This document summarizes a webinar on stroke prevention in patients with atrial fibrillation. It reviews the evidence for using novel oral anticoagulants (NOACs), provides a clinical guide on how to use NOACs in practice, and discusses strategies to reduce ischemic and bleeding risks using real-world cases. The document also includes a quiz on the clinical use of NOACs and summarizes key advantages of NOACs over warfarin. Real-world cases demonstrate the impact of NOAC introduction on optimizing anticoagulation and reducing strokes in atrial fibrillation patients.

1. STROKE PREVENTION IN PATIENTS WITH ATRIAL FIBRILATION
Ricardo Fontes-Carvalho
MD, PhD, FESC, FACC
Email: fontes.carvalho@gmail.com
@RFontesCarvalho
Cardiologist, Department of Cardiology, Centro Hospitalar Gaia, Portugal
Professor Faculty of Medicine University of Porto

2. WEBINAR SUMMARY
1. ARE NOACS EVIDENCE BASED?
- REVIEWING THE EVIDENCE ABOUT THE USE OF NOACS;
IMPLICATIONS IN CLINICAL GUIDELINES
2. CLINICAL GUIDE ON HOW TO USE NOACs IN CLINICAL PRACTICE
3. STRATEGIES TO REDUCE ISCHEMIC AND BLEEDING RISKS WITH REAL
WORLD CLINICAL CASES

3. WHAT IS THE THE CLINICAL REALITY IN MY COUNTRY REGARDING THE PRESCRIPTION OF NOACS IN PATIENTS
WITH ATRIAL FIBRILLATION?
1. I STILL USE WARFARIN IN MOST OF MY PATIENTS WITH ATRIAL FIBRILLATION
2. I USE NOACS IN MOST OF MY PATIENTS WITH ATRIAL FIBRILLATION
3. I USE NOACS ONLY IN PATIENTS WHICH ARE NOT WELL CONTROLED WITH WARFARIN
4. I DON’T START ANTICOAGULATION – I SEND MY PATIENTS TO CARDIOLOGY OR OTHER HOSPITAL SPECIALTY
QUIZZ

4. ADVANTAGES OF NOACS IN CLINICAL PRACTICE
R. Fontes-Carvalho 2015 J Am Coll Cardiol 2012; 59:1413–25
RAPID ONSET
(~2h)
NOACS ARE MORE “CONFORTABLE” BOTH FOR THE PATIENT AND FOR THE DOCTOR
SHORT-DURATION OF
EFFECT
(REVERSIBILITY)
FEW INTERACTIONS
PREDICTABLE
EFFECT
(NO MONITORING)

5. MAIN INDICATIONS FOR THE USE OF NOACS IN CLINICAL PRACTICE
VENOUS THROMBOSIS PULMONARY EMBOLISM ATRIAL FIBRILATION

6. NEW INDICATIONS FOR THE USE OF NOACS: UNSUCESSFULL STORIES
CRYPTOGENIC STROKE HEART FAILURE REDUCED
EJECTION FRACTION
MECHANICAL PROTHESIS

7. NEW INDICATIONS FOR THE USE OF NOACS: SUCESSFULL STORIES
RIVAROXABAN 2.5 MG BID IN PATIENTS WITH CHRONIC
CORONARY ARTERY DISEASE
N Engl J Med 2017; 377:1319-1330

8. IN ATRIAL FIBRILATION NOACS ARE EVIDENCE-BASED – DATA FROM SEVERAL LARGE SCALE CLINICAL TRIALS
RELY
N= 18.113 ROCKET AF
N= 14.264
ARISTOTLE
N= 18.201
ENGAGE-AF
N= 21.105

9. HETEROGENEITY IN THE POPULATION INCLUDED IN CLINICAL TRIALS
RE-LY
(Dabigatran)1
ROCKET-AF
(Rivaroxaban)2
ARISTOTLE
(Apixaban)3
ENGAGE AF-TIMI 48
(Edoxaban)4
# enrolled 18,113 14,264 18,201 21,105
Age mean, yrs
≥75 yrs
≥80 yrs
72 ± 9
n/a
n/a
73 (65–78)
25% aged ≥78
70 (63–76)
31%
n/a
72 (64–77)
40%
n/a
Female 36% 40% 35% 38%
CHADS2 score, mean
Score 0–1
Score 2
Score ≤3
Score ≥3
Score 4–6
2.1
32%
35%
n/a
33%
n/a
3.5
0%
13%
57%#
87%#
44%#
2.1
34%
36%
n/a
30%
n/a
2.8
0%
n/a
77%
n/a
23%
#scores were 2–3 y 4–6 in ROCKET-AF.
1. Connolly et al. N Engl J Med 2009;361:1139–1151; 2. Patel et al. N Engl J Med 2011;365:883–891;
3. Granger et al. N Engl J Med 2011;365:981–992; 4. Giugliano et al. N Engl J Med 2013;369:2093–2104
RE-LY
(Dabigatran)
ROCKET-AF
(Rivaroxaban)
ARISTOTLE
(Apixaban)
ENGAGE AF
(Edoxaban)
Median Follow-Up, years 2.0 1.9 1.8 2.8
Median TTR 66 58 66 68
Lost to Follow-Up, N 20 32 90 1

10. META-ANALYSIS OF 4 CLINICAL TRIALS: NOACS VERSUS WARFARIN IN PATIENTS WITH AF
ê 19% STROKE AND SYSTEMIC EMBOLISM
ê 52% INTRACRANIAL BLEEDING
ê 10% ALL-CAUSE MORTALITY
Ruff et al. Lancet. 2014;383(9921):955-62

11. META-ANALYSIS OF 4 CLINICAL TRIALS: NOACS VERSUS WARFARIN IN PATIENTS WITH AF
MAJOR BLEEDING
Ruff et al. Lancet. 2014;383(9921):955-62

12. DATA FROM “REAL WORLD” (OBSERVATIONAL) – EFICACCY AND SAFETY OF NOACS IN ATRIAL FIBRILLATION

13. IN ATRIAL FIBRILLATION, NOACS IS AN EXAMPLE OF EVIDENCE-BASED MEDICINE

14. IMPLICATIONS FOR SCIENTIFIC GUIDELINES AND FOR CLINICAL PRACTICE?

15. IN ATRIAL FIBRILATION GUIDELINES, NOACS ARE NOW THE PREFERED ANTI-TROMBOTIC THERAPY
ESC Guidelines; Eur Heart J. 2016; 37: 2893-2962
#1

16. IN ATRIAL FIBRILATION GUIDELINES, NOACS ARE NOW THE PREFERED ANTI-TROMBOTIC THERAPY
ESC Guidelines; Eur Heart J. 2016; 37: 2893-2962

17. THE INTRODUCTION OF NOACS IN CLINICAL PRACTICE IMPROVED OUR UNDERSTANDING OF THE DISEASE
EXAMPLE #1:
NO ROLE FOR ASPIRIN FOR
STROKE PREVENTION IN AF
EXAMPLE #2:
REDUCE THE DURATION OF TRIPLE
THERAPY IN PATIENTS WITH AF+PCI

18. EXAMPLE #1: NO ROLE FOR ASPIRIN IN THROMBOEMBOLIC PROTECTION IN PATIENTS WITH ATRIAL FIBRILLATION
STROKE/SYSTEMICEMBOLISM
MONTHS
AT RISK
Apixaban 2808 2758 2566 2125 1522 615
AAS 2791 2716 2530 2112 1543 628
Apixaban
ASPIRIN
0,00
0,01
0,02
0,03
0,04
0,05
0 3 6 9 12 18
RR 0.45 (IC a 95%: 0.32-0.62)
(p < 0.001)
Connolly et al. N Engl J Med 2011;364:806-17.
-55%
AVERROES CLINICAL TRIAL

19. EXAMPLE #1: NO ROLE FOR ASPIRIN IN THROMBOEMBOLIC PROTECTION IN PATIENTS WITH ATRIAL FIBRILLATION
Connolly et al. N Engl J Med 2011;364:806-17.
AVERROES CLINICAL TRIAL
N.º em risco
Apixabano 2808 2759 2566 2120 1521 622
AAS 2791 2738 2557 2140 1571 642
0 3 6 9 12 18
0,000
0,005
0,010
0,015
0,020
MAJORBLEEDING
Meses
Apixaban AAS
RR 1.13 (IC a 95%: 0.74-1.75);
p = 0.57

20. EXAMPLE #1: NO ROLE FOR ASPIRIN IN THROMBOEMBOLIC PROTECTION IN PATIENTS WITH ATRIAL FIBRILLATION
Lau Y and Lip G. EuroPace 2014; 16: 619-20

21. EXAMPLE #1: NO ROLE FOR ASPIRIN IN THROMBOEMBOLIC PROTECTION IN PATIENTS WITH ATRIAL FIBRILLATION
2
1

22. EXAMPLE #2: REDUCE THE DURATION OF TRIPLE ANTI-THROMBOTIC THERAPY
≠
STENT
ATRIAL FIBRILLATION
TRIPLE ANTI-THROMBOTIC THERAPY ????
ASPIRIN
+
CLOPIDOGREL
+
WARFARIN

23. EXAMPLE #2: REDUCE THE DURATION OF TRIPLE ANTI-THROMBOTIC THERAPY
N=2.124
N=4.614
N=2.725
AUGUSTUS CLINICAL TRIAL

24. EXAMPLE #2: REDUCE THE DURATION OF TRIPLE ANTI-THROMBOTIC THERAPY
N Engl J Med 2019; 380:1509-1524

25. NEW RECOMMENDATIONS FOR ANTICOAGULATION IN PATIENTS UNDERGOING CORONARY INTERVENTION

26. TH IMPACT OF THE INTRODUCTION OF NOACS IN CLINICAL PRACTICE

27. HOW WAS THE USE OF ANTI-TROMBOTIC THERAPY IN ATRIAL FIBRILLATION ~5 YEARS AGO
Eur Heart J (2016) 37 (38): 2882-2889.
~45% ARE “UNDERTREATED”
~70%
ARE
“OVERTREATED”

28. THE INTRODUCTION OF NOACS ALLOW THAT MORE PATIENTS WITH AF RECEIVED ANTITROMBOTIC THERAPY
54.7% 73.9%
Apenteg et al. BMJ Open 2018; 8: e018905
“DEMOCRATIZATION” IN THE USE OF
ANTI-THROMBOTIC THERAPY IN AF

29. THE INTRODUCTION OF NOACS ALLOW THAT MORE PATIENTS COULD BE TREATED WITH A REDUCTION IN STROKE RATES

30. INCREASE IN THE USE OF ANTICOAGULATION AND ITS ASSOCIATED DECREASE IN STROKE RATE
European Heart Journal (2018) 39, 2975–2983
~4000 STROKES ARE
PREVENTED EACH
YEAR IN UK
STROKE RATE
NOAC USE
ASPIRIN USE

31. WEBINAR SUMMARY
1. ARE NOACS EVIDENCE BASED?
- REVIEWING THE EVIDENCE BEHIND THE USE OF NOACS AND ITS
IMPLICATIONS IN CLINICAL GUIDELINES
2. CLINICAL GUIDE ON HOW TO USE NOACs IN CLINICAL PRACTICE
3. STRATEGIES TO REDUCE ISCHEMIC AND BLEEDING RISKS WITH REAL
WORLD CLINICAL CASES

32. PRACTICAL GUIDE ABOUT THE USE OF NOACS IN CLINICAL PRACTICE

33. CLINICAL CASE #1

34. • 89 years, male, retired, living alone
• CV RISK FACTORS: Hypertension
• PAST MEDICAL HYSTORY:
• Benign prostatic hyperplasia
• Coxofemoral arthrosis (walking stick)
• REGULAR / ROUTINE APPOINTMENT:
• No new symptoms
• Arrythmic pulse; heart rate 70 ppm
• Previous Echocardiogram (3 months ago): moderate aortic stenosis;
normal systolic function (EF: 65%)
CLINICAL CASE #1

35. CLINICAL CASE #1 - ELECTROCARDIOGRAM

36. CLINICAL CASE #1 - ELECTROCARDIOGRAM
NO P WAVES; IRREGULAR R-R INTERVAL
ATRIAL FIBRILATION
VENTRICULAR PREMATURE
BEAT

37. TAKE HOME MESSAGE #1 – PERFORM AF SCREENING BY PULSE TAKING IN PATIENTS > 65 YEARS
Eur Heart J. 2016 Aug 27 [Epub ahead of print]

38. “Ciência e Caridade”
Pablo Picasso, 1897
Museu Picasso, Barcelona

39. WHAT IS THE RECOMMENDED ANTI-THROMBOTIC TREATMENT IN THIS PATIENT?
1. NOAC SHOULD BE AVOIDED BECAUSE THIS PATIENT HAS “VALVULAR”
ATRIAL FIBRILLATION
2. ANTICOAGULATION SHOULD BE AVOIDED BECAUSE THE PATIENT IS
ELDERLY AND HAS A SIGNIFICANT RISK OF FALLS
3. ASPIRIN IS RECOMMENDED
4. NOAC IS RECOMMENDED
5. WARFARIN WOULD BE MY FIRST OPTION
CLINICAL CASE #1 - TELEVOTER

40. FIRST STEP: EVALUATE THE CHADSVASC SCORE AND START ANTICOAGULANT THERAPY IF SCORE >1
C
H
A2
D
S2
“Congestive Heart Failure”
“Hypertension”
“Age” (> 75 years)
“Diabetes”
“Stroke” (AVC)
V
A
S
(EF < 40 % ou recente HF hospitalization )
2 POINTS
2 POINTS
“Vascular Disease”
“Age” (> 65 years)
“Sex” (woman)
3 POINTS

41. WHAT IS “VALVULAR” ATRIAL FIBRILLATION?
MARM-AF
“MECHANICAL AND RHEUMATIC MITRAL VALVULAR AF”
Eur Heart J. 2014 Dec 14;35(47):3328-35

42. European Heart Journal (2018) 00, 1–64
NOACS ARE CONTRA-INDICATED ONLY IN PATIENTS
WITH MECHANICAL PROTHESIS AND MITRAL STENOSIS

43. TAKE HOME MESSAGE #2 – AGE, “RISK OF FALLS” AND HASBLED SCORE ARE NOT CONTRAINDICATIONS
FOR ANTICOAGULANT THERAPY IN ATRIAL FIBRILLATION
1) AGE, PER SE, IS NOT A CONTRAINDICATION FOR
ANTICOAGULATION
2) ARBITRARY “RISK OF FALLS” IS NOT A
CONTRAINDICATION FOR ANTICOAGULATION IN AF
3) HASBLED SCORE IS NOT A CONTRAINDICATION
FOR ANTICOAGULATION IN AF
DE Singer et. al. Ann. Intern. Med. 2009;151:297
Camm et al. Eur Heart Journal 2010; 31: 2369-2429
Friberg et al. Circulation 2012;125:2298-307

44. TAKE HOME MESSAGE #3 – IN PATIENTS WITH HIGHER RISK PREFER NOAC OVER WARFARIN

45. • The patient started NOAC (apixaban 5 mg , bid)
• After 8 months of therapy the patient has hypochromic and microcytic
anemia (Hb 11.0 g/dL)
ENDOSCOPY AND COLONOSCOPY
CLINICAL CASE #1 – PATIENT FOLLOW-UP

46. WHAT IS THE RECOMENDATION ABOUT ANTITROMBOTIC TREATMENT BEFORE THE PROCEDURE?
1. THE PATIENT SHOULD STOP NOAC IMMEDIATLY
2. THE PATIENT SHOULD STOP NOAC 5 DAYS BEFORE THE ENDOSCOPY AND STRAT BRIDGING THERAPY WITH ENOXAPARIN
3. THE PATIENT SHOULD STOP NOAC 3 DAYS BEFORE THE PROCEDURE
4. THE PATIENT SHOULD STOP NOAC 1 DAY BEFORE THE PROCEDURE
5. NOAC SHOULD BE CONTINUED
CLINICAL CASE #1 – FOLLOW-UP

47. European Heart Journal (2018) 00, 1–64
RECOMMENDATIONS ABOUT THERAPY INTERRUPTION BEFORE SURGICAL PROCEDURES
INTERVENTIONS WITH MINOR BLEEDING RISK
NO NEED TO INTERRUPT ANTI-THROMBOTIC
THERAPY

48. European Heart Journal (2018) 00, 1–64
RECOMMENDATIONS ABOUT THERAPY INTERRUPTION BEFORE SURGICAL PROCEDURES
INTERVENTIONS WITH HIGH BLEEDING RISK
INTERRUPT 2 DAYS
INTERVENTIONS WITH LOW BLEEDING RISK
INTERRUPT 1 DAY

49. European Heart Journal (2018) 00, 1–64
RECOMMENDATIONS ABOUT THERAPY INTERRUPTION BEFORE SURGICAL PROCEDURES

50. European Heart Journal (2018) 00, 1–64
RECOMMENDATIONS ABOUT THERAPY INTERRUPTION BEFORE SURGICAL PROCEDURES
IF THE PATIENT HAS RENAL DYSFUNCTION, MORE TIME OF INTERRUPTION IS ADVISED
IF TREATED WITH DABIGATRAN

51. European Heart Journal (2018) 00, 1–64
HOW CAN I REDUCE THE RISK OF BLEEDING?

52. European Heart Journal (2018) 00, 1–64
1. CALCULATE CREATININ CLEARANCE AND AJUST THE NOAC DOSE (IF NEEDED)
2. AVOID SIMULTANEOUS USE OF ANTI-PLATELET THERAPY, NSAIDS, CORTICOSTEROID THERAPY
AND ALCHOOL
3. CONTROL BLOOD PRESSURE
4. AVOID SIGNIFICANT OSCILATIONS IN INR AND CONSIDER SWITCHING TO WARFARIN TO NOAC
5. IN CASE OF HIGH BLEEDING RISK, CONSIDER PROPHYLATIC PROTON PUMP INHIBITOR
MEASURES THAT CAN REDUCE THE RISK OF BLEEDING

53. CLINICAL CASE #2
Mr Burns

54. • 82 years old, male, businessman (still working)
• CV RISK FACTORS: Hypertension, type 2 diabetes
• PAST MEDICAL HYSTORY:
• Peripheral artery disease (claudication)
• Diabetic retinopathy
• CURRENT MEDICAL HISTORY:
• Dyspnea with moderate exercise in tha last 4 weeks
• MEDICATION: Aspirin 100 mg, atorvastatin 40 mg, valsartan 160 +
amlodipine 5 mg, Pentoxifilin 400 mg, Insulin
CLINICAL CASE #1

55. CLINICAL CASE #2 - ELECTROCARDIOGRAM

56. “SAWTOOTH” PATTERN
ATRIAL FLUTTER
CLINICAL CASE #2 - ELECTROCARDIOGRAM

57. • Moderate dilatation of left atrium (45 ml/m2)
• Mild left ventricular hypertrophy
• Normal systolic function (EF: 58%)
• Hemoglobin: 14 g/dL
• Glucose- 203 mg/dL Hb A1c- 8.6%
• Creatinine: 1.3 mg/dL
• Creatinine Clearance (Cockcroft-Gault Equation): 39 ml/min
BLOOD TESTS
CLINICAL CASE #2 – ADITIONAL INFORMATION
ECHOCARDIOGRAM

58. WHAT IS THE RECOMENDATION ABOUT ANTITROMBOTIC TREATMENT IN THIS PATIENT?
1. NOAC SHOULD NOT BE USED BECAUSE THE PATIENT HAS RENAL DYSFUNCTION
2. NOAC IN STANDARD DOSE
3. PREFER NOAC BUT USE THE “LOW DOSE”
4. PREFER WARFARIN OR OTHER VITAMIN K ANTAGONIST
5. PREFER ASPIRIN
CLINICAL CASE #2 – QUIZZ

59. PRACTICAL GUIDE ABOUT THE USE OF NOACS ACCORDING TO CREATININ CLEARANCE

60. RENAL EXCRETION OF DIFFERENT NOACS

61. RECOMMENDATIONS FOR THE EVALUATION OF RENAL FUNCTION IN PATIENTS WITH NOAC THERAPY
• IN PATIENTS TREATED WITH NOACs EVALUATE CREATININ CLEARANCE WITH THE COCKCROFT-GAULT FORMULA
• RECOMENTATIONS FOR RENAL FUNCTION MONITORING:
• ANNUALLY: if renal function is normal
• If renal renal function is < 60 ml/min, recomended monitoring of renal function can be calculated by
dividing creatinin clearance by 10 (example):
• If Creatinin Clearance 60 ml/min: every 6 months
• If Creatinin Clearance 40 ml/min: every 4 months
• If Creatinin Clearance 30 ml/min: every 3 months
European Heart Journal (2018) 00, 1–64

62. DABIGATRAN 150 MG,
2 X / DAY
APIXABAN 5 MG,
2 X / DAY
> 80 years
Diltiazem
Cl. Creat. 30-45 ml/min
High bleeding risk
Two of the following criteria:
- Creat. > 1.5mg/dL
- > 80 years
- weight < 60 Kg
Cl Creat. 15-29 ml/min
DABIGATRAN 110 MG, twice/day
APIXABAN 2.5 MG, twice/day
RIVAROXABAN 20MG, 1 X /DAY
Cl. Creat. 15-49 ml/min
RIVAROXABAN 15 MG, once/day
EDOXABAN 60MG, 1 X / DAY EDOXABAN 30 MG, once/day
Cl. Creat. 15-49 ml/min
Weight < 60 kg
Ciclosporin, cetoconazol, eritromicin

63. Steinberg et al. J Am Coll Cardiol 2016;68:2597–604
THE IMPORTANCE OF USING THE CORRECT DOSE OF NOAC
• 5738 PATIENTS FROM ORBIT-AF II
• NOAC DOSING
• 87% CORRECT DOSE
• 9.4% UNDERDOSING
• 3.4% OVERDOSING

64. 2
1
Eur Heart J. 2016 Aug 27 [Epub ahead of print]
AVOID THE COMBINATION OF ANTI-PLATELET + ANTICOAGULANT THERAPY
STOP ASPIRIN
IN THIS PATIENT

65. CLINICAL CASE #3
NED FLANDERS

66. • 45 years, male, engineer
• CV RISK FACTORS: none
• PAST MEDICAL HYSTORY: none
• Palpitations with one-hour duration after exercise (running)
CLINICAL CASE #3

67. CLINICAL CASE #3 - ELECTROCARDIOGRAM

68. CLINICAL CASE #3 - ELECTROCARDIOGRAM
ATRIAL FIBRILLATION SYNUS RYTHM
P WAVE
P WAVE

69. WHAT IS THE RECOMMENDED ANTI-TROMBOTIC THERAPY:
1. NO NEED FOR ANTI-THROMBOTIC THERAPY
2. ASPIRIN 100 MG
3. NOAC
4. WARFARIN OR OTHER VITAMIN K ANTAGONIST
CLINICAL CASE #3 – QUIZZ

70. ANTITHROMBOTIC THERAPY SHOULD BE THE SAME IN PATIENTS WITH PAROXYSMAL ATRIAL FIBRILLATION
J Am Coll Cardiol 2007;50:2156–61

71. FIRST STEP: EVALUATE THE CHADSVASC SCORE AND START ANTICOAGULANT THERAPY IF SCORE >1
C
H
A2
D
S2
“Congestive Heart Failure”
“Hypertension”
“Age” (> 75 years)
“Diabetes”
“Stroke” (AVC)
V
A
S
(EF < 40 % ou recente HF hospitalization )
2 POINTS
2 POINTS
“Vascular Disease”
“Age” (> 65 years)
“Sex” (woman)
0 POINTS

72. AF GUIDELINES: IF CHADSVASC SCORE IS 0, NO ANTITHROMBOTIC THERAPY IS NEEDED

73. Eur Heart J. 2016 Aug 27.[Epub ahead of print]
THE RISK OF STROKE IN PATIENTS WITH CHADSVASC = 0 IS VERY LOW

74. FINAL TAKE-HOME MESSAGES

75. PRACTICAL GUIDE ABOUT THE USE OF NOACS IN CLINICAL PRACTICE

76. “Superior doctors prevent the disease.
Mediocre doctors treat the disease before evident.
Inferior doctors treat the full-blown disease”.
Huang Dee Nai-Chang
2600 AC
“THE BEST TREATMENT FOR BLEEDING IS ALSO ITS PREVENTION”
“THE BEST TREATMENT FOR STROKE IS IT’S PREVENTION”

77. STROKE PREVENTION IN PATIENTS WITH ATRIAL FIBRILATION
Ricardo Fontes-Carvalho
MD, PhD, FESC, FACC
Email: fontes.carvalho@gmail.com
@RFontesCarvalho