**5. Choosing therapy following elective percutaneous coronary intervention**

In elective percutaneous coronary interventions (PCI), if there is no obligatory indication (long lesion, small vessel, diabetes, etc.) the intervention must be limited to a bare metal stent (BMS). Because after the implantation of a drug eluting stent (DES), there is a require‐ ment for a triple antiplatelet for a longer time (3 months for sirolimus, 6 months for paclitax‐ el) and this may lead to a higher mortality rate associated with increased bleeding risk. While the post BMS triple anti platelet therapy is limited to a 4 week period, it has to be used longer following DES. In patients with low-medium bleeding risk but low embolic risk, during the first four weeks after BMS, triple anti platelet therapy is suggested. After 4 weeks, lifelong OAC (INR=2-3) should be preferred. As an approach, there is a difference between ESC guidelines and USA clinical practice [12]. In patients with low-medium hemor‐ rhagic risk both the ESC and the USA approaches suggest triple anti platelet therapy for BMS and DES, but in the USA approach, only DAPT is suggested in patients with a high bleeding risk. However, in ESC guidelines, despite the high bleeding risk, during the 2-4 week interval after BMS elective implantation, triple anti platelet therapy is advised.

**Figure 1.** US Approach-Adapted from Paikin et al [12]

As a therapy regime, OAC (INR=2 – 2.5), aspirin daily ≤100 mg and clopidogrel 75 mg daily is included. In patients with a high risk of bleeding, it has been stressed in both guidelines that DES should be avoided and if possible BMS should be implanted. Among patients hav‐ ing a low and medium bleeding risk, for those who have been implanted BMS, 1 month of triple anti platelet therapy is advised. Among those patients who are DES implanted, for the limus group, 3 months of triple antiplatelet therapy is advised while for the paclitaxel group, 6 months of DAPT is advised. Furthermore, in DES implanted patients, a dual thera‐ py of OAC plus aspirin up to 1 year or OAC plus clopidogrel is advised and after 1 year only OAC mono therapy is advised. Therefore, DES implantation should be avoided be‐ cause it requires long term dual and triple therapy (Table3).

rhage is high, because of the high incidence of intracranial and extra cranial bleeding

In the abovementioned patients the low dose dabigatran option must be considered and if they are treated with VKA, a lower INR (1.8-2.5) target should be chosen. However accord‐ ing to the studies made, patients with an INR <2 have double the risk of stroke compared to

In elective percutaneous coronary interventions (PCI), if there is no obligatory indication (long lesion, small vessel, diabetes, etc.) the intervention must be limited to a bare metal stent (BMS). Because after the implantation of a drug eluting stent (DES), there is a require‐ ment for a triple antiplatelet for a longer time (3 months for sirolimus, 6 months for paclitax‐ el) and this may lead to a higher mortality rate associated with increased bleeding risk. While the post BMS triple anti platelet therapy is limited to a 4 week period, it has to be used longer following DES. In patients with low-medium bleeding risk but low embolic risk, during the first four weeks after BMS, triple anti platelet therapy is suggested. After 4 weeks, lifelong OAC (INR=2-3) should be preferred. As an approach, there is a difference between ESC guidelines and USA clinical practice [12]. In patients with low-medium hemor‐ rhagic risk both the ESC and the USA approaches suggest triple anti platelet therapy for BMS and DES, but in the USA approach, only DAPT is suggested in patients with a high bleeding risk. However, in ESC guidelines, despite the high bleeding risk, during the 2-4

week interval after BMS elective implantation, triple anti platelet therapy is advised.

Yes

No

DAPT (Aspirin + Clopidogrel)

Atrial fibrillation plus Coronary artery stent

High risk of stroke? CHADS >1

High risk of bleeding?

**Figure 1.** US Approach-Adapted from Paikin et al [12]

Triple therapy (Aspirin + OAC + Clopidogrel)

No

Yes

**5. Choosing therapy following elective percutaneous coronary**

incidence, the option of DAPT should not be preferred.

patients whose INR is > 2.

232 Atrial Fibrillation - Mechanisms and Treatment

**intervention**


ACS=Acute coronary syndrome, BMS=Bare metal stent, DES=Drug eluted stent, INR=International normalized ratio

\*Combination of warfarin (INR 2.0–2.5) + aspirin ≤ 100 mg/day may be considered as an alternative.

Drug-eluting stents should be avoided.Adapted from Lip et al

**Table 3.** ESC suggestions for anticoagulation in patients with coronary stent who have medium and high emboli risk

### **6. Acute coronary syndrome**

In patients with non-valvular AF who have acute coronary syndrome (ACS), the puncture site for PCI is important. In anti- coagulated patients, how the therapy will be conducted in the hospital and choosing the right type of stent bears an importance. As for those patients who are not anti coagulated, the antithrombotic therapy during discharge is important. In anticoagulated patients, femoral intervention is an independent predictor for major hemor‐ rhage and other vascular complications and therefore in those patients radial intervention is preferred because it causes less bleeding and better results [13,14].

**4.** In patients having a high bleeding risk hypertension should be treated aggressively. **5.** Hepatic and renal functions should be followed closely in patients who take OAC.

Anticoagulant Therapy in Patients with Atrial Fibrillation and Coronary Artery Disease

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235

**7.** During ACS, additional heparin, GP IIb/IIIa inhibitor or bivaluridin should not be given

**8.** Radial intervention should be applied to patients who take OAC and who are inter‐

**9.** Triple antiplatelet therapy should not be used for more than 1 month in patients whose

**10.** DAPT should not be given for a long time, instead only OAC should be given in long

**12.** In long term therapy, dabigatran 110 mg twice a day or rivaroxaban once a day should be considered for use (compared to VKA lower bleeding incidence, equal stroke rates)

In AF patients, oral anticoagulation is traditionally done with VKA. However, due to per‐ sonal differences in responses, the need for a balance in dose, labile INR and bleeding risk; studies have been made on new drugs which do not require follow-up. With these new drugs such as direct thrombin inhibitor dabigatran, factor Xa inhibitors apixaban and rivar‐ oxaban, the incidence of major bleeding is significantly lower compared to VKA. When Da‐ bigatran 110 mg twice a day is compared with VKA, nonvalvular AF stroke prevention in the RELY study (Randomized Evaluation of Long-term Anticoagulant Therapy) there is no difference between stroke and systemic embolism, but the rate of major hemorrhage is meaningfully less in 110 mg Dabigatran than it is in VKA [18]. In the dose of 150 mg, the rates of major bleeding and stroke were determined to be similar. In patients with non valv‐ ular AF whose INR values were labile, if they cannot be followed closely and if they do not have an advanced hepatic and renal problem, dabigatran is an alternative to warfarin. In non- valvular AF patients, in the ARISTOTLE study done with Apixaban, apixaban is relat‐ ed to lower hemorrhage complication and lower mortality compared to warfarin [19]. In the ROCKET-AF [20] study, while there was no difference between the major hemorrhage rates of patients using rivaroxaban and warfarin, the fatal and intracranial hemorrhage rates were lower in patients using rivaroxaban than in those patients using warfarin. The systemic em‐

The results of this study are hopeful for long term anticoagulation regimes. There is no suffi‐ cient clinical evidence regarding the fact that these drugs are appropriate for a combination

in patients whose bleeding risk is high (especially in the presence of INR labile).

**6.** In case of stent requirement, BMS should be preferred as much as possible.

to those patients who have an effective INR and who take OAC.

**11.** Proton pump inhibitors may be added to the therapy.

boli and stroke prevention rates between the two were equal.

vened with STEMI.

bleeding risk is high.

**7. New anticoagulant drugs**

term therapy.

In patients with ACS, especially those in whom primary PCI have been applied, BMS should be preferred because it requires a shorter duration triple antithrombotic therapy. OAC should be given to non-STEMI patients when they are hospitalized and DAPT and heparin should be given to those patients who have no therapy. If the thromboembolic risk is too high, OAC therapy might as well be started in those patients during in-hospital period. There are two approaches for patients who receive OAC during hospitalization. The first and mostly used approach in clinical practice is the bridge therapy which involves stopping OAC therapy and starting heparin. The second approach is to continue OAC therapy so that INR will be in the 2-2.5 interval. The main drawback of the bridge therapy is when the ther‐ apy is stopped and then restarted, Protein –C and –S are not suppressed, and they increase embolic complications paradoxically in patients with a very high emboli risk [15]. Therefore, in patients with ACS having a very high embolic risk, it is advised that DAPT should be added to the therapy without stopping OAC and without adding heparin (if the INR <2, then heparin may be added) [16,17]. In STEMI patients for whom P-PCI is applied, if the INR is within the interval of 2 – 3, then a similar approach is applicable. However, glycopro‐ tein (GP) IIb/IIIa inhibitors may have to be used due to the high thrombus burden. In those patients with a high thrombus burden, if the INR>2, then GP IIb/IIIa inhibitor must not be started, and, if possible thrombectomy should be considered instead. Alternatively, in pa‐ tients with INR<2, bivaluridin might be considered for use instead of GP IIb/IIIa inhibitor + heparin. Due to high hemorrhagic risks, in patients using OAC and having optimal INR, ad‐ ditional heparin should not be used. In patients whose bleeding risk is high, triple therapy should not be used for more than 1 month. Due to the need for short triple therapy, BMS should always be preferred. Following ACS, triple therapy should be given for 1 month, du‐ al therapy including OAC should be given up to 12 months, and after 12 months only OAC should be given lifelong. The short and long term antithrombotic therapy regimen of the ACS patients is summarized in table 3.

#### **Advice On Decreasing Hemorrhagic Risk:**


#### **7. New anticoagulant drugs**

**6. Acute coronary syndrome**

234 Atrial Fibrillation - Mechanisms and Treatment

ACS patients is summarized in table 3.

well.

bolic risk.

**Advice On Decreasing Hemorrhagic Risk:**

In patients with non-valvular AF who have acute coronary syndrome (ACS), the puncture site for PCI is important. In anti- coagulated patients, how the therapy will be conducted in the hospital and choosing the right type of stent bears an importance. As for those patients who are not anti coagulated, the antithrombotic therapy during discharge is important. In anticoagulated patients, femoral intervention is an independent predictor for major hemor‐ rhage and other vascular complications and therefore in those patients radial intervention is

In patients with ACS, especially those in whom primary PCI have been applied, BMS should be preferred because it requires a shorter duration triple antithrombotic therapy. OAC should be given to non-STEMI patients when they are hospitalized and DAPT and heparin should be given to those patients who have no therapy. If the thromboembolic risk is too high, OAC therapy might as well be started in those patients during in-hospital period. There are two approaches for patients who receive OAC during hospitalization. The first and mostly used approach in clinical practice is the bridge therapy which involves stopping OAC therapy and starting heparin. The second approach is to continue OAC therapy so that INR will be in the 2-2.5 interval. The main drawback of the bridge therapy is when the ther‐ apy is stopped and then restarted, Protein –C and –S are not suppressed, and they increase embolic complications paradoxically in patients with a very high emboli risk [15]. Therefore, in patients with ACS having a very high embolic risk, it is advised that DAPT should be added to the therapy without stopping OAC and without adding heparin (if the INR <2, then heparin may be added) [16,17]. In STEMI patients for whom P-PCI is applied, if the INR is within the interval of 2 – 3, then a similar approach is applicable. However, glycopro‐ tein (GP) IIb/IIIa inhibitors may have to be used due to the high thrombus burden. In those patients with a high thrombus burden, if the INR>2, then GP IIb/IIIa inhibitor must not be started, and, if possible thrombectomy should be considered instead. Alternatively, in pa‐ tients with INR<2, bivaluridin might be considered for use instead of GP IIb/IIIa inhibitor + heparin. Due to high hemorrhagic risks, in patients using OAC and having optimal INR, ad‐ ditional heparin should not be used. In patients whose bleeding risk is high, triple therapy should not be used for more than 1 month. Due to the need for short triple therapy, BMS should always be preferred. Following ACS, triple therapy should be given for 1 month, du‐ al therapy including OAC should be given up to 12 months, and after 12 months only OAC should be given lifelong. The short and long term antithrombotic therapy regimen of the

**1.** The balance between hemorrhagic risk and embolic risk should be maintained very

**2.** No therapy may be given to patients who are under 65 years of age having a low em‐

**3.** In combined therapies, the dose of aspirin should be kept low (75 – 100 mg).

preferred because it causes less bleeding and better results [13,14].

In AF patients, oral anticoagulation is traditionally done with VKA. However, due to per‐ sonal differences in responses, the need for a balance in dose, labile INR and bleeding risk; studies have been made on new drugs which do not require follow-up. With these new drugs such as direct thrombin inhibitor dabigatran, factor Xa inhibitors apixaban and rivar‐ oxaban, the incidence of major bleeding is significantly lower compared to VKA. When Da‐ bigatran 110 mg twice a day is compared with VKA, nonvalvular AF stroke prevention in the RELY study (Randomized Evaluation of Long-term Anticoagulant Therapy) there is no difference between stroke and systemic embolism, but the rate of major hemorrhage is meaningfully less in 110 mg Dabigatran than it is in VKA [18]. In the dose of 150 mg, the rates of major bleeding and stroke were determined to be similar. In patients with non valv‐ ular AF whose INR values were labile, if they cannot be followed closely and if they do not have an advanced hepatic and renal problem, dabigatran is an alternative to warfarin. In non- valvular AF patients, in the ARISTOTLE study done with Apixaban, apixaban is relat‐ ed to lower hemorrhage complication and lower mortality compared to warfarin [19]. In the ROCKET-AF [20] study, while there was no difference between the major hemorrhage rates of patients using rivaroxaban and warfarin, the fatal and intracranial hemorrhage rates were lower in patients using rivaroxaban than in those patients using warfarin. The systemic em‐ boli and stroke prevention rates between the two were equal.

The results of this study are hopeful for long term anticoagulation regimes. There is no suffi‐ cient clinical evidence regarding the fact that these drugs are appropriate for a combination therapy (DAPT plus OAC). However, regarding these three studies (RELY, ROCKET-AF, and ARISTOTLE), when the dual therapy using VKA is compared with dual therapy using new anticoagulant drugs (apixaban, rivaroxaban, dabigatran), there is no additional differ‐ ence in terms of hemorrhage rate. Thus, when the combination of DAPT with new drugs is compared to the combination of VKA and DAPT, there is no additional increase in hemor‐ rhage. Nevertheless, in the monotherapy with OAC, the risk of hemorrhage is at its lowest. However, regarding the safety of the combined use of the new anticoagulant drugs with du‐ al antiplatelet therapy, there is no sufficient evidence regarding long-term use and there is a need for further studies.

[7] Camm AJ, Kirchhof P, Lip GY et al. Guidelines for the management of atrial fibrilla‐ tion: The Task Force for the Management of Atrial Fibrillation of the European Soci‐

Anticoagulant Therapy in Patients with Atrial Fibrillation and Coronary Artery Disease

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