficiência cardíaca (IC) ou fração de ejeção do ventrículo esquerdo (FEVE) reduzida, implante de stent em enxerto de veia safena, infarto agudo do miocárdio (IAM) na apresentação inicial, IAM ou ICP prévia, stent eluído com paclitaxel, diabetes, diâmetro do stent < 3 mm, tabagismo atual, resultando em uma somatória de pontos que variam de -2 a +10. Pacientes com escore DAPT alto (³ 2) têm maiores benefícios com o uso prolongado da dupla terapia antiagregante, avaliados no estudo em questão em um período médio de 30 meses, visto redução de IAM, trombose de stent e eventos cardio e cerebrovasculares, frente a um pequeno aumento do risco de sangramento (NNT = 34 versus NNH = 272). Por outro lado, pacientes com DAPT escore baixo (< 2) apresentaram aumento do risco de eventos relacionados a sangramentos sem reduzir a taxa de eventos cardio e cerebrovasculares (NNH 64).32

Fatores utilizados para o cálculo do escore DAPT. Escore ≥ 2 está associado a risco-benefício favorável enquanto escore < 2 está associado a um risco-benefício desfavorável
Variáveis Pontos
Idade ≥ 75 anos -2
Idade entre 65 e < 75 anos -1
Idade < 65 anos 0
Tabagismo atual 1
Diabetes melito 1
IAM na apresentação inicial 1
ICP ou IAM prévio 1
Diâmetro do stent <3mm 1
Stent eluído com paclitaxel 1
IC ou FEVE reduzida 2
ICP em enxerto de veia safena 2

IAM: infarto agudo do miocárdio; IC: insuficiência cardíaca; ICP: intervenção coronária percutânea; FEVE: fração de ejeção do ventrículo esquerdo.

O PRECISE-DAPT (Predicting bleeding complications in patients undergoing stent implantation and subsequentes dual antiplatelet therapy) incluiu 14.963 pacientes submetidos à ICP eletiva, urgente ou emergencial randomizados em diferentes tempo de duração da dupla terapia antiagregante − longa duração (12 a 24 meses) e curta duração (3 a 6 meses) − em relação a um risco de sangramento baseados em 5 fatores: idade, clearance de creatinina, hemoglobina, contagem de leucócitos ou sangramento espontâneo prévio (calculadora disponível em www.precisedaptscore.com). Nos pacientes com escore PRECISE-DAPT alto (≥ 25), a terapia prolongada foi associada a elevadas taxas de sangramento, frente a nenhum benefício isquêmico, diferentemente dos pacientes com escore PRECISE-DAPT baixo que apresentaram eventos isquêmicos adversos combinados baixos sem aumento significativo do risco de sangramento.33

Faltam evidências científicas testadas em estudos randomizados para avaliarem o real valor desses escores em melhorar os desfechos em longo prazo dos pacientes em uso de dupla terapia antiagregante submetidos à ICP. No entanto, sua utilização pode ser considerada para individualizar a decisão, ponderando-se os riscos e benefícios de se prolongar a dupla antiagregação plaquetária.

 3.3. Duração de Dupla Antiagregação Plaquetária Após Intervenção Coronária Percutânea em Doença Arterial Coronária Estável

A dupla antiagregação em pacientes estáveis não é indicada de rotina para pacientes em tratamento clínico. Sua indicação só é efetivamente necessária após ICP, sendo preferencial a combinação AAS e clopidogrel.

Não há evidência com estudos randomizados do uso de prasugrel e ticagrelor como opção ao clopidogrel nesse perfil de pacientes. Entretanto, são opções que podem ser consideradas em pacientes com alto risco aterotrombótico em que há evidência da não efetividade do clopidogrel baseado em desfechos clínicos prévios ou quando submetido a implante de stent absorvível.

Dos estudos que avaliaram a duração da dupla antiagregação plaquetária (AAS e clopidogrel) em pacientes estáveis, 3 são mais recentes e compararam 6 meses contra 12 a 24 meses do tratamento. O ISAR-SAFE (Safety and efficacy of 6 months of dual antiplatelet therapy after drug eluting stenting),34 o maior deles, randomizou 4.005 pacientes e confirmou que não há benefício e redução de eventos isquêmicos com o uso da dupla antiagregação por 12 meses em comparação a 6 meses. Achados semelhantes também foram encontrados no ITALIC (Is there a life for DES after discontinuation of clopidogrel?)35 e SECURITY (Second generation drug-eluting stent implantation followed by six-versus twelve-month dual antiplatelet therapy).36

Outras metanálises37,38 mostraram que a duração de 12 meses da terapia não acrescentou benefícios em relação à redução de eventos isquêmicos quando comparada à duração mais curta (< 6 meses, incluindo avaliação de estudos que analisaram 3 meses da terapia), sendo uma opção para pacientes com risco maior de sangramento.

Tanto o DAPT trial assim como outras metanálises37-39 demonstraram que, além de redução de eventos isquêmicos, trombose de stent, taxas de infarto e aumento das taxas de sangramento, a terapia muito prolongada com mais de 12 meses mostrou uma relação possível, porém fraca, com aumento da mortalidade geral.

Assim sendo, a recomendação dessa diretriz baseia-se na duração média de 6 meses para dupla antiagregação após ICP em pacientes estáveis, sendo possível considerar um período de 3 meses para os pacientes com alto risco de sangramento. O uso muito prolongado (> 12 meses) não é indicado de rotina e pode ser considerado de acordo com perfil clínico e anatômico dos pacientes (Tabela 6).

Recomendações sobre duração de dupla antiagregação plaquetária após intervenção coronária percutânea em doença arterial coronária estável
Indicações Classe de recomendação Nível de evidência
Em pacientes com DAC estável submetidos à ICP e necessidade de dupla antiagregação plaquetária, o clopidogrel (75 mg) associado a uma dose de AAS (75 a 200 mg) é a associação preferencial I A
O uso de stent farmacológico é sempre preferencial ao stent convencional, independente da duração da dupla antiagregação plaquetária I A
Em paciente com DAC estável, submetidos à ICP com stent farmacológico, a dupla antiagregação plaquetária deve ser mantida por um período mínimo de 6 meses, independentemente do tipo de stent I A
Em paciente com DAC estável submetidos à ICP com stent convencional, a dupla antiagregação plaquetária pode ser mantida por um período mínimo de 1 mês frente a um risco alto de sangramento I A
Em paciente com DAC estável submetidos à ICP com stent farmacológico que apresentam alto risco de sangramento, a suspensão da dupla antiagregação plaquetária pode ser considerada IIa B
Em pacientes com DAC estável submetidos à ICP com stent farmacológico, que toleraram o tempo habitual da dupla antiagregação plaquetária sem apresentar sangramentos, que apresentem baixo risco de sangramentos e alto risco aterotrombótico (DAPT escore ≥ 2 e PRECISE-DAPT < 25), é possível manter a terapia antiagregante por > 6 meses e ≤ 30 meses IIb A

AAS: ácido acetilsalicílico; DAC: doença arterial coronária; ICP: intervenção coronária percutânea.

 3.4. Duração da Dupla Antiagregação Após Intervenção Coronária Percutânea em Síndrome Coronária Aguda

O ticagrelor e prasugrel são inibidores P2Y12 preferenciais para os pacientes submetidos à ICP após SCA.

Em pacientes que apresentaram uma SCA, o risco isquêmico permanece mais elevado até aproximadamente um ano após o evento, mesmo após tratadas as lesões culpadas e não culpadas.22,20,40,41 Os grandes estudos que afirmaram os benefícios do ticagrelor e prasugrel frente ao clopidogrel contemplaram a redução de eventos com a duração do tratamento por uma média de 12 meses.

Uma metanálise de 3 estudos que comparavam 3, 6 e 12 meses da dupla terapia, incluindo 11.473 pacientes, dos quais 4.758 eram portadores de SCA, demonstrou que a duração da dupla antiagregação por £ 6 meses foi associado a um aumento do risco de infarto, mas sem significância estatística. Levando em consideração o número menor de pacientes agudos comparativamente aos estudos que demonstraram os reais benefícios da dupla antiagregação intensificada com ticagrelor e prasugrel (TRITON e PLATO), a descontinuação da terapia antiplaquetária dupla pode ser considerada em pacientes com risco aumentado de sangramento a partir de 6 meses.42

O estudo PEGASUS avaliou pacientes que sofreram infarto 1 a 3 anos antes da randomização. Foram estudados a dose habitual de ticagrelor (90 mg a cada 12 horas), uma dose menor (ticagrelor 60 mg a cada 12 horas) e placebo, sendo que todos receberam AAS e foram acompanhados por um período médio de 33 meses. Houve redução significativa das taxas de infarto, morte de causa cardiovascular e AVE à custa de aumento de eventos relacionados a sangramento. Entretanto, a dose de 60mg demonstrou menores taxas de sangramento comparativamente à dose de 90mg de ticagrelor.43

Dessa forma, a recomendação dessa diretriz orienta a realização da dupla antiagregação plaquetária por um mínimo de 12 meses em pacientes submetidos à ICP após SCA, podendo ser modificada para um tempo mínimo de 6 meses em caso de risco aumentado de sangramento. Da mesma forma que a doença coronária estável, o uso muito prolongado (>12 meses) não é indicado de rotina e pode ser considerado de acordo com perfil clínico e anatômico dos pacientes. Quando se opta por esse tratamento mais prolongado, a dose de ticagrelor 60mg a cada 12 horas por ser considerada em associação com AAS (Tabela 7).

Recomendações sobre duração de dupla antiagregação plaquetária após intervenção coronária percutânea em síndrome coronária aguda
Indicações Classe de recomendação Nível de evidência
Em pacientes com SCA submetidos à ICP, independentemente do tipo do stent, a dupla antiagregação deve ser mantida por um período mínimo de 12 meses I A
Em pacientes com SCA submetidos à ICP com risco aumentado de sangramento, pode-se considerar manter o tempo de dupla antiagregação plaquetária por um período mínimo de 6 meses IIa B
Em pacientes com SCA submetidos à ICP com stent farmacológico, que toleraram o tempo habitual da dupla antiagregação plaquetária sem apresentar sangramentos, que apresentem baixo risco de sangramentos e alto risco aterotrombótico (DAPT escore ≥ 2 e PRECISE-DAPT < 25), é possível manter a terapia antiagregante por > 12 meses e ≤ 30 meses IIb A

ICP: intervenção coronária percutânea; SCA: síndrome coronária aguda.

 4. Reversão dos Novos Anticoagulantes 4.1. Introdução

Apesar de os NOACs serem não inferiores aos antagonistas de vitamina K na prevenção de acidente vascular encefálico isquêmico (AVEi) em pacientes com fibrilação atrial e tratamento de trombose venosa profunda, os primeiros estão relacionados com menor risco de sangramentos maiores, particularmente acidente vascular encefálico hemorrágico (AVEh).44

Além disso, apesar da atual indisponibilidade de antídotos para todos os NOACs, sangramentos maiores causados por esses fármacos não parecem levar a piores desfechos clínicos comparados com sangramentos em pacientes usuários de antagonistas de vitamina K que podem ter o efeito anticoagulante revertido rapidamente.45

Com o aumento do uso na prática clínica de NOACs, o controle de eventos hemorrágicos e a necessidade de reversão do efeito anticoagulante para procedimentos de urgência em pacientes utilizando essas medicações tornou-se comum em unidades de emergência.

Além de medidas gerais (Tabela 8), a utilização de antídotos, terapias alternativas (p. ex., complexo protrombínico, fator VIIa, ácido tranexâmico) e acionamento de equipes especializadas (p. ex., hematologistas, endoscopistas, neurologista, neurocirurgiões, cirurgiões gerais, vasculares etc.) devem fazer parte de protocolos institucionais de reversão de anticoagulação em casos de sangramentos maiores ou procedimentos cirúrgicos de urgência em pacientes utilizando NOACs.46

Medidas gerais no controle de sangramentos maiores em pacientes utilizando NOACs
Compressão mecânica quando possível
Determinação da última dose de NOAC
Coleta de exames (função renal, hepática, hemograma, coagulograma completo e fator anti-Xa)
Expansão volêmica e concentrado de hemácias quando necessário
Carvão ativado se ingestão de NOAC < 2 horas

NOAC: novo anticoagulante oral.

 4.2. Antídotos

Três antídotos estão em diversas fases de desenvolvimento (Tabela 10). Até o momento, apenas o anticorpo monoclonal idarucizumabe, antidoto da dabigratana, é aprovado para uso comercial. O adexanet alfa, antídoto dos inibidores do fator Xa (rivaroxabana, apixabana e edoxabana), ainda não foi aprovado para uso comercial no Brasil. Por fim, o ciraparantag, ainda em estudos iniciais, é potencialmente capaz de neutralizar os efeitos tanto dos inibidores diretos da trombina, quanto dos inibidores do fator Xa (Tabelas 9 e 10).

Reversão de efeito anticoagulante dos NOACs<xref ref-type="bibr" rid="B8">8</xref>
NOAC Antídoto específico Opções terapêuticas alternativas
Dabigratana Idarucizumabe 5 g IV (dividido em 2 doses de 2,5 g) • CCP 50 UI/kg IV• Fator VIIa 90 mcg/kg IV a cada 2 horas• Ácido tranexâmico 15 a 30 mg/kg IV• Hemodiálise
Rivaroxabana Anti fator XA (p. ex., adexanet alfa - não aprovado) • CCP 50 UI/kg IV• Fator VIIa 90 mcg/kg IV a cada 2 horas• Ácido tranexâmico 15 a 30 mg/kg IV
Apixabana Anti fator XA (p. ex., adexanet alfa - não aprovado) • CCP 50 UI/kg IV• Fator VIIa 90 mcg/kg IV a cada 2 horas• Ácido tranexâmico 15 a 30 mg/kg IV
Edoxabana Anti fator XA (p. ex., adexanet alfa - não aprovado) • CCP 50 UI/kg IV• Fator VIIa 90 mcg/kg IV a cada 2 horas• Ácido tranexâmico 15 a 30mg/kg IV

CCP: concentrado de complexo protrombínico; Fator VIIa: fator VII recombinante ativado; IV: via intravenosa; NOAC: novo anticoagulante oral.

 Recomendações sobre o uso de antídotos de NOACs
Indicações Classe de recomendação Nível de evidência
O uso de idarucizumabe em pacientes em uso de dabigatrana está indicado na dose de 5 g intravenosos quando houver necessidade de intervenção ou cirurgia de emergência em pacientes que não possam esperar o tempo de metabolização do anticoagulante ou em sangramentos ameaçadores a vida ou sangramentos incontroláveis IIa B
Em casos de cirurgias ou procedimentos eletivos ou que possam esperar o tempo de clareamento do NOACs, sangramentos controlados ou overdose de anticoagulante sem sangramento, o uso dos antídotos não deve ser indicado III C

NOAC: novo anticoagulante oral.

As potenciais indicações para uso de antídotos dos NOACs incluem:

Sangramento ameaçador a vida (p. ex., AVEh) ou sangramentos incontroláveis;

Sangramentos persistentes apesar de medidas hemostáticas;

Risco de sangramentos recorrentes por overdose de NOACs ou expectativa de retardo no metabolismo (p. ex., insuficiência renal);

Sangramento em locais não compressíveis ou órgãos vitais (p. ex., retroperitônio, sangramento pericárdico, intraocular ou intramuscular com síndrome compartimental);

Necessidade de intervenção ou cirurgia de emergência em pacientes de alto risco para sangramento que não possam esperar o tempo de metabolização do NOAC.

O uso de antídotos não parece ser necessário em pacientes que tenham tomado a última dose de NAOC há mais de 24 horas e apresentem clearance de creatinina > 60 mL/min. Em casos de cirurgias ou procedimentos eletivos ou que possam esperar o tempo de clareamento do NOACs, sangramentos controlados ou overdose de anticoagulante sem sangramento, o uso dos antídotos não deve ser indicado.47

4.3. Idarucizumabe

O idarucizumabe é um fragmento de anticorpo monoclonal que neutraliza o efeito anticoagulante da dabigatrana por ligação direta. Tanto a dabigatrana quanto o idarucizumabe e a dabigatrana-idarucizumabe apresentam eliminação renal.

O estudo prospectivo de fase 3 REVERSE-AD (Reversal Effects of Idarucizumab on Active Dabigatran) mostrou que o uso intravenoso de 5 g de idarucizumabe (2 doses consecutivas de 2,5 g com intervalo de 15 minutos) reverteu o efeito anticoagulante da dabigatrana com a normalização do tempo de trombina em mais de 98% dos pacientes, levando a uma hemostasia precoce em pacientes com sangramentos maiores e baixa taxa de eventos hemorrágicos em pacientes submetidos a cirurgias de urgência.48

4.3.1. Adexanet Alfa

Adexanet alfa é uma proteína recombinante do fator Xa que se liga aos inibidores diretos e indiretos do fator Xa, removendo-os da circulação.

Estudo de fase 2 em idosos saudáveis demonstrou que a droga administrada por via intravenosa em bolus com posterior infusão contínua de 2 horas reverteu mais de 90% a atividade do fator anti-Xa da rivaroxabana e da apixabana.49 O estudo de fase 3 em andamento ANNEXA-4 (The Ability of Andexanet Alfa to Reverse the Anticoagulant Activity-4) avaliará a eficácia e segurança do adexanet no controle de hemostasia de pacientes utilizando rivaroxabana, apixabana e edoxabana com sangramentos maiores. Uma análise interina do estudo com 67 pacientes mostrou uma redução da atividade de fator anti-Xa de 89% e 93% naqueles utilizando rivaroxabana e apixabana com 70% de hemostasia clínica.50

4.4. Terapias Alternativas

O uso de plasma fresco congelado (PFC), concentrado de complexo protrombínico (CCP), fator VII recombinante ativado e ácido tranexâmico é sugerido como terapias alternativas em pacientes usuários de NOACs com eventos hemorrágicos ameaçadores à vida ou que necessitam de procedimentos de urgência na ausência de antídoto específico (Tabela 9).46

Estudos em modelo animal, in vitro e série de casos demostraram melhora de parâmetros laboratoriais de coagulação em pacientes que utilizaram rivaroxabana.51-53 Por outro lado, novas evidências sugerem uma superioridade de fator VII recombinante ativado e concentrado de complexo protrombínico parcialmente ativado (FEIBA) em relação ao CCP também em pacientes utilizando rivaroxabana.54,55 Em indivíduos saudáveis utilizando dabigatrana, um estudo randomizado e placebo-controlado falhou em mostrar benefícios do uso de CCP na melhora de parâmetros laboratoriais de coagulação.56 Além disso, séries de casos mostram resultados controversos com a utilização de PFC, CCP, fator VII recombinante ativado e fibrinogênio.57

A ausência de evidência de reversão clínica dos efeitos anticoagulantes dos NOACs com a utilização desses agentes hemostáticos alternativos, bem como dados conflitantes em relação a efeitos e dosagens ótimas, tornam controverso o uso rotineiro dessas medicações.

Por fim, a hemodiálise pode remover cerca de 49 a 57% da dabigatrana circulante em até 4 horas, visto que apenas 35% da droga é ligada a proteínas plasmáticas. Pacientes com insuficiência renal e overdose de dabigatrana podem se beneficiar da hemodiálise no contexto de eventos hemorrágicos maiores ou necessidade de procedimentos de urgência (Tabela 10). Rivaroxabana e apixabana, por serem altamente ligados a proteínas plasmáticas, não são removidos por hemodiálise.46

5. Anticoagulação na Cardioversão de Fibrilação Atrial 5.1. Introdução

A FA é a arritmia sustentada mais frequente na prática clínica. Sua incidência e prevalência aumentam com a idade, sendo que nos maiores de 80 anos a prevalência chega a 8% da população.58 Além disso, alguns estudos americanos mostram que essa prevalência vem aumentando cerca de 0,3% ao ano, com crescimento absoluto entre 1997 e 2007 de 4,5%.58 O motivo para esse aumento, além do envelhecimento populacional, está relacionado à melhoria no tratamento de doenças cardíacas crônicas, que aumenta o número de indivíduos suscetíveis, assim como à melhoria das ferramentas diagnósticas, com maior documentação dessa arritmia.59

A FA está associada a aumento do risco de AVE, além de insuficiência cardíaca e mortalidade total.60-64 Pelo menos 20% dos casos de AVE têm a FA como causa e, nesses casos, o AVE geralmente é mais grave e incapacitante que um AVE de origem isquêmica.65-67 Alguns estudos ainda mostram risco aumentado de distúrbios cognitivos nessa população, secundários a eventos embólicos assintomáticos.68

A terapêutica antitrombótica tem papel fundamental na prevenção de eventos embólicos na presença de fatores de risco, sendo esse um dos principais pilares do tratamento, independentemente da estratégica adotada (controle de ritmo ou de frequência cardíaca).69,70 O risco poder ser calculado pelo escore de CHA2DS2-VASC71 (vide Tabela 11), com indicação de anticoagulação cronicamente se houver pontuação maior ou igual a dois nesse escore, desde que não haja contraindicação e o risco de sangramento seja aceitável.

Recomendações sobre anticoagulação cardioversão de fibrilação atrial
Indicações Classe de recomendação Nível de evidência
Cardioversão elétrica é recomendada para pacientes com instabilidade hemodinâmica para restabelecer o débito cardíaco I B
Anticoagulação com heparina ou com um novo anticoagulante oral deve ser iniciado assim que possível antes de toda cardioversão para FA ou flutter IIa B
Em pacientes estáveis, com FA persistente, que vão se submeter à cardioversão elétrica ou química, recomenda-se a ACO por pelo menos 3 semanas antes e 4 semanas após cardioversão na faixa terapêutica (RNI entre 2 a 3). Após 4 semanas, a manutenção da ACO deve ser de acordo com score de risco de CHA2DS2VASC I B
ECOTE é recomendado para excluir trombos como alternativa à anticoagulação periprocedimento quando a cardioversão precoce é programada I B
Se for identificado trombo, anticoagulação dever ser mantida por 3 semanas I C
Recomenda-se repetir o ECOTE após 3 semanas de anticoagulação para garantir que houve resolução do trombo antes da cardioversão IIa C
No período pericardioversão, pode-se optar por ACO durante o período descrito acima, com antagonistas da vitamina K ou com os novos anticoagulantes IIa B
O uso de ACO está indicado para os pacientes com flutter atrial nas mesmas considerações que na FA I C
A dose preferencial de rivaroxabana deve ser de 20 mg/dia, desde que tenham baixo risco de sangramento I B
A dose preferencial de dabigatrana deve ser de 150 mg 2x/dia, desde que tenham baixo risco de sangramento I B
A dose preferencial de apixabana dever ser de 5 mg 2x/dia, desde que tenham baixo risco de sangramento I B
Para paciente submetidos à cardioversão elétrica guiada por ECOTE e sem trombos, recomenda-se a HNF EV (bolus seguido de infusão contínua) antes da cardioversão e deve-se mantê-la até que a ACO plena seja atingida I B
Para pacientes com FA que necessitam de cardioversão elétrica de emergência, recomenda-se a HNF EV (bolus seguido de infusão contínua) I C
Para paciente submetidos à cardioversão elétrica guiada por ECOTE e sem trombos, recomenda-se a HBPM antes da cardioversão e deve-se mantê-la até que a anticoagulação oral plena seja atingida I B
Para pacientes com FA que necessitam de cardioversão elétrica de emergência, recomenda-se dose plena de HBPM I C

ACO: anticoagulação oral; ECOTE: ecocardiograma transesofágico; EV: via endovenosa; FA: fibrilação atrial; HBPM: heparina de baixo peso molecular; HNF: heparina não fracionada; RNI: relação normatizada internacional.

A varfarina é altamente eficaz na prevenção de fenômenos tromboembólicos na FA, com redução de 64% do risco nos pacientes adequadamente tratados.72-74 Porém, pelo menos metade dos pacientes não são adequadamente tratados, por motivos que variam desde a dificuldade de controle frequente de RNI até alto risco de sangramento.72,73 Além disso, pacientes em uso de varfarina nem sempre se encontram na faixa terapêutica adequada (em geral RNI entre 2 e 3), por ocorrência de interação medicamentosa (principalmente antibióticos e anti-inflamatórios), interação com alimentos, uso irregular da medicação, intercorrências clínicas agudas, entre outros.

Com a disponibilidade dos novos anticoagulantes nos últimos anos, houve melhoria em relação ao controle da anticoagulação, já que eles não requerem monitoração da RNI, têm pouca interação com medicamentos e alimentos e elevada eficácia e segurança, possibilitando aumentar a aderência ao tratamento e o número de pacientes tratados.75 Os anticoagulantes já investigados são dabigatrana, rivaroxabana, apixabana e edoxabana. A dabigatrana é um inibidor direto da trombina e os outros três são bloqueadores do fator Xa e estão em uso na prática clínica para os pacientes com FA não valvar.

 5.2. Estratégias para Anticoagulação Pericardioversão de Fibrilação Atrial

Quando há reversão da FA para ritmo sinusal, de forma espontânea ou intencional (cardioversão química ou elétrica), o risco de tromboembolismo em curto prazo aumenta ainda mais, sendo que a maioria dos eventos ocorre nos primeiros 10 dias após a reversão de ritmo.76-81 O grupo com maior risco é o de pacientes com FA de duração maior que 48 horas (1 a 5% no primeiro mês, na ausência de anticoagulação).82,83

A embolização é consequente ao deslocamento de trombo do átrio esquerdo após o retorno da contração síncrona, porém, também pode haver formação de trombo após a cardioversão, sendo esse o motivo de indicar-se a anticoagulação por pelo menos 4 semanas após a cardioversão mesmo para os pacientes de baixo risco.84-86

O risco de tromboembolismo pode ser reduzido para 0 a 0,9% com o uso de anticoagulação por pelo menos três semanas antes da cardioversão e por um mês após o procedimento.85-89 Ainda, outra opção, com menor tempo de anticoagulação, é a avaliação da presença de trombos atriais através da ecocardiografia transesofágica (ECOTE) e, na ausência de trombos, proceder à cardioversão, iniciando anticoagulação plena no momento do procedimento e mantendo por pelo menos 4 semanas.

A varfarina é o anticoagulante mais estudado neste cenário,90-99 porém há evidência suficiente para o uso dos novos anticoagulantes orais para a realização do procedimento e, inclusive, são preferíveis em alguns casos, como quando o paciente já faz uso de um anticoagulante novo, para encurtar o período de anticoagulação pré-cardioversão (com a varfarina, o tempo médio para ajuste e RNI adequado por pelo menos 3 semanas é de 6-8 semanas), ou quando há dificuldade para o controle da RNI.

No cenário pericardioversão, a rivaroxabana foi comparada a antagonistas da vitamina K no estudo X-VeRT, que randomizou 1.504 pacientes com FA de duração maior que 48 horas ou desconhecida para receber um dos dois anticoagulantes. Não houve diferença significativa no desfecho primário, composto de ataque isquêmico transitório, AVE, embolia periférica, IAM e morte cardiovascular (0,51% × 1,02%; risco relativo: 0,5; intervalo de confiança de 95%: 0,15 a 1,73) ou no desfecho de segurança, sangramento maior (0,6% × 0,8%; risco relativo: 0,76; intervalo de confiança de 95%: 0,21 a 2,67). O tempo para se realizar cardioversão foi inferior no grupo rivaroxabana.79 Além disso, análise post hoc do estudo ROCKET-AF também não mostrou diferença de eventos nos pacientes submetidos a cardioversão em uso de rivaroxabana ou varfarina (HR 1,38; 95% IC 0,61 a 3,11).100

Em relação à dabigatrana, inibidor direto da trombina, em uma análise post-hoc do estudo RE-LY, observou-se que 1.983 cardioversões foram realizadas em 1.270 pacientes (dentre o total de mais de 18 mil pacientes randomizados no estudo original). A ocorrência de AVE ou embolia sistêmica em até 30 dias após a cardioversão foi similar entre os grupos que estavam recebendo anticoagulação pericardioversão com varfarina ou dabigatrana 110 mg 2×/dia ou dabigatrana 150 mg 2×/dia (respectivamente, 0,6%, 0,8% e 0,3%; p > 0,05). Da mesma maneira, não houve diferença nas taxas de sangramento entre os grupos (respectivamente, 0,6%; 1,7% e 0,6%; p > 0,05). Os resultados não foram alterados pela realização prévia de ECOTE.77.Ainda, um estudo observacional dinamarquês evidenciou que ao comparar 456 pacientes com FA não valvar em uso de dabigatrana com 774 pacientes em uso de varfarina, houve redução na mediana do tempo para se realizar a primeira cardioversão (4,0 semanas, com intervalo interquartil [IIQ] de 2,9 a 6,5, e 6,9 semanas, com IIQ de 3,9 a 12,1, para dabigatrana e varfarina, respectivamente). Não foram observadas diferenças de eficácia ou segurança com ambos os fármacos.101

Em relação à apixabana, análise post-hoc do estudo ARISTOTLE comparou pacientes submetidos à cardioversão em uso de apixabana ou varfarina. Setecentas e quarenta e três cardioversões ocorreram em 540 pacientes, sendo 265 pacientes do grupo apixabana e 275 no grupo varfarina. A média etária em ambos os grupos foi similar (67 anos), a fração de ejeção média em ambos os grupos também foi parecida (ao redor de 52%) e o escore de CHADS2 médio no grupo apixabana foi de 1,8 (± 1,0) e no grupo varfarina foi de 1,9 (± 1,1; p = 0,17). Não foram evidenciados (zero) AVEs ou eventos embólicos em 30 dias em nenhum dos grupos e apenas 1 episódio de sangramento maior ocorreu em cada grupo.78 Esses dados foram posteriormente confirmados no EMANATE trial, apresentado no Congresso Europeu de Cardiologia de 2017 (aguarda publicação). Neste estudo, 1.500 pacientes foram randomizados para receber apixabana ou heparina/varfarina (tratamento convencional) até 48h antes da cardioversão. A idade média de ambos os grupos foi ao redor de 64 anos e o escores de CHA2DS2-VASC médio foi de 2,4 nos dois tratamentos. Não foram observados eventos isquêmicos no grupo apixabana, enquanto 6 eventos ocorreram no grupo tratamento convencional (p = 0,016). Por fim, a edoxabana foi avaliada no período pericardioversão em 2.199 pacientes no estudo prospectivo randomizado ENSURE-AF, em comparação à enxaparina e varfarina com suspensão da enoxaparina se RNI > 2. Não houve diferença no desfecho primário composto por AVE, embolia sistêmica, infarto do miocárdio ou mortalidade cardiovascular (odds ratio 0,46, intervalo de confiança de 95% 0,12 a 1,4) ou no desfecho de segurança de sangramento (odds ratio 1,48, intervalo de confiança de 95% = 0,64 - 3,55) em um período total de 28 dias de tratamento, seguidos por mais 30 dias de seguimento.80

Em situações específicas, como quando o paciente é muito sintomático ou naqueles com alto risco de sangramento, podemos realizar a cardioversão mais precocemente, sem a anticoagulação por 3 semanas, desde que não haja trombo nos átrios ou apêndice atrial na avaliação por ECOTE. A partir daí, mantém-se a anticoagulação por pelo menos 4 semanas.71,102 Se o ECOTE evidenciar a presença de trombos, mantém-se anticoagulação por 3 semanas e, caso a cardioversão seja programada, deve-se repetir o ECOTE antes do procedimento. Se houver dúvida em relação à adesão medicamentosa, também está indicado o ECOTE para exclusão de trombo.78,103

Essa estratégia foi primeiramente avaliada de maneira randomizada no estudo ACUTE, que comparou realização de ECOTE versus estratégia convencional (anticoagulação por 3 semanas antes da cardioversão). Pacientes randomizados para o ECOTE recebiam heparina se estivessem hospitalizados, ou varfarina por 5 dias antes do ECOTE se não hospitalizados e, na ausência de trombo, realizava-se a cardioversão. Caso houvesse trombo (12% dos pacientes), a cardioversão era adiada por 3 semanas, mantendo-se anticoagulação nesse período. Não houve diferença entre os grupos do ECOTE e o convencional na incidência de AVE isquêmico (0,6% × 0,3%, respectivamente, RR 1,95, IC 95% 0,36 a 10,60) ou de eventos embólicos no geral (0,8% × 0,5%, respectivamente, RR 1,62, IC 95% 0,39 a 6,76) no período de 8 semanas após a cardioversão. A maioria dos eventos no grupo do ECOTE foi em pacientes que tiveram recorrência da FA ou que ficaram fora da faixa terapêutica no momento do evento. Já nos pacientes que estavam em uso de varfarina, os eventos ocorreram mesmo em ritmo sinusal e na faixa terapêutica. Também é interessante notar que menos sangramentos foram observados no grupo guiado por ECOTE (2,9% versus 5,5%; p = 0,03). Nesse grupo, também foi menor o intervalo de tempo para se realizar a cardioversão (3,0 ± 5,6 dias versus 30,6 ± 10,6 dias; p < 0,001) e foi maior a taxa de sucesso de reversão da FA comparado à estratégia convencional (71% × 65,2%; p = 0,03), embora não houvesse diferença no percentual de pacientes que permaneceu em ritmo sinusal em 8 semanas.104

Caso a FA tenha duração menor de 48 horas, facilmente determinada pelo inquérito dos sintomas, e o paciente não seja de alto risco para o tromboembolismo (doença valvar, disfunção ventricular, próteses, história prévia de tromboembolismo), o risco de tromboembolismo é muito baixo e pode-se realizar a cardioversão105,106 sem anticoagulação plena prévia. A manutenção de anticoagulação por 4 semanas após o procedimento é controversa e não há estudos comparando diferentes heparinas ou heparina aos novos anticoagulantes na FA com duração menor que 48 horas.

Já no caso de FA com duração menor de 48 horas em pacientes de risco moderado a alto de eventos tromboembólicos (CHA2DS2-VASC > 1) recomenda-se a realização de heparina não fracionada ou de baixo peso molecular antes da cardioversão e sua manutenção em longo prazo.86

Nos casos de fibrilação atrial com instabilidade hemodinâmica, deve-se sempre realizar cardioversão de urgência, com realização de bolus de heparina pré-procedimento.86

Em relação às heparinas, a heparina não fracionada tem perdido espaço para as heparinas de baixo peso molecular. As indicações para uso das heparinas são: (1) após cardioversão elétrica ou química em pacientes internados, (2) uso combinado com anticoagulação oral enquanto o ajuste de RNI é realizado; (3) quando se interrompe o uso provisoriamente de anticoagulante varfarínico para a realização de procedimentos diagnósticos ou terapêuticos com risco de hemorragia (estratégia comumente conhecida como “ponte de heparina”). Embora haja 3 tipos de heparinas de baixo peso molecular (dalteparina, enoxaparina e nadroparina), na prática clínica a enoxaparina tem sido mais utilizada.107

O algoritmo da Figura 2 resume as recomendações em relação à anticoagulação pericardioversão da FA.

Recomendações em relação à anticoagulação pericardioversão da fibrilação atrial.

FA: fibrilação atrial; ECOTE: ecocardiograma transesofágico; HNF: heparina não fracionada; HBPM: heparina de baixo peso molecular; NOAC: novo anticoagulante oral; RNI: relação normatizada internacional.

6. Anticoagulação e Antiagregação Plaquetária em Pacientes com Forame Oval Patente 6.1. Introdução

O forame oval patente (FOP) é a cardiopatia congênita mais comum de origem fetal108-110 e está presente em aproximadamente 15 a 35% da população adulta (15 a 25% em estudos que utilizaram o ecocardiograma111,112 como método diagnóstico e 15 a 35% em autópsias).113-115 Existem diversos relatos da relação entre o FOP e diversas patologias, com força de associação distintas: síndrome de ortodeóxia-platipnéia,116 síndrome de descompressão,117,118 embolização sistêmica e coronária,119,120 síndrome de apneia/hipopneia obstrutiva do sono (SAHOS),121 migrânea com aura122-125 e AVE.126

6.2. Relação entre Forame Oval Patente e Acidente Vascular Encefálico Criptogênico

A relação causal entre o FOP e AVE criptogênico - através de uma embolização paradoxal pelo shunt direita-esquerda, é duvidosa e muito debatida entre autores.112,127 Dados de metanálise128 estabeleceram possível relação causal entre FOP e AVE criptogênico em pacientes < 55 anos. Outro estudo129 avaliou a presença de FOP no ecocardiograma transesofágico em pacientes com AVE e identificou uma maior incidência de FOP em pacientes com AVE criptogênico quando comparados a pacientes com AVE de causa conhecida, tanto nos pacientes < 55 anos como naqueles > 55 anos. Um estudo brasileiro130 retrospectivo também identificou a presença de FOP como fator de risco para AVE criptogênico, com razão de chances de 3,3 em pacientes com FOP comparados a pacientes sem FOP. Já em estudos populacionais prospectivos, a presença de FOP não se relacionou com aumento do risco de AVE, tanto em pacientes que já tinham tido um AVE131 (prevenção secundária), como em pacientes assintomáticos (prevenção primária).111,132,133

Conclui-se, assim, que o diagnóstico de FOP em um paciente com AVE criptogênico não estabelece relação causal entre as duas entidades,134 sendo que o risco atribuível ao FOP diminui de acordo com a idade e a presença de fatores de risco como HAS, diabetes melitos, tabagismo, antecedente pessoal de acidente isquêmico transitório ou AVE prévio.135 Baseando-se em dados de uma metaanálise135 de 12 estudos de coorte que acompanharam pacientes com AVE criptogênico desenvolveu-se o escore RoPE (Escore de Risco de Embolia Paradoxal), que quantifica o risco do AVE que é atribuível ao FOP (Tabela 12). Nesse estudo, evidenciou-se que pacientes com escores mais elevados (em que se aumenta o risco atribuível ao FOP como fator causal do AVE) eram também os que apresentavam o menor risco de recorrência de AVE durante o seguimento. Concluindo, a relação causal entre FOP e AVE ainda é incerta e, mesmo em pacientes em que se atribui o FOP/embolia paradoxal como mecanismo do AVE, a taxa de recorrência de eventos é muito baixa (1-3% em 2 anos em pacientes com escore RoPE 9 ou 10).134,135

Escore RoPE (Escore de Risco de Embolia Paradoxal). Quanto maior o escore RoPE, maior a causalidade entre o forame oval patente e acidente vascular encefálico
Característica Pontos
Sem AP de HAS 1
Sem AP de Diabetes 1
Sem AP de AVE/AIT 1
Não tabagista 1
Infarto cortical em exame de imagem 1
Idade (em anos):18 a 2930 a 3940 a 4950 a 5960 a 69≥ 70 543210

AIT: acidente isquêmico transitório; AP: antecedente pessoal; AVE: acidente vascular encefálico; HAS: hipertensão arterial sistêmica.

Algumas características ecocardiográficas do FOP podem estar relacionadas a um maior risco de embolização paradoxal, como: shunt direito-esquerdo importante, shunt direito-esquerdo espontâneo, maior mobilidade do flap do FOP, rede de Chiari ou válvula de Eustáquio proeminente e a presença de um aneurisma do septo atrial.109,136-141 No entanto, algumas destas características não se mostraram consistentemente relacionadas a uma maior taxa evento embólico em outros estudos.111,132,142-145

6.3. Evidências oara Uso de Antiagregantes Plaquetários ou Anticoagulantes em Pacientes com Forame Oval Patente

Pela hipótese de que o evento embólico relacionado ao FOP ocorra ou por embolização paradoxal ou pela embolização de um trombo formado no átrio esquerdo, justifica-se a antiagregação ou anticoagulação nas seguintes situações:

Prevenção primária: nenhum estudo avaliou a prevenção primária de eventos embólicos em pacientes com FOP. Considerando-se que a relação causal entre FOP e embolia sistêmica é ainda incerta, que a taxa de evento embólico em pacientes apenas com FOP é extremamente baixa e que os riscos inerentes às terapias anticoagulantes e antiplaquetárias não são desprezíveis, não se recomenda o uso de antiagregantes plaquetários ou anticoagulação para prevenção primária de eventos embólicos em pacientes com FOP.146

Prevenção secundária: a melhor estratégia terapêutica após evento embólico na presença de FOP ainda é foco de debates e controvérsias devido à correlação duvidosa existente entre ambos. Em 2002, o subestudo PICSS do estudo WARSS144 comparou o uso da varfina ao AAS (dose de 325mg ao dia) em pacientes com AVE e FOP, em um subgrupo de 265 pacientes com AVE criptogênico. Não houve diferença estatisticamente significante na taxa de eventos embólicos recorrentes entre o grupo varfarina e o grupo AAS nesta situação. Um outro estudo147 randomizou 47 pacientes após AVE criptogênico para AAS (240 mg/dia) ou varfarina (meta de RNI entre 2 e 3), sendo que os autores não observaram diferença entre risco de AVE isquêmico ou AIT entre os grupos. Uma metanálise148 com dados apenas desses dois estudos randomizados não identificou diferença a favor da varfarina quando comparada ao AAS em prevenção de AVE. Uma outra metanálise recente149 comparou o uso de antiagregação plaquetária com anticoagulação oral em pacientes com AVE criptogênico, com dados individuais de 2.385 pacientes de 12 estudos observacionais e não observou diferença nas taxas de AVE recorrente entre paciente submetidos à anticoagulação oral ou antiagregação plaquetária. Em 2017, foram publicados os resultados do estudo CLOSE, que comparou o fechamento percutâneo do FOP à terapia medicamentosa com antiagregação plaquetária ou anticoagulação, sendo que não foi realizada a análise estatística para comparação entre os grupos de tratamento clínico (o estudo não recrutou o alvo de 900 pacientes e a taxa de eventos foi abaixo da esperada). Porém, ao avaliar os dados em valores absolutos, observou-se uma incidência de 3 casos no grupo anticoagulação e 7 casos no grupo antiagregação, com uma probabilidade de AVE estimada em 5 anos de 1,5% e 3% respectivamente.45 O fechamento do FOP, percutâneo ou cirúrgico, também deve ser considerado em casos selecionados, porém sua discussão foge do escopo deste documento.

Assim, não existe evidência suficiente para recomendar-se o uso preferencial de anticoagulação oral sobre antiagregação plaquetária, dada a baixa taxa de recorrência de evento embólico em pacientes jovens e com AVE criptogênico. Portanto, o uso de antiagregantes plaquetários parece ser adequado devido ao risco acumulado de complicações hemorrágicas destes pacientes se submetidos à anticoagulação oral e à eficácia já comprovada dos antiagregantes em redução do risco de evento embólico na população geral (Tabela 13). Ressalta-se que os estudos para prevenção secundária em que foi baseada essa diretriz144,147,150 não foram desenhados para mostrar superioridade da anticoagulação oral sobre antiagregação plaquetária e, portanto, não têm poder estatístico para evidenciar um possível benefício da anticoagulação oral sobre a antigregação plaquetária.

Recomendações para uso de antiagregantes plaquetários e anticoagulantes na prevenção primária e secundária de acidente vascular encefálico criptogênico em pacientes com forame oval patente
Indicações Classe de recomendação Nível de evidência
Pacientes sem indicação de anticoagulação por outros motivos devem iniciar antiagregação plaquetária para prevenção secundária I B
Uso de varfarina como primeira opção após primeiro evento IIb B
Após evento recorrente em uso de antiagregante plaquetário, o uso de varfarina com alvo de RNI entre 2 e 3 deve ser considerado IIa C
Uso dos inibidores do fator XA e do inibidor da trombina após primeiro evento como alternativa à varfarina IIb C
Uso de antiagregantes plaquetários ou de anticoagulantes como prevenção primária III C

RNI: relação normatizada internacional.

 7. Terapia Antitrombótica em Pacientes Oncológicos com Trombocitopenia 7.1. Introdução

Doenças cardiovasculares e câncer são as maiores causas de óbitos no Brasil.151 O avanço no tratamento das neoplasias aumentou a sobrevida dessa população, que passou a ter maior exposição aos fatores de risco tradicionais para desenvolvimento de doença aterosclerótica.

Por outro lado, pacientes oncológicos, por estarem submetidos a um estado pró- inflamatório e pró-trombótico, podem desenvolver aterosclerose de forma mais acelerada, com maior risco de desenvolvimento de SCA.152

O próprio tratamento da neoplasia com radioterapia e quimioterapia tem efeitos colaterais coronários deletérios, tais como a ocorrência de vasoespasmo e injúria endotelial.153

Por fim, a presença de trombocitopenia eleva tanto o risco de sangramento como o risco de fenômenos isquêmicos. Uma avaliação retrospectiva no Hospital MD Anderson mostrou que 39% dos pacientes com SCA possuíam contagem de plaquetas < 100.000 células/mm3.154

7.2. Terapia Antitrombótica

Não existem estudos randomizados de terapia antitrombótica em pacientes trombocitopênicos, uma vez que essa população normalmente é excluída dos grandes ensaios clínicos.

Um estudo retrospectivo de 70 pacientes oncológicos com SCA mostrou menor mortalidade em 7 dias nos pacientes plaquetopênicos que receberam AAS.155

Em uma série de casos avaliando pacientes com contagem de plaquetas > 50.000 células/mm3 submetidos à angioplastia, o uso de antiagregantes e anticoagulantes não aumentou a incidência de sangramentos.156

Já nos pacientes com contagem de plaquetas entre 30.000 e 50.000 células/mm3, o uso de AAS e clopidogrel foi seguro, porém menores doses de heparina não fracionada (30 UI/kg a 50 UI/kg) foram suficientes para atingir alvo terapêutico nessa população.156 Em pacientes com contagem de plaquetas inferior a 10.000, o risco benefício deve ser avaliado individualmente, sendo a transfusão de plaquetas e uso de antiagregantes plaquetários uma possibilidade na terapêutica (Tabela 14).156

Recomendações para uso de antiagregantes plaquetários e anticoagulantes em pacientes oncológicos com trombocitopenia
Indicações Classe de recomendação Nível de evidência
Uso do ácido acetilsalicílico em pacientes com doença coronária I A
Uso de clopidogrel e ácido acetilsalicílico em associação em pacientes com síndrome coronária aguda de alto risco ou após angioplastia coronária I A
O ácido acetilsalicílico deve ser usado sempre em dose mínima, preferencialmente ≤ 100 mg ao dia IIa C
Uso de terapia antiplaquetária e/ou anticoagulante em pacientes com síndrome coronária aguda, mesmo com plaquetopenia IIa C
Uso de dose reduzida de enoxaparina e heparina não fracionada em pacientes com contagem de plaquetas < 50.000. Monitorização de alvo terapêutico IIa C

Não existem estudos com novos antiplaquetários ou anticoagulantes não vitamina- K dependentes nessa população.

Este posicionamento deverá ser citado como: Serrano Jr. CV, Soeiro AM, Leal TCAT, Godoy LC, Biselli B, Hata LA et al. Posicionamento sobre Antiagregantes Plaquetários e Anticoagulantes em Cardiologia - 2019. Arq Bras Cardiol. 2019; 113(1):111-134.

Nota: estas Diretrizes se prestam a informar e não a substituir o julgamento clínico do médico que, em última análise, deve determinar o tratamento apropriado para seus pacientes.