rocking the boat on rivaroxaban

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Rocking the boat on Rivaroxaban Manish Khullar, BSc Pharm Interior Health Pharmacy Resident August 15, 2013

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Rocking the boat on Rivaroxaban. Manish Khullar, BSc Pharm Interior Health Pharmacy Resident August 15, 2013. Learning Objectives. Describe the risk assessment of stroke for atrial fibrillation List therapeutic alternatives for stroke prevention - PowerPoint PPT Presentation

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Page 1: Rocking the boat on  Rivaroxaban

Rocking the boat on Rivaroxaban

Manish Khullar, BSc PharmInterior Health Pharmacy Resident

August 15, 2013

Page 2: Rocking the boat on  Rivaroxaban

Learning Objectives

• Describe the risk assessment of stroke for atrial fibrillation

• List therapeutic alternatives for stroke prevention

• Explain the role of rivaroxaban in patients with atrial fibrillation and aortic valve replacement

Page 3: Rocking the boat on  Rivaroxaban

Our PatientID A 74 year old male admitted to the CTU on August 6th, 2013

CC/HPI Shortness of breath for 3 days that has been getting progressively worseFatigue/weaknessMild non-productive cough

Allergies No known drug allergies

Social History

Lives at home with spouseNo alcoholQuit smoking 40 years ago

Page 4: Rocking the boat on  Rivaroxaban

Anticoagulant history

• Diagnosed with atrial fibrillation this year and placed on warfarin (INR 2-3) 2 months ago

• Was on warfarin for 1 month but did not tolerate side effects (insomnia, headaches, vomiting)

• GP switched him to rivaroxaban last month and has been on it since admission

Page 5: Rocking the boat on  Rivaroxaban

Our PatientPast Medical History Medications Prior to AdmissionCongestive Heart Failure Carvedilol 25 mg po BID

Valsartan 80mg po dailyFurosemide 20mg po daily

Atrial Fibrillation Rivaroxaban 20mg po daily Carvedilol 25mg po BID

Secondary prevention MI Carvedilol 25 mg po BIDValsartan 80mg po dailyAtorvastatin 40mg po daily

AVR (bioprosthetic) Rivaroxaban 20mg po daily

Ventricular tachycardia ICD implant Amiodarone 200mg po daily

Type 2 diabetes Metformin 500mg po TID

Page 6: Rocking the boat on  Rivaroxaban

Our PatientPast Medical History Medications Prior to Admission

Hypertension Carvedilol 25 mg po BIDValsartan 80mg po daily

Secondary Prevention of Stroke Rivaroxaban 20mg po dailyAtorvastatin 40mg po daily

Dyslipidemia Atorvastatin 40mg po daily

CKD Valsartan 80mg po daily

Depression Escitalopram 20mg po daily

Osteoarthritis (left hip) Acetaminophen 1 gram po daily prn

Page 7: Rocking the boat on  Rivaroxaban

Review of SystemsVitals T: 36.7 BP: 94/62 HR: 92 RR: 20 SaO2: 95% RA

CNS GCS X 15, A+O x 3

HEENT Normal

RESP Shortness of breath upon moving Wheezes when laying downDecreased breath sounds left lungØ crackles on right lung Non-productive cough

CVS JVP >3cm ASA, pedal edema, CHADS2: 5

GI Distended abdomen

GU SrCr: 206 (baseline SrCr 156) eGFR: 28

MSK/DERM Pedal edema

ENDO Ø

HEME Hg: 86 MCV: 82.4 Plt: 209 INR: 3.7 WBC: 7.9 Neuts: 6.6

LYTES Na: 131 K: 4.9 Cl: 98

Page 8: Rocking the boat on  Rivaroxaban

Investigations

• Diagnostics:– Chest x-ray (upon admission):• Left sided pleural effusion• Mild right sided pleural effusion

– ECHO: • Pending• Ejection fraction from Jan 2013: 40-45%

– Endoscopy• Pending

Page 9: Rocking the boat on  Rivaroxaban

Current Problems and Medications

CHF Carvedilol 25 mg po BID

Furosemide 60mg po daily

Anemia NoneAcute onchronic renal failure NoneType 2 diabetes Metformin 250mg po TIDAortic valve replacement NoneMI- 2o prevention Atorvastatin 40 mg po daily

Carvedilol 25 mg po BIDAtrial fibrillation Amiodarone 20mg po dailyCKD None Depression Escitalopram 20mg po dailyOsteoarthritis (left hip) Acetaminophen+caffeine+

codeine 2 tablets po HS

Page 10: Rocking the boat on  Rivaroxaban

Course in Hospital

• Admitted to investigate shortness of breath and worsening CHF

• Endoscopy identified gastric ulcer

• Transfused with 2 units of blood

Page 11: Rocking the boat on  Rivaroxaban

List of DRPs1) JF is at risk of stroke secondary to not receiving any anticoagulation therapy

for his atrial fibrillation and would benefit from reassessment of his stroke prophylaxis therapy.

2) JF is at risk of stroke secondary to not receiving antithrombotic therapy with AVR and would benefit from reassessment of his stroke prophylaxis therapy.

3) JF is at risk of death and hospitalizations secondary to receiving too low dose of atorvastatin despite his high risk and would benefit from reassessment from his prophylaxis therapy.

4) JF is at risk of death and hospitalizations secondary to not receiving an ACE inhibitor or ARB for MI prophylaxis and would benefit from reassessment of therapy.

Page 12: Rocking the boat on  Rivaroxaban

List of DRPs5) JF is at risk of death and hospitalizations secondary to not receiving antiplatelet

therapy for post-MI and would benefit from reassessment of therapy.

6) JF is at risk of death and hospitalizations secondary to not receiving an ACE inhibitor or ARB despite having congestive heart failure and would benefit from reassessment of his congestive heart failure therapy.

7) JF is at risk of experiencing adverse effects of metformin secondary to being on metformin despite poor renal function and would benefit from reassessment of his therapy.

8) JF is at an increased risk of bleeding, stroke/death due to unclear efficacy in rivaroxaban in AVR patients and would benefit from reassessment of therapy.

Page 13: Rocking the boat on  Rivaroxaban

DRP Focus• JF is at risk of stroke secondary to not receiving any anticoagulation

therapy for his atrial fibrillation and would benefit from reassessment of his stroke prophylaxis therapy.

• JF is at risk of stroke secondary to not receiving antithrombotic therapy with AVR and would benefit from reassessment of his stroke prophylaxis therapy.

• JF is at an increased risk of bleeding, stroke/death due to unclear efficacy in rivaroxaban in AVR patients and would benefit from reassessment of therapy.

Page 14: Rocking the boat on  Rivaroxaban

Background

• Stroke occurs in atrial fibrillation due to blood stasis in atria leading to clot formation inside the chambers

• Upon cardioversion to NSR, the clot may eject and stroke can occur

Page 15: Rocking the boat on  Rivaroxaban

Assessing Risk of Stroke in Atrial Fibrillation

• Stroke assessment tool: CHADS2

CHADS2 Score Stroke Risk/year

0 1.9%

1 2.8%

2 4%

3 5.9%

4 8.5%

5 12.5%

6 18.2 %

Page 16: Rocking the boat on  Rivaroxaban

Need for Antithrombotics in AVR

• Patients with prosthetic valves are at risk of thromboembolic complications (stroke, valve obstruction and/or regurgitation)

• Risk is higher with mechanical valves than with bioprosthetic valves

• Risk is higher with mitral than aortic prosthetic valves

• Making antithrombotic therapy necessary in these patients

Page 17: Rocking the boat on  Rivaroxaban

Goals of Therapy

• Reduce mortality• Reduce morbidity (strokes, hospitalizations)• Prevent adverse events• Improve quality of life

Page 18: Rocking the boat on  Rivaroxaban

Antithrombotic Alternatives for AVR

• CHEST guidelines:

• “in patients with aortic bioprosthetic valves, who are in sinus rhythm, and have no other indication for VKA therapy, we recommend ASA (50-100mg/d)”

CHEST 2008

Page 19: Rocking the boat on  Rivaroxaban

Antithrombotic Alternatives for AVR

• CHEST guidelines:

– “in patients with bioprosthetic valves who have additional risk factors for thromboembolism, including AF, hypercoaguable state or low ejection fraction, we recommend VKA therapy (target INR 2-3)…low dose aspirin should be considered, particularly in patients with history of atherosclerotic vascular disease. We suggest ASA not be added to long-term VKA therapy in patients with bioprosthetic heart valves who are at particularly high risk of bleeding…”

CHEST 2008

Page 20: Rocking the boat on  Rivaroxaban

Therapeutic Alternatives for Atrial Fibrillation

• Aspirin• Aspirin + Clopidogrel• Warfarin• Dabigatran• Rivaroxaban• Apixaban

Page 21: Rocking the boat on  Rivaroxaban

Clinical Question

• In a 74 year old patient who is at high risk of ischemic stroke secondary to atrial fibrillation and bioprosthetic aortic valve replacement, is rivaroxaban as compared to warfarin, effective at reducing stroke risk without increasing risk of bleeding?

Page 22: Rocking the boat on  Rivaroxaban

Literature ReviewDatabases Pubmed, medline, google scholar Search Terms

Warfarin, atrial fibrillation, rivaroxaban, stroke, aortic valve replacement

Limits a. meta-analysesb. RCTs, english, human

Results 0 trials

Databases Pubmed, medline, google scholar

Search Terms Rivaroxaban, atrial fibrillation, stroke

Limits a. meta-analysesb. RCTs, english, human

Results 1 RCT

Page 23: Rocking the boat on  Rivaroxaban

ROCKET-AFDesign Randomized, multicenter, double blind, double-dummy, non-inferiority

trialPopulation Atrial fibrillation, age > 18, CHADS2 > 2

Excluded patients with prosthetic heart valves

At baseline:(n=14, 264) median age 73 years old, male 60%, 90% with CHADS2 > 2 (mean 3.48), CrCl 67

Prior CVA (~55%), HF (~63%), HTN (~90%), DM (~40%), MI (~16.6%), PVD (~5%), COPD (~11%)

BB (65%), diuretic (60%), ACEI (55%), statin (43%), digitalis (39%), aspirin (38%)

Intervention Rivaroxaban 20mg po daily or 15mg po daily if CrCl 30-49mL/min vs dose-adjusted warfarin (INR 2-3)

Primary Outcome 1. Composite of stroke and systemic embolism 2. Composite of major and clinically relevant nonmajor

bleeding

ROCKET-AF. NEJM 2011;10.1056/NEJMoa1009638

Page 24: Rocking the boat on  Rivaroxaban

Results: Efficacy Rivaroxaban Warfarin Hazard

Ratio (95% CI)

p-value

Patients(n)

Events (n)

Event rate/100 patient years

Patients(n)

Events (n)

Event rate/100

patient years

Rivaroxaban vs warfarin

Noninfe-riority

6958 188 1.7 7004 241 2.2 0.79 (0.66-0.96)

<0.001

ROCKET-AF. NEJM 2011;10.1056/NEJMoa1009638

Page 25: Rocking the boat on  Rivaroxaban

Results: Safety Rivaroxaban

(n=7111)Warfarin (n=7125)

Hazard Ratio (95% CI)

p-value

Event number

Major and nonmajor clinically relevant bleeding

1475 (20.7%)

1449 (20.3%)

1.03 (0.96-1.11)

0.44

Any major bleed 395 (5.6%) 386 (5.4%)

1.04 (0.9-1.20)

0.58

Nonmajor clinically relevant bleeding

1185 (16.7%)

1181 (16.2%)

1.04 (0.96-1.13)

0.35

ROCKET-AF. NEJM 2011;10.1056/NEJMoa1009638

Page 26: Rocking the boat on  Rivaroxaban

Study Limitations

• Methodology:– 1 site violated Good Clinical Practice; when patients excluded,

should have re-analyzed distribution of baseline characteristics

– Did not specify in detail who collected the results (more potential for bias)

• Clinically– patients in this study differs to JF (ie. no prosthetic heart

valve)– patients in the study on warfarin were only in the therapeutic

range 55% of the time

Page 27: Rocking the boat on  Rivaroxaban

Assessment of Therapeutic Alternatives for Atrial Fibrillatrion

http://www.sparctool.com/

No Therapy ASA ASA+Clopidogrel Warfarin Dabigatran Rivaroxaban Apixaban

Efficacy(risk of stroke)

12.6% 9.8%RRR: 22%ARR: 2.8%

7.1%RRR: 44%ARR: 5.5%

4.2%RRR: 66% ARR: 8.4%

110mg: 4.2%RRR: 66%ARR: 8.4%150mg: 2.7%RRR: 79%ARR: 9.9%

4.2%RRR: 66%ARR: 8.4%

3.3%RRR: 74%ARR: 9.3%

Safety (major bleed risk)

0.6% (pop) 1.1% (pop) 3.8% (pop) 3.8% (pop)9.4% (HAS-BLED)

110mg: 3% (pop) 7.5% (HAS-BLED)150mg: 3.8% (pop)9.4% (HAS-BLED)

3.8% (pop)9.4% (HAS-BLED)

2.6% (pop)6.5% (HAS-BLED)

Patient specific factors

- -High stroke risk patient (CHADS2>1)

-Less effective than other agents and same bleed risk as Warfarin

-Patient didn’t tolerate warfarin -Patient doesn’t want to go for INR testing

-Indicated for A. fib-Shown to be harmful in those with mechanical valves-Renal failure -Twice daily -Expensive

-Indicated for A.fib-No evidence/studies and harm suggested with similar agent-Once daily-Expensive

-Indicated for A. fib-Twice daily-Expensive

http://www.sparctool.com/

Page 28: Rocking the boat on  Rivaroxaban

Assessment of Therapeutic Alternatives for AVR

ASA ASA + Clopidogrel Warfarin Dabigatran Rivaroxaban Apixaban

Stroke Reduction

√ - √ -Studied in mechanica

l valves

- -

Bleed Risk √ √ √ √Increased harm (RE-

ALIGN)

√ √

Page 29: Rocking the boat on  Rivaroxaban

Therapeutic Recommendation and Justification

• Do not restart rivaroxaban for stroke prophylaxis

• Suggest starting warfarin at a low dose such as 3mg po daily to target INR 2-3 once clinically stable and active bleeding ruled out

Page 30: Rocking the boat on  Rivaroxaban

Monitoring: Efficacy

• S: Ø dizziness, blurred vision, numbness, paralaysis or weakness, fatigue, shortness of breath

• O: Ø loss of coordination, slurred speech

Page 31: Rocking the boat on  Rivaroxaban

Monitoring: Safety

• S: Dizziness, fatigue, headache, lethargy, GI upset, abdominal pain,

• O: vitals, Hgb, MCV, INR, AST, ALT, rash, urticaria, bruising

Page 32: Rocking the boat on  Rivaroxaban

Follow-up

• August 12:• Discussed pros and cons of warfarin therapy with

patient

• After learning more about the drug and importance of INR monitoring and interactions, the patient and his family were amenable to trying warfarin again

• Initiated warfarin 3mg po daily with daily INRs

Page 33: Rocking the boat on  Rivaroxaban

Questions…

?