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. Learning Objectives. Describe the risk assessment of stroke for atrial fibrillation List therapeutic alternatives for stroke prevention - PowerPoint PPT PresentationTRANSCRIPT
Rocking the boat on Rivaroxaban
Manish Khullar, BSc PharmInterior Health Pharmacy Resident
August 15, 2013
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
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
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
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
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
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
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
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
Course in Hospital
• Admitted to investigate shortness of breath and worsening CHF
• Endoscopy identified gastric ulcer
• Transfused with 2 units of blood
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.
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.
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.
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
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 %
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
Goals of Therapy
• Reduce mortality• Reduce morbidity (strokes, hospitalizations)• Prevent adverse events• Improve quality of life
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
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
Therapeutic Alternatives for Atrial Fibrillation
• Aspirin• Aspirin + Clopidogrel• Warfarin• Dabigatran• Rivaroxaban• Apixaban
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?
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
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
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
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
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
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/
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)
√ √
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
Monitoring: Efficacy
• S: Ø dizziness, blurred vision, numbness, paralaysis or weakness, fatigue, shortness of breath
• O: Ø loss of coordination, slurred speech
Monitoring: Safety
• S: Dizziness, fatigue, headache, lethargy, GI upset, abdominal pain,
• O: vitals, Hgb, MCV, INR, AST, ALT, rash, urticaria, bruising
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
Questions…
?