Frequency of Monitoring, Non-adherence, and Other Anticoagulation Topics

Nathan Clark, Pharm D, BCPS

Clinical Pharmacy Supervisor

Anticoagulation and Anemia Services

Kaiser Permanent Colorado

Objectives

• Review recommendations from ACCP regarding INR monitoring intervals

• Discuss the consequences of non-adherence with INR monitoring

• Review recommendations from ACCP regarding the management of first episode, near-miss INR

• Discuss the risk of thromboembolism among stable patients presenting with a significantly low INR

Survey:

What is the maximum duration between INR checks at your institution for stable warfarin patients?

a. 4 weeks

b. 8 weeks

c. 12 weeks

d. Something else?

Frequency of INR Monitoring

“…VKA therapy with consistently stable INRs, we suggest INR testing up to every 12 weeks rather than every 4 weeks” (Grade 2B)

CHEST 2012; 141(2)(Suppl):e152S–e184S

Frequency of INR Monitoring

Frequency of INR testing has evolved from expert opinion

Data regarding extended INR recall intervals is conflicting

4 weeks versus 12 weeks

250 patients were randomized to either 4 week or 12 week recheck INR intervals

• Target INR 2–3 or 2.5–3.5• No dose change in previous 6 months

Primary outcome was TTR

Ann Intern Med. 2011;155:653-659

4 weeks versus 12 weeks

Outcome 4 week (n=126)

12 week(n=124)

TTR % (SD %) 74.1 (18.8) 71.6 (20.0)1

≥ 1 dose changes; n (%) 70 (55.6) 46 (37.1)2

INR ≥ 4.5; n (%) 15 (11.9) 8 (6.5)

INR ≤ 1.5; n (%) 12 (9.5) 11 (8.9)

Clinical Events; n (%) Major bleeding 1 (0.8) 2 (1.6)

Thromboembolism 1 (0.8) 0 (0)

Death 5 (4.0) 2 (1.6)TTR – time in therapeutic range; SD – standard deviation; INR – international normalized ratio1-Noninferiority established, absolute difference = 2.5% (1 sided 97.5% CI upper bound 7.3%)2- Absolute difference = 18.5% (6.1 to 30.0); p=0.004

Survey:

How much staff time is spent reminding patients to come in for repeat INR testing each week at your center?

a. Less than one hour

b. 1 to 5 hours

c. More than 5 hours

d. No idea, but more time than I care to think about

Nonadherence

Most studies of adherence have evaluated pill taking behavior•Less reliable pill taking = poor INR control

ART-DECO study evaluated adherence with lab monitoring•Less reliable INR monitoring = greater risk of TE

Arch Intern Med 2007 Feb 12;167(3):229-35

Improving Adherence with INR Monitoring

Interactive voice response (IVR) calls

Study evaluated IVR to provide INR results, warfarin dose details and recheck INR plus reminders

• No change in INR control • 80.3% vs 79.9%

• Reduced workload

CMAJ 2009 Apr 28;180(9):927-33

Improving Adherence with INR Monitoring

Down side to IVR?• Many patients don’t like the calls (some

strongly dislike them)• Elderly patients are often unable to

interact or operate IVR• 1 in 5 patients older than 65 were unable

perform any IVR task

J Gerontol B Psychol Sci Soc Sci 2012 Oct 25. [Epub ahead of print]

Improving Adherence with Pill Taking

Lottery-based incentive program RCT

Lottery arm:• 1 in 5 chance of getting $10 each day• 1 in 100 chance of getting $100 each day

Control arm:• No incentive

Am Heart J 2012;164:268-74

Improving Adherence with Pill Taking

Overall, no change in out of range INRs:• 23.0% lottery vs 25.9% control; p>0.05

In-range INR at study entry:• No change in out of range INRs: OR=1.26

(95% CI, 0.76-2.09, p=0.37)

Low INR at study entry:• Reduction in out of range INRs; OR=0.39

(95% CI, 0.25-0.62, p<0.001)

Am Heart J 2012;164:268-74

Case 1

C.Y. is a 76 yoF with AF and HTN. No other notable risk factors for stroke or bleeding. Her warfarin dose has been stable for months with therapeutic INR control. Today she presents with an INR of 1.7 (target 2-3). There are no identifiable causes for the low INR.

Survey:

Which do you recommend?

a.Increase weekly warfarin dose 10%

b.Increase weekly warfarin dose 15% and start LMWH bridge

c.No change in warfarin dose

d.Follow DAWN AC suggestion

e.Something else?

Isolated out-of-range INRs

“…previously stable therapeutic INRs who present with a single out-of-range INR of ≤0.5 below or above, we suggest continuing the current dose…” (Grade 2C)

CHEST 2012 141(2)(Suppl):e152S–e184S

Survey:

When would you recheck the INR for C.Y.?

a. 1 week

b. 2 weeks

c. 4 weeks

d. Follow DAWN AC suggestion

e. Something else?

Isolated out-of-range INRs

“…single out-of-range INR of ≤0.5 below or above, we suggest continuing the current dose and testing the INR within 1 to 2 weeks” (Grade 2C)

CHEST 2012; 141(2)(Suppl):e152S–e184S

Low INRs

Over 2 years of follow up, 1 in 3 patients will have an INR ≤ 1.5

Causes of subtherapeutic INR include: Nonadherence (17%) Invasive procedures (16%) Dose reduction (15%) Unexplained (15%) Second or greater consecutive low INR (13%)

Circ Cardiovasc Qual Outcomes 2009; 2: 591-597

Low INR: Risk of Thromboembolism

Retrospective cohort studies have attempted to isolate and quantify the risk of significantly low INR values

INR ≥ target range

INR ≥ target range

INR ≥ 0.5 below target

range90 day follow up for TE

≥ 2 weeks

≥ 2 weeks

Low INR: Risk of Thromboembolism

Anticoagulation characteristics were comparable:•Therapeutic doses of LMWH for bridging were uncommon (1.2 to 3.2%)•Median index INR 1.4 to 1.75•Mean duration of subtherapeutic anticoagulation ~ 16 days (2 studies)

1. Am J Hematol 2012; 87:384–3872. J Thorac Cardiovasc Surg 2009;137:91-33. Pharmacotherapy 2008;28(8):960–967

Low INR: Risk of Thromboembolism

Indication for VKA (n)

1 2 3

Influence of LMWH Bridge Therapy

Dentali [2] described LMWH bridging in 12.8% (64 of 501 patients)• Prophylactic dose (n=11, 2.2%)• Intermediate dose (n=37, 7.4%)• Therapeutic dose (n=16, 3.2%)

• Baseline characteristics did not differ between those who did or did not receive LMWH bridging

Am. J. Hematol 2012; 87:384–387

Low INR: Risk of Thromboembolism

Am. J. Hematol 2012; 87:384–387

MVR or AF patients

The Low INR Study: Case-Control Design

INR ≥ target range

Index INR ≤ 0.5 below target range

Index INR within target INR range

90 day follow up: No INR criteria

90 day follow up: No INR ≥ 0.2 below target

Low INR Cohort

Therapeutic Cohort

≥ 2 weeks ≥ 2 weeks

The Low INR Study

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

Thromboembolism Bleeding AC-Related Death

% a

t 90

day

s

Low INR Study Outcomes (n=2597)

Low INR Control *p>0.05 for all comparisons

Pharmacotherapy 2008;28(8):960–967

Thromboembolic Outcomes

Thromboembolic events(3 studies) (n,%)• Stroke, SE, or valve thrombosis (7, 58%)• Transient ischemic attack (4, 33%)• Myocardial infarction (1, 8%)

1. Am J Hematol 2012; 87:384–3872. J Thorac Cardiovasc Surg 2009;137:91-33. Pharmacotherapy 2008;28(8):960–967

Low INRs

“For patients with stable therapeutic INRs presenting with a single subtherapeutic INR value, we suggest against routinely administering bridging with heparin” (Grade 2C)

CHEST 2012; 141(2)(Suppl):e152S–e184S