J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Original Article

Volume 8, Number 2, February 2016, pages 153-161

Clinical Relevance of Anticoagulation and Dual Antiplatelet Therapy to the Outcomes of Patients With Atrial Fibrillation and Recent Percutaneous Coronary Intervention With Stent

Figure 1. Distribution of total MACEs across the three treatment groups. No significant differences were found between groups as regards the frequency of total MACEs (21%, 12.9% and 27.1% in DAPT, DT and TT groups, respectively; Chi-square test, P = 0.324). TT: triple therapy (warfarin + acetylsalicylic acid (ASA) and clopidogrel); DT: dual therapy (warfarin + ASA or clopidogrel); DAPT: dual antiplatelet therapy (ASA + clopidogrel); MACE: major adverse cardiovascular event; pts, patients.

Figure 2. Distribution of total bleeding events across the three treatment groups. No significant differences were found between groups as regards the frequency of total bleeding events (21%, 19.35% and 16.6% in DAPT, DT and TT groups, respectively; Chi-square test, P = 0.903). TT: triple therapy (warfarin + acetylsalicylic acid (ASA) and clopidogrel); DT: dual therapy (warfarin + ASA or clopidogrel); DAPT: dual antiplatelet therapy (ASA + clopidogrel); pts: patients.

Figure 3. The type of antithrombotic regimen at the time of major bleeding is highlighted. Four out of seven major bleeding events occurred in the course of TT regimen; however, no significant difference (Chi square test, P = 0.893) was demonstrated for the incidence of major bleeding across the three treatment groups, among whom the TT group was the most numerous (48 pts vs. 31 pts in the DT group and only 19 patients in the DAPT group). TT: triple therapy (warfarin + acetylsalicylic acid (ASA) and clopidogrel); DT: dual therapy (warfarin + ASA or clopidogrel); DAPT: dual antiplatelet therapy (ASA + clopidogrel); pts: patients.

Figure 4. The Kaplan-Meier curve is used to compare the respective probabilities of being involved by an MACE across the three antithrombotic treatment groups. No significant differences across the three pharmacologic regimens were observed in the survival free from total MACE over a 1-year follow-up (log-rank test, P = 0.284). DAPT: dual antiplatelet therapy (acetylsalicylic acid (ASA) + clopidogrel); DT: dual therapy (warfarin + ASA or clopidogrel); TT: triple therapy (warfarin + ASA and clopidogrel).

Figure 5. The Kaplan-Meier curve is used to compare the respective probabilities of being involved by one or more bleeding events (major or minor) across the three antithrombotic treatment groups. No significant differences across the three pharmacologic regimens were observed in the survival free from total bleeding events over a 1-year follow-up (log-rank test, P = 0.955). DAPT: dual antiplatelet therapy (acetylsalicylic acid (ASA) + clopidogrel); DT: dual therapy (warfarin + ASA or clopidogrel); TT: triple therapy (warfarin + ASA and clopidogrel).

**Table 1.** CHA₂DS₂-VASc Score for Estimating the Risk of Stroke in Patients With Atrial Fibrillation
	Condition	Points
The CHA₂DS₂-VASc score is a refinement of CHADS₂ score and extends the latter by including additional common stroke risk factors, such as vascular disease, age 65 - 74 years and sex category (i.e. female sex). The maximum CHA₂DS₂-VASc score is 9 (for age, either the patient is ≥ 75 years and gets two points, is between 65 and 74 and gets one point, or is under 65 and does not get points). Note that female gender only scores one point if the patient has at least one other risk factor, and does not score any points in isolation. TIA: transient ischemic attack.
C	Congestive heart failure (or left ventricular systolic dysfunction)	1
H	Hypertension: blood pressure consistently above 140/90 mm Hg (or treated hypertension on medication)	1
A₂	Age ≥ 75 years	2
D	Diabetes mellitus	1
S₂	Prior stroke or TIA or thromboembolism	2
V	Vascular disease (e.g. peripheral artery disease, myocardial infarction, aortic plaque)	1
A	Age 65 - 74 years	1
Sc	Sex category (i.e. female sex)	1

Table 1. CHA₂DS₂-VASc Score for Estimating the Risk of Stroke in Patients With Atrial Fibrillation

Condition

Points

The CHA₂DS₂-VASc score is a refinement of CHADS₂ score and extends the latter by including additional common stroke risk factors, such as vascular disease, age 65 - 74 years and sex category (i.e. female sex). The maximum CHA₂DS₂-VASc score is 9 (for age, either the patient is ≥ 75 years and gets two points, is between 65 and 74 and gets one point, or is under 65 and does not get points). Note that female gender only scores one point if the patient has at least one other risk factor, and does not score any points in isolation. TIA: transient ischemic attack.

Congestive heart failure (or left ventricular systolic dysfunction)

Hypertension: blood pressure consistently above 140/90 mm Hg (or treated hypertension on medication)

A₂

Age ≥ 75 years

Diabetes mellitus

S₂

Prior stroke or TIA or thromboembolism

Vascular disease (e.g. peripheral artery disease, myocardial infarction, aortic plaque)

Age 65 - 74 years

Sex category (i.e. female sex)

**Table 2.** HAS-BLED Score for Assessing the Bleeding Risk During Oral Anticoagulation Among Patients With AF
	Clinical feature	Points
Risk of major bleeding: score 0 = 1%/year, score 5 = 12.5%/year. HAS-BLED score interpretation A score of 3 or more indicates an increased risk of bleeding that would be sufficient to justify the prudence or more frequent assessment. Physicians should also remember that the risk of bleeding may be changed and the HAS-BLED score can help you understand what correct: for example, discontinuation of therapy with aspirin and a better blood pressure control may be two ways to reduce the risk of bleeding. AST: aspartate aminotransferase; ALT: alanine aminotransferase; ALP: alkaline phosphatase; INR: international normalized ratio; NSAIDs: non-steroidal anti-inflammatory drugs.
H	Hypertension (systolic blood pressure > 160 mm Hg)	1
A	Abnormal renal function (defined as the presence of chronic dialysis or renal transplantation or serum creatinine ≥ 200 µmol/L (> about 2.3 mg/dL))	1
	Abnormal liver function (defined as chronic hepatic disease (e.g. cirrhosis) or biochemical evidence of significant hepatic derangement (e.g. bilirubin > × 2upper limit of normal, in association with AST/ALT/ALP > × 3 upper limit normal)	1
S	Stroke (previous history of stroke)	1
B	Bleeding (major bleeding history (anemia or predisposition to bleeding))	1
L	Labile INRs (refers to unstable/high INRs or poor time in therapeutic range (e.g. < 60%))	1
E	Elderly (age ≥ 65 years)	1
D	Drug therapy (concomitant therapy such as antiplatelet agents, NSAIDs, steroids)	1
	Alcohol intake (consuming 8 or more alcoholic drinks per week)	1
		Maximum score: 9 points

Table 2. HAS-BLED Score for Assessing the Bleeding Risk During Oral Anticoagulation Among Patients With AF

Clinical feature

Points

Risk of major bleeding: score 0 = 1%/year, score 5 = 12.5%/year. HAS-BLED score interpretation A score of 3 or more indicates an increased risk of bleeding that would be sufficient to justify the prudence or more frequent assessment. Physicians should also remember that the risk of bleeding may be changed and the HAS-BLED score can help you understand what correct: for example, discontinuation of therapy with aspirin and a better blood pressure control may be two ways to reduce the risk of bleeding. AST: aspartate aminotransferase; ALT: alanine aminotransferase; ALP: alkaline phosphatase; INR: international normalized ratio; NSAIDs: non-steroidal anti-inflammatory drugs.

Hypertension (systolic blood pressure > 160 mm Hg)

Abnormal renal function (defined as the presence of chronic dialysis or renal transplantation or serum creatinine ≥ 200 µmol/L (> about 2.3 mg/dL))

Abnormal liver function (defined as chronic hepatic disease (e.g. cirrhosis) or biochemical evidence of significant hepatic derangement (e.g. bilirubin > × 2upper limit of normal, in association with AST/ALT/ALP > × 3 upper limit normal)

Stroke (previous history of stroke)

Bleeding (major bleeding history (anemia or predisposition to bleeding))

Labile INRs (refers to unstable/high INRs or poor time in therapeutic range (e.g. < 60%))

Elderly (age ≥ 65 years)

Drug therapy (concomitant therapy such as antiplatelet agents, NSAIDs, steroids)

Alcohol intake (consuming 8 or more alcoholic drinks per week)

Maximum score: 9 points

**Table 3.** Baseline Characteristics
	Total (n = 98)	TT (n = 48)	DT (n = 31)	DAPT (n = 19)	P-value
Data are reported as absolute number (percentage) or mean ± standard deviation. TT: triple therapy (warfarin + acetylsalicylic acid and clopidogrel); DT: dual therapy (warfarin + acetylsalicylic acid or clopidogrel); DAPT: dual antiplatelet therapy (acetylsalicylic acid + clopidogrel); TIA: transient ischemic attack; AMI: acute myocardial infarction; PCI-S: percutaneous coronary intervention with stent; CABG: coronary artery bypass graft; LVEF: left ventricular ejection fraction; eGFR: estimated glomerular filtration rate; MDRD: Modification of Diet in Renal Disease Study equation; AF: atrial fibrillation; VTE: venous thromboembolism; BMS: bare metal stent; DES: drug-eluting stent; NSTE-ACS: non-ST elevation acute coronary syndrome; STEMI: ST-elevation myocardial infarction.
Age(years)	73 ± 7.5	72 ± 7.5	73 ± 8	77 ± 5	0.045
Male gender	44 (45%)	22 (46%)	12 (39%)	10 (53%)	0.62
Hypertension	76 (77.5%)	36 (75%)	27 (87%)	13 (68%)	0.257
Diabetes	34 (35%)	18 (37.5%)	10 (32%)	6 (31.5%)	0.848
Hypercholesterolemia	54 (55%)	27 (56%)	18 (57%)	9 (47%)	0.742
Current smoking	16 (16.5%)	6 (12.5%)	6 (19.3%)	4 (21%)	0.596
Body mass index	27.7 ± 2	27 ± 2	28 ± 2	29 ± 2	0.006
Previous TIA/stroke	13 (13.2%)	10 (20.8%)	2 (6.45%)	1 (5.2%)	0.095
Previous AMI	24 (24.5%)	12 (25%)	6 (19.3%)	6 (31.5%)	0.617
Previous PCI-S/CABG	34 (34.6%)	17 (35%)	10 (32%)	7 (37%)	0.936
Previous major bleeding	4 (4%)	0	2 (6.45%)	2 (10.5%)	0.125
Chronic heart failure	15 (15.3%)	12 (25%)	3 (9.6%)	0	0.022
Chronic kidney disease	28 (28.5%)	13 (27%)	8 (26%)	7 (37%)	0.668
Anemia	12 (11.2%)	1 (2%)	5 (16%)	6 (31.5%)	0.003
LVEF	50 ± 5	50.7 ± 4.7	49.8 ± 6	50 ± 5	0.738
eGFR(MDRD)	68 ± 15.6	72 ± 14	64 ± 14	66 ± 11.5	0.068
AF	90 (92%)	48 (100%)	23 (74%)	19 (100%)	0.0001
Indication for prophylaxis of cardioembolism or venous thromboembolism
AF	74 (75.5%)	32 (85.4%)	28 (90%)	14 (73.6%)	0,056
Previous VTE/cardiac embolism	3 (3.06%)	3 (6.25%)	0	0	0.199
Dilated cardiomyopathy without AF	1 (1.02%)	0	0	1 (5%)	0.335
Mechanical valve with or without AF	20 (20.4%)	13 (27%)	3 (25.8%)	4 (15.8%)	0.172
Indication for PCI -S requiring antiaggregant agents for a period of 1 month (BMS) or 9 - 12 months (DES)
Stable exertional angina	30 (30.6%)	12 (25%)	12 (38.7%)	6 (31.6%)	0.432
NSTE-ACS	49 (50%)	23 (48%)	13 (42%)	13 (68.4%)	0.176
Acute STEMI	19 (19.3%)	13 (21%)	6 (19.3%)	0	0.043

Table 3. Baseline Characteristics

Total (n = 98)

TT (n = 48)

DT (n = 31)

DAPT (n = 19)

P-value

Data are reported as absolute number (percentage) or mean ± standard deviation. TT: triple therapy (warfarin + acetylsalicylic acid and clopidogrel); DT: dual therapy (warfarin + acetylsalicylic acid or clopidogrel); DAPT: dual antiplatelet therapy (acetylsalicylic acid + clopidogrel); TIA: transient ischemic attack; AMI: acute myocardial infarction; PCI-S: percutaneous coronary intervention with stent; CABG: coronary artery bypass graft; LVEF: left ventricular ejection fraction; eGFR: estimated glomerular filtration rate; MDRD: Modification of Diet in Renal Disease Study equation; AF: atrial fibrillation; VTE: venous thromboembolism; BMS: bare metal stent; DES: drug-eluting stent; NSTE-ACS: non-ST elevation acute coronary syndrome; STEMI: ST-elevation myocardial infarction.

Age(years)

73 ± 7.5

72 ± 7.5

73 ± 8

77 ± 5

0.045

Male gender

44 (45%)

22 (46%)

12 (39%)

10 (53%)

0.62

Hypertension

76 (77.5%)

36 (75%)

27 (87%)

13 (68%)

0.257

Diabetes

34 (35%)

18 (37.5%)

10 (32%)

6 (31.5%)

0.848

Hypercholesterolemia

54 (55%)

27 (56%)

18 (57%)

9 (47%)

0.742

Current smoking

16 (16.5%)

6 (12.5%)

6 (19.3%)

4 (21%)

0.596

Body mass index

27.7 ± 2

27 ± 2

28 ± 2

29 ± 2

0.006

Previous TIA/stroke

13 (13.2%)

10 (20.8%)

2 (6.45%)

1 (5.2%)

0.095

Previous AMI

24 (24.5%)

12 (25%)

6 (19.3%)

6 (31.5%)

0.617

Previous PCI-S/CABG

34 (34.6%)

17 (35%)

10 (32%)

7 (37%)

0.936

Previous major bleeding

4 (4%)

2 (6.45%)

2 (10.5%)

0.125

Chronic heart failure

15 (15.3%)

12 (25%)

3 (9.6%)

0.022

Chronic kidney disease

28 (28.5%)

13 (27%)

8 (26%)

7 (37%)

0.668

Anemia

12 (11.2%)

1 (2%)

5 (16%)

6 (31.5%)

0.003

LVEF

50 ± 5

50.7 ± 4.7

49.8 ± 6

50 ± 5

0.738

eGFR(MDRD)

68 ± 15.6

72 ± 14

64 ± 14

66 ± 11.5

0.068

90 (92%)

48 (100%)

23 (74%)

19 (100%)

0.0001

Indication for prophylaxis of cardioembolism or venous thromboembolism

74 (75.5%)

32 (85.4%)

28 (90%)

14 (73.6%)

0,056

Previous VTE/cardiac embolism

3 (3.06%)

3 (6.25%)

0.199

Dilated cardiomyopathy without AF

1 (1.02%)

1 (5%)

0.335

Mechanical valve with or without AF

20 (20.4%)

13 (27%)

3 (25.8%)

4 (15.8%)

0.172

Indication for PCI -S requiring antiaggregant agents for a period of 1 month (BMS) or 9 - 12 months (DES)

Stable exertional angina

30 (30.6%)

12 (25%)

12 (38.7%)

6 (31.6%)

0.432

NSTE-ACS

49 (50%)

23 (48%)

13 (42%)

13 (68.4%)

0.176

Acute STEMI

19 (19.3%)

13 (21%)

6 (19.3%)

0.043

**Table 4.** Incidence of Adverse Events According to Therapeutic Strategy at Discharge, After a Follow-Up of 1-Year
	Total (n = 98)	TT (n = 48)	DT (n = 31)	DAPT (n = 19)	P-value
Data are reported as absolute number (percentage). TT: triple therapy (warfarin + acetylsalicylic acid and clopidogrel); DT: dual therapy (warfarin + acetylsalicylic acid or clopidogrel); DAPT: dual antiplatelet therapy (acetylsalicylic acid + clopidogrel); MACE: major adverse cardiovascular event; ACS: acute coronary syndromes; AMI: acute myocardial infarction; TIA: transient ischemic attack; DVT: deep vein thrombosis; PE: pulmonary embolism.
Exertional angina	10 (10.2%)	5 (10.4%)	3 (9.6%)	2 (10.5%)	0.993
Total MACE	21 (21.43%)	13 (27.1%)	4 (12.9%)	4 (21%)	0.324
Death from all causes	5 (5.1%)	4 (8.3%)	0	1 (5.3%)	0.258
Total ACS	5 (5.1%)	2 (4.2%)	1 (3.22%)	2 (10.5%)	0.480
Unstable angina	4 (4.08%)	1 (2%)	1 (3.22%)	2 (10.5%)	0.277
Non-fatal AMI	1 (1.02%)	1 (2%)	0	0	0.591
Repeat revascularization	6 (6.12%)	2 (4.2%)	3 (9.6%)	1 (5.3%)	0.599
Stent thrombosis	1 (1.02%)	1 (2%)	0	0	0.591
DVT/PE	3 (3.06)	3 (6.25%)	0	0	0.199
Stroke/TIA	1 (1.02%)	1 (2%)	0	0	0.591
Total bleeding	18 (18.4%)	8 (16.66%)	6 (19.35%)	4 (21%)	0.903
Major	7 (7.1%)	4 (8.3%)	2 (6.45%)	1 (5.3%)	0.893
Minor	11 (11.33%)	4 (8.3%)	4 (12.9%)	3 (15.8%)	0.642

Table 4. Incidence of Adverse Events According to Therapeutic Strategy at Discharge, After a Follow-Up of 1-Year

Total (n = 98)

TT (n = 48)

DT (n = 31)

DAPT (n = 19)

P-value

Data are reported as absolute number (percentage). TT: triple therapy (warfarin + acetylsalicylic acid and clopidogrel); DT: dual therapy (warfarin + acetylsalicylic acid or clopidogrel); DAPT: dual antiplatelet therapy (acetylsalicylic acid + clopidogrel); MACE: major adverse cardiovascular event; ACS: acute coronary syndromes; AMI: acute myocardial infarction; TIA: transient ischemic attack; DVT: deep vein thrombosis; PE: pulmonary embolism.

Exertional angina

10 (10.2%)

5 (10.4%)

3 (9.6%)

2 (10.5%)

0.993

Total MACE

21 (21.43%)

13 (27.1%)

4 (12.9%)

4 (21%)

0.324

Death from all causes

5 (5.1%)

4 (8.3%)

1 (5.3%)

0.258

Total ACS

5 (5.1%)

2 (4.2%)

1 (3.22%)

2 (10.5%)

0.480

Unstable angina

4 (4.08%)

1 (2%)

1 (3.22%)

2 (10.5%)

0.277

Non-fatal AMI

1 (1.02%)

1 (2%)

0.591

Repeat revascularization

6 (6.12%)

2 (4.2%)

3 (9.6%)

1 (5.3%)

0.599

Stent thrombosis

1 (1.02%)

1 (2%)

0.591

DVT/PE

3 (3.06)

3 (6.25%)

0.199

Stroke/TIA

1 (1.02%)

1 (2%)

0.591

Total bleeding

18 (18.4%)

8 (16.66%)

6 (19.35%)

4 (21%)

0.903

Major

7 (7.1%)

4 (8.3%)

2 (6.45%)

1 (5.3%)

0.893

Minor

11 (11.33%)

4 (8.3%)

4 (12.9%)

3 (15.8%)

0.642

**Table 5.** Sites of Bleeding Found During 1-Year Follow-Up
	Total no. of pts (n = 98)	TT (n = 48)	DT (n = 31)	DAPT (n = 19)	P-value
Data are reported as number (percentage). pts: patients; TT: triple therapy (warfarin + acid acetylsalicylic acid and clopidogrel); DT: dual therapy (warfarin + acid acetylsalicylic or clopidogrel); DAPT: dual antiplatelet therapy (acetylsalicylic acid + clopidogrel).
Bleeding events (major and minor)	18 (18.4%)	8 (16.66%)	6 (19.35%)	4 (21%)	0.903
Major bleeding events
Total	7 (7.1%)	4 (8.3%)	2 (6.45%)	1 (5.2%)	0.893
Intracranial	2 (2.04%)	1 (2.1%)	1 (3.2%)	0	0.735
Gastrointestinal	2 (2.04%)	1 (2.1%)	1 (3.2%)	0	0.735
Genitourinary	2 (2.04%)	1 (2.1%)	0	1 (5.2%)	0.442
Other (iliopsoas hematoma)	1 (1.02%)	1 (2.1%)	0	0	0.591
Minor bleeding events
Total	11 (11.33%)	4 (8.3%)	4 (12.9%)	3 (15.8%)	0.642
Nose	7 (7.1%)	4 (8.3%)	3 (9.6%)	0	0.394
Genitourinary	4 (4.1%)	0	1 (3.2%)	3 (15.8%)	0.013
Relapses of minor bleeding
Minor bleeding events > 1 in the same patient	8 (8.16%)	5 (10.4)	2 (6.45%)	1 (5.26%)	0.719

Table 5. Sites of Bleeding Found During 1-Year Follow-Up

Total no. of pts (n = 98)

TT (n = 48)

DT (n = 31)

DAPT (n = 19)

P-value

Data are reported as number (percentage). pts: patients; TT: triple therapy (warfarin + acid acetylsalicylic acid and clopidogrel); DT: dual therapy (warfarin + acid acetylsalicylic or clopidogrel); DAPT: dual antiplatelet therapy (acetylsalicylic acid + clopidogrel).

Bleeding events (major and minor)

18 (18.4%)

8 (16.66%)

6 (19.35%)

4 (21%)

0.903

Major bleeding events

Total

7 (7.1%)

4 (8.3%)

2 (6.45%)

1 (5.2%)

0.893

Intracranial

2 (2.04%)

1 (2.1%)

1 (3.2%)

0.735

Gastrointestinal

2 (2.04%)

1 (2.1%)

1 (3.2%)

0.735

Genitourinary

2 (2.04%)

1 (2.1%)

1 (5.2%)

0.442

Other (iliopsoas hematoma)

1 (1.02%)

1 (2.1%)

0.591

Minor bleeding events

Total

11 (11.33%)

4 (8.3%)

4 (12.9%)

3 (15.8%)

0.642

Nose

7 (7.1%)

4 (8.3%)

3 (9.6%)

0.394

Genitourinary

4 (4.1%)

1 (3.2%)

3 (15.8%)

0.013

Relapses of minor bleeding

Minor bleeding events > 1 in the same patient

8 (8.16%)

5 (10.4)

2 (6.45%)

1 (5.26%)

0.719

**Table 6.** Frequency of the Bleeding Events Within the Two AF Subsets Enrolled in the Study: AF Pre-Existing With Respect to PCI-S (78 Patients) or Arisen After PCI-S (20 Patients)
	AF already present before the interventional procedure of coronary stenting (no. 78 patients)	AF arisen during the year following the interventional procedure of coronary stenting (no. 20 patients)	P-value (Chi-square test)
AF: atrial fibrillation; PCI-S: percutaneous coronary intervention with stent implantation.
Bleeding events	14	4	0.9106

Table 6. Frequency of the Bleeding Events Within the Two AF Subsets Enrolled in the Study: AF Pre-Existing With Respect to PCI-S (78 Patients) or Arisen After PCI-S (20 Patients)

AF already present before the interventional procedure of coronary stenting (no. 78 patients)

AF arisen during the year following the interventional procedure of coronary stenting (no. 20 patients)

P-value (Chi-square test)

AF: atrial fibrillation; PCI-S: percutaneous coronary intervention with stent implantation.

Bleeding events

0.9106