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MEDICATION UTILISATION
EVALUATION (MUE) ON
RIVAROXABAN USE IN
KHOO TECK PUAT HOSPITAL (KTPH)
Jeremy Chia
Pharmacist
Event
10 DecName
2016
Date
Scope
2
A.
B.
C.
D.
E.
F.
Introduction to MUE and Rivaroxaban
Objectives
Methodology
Results and Discussion
Limitations
Conclusion
A. Medication Utilisation Evaluation (MUE)
3

What?1
 An
evaluation of the use of medications in a healthcare
setting

Why?1
 Determine
appropriateness of use of a particular
medication in a healthcare setting
 Review outcomes for safety and effectiveness of a
particular medication
 Ultimately: to improve patient’s quality of life
1American
Society of Health-System Pharmacists. ASHP guidelines on medication-use evaluation. Am J Health-Syst Pharm.
1996; 53:1953–5.
MUE For Rivaroxaban
4


Relatively new drug compared to warfarin
Less need to monitor, less drug-drug or drug-food
interactions
But…
 No reversal agents (unlike warfarin)
 Expensive – may lead to non-compliance
 May be used inappropriately – not according to
guidelines
 Need to evaluate the use of this newer drug to ensure
adequate usage and monitoring
B. Objectives
5

Conduct MUE for Rivaroxaban 15mg and 20mg use
in KTPH, to evaluate for:
 Dose-appropriateness
 Outcomes
(for newly started patients)
 Monitoring frequency
C. Methodology
6



Retrospective study
Patients who collected at least 1 dose of Rivaroxaban
15mg and/or 20mg at KTPH Outpatient Pharmacy within
1st Dec 2015 to 31st Jan 2016
Information obtained from SCM and NEHR (hospital and
national database records)
Methodology
7
Table 1: Baseline Demographics
Parameters (Total N = 191)
Mean Age – years (SD)
70.38 (12.68)
Mean Weight – kg (SD)
66.8 (17.18) [n=176, 15 patients without weight recorded]
Male sex – n (%)
84 (44.0)
Ethnic Groups
– n (%)
Prescribed by
– n (%)
Chinese
132 (69.1)
Malay
38 (19.9)
Indian
6 (3.14)
Others
15 (7.85)
Cardiology
121 (63.35)
Geriatric
25 (13.09)
General Med
21 (10.99)
Others*
24 (12.57)
*Others include: Diabetes (6), Neurology (7), Resp & Critical Care (3), Dementia Care (2), Pharmacy (1), Gastroenterology (1),
Hematology (1), Renal (1), Vascular (1), Rheumatology (1)
Methodology
8

3 aspects are tabulated and discussed:
 1.
Dose-appropriateness
 based
on manufacturer’s standards for approved indications
and renal function adjustments2
 2.
Outcomes
patients newly started on Rivaroxaban from 1st Apr
2015 to 31st Jan 2016
 for
 3.
Monitoring parameters and frequency
appropriateness
 based
2Janssen
on EHRA 2015 guidelines3
Pharmaceuticals Inc. (2016, May). Xarelto (R) Package Insert. Titusville, NJ
3Heidbuchel,
H et al. (2015). Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K
antagonist anticoagulants in patients with non-valvular atrial fibrillation. EUROPACE , 4-7.
9
D. Results and Discussion
1. Dose appropriateness
10


Based on indications
Based on renal functions
Table 2: Rivaroxaban dosing based on indications and renal functions2
Indications
CrCl (ml/min)
Dosage
Prevention of Stroke and Systemic
Embolism in Non-Valvular Atrial
Fibrillation
>50
20mg OD
15-50
15mg OD
<15
Avoid use
Treatment of Deep Vein
Thrombosis (DVT)/Pulmonary
Embolism (PE) and Prevention of
Recurrent DVT/PE
≥30
15mg BD for 21 days,
followed by 20mg OD
<30
Avoid use
2Janssen
Pharmaceuticals Inc. (2016, May). Xarelto (R) Package Insert. Titusville, NJ
1. Dose appropriateness
11
Dose Appropriateness based on approved indications
(N = 191)
140
127
120
~20%
inappropriate dosing
100
80
60
40
27
22
20
11
4
0
AF
DVT/PE
Appropriate
Other Indications*
Not Appropriate
*Other Indications:
-Ventricular fibrillation (1), Carotid artery thrombosis (1), Post stroke event (1), not reflected in records (8)
-Considered as ‘Not Appropriate’
1. Dose appropriateness
12
Reasons for dose-inappropriateness
(n = 42)
30
25
4
20
11
15
Inappropriate dosing
for this indication
(38%)
10
5
Not renally-adjusted
(26%)
12
11
4
0
AF
DVT/PE
Inappropriate dose for indication
*Others
-AF: no sCr to determine appropriate or not (4)
-Other Indications: considered as ‘Not Appropriate’ (11)
Not renally adjusted
Other Indications
Others*
2. Outcomes
15



Outcomes measured for patients newly started from
1st Apr 2015 to 31st Jan 2016
Efficacy – reported thrombo-embolic events
Safety – reported bleeding events
2. Outcomes
16
Whether patients were newly started from
1st Apr 2015 to 31st Jan 2016
(n = 190)*
Nil events
79
(41.6%)
No;
99
(52.1%)
*1 patient without initial dose date
Yes; 91
(47.9%)
Thrombo-embolic
events Bleeding events
10
2
(5.3%)
(1.1%)
2. Outcomes
17

Out of the 91 patients (100%) newly started
between 1st Apr 2015 to 31st Jan 2016:
2
patients (2.2%) had reported thrombo-embolic
incidents
1
patient had recurrent DVT
 1 patient had lower limb pain 2o to DVT: reported may be
due to non-compliance because of cost
 10
4
patients (11.0%) had reported bleeding incidents
patients had bleeding not directly due to Rivaroxaban use
(from trauma [3], from cut [1])
 1 patient had increase bleeding risk (↑aPTT and PT) without
actual bleed
2. Outcomes
18

Bleeding outcomes in 10 patients (11.0%), compared to
that reported in clinical trials ROCKET-AF (14.9%)4, and
in EINSTEIN (9.4%)5
8 patients for AF, 2 patient for DVT
 Could be due to retrospective surveillance in this MUE, as
compared to extensive observation during clinical trials
 Number of patients recalled for this study was also much
smaller than in those clinical trials

4Patel
MR, Mahaffey KW, Garg J et al (2011). Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. New England Journal
of Medicine (N ENGL J MED), 883-891.
5Prins,
M. et al (2013). Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a
pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thrombosis Journal (THROMB J), 21-30.
3. Monitoring Parameters
19

According to EHRA 2015 guidelines3
 Blood
Sampling (Renal functions and FBC)
 If
≥ 75yo: monitor every 6 months
 If CrCl < 60ml/min: monitor at frequency of every
(CrCl/10) month


Eg. CrCl 40ml/min, should monitor at every (40/10 = ) 4 months
Assumption: CrCl rounded to nearest 10s to calculate for
frequency
 DDIs
3Heidbuchel,
H et al. (2015). Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist
anticoagulants in patients with non-valvular atrial fibrillation. EUROPACE , 4-7&12-13.
3. Monitoring Parameters
20

Assumption:
 Monitoring
parameters for non-valvular AF extend to
recurrent DVT
 EHRA
2015 guidelines only meant for non-valvular AF
3. Monitoring Parameters
21
Table 4: Number and Percentage of patients monitored at appropriate intervals
N = 176*
Renal Functions – n (%)
FBC – n (%)
Appropriate intervals
90 (51.1)
79 (44.9)
Not appropriate intervals 86 (48.9)
97 (55.1)
Renal functions monitored at appropriate
frequency
90, 51%
FBC monitored at appropriate
frequency
97, 55%
86, 49%
No*
79, 45%
Yes
*15 patients without CrCl, unable to determine appropriate frequency
No*
Yes
3. Monitoring Parameters
22
Appropriateness of renal functions monitoring frequency
(N = 176)
60
56
50
40
30
30
20
19
19
13
8
10
7
7
6
6
4
1
0
Yearly
6 monthly
5 monthly
Not appropriate
4 monthly
Appropriate
3 monthly
2 monthly
3. Monitoring Parameters
24
Appropriateness of FBC monitoring frequency
(N = 176)
60
50
45
40
30
30
28
19
20
15
10
7
8
7
9
3
4
1
0
Yearly
6 monthly
5 monthly
Not appropriate
4 monthly
Appropriate
3 monthly
2 monthly
3. Monitoring Parameters
26
Drug-drug Interactions
(N = 191)
Amiodarone, 8
None, 172
Other, 19
Clarithromycin, 5
Diltiazem, 3
Phenytoin, 2
Ketoconazole, 1
3. Monitoring Parameters
27

Discussion
 Only
60 patients (31.4%) were monitored for BOTH
renal functions and FBC at appropriate frequency
 19 (9.9%) patients with DDIs
3
patients on Amiodarone and 2 patients on Diltiazem with
CrCl <50ml/min: to be used with caution
 Monitoring
for renal functions and FBC coupled with
appropriate dose adjustments is critical to avoid
undesirable outcomes
 Could be due to lack of awareness for the need to
monitor for such parameters at such intervals
Compliance
28

20 random patients who are currently on
Rivaroxaban were called and asked about
compliance for the past 7 days
 19
7
1
patients had claimed compliance
patients had a family member to help administer
patient was not compliant to prescribed instructions
 Experienced
headache, self reduced dose to alternate days
without doctor’s instructions
 Upon listening to friend dealing with TCM
 For months
Limitations/Future Directions
29

Minor thrombo-embolic events or bleeding events
may not have been reported
 Under-estimation

Monitoring parameters
 PD
interactions with Rivaroxaban may not be detected
 Under-estimation

of undesirable outcomes
of DDI
Future directions for project
 Larger
patient pool, surveying other NOACs
 Compliance of patients
 Transition between anticoagulants
Conclusion
30


Newer drugs such as Rivaroxaban and other
NOACs are prone to inappropriate use and
monitoring, leading to undesirable outcomes.
Use of such drugs could be referred to pharmacistled NOAC clinics, to better manage care of such
patients.
31
Thank You!
1. Dose appropriateness
33

Assumptions:
 Weight
to calculate CrCl based on current weight
recorded in SCM, assumed to not be much different
from first started Rivaroxaban
 sCr to calculate CrCl based on when Rivaroxaban was
initially started. If not available, the next nearest sCr
result when pt was on Rivaroxaban was used
 34
patients (28.3%) were not monitored for renal functions
initially
 1 out of these 34 patients did not have sCr result within 1
year prior to starting Rivaroxaban
 3 out of these 34 patients do not have any sCr results
Suggested
structured follow-up
www.escardio.org/EHRA
At each follow-up session….
Interval
Actions
Compliance
Each visit
 Inspect remaining medication
 Stress importance of compliance
 Inform about compliance aids
Thromboembolism
Each visit
Cerebral, systemic and pulmonary circulation
Bleeding
Each visit
Side effects
Each visit
Co-medications
Each visit
Blood sampling
Yearly
6-monthly
x-monthly
On indication
 “Nuisance” bleeding – prevention possible? Try to keep on
anticoag as much as possible. Any mitigation measures?
 Bleeding with risk or impact on QoL – prevention possible?
Need to revise dose?
Continuation? Temporary cessation with bridging? Change of
anticoagulant drug?
 Prescription or over-the counter drugs, aspirin, NSAIDs
 Even temporary use can be risky
 Haemoglobin, renal, liver function
 ≥75 – 80yo, esp if on dabigatran or edoxaban; or frail#
 ≤ 60ml/min: recheck interval = CrCl/10
 If inter-current condition may impact renal or hepatic function.
#Frailty:
Three or more criteria of unintentional weight loss, self-reported exhaustion, weakness assessed by
handgrip test, slow walking speed, or low physical activity http://www.biomedcentral.com/1471-2318/10/57
EHRA Practical Guide on the use of new oral anticoagulants in patients with non-valvular AF. Europace 2013; 15:625-51