Inappropriate clopidogrel adherence explains stent related adverse outcomes

Leonardo Tamariz, MD, MPHUniversity of Miami

Antiplatelet use post-stent

• Angioscopic studies show lack of neo-intimal coverage and thrombi post-stent.

• Drug eluting stents have been associated to late MI.

• ACC/AHA/SCAI recommends in patients with low bleeding risk maintaining clopidogrel for 12 months after a stent.

• Clopidogrel is now a chronic medication.

Consequences of lack of medication adherence in CV

disease• Inadequate disease control.• Low adherence to beta-blockers or statins

in post MI patients increases the death rate.

• Represents a significant burden to healthcare utilization – the estimated yearly cost is $396 to $792 million.

• One – two thirds of all medication-related hospital admissions are attributed to nonadherence.

Specific aims

• To evaluate clopidogrel medication adherence in a cohort of patients with stents.

• To evaluate if clopidogrel adherence affects stent related outcomes.

Methods: Data source

Humana EDW

Medical FileICD 9 codesMember File

DemographicsCostsProvider information

Pharmacy FileGPI codes DosageRefill patterns

Methods: Study design

3.2 ± 0.7 years

Clopidogrel adherenceClopidogrel adherence

Inclusion criteria•18 years or older• Procedure claim for bare metal stent (36.06) or drug eluting stent (36.07) between January 1, 2003-June 1, 2005.

Stents(n=7,091)

Clopidogrel users(n=5,838)

Non- clopidogrel users(n=1,253)

MIDeath

Methods: Clopidogrel adherence

• Clopidogrel use defined by Generic Product Identifiers (GPI code:85158020)

• Adherence defined by medication possesion ratios (MPR).– Appropriate adherence: 80% or more MPR– Innapropriate adherence: <80% MPR.

∑ days supply of medication

∑ number of days between first and last refill + days supply of last refill

MPR =

Methods: Outcomes

• Myocardial infarction– ICD 9 code 410.x with a hospitalization

• Death (all cause mortality)– Social security death index match

• Combined– MI or death

Methods: CV risk factors (ICD-9 definitions)

• Diabetes (250.xx)• Hypertension (401.xx, 402.xx,

403.xx,404.xx,405.xx)• Abnormal lipid panel (272.xx),• Obesity (278, 278.0, 278.00, 278.01,

278.1).

Methods: Statistical analysis

• Baseline characteristics with chi-square and t-test• Predictors of innapropriate use with logistic

regression• Person-time and hazard ratios of events using

Cox proportional adjusted for demographics, claims for CV risk factors, claims for heart failure, type of stent and MI at presentation.

Results: Baseline characteristics

CharacteristicCharacteristic Entire Entire cohortcohort(n=5,838)(n=5,838)

Clopidogrel Clopidogrel users with users with

appropriate appropriate adherence adherence (n=4,548)(n=4,548)

Clopidogrel users Clopidogrel users with with

inappropriate inappropriate adherenceadherence(n=1,290)(n=1,290)

p-valuep-value

Age, years 63.311.6 63.511.5 62.711.9 0.04

Female gender, % 33 24 21 <0.01

Previous history of myocardial infarction, %

18 18 18 0.92

Previous history of hypertension, %

55 54 57 0.18

Previous history of diabetes, %

28 27 32 <0.01

Previous history of abnormal lipids, %

48 48 48 0.95

Previous history of heart failure, %

10 9 11 0.01

Medicare, %

58 55 59 0.08

Drug eluting stents, %

84 84 85 0.49

Results: Distribution of MPRs0

1020

3040

Per

cent

0 .2 .4 .6 .8 1Medication possesion ratio

Results: Predictors of inappropriate clopidogrel use

Predictors OR (95% C.I)

Age 0.97 (0.97-0.98)

Female gender 0.79 (0.69-0.91)

Diabetes 1.2 (1.0-1.4)

Medicare insurance 1.5 (1.26-1.81)

0.02

0.04

0.06

0.08

0.10

Cu

mm

ulat

ive

inci

den

ce

0 1 2 3Years

Appropriate clopidogrel adherence

Innappropriate clopidogrel adherence

Results: Incidence of MI by adherence to clopidogrel

HR 1.35(1.08-1.70)p=0.009

0.00

0.10

0.20

0.30

0.40

Cu

mm

ulat

ive

inci

den

ce

0 1 2 3Years

Appropriate clopidogrel adherenceInnappropriate clopidogrel adherence

Results: Incidence of death by adherence to clopidogrel

HR 1.32(1.12-1.55)p<0.01

0.00

0.05

0.10

0.15

Cu

mm

ulat

ive

inci

den

ce

0 1 2 3Years

Appropriate clopidogrel adherenceInnappropriate clopidogrel adherence

Results: Incidence of combined outcome by adherence to

clopidogrel

HR 1.31(1.11-1.54)p<0.01

Conclusions

• Twenty eight percent of clopidogrel users post-stent deployment are not adherent.

• Lack of adherence to clopidogrel post-stent increases the risk of myocardial infarction and death.

Limitations

• Lack of validation of exposure and outcomes.

• Insured patient population, less burden of disease compared to other studies.

• Unable to document ASA use, coronary anatomy where stent was placed due to use of administrative claims.

Clinical implications and unresolved issues

• We need to stress the importance of clopidogrel adherence after a stent.

• We need to inquire patients about clopidogrel adherence post-stent.

• We need to identify individual reasons for lack of clopidogrel adherence.

• Need a randomized trial to determine the efficacy of different interventions to improve clopidogrel adherence.