Epidemiology research using administrative database: a nested case-control study
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Author: Xuanqian Xie Juurlink et al. published an article on drug interaction between proton pump inhibitors and

Author: Xuanqian Xie

Juurlink et al. published an article on drug interaction between proton pump inhibitors and clopidogrel (Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009; 180(7):713-8.). I used an administrative database to examine whether their conclusions are valid in other datasets.


Methods:

 

Data Source

We performed a retrospective, nested case-control study by using the computerized health insurance and vital statistics databases of XXXXX. These databases contain comprehensive health care utilization data, including basic demographic information, hospitalization services, outpatient prescription claims, physician services, and death records. We used encrypted unique 12-digit identifier to link datasets and created person-specific longitudinal records of health service utilization. The reliability of the hospital administrative databases and the coding accuracy has been extensively validated.

 

Cohort, Case and Control

 

The study population consisted of XXXXX residents aged 66 years or older receiving PCI between July 1st, 1998 and December 31st, 2004, and filling clopidogrel within 1 day after discharge from hospital. The date of discharge is then taken as cohort entry. To ensure at least one year of patient information before cohort entry, we excluded people aged 66 years old or less. We also excluded patients filling clopidogrel, ticlopidine or dipyridamole, the year prior to cohort entry. We followed patients taking clopidogrel after hospital discharge for maximum of 90 days, regardless of the cessation of clopidogrel use in the follow up period.  

 

The composite primary outcomes were acute MI, stroke, repeated PCI, coronary artery bypass graft (CABG) and death. All cases of acute MI or stroke must have at least two days of hospitalization with the corresponding disease as a primary diagnosis. There is no minimal requirement of hospitalization time for repeated PCI. The date of the first event was used as the index date. The secondary outcomes are primary outcomes taken individually. We followed the individuals until the earliest of one of the following: the date of any event (MI/stroke/repeated PCI/CABG/death), 90 days later, or the end of the study on December 31st, 2004. We randomly selected up to 10 controls per case from eligible patients who were at risk at the time of the case event. The controls are matched by gender, age (±3 years), and date of cohort entry (±90 days). We assigned control participants the same index date as their matched case patients.  

 

Exposure

Using the prescription drugs database from XXXXX, we identified proton pump inhibitors (PPI) exposure using 5 drugs: omeprazole, esomeprazole, rabeprazole, pantoprazole and lansoprazole.A subject is considered to be exposed if he(she) is prescribed a medication 30 days prior to index date. We then classified exposure into four (4) mutually exclusive groups: exposure to both clopidogrel and PPI, exposure to clopidogrel only, exposure to PPI only, and finally not exposed to none of the drugs. Note any group can be taken as a reference.

 

Covariates

 

Using hospitalization and outpatient prescription claims databases we defined covariates, by looking one year prior to cohort entry i.e.: at baseline. We included some comorbidity conditions that might impact risks of acute MI: hypertension, diabetes mellitus, heart failure, stroke, ischemic heart disease, peripheral vascular disease and renal diseases. We also considered other risk factors for CAD, such as demographics, medication use, etc…

 

Statistical analysis 

 

To compare cases and controls at baseline, we conducted descriptive statistics of some characteristics of. Categorical and continuous variables were presented as percentages and means ± standard deviations, respectively. We used conditional logistic regression for the estimation of the odds ratios (ORs) with 95% confidence intervals (CI) for composite primary outcomes associated with clopidogrel and PPI use, regarding first the non use of both medications group as a reference, then the clopidogrel users as a reference. We adjusted for possible confounding effects of demographics characteristics, comorbidities. We selected p value less than 0.05 as statistical significance. 

Furthermore, we performed sensitivity analyses to examine the robustness of our findings. First, we used the time-dependent Cox proportional-hazards regression model using daily exposure. Secondly, we analyzed the five (5) secondary outcomes individually. All analyses were performed using SAS 9.1 (SAS Institute, Cary, North Carolina).

 

Results:

 

 

Figure 1: Study flow diagram

 

 

 

 

 

Table 1: Characteristics of case-patients and Controls 

variable

Control N(%)

Case N(%)

Exposure:

 

 

Both PPI use and clopidogrel use

1350(17.2)

131(16.6)

PPI use alone

242(3.1)

32(4.0)

Clopidogrel use alone

4794(61.1)

465(58.8)

Neither PPI use nor clopidogrel use

1460(18.6)

163(20.6)

sum

7846(100)

791(100)

 

 

 

Mean age ±SD, y

74.47(5.30)

74.77(5.65)

Male

4785(61.0)

483(61.1)

 

 

 

Comorbid conditions

 

 

hypertension

4608(58.7)

514(65.0)

Disorders of lipoid metabolism

4254(54.2)

447(56.5)

Heart failure

1802(23.0)

263(33.2)

ischemic heart disease

7080(90.2)

714(90.3)

cerebrovascular disease

395(5.0)

82(10.4)

peripheral vascular disease

1078(13.7)

177(22.4)

Conduction disorders & Cardiac dysrhythmias

2040(26.0)

230(29.1)

Glaucoma

206(2.6)

19(2.4)

Blindness and low vision

34(0.4)

6(0.8)

Renal diseases

535(6.8)

99(12.5)

diabetes

1682(21.4)

247(31.2)

 

 

 

Medication use

 

 

diuretic drug

1732(22.1)

174(22.0)

angiotensin converting enzyme (ACE) inhibitor plus diuretic drug

549(7.0)

54(6.8)

beta blocker

3717(47.4)

393(49.7)

calcium channel blockers

3413(43.5)

399(50.4)

angiotensin converting enzyme (ACE) inhibitor

2516(32.1)

319(40.3)

angiotensin II antagonist

976(12.4)

104(13.1)

a1 - Receptor Blocker

121(1.5)

16(2.0)

Hydralazine, Reserpine...

108(1.4)

27(3.4)

stain

3879(49.4)

414(52.3)

digitoxine

423(5.4)

62(7.8)

carvedilol

26(0.3)

2(0.3)

antiplatelet drug

1130(14.4)

179(22.6)

Glyceryl trinitrate (GTN) has been used to treat angina and heart failure

3800(48.4)

433(54.7)

antiarrhythmic medication

214(2.7)

28(3.5)

glaucoma

597(7.6)

59(7.5)

Aspirin

4408(56.2)

464(58.7)


 

 

Table 2:  Crude and adjusted odds ratios (reference group=using none)

 

Variable

Crude OR (95% CI)

Adjusted OR (95% CI)

Exposure:

 

 

Both PPI use and clopidogrel use

0.85(0.66-1.11)

0.78(0.60-1.01)

PPI use alone

1.16(0.77-1.75)

1.09(0.72-1.65)

Clopidogrel use alone

0.86(0.71-1.04)

0.85(0.70-1.03)

Neither PPI use nor clopidogrel use

1

1

 

 

 

Comorbid conditions

 

 

hypertension

1.31(1.12-1.53)

1.15(0.97-1.35)

Disorders of lipoid metabolism

1.11(0.96-1.29)

1.02(0.88-1.19)

Heart failure

1.68(1.43-1.96)

1.46(1.23-1.72)

ischemic heart disease

1.00(0.78-1.29)

0.89(0.69-1.14)

cerebrovascular disease

2.21(1.72-2.84)

1.83(1.40-2.39)

peripheral vascular disease

1.83(1.53-2.20)

1.45(1.20-1.76)

Conduction disorders & Cardiac dysrhythmias

1.17(0.99-1.37)

0.99(0.83-1.17)

Glaucoma

0.91(0.57-1.47)

0.88(0.54-1.43)

Blindness and low vision

1.77(0.74-4.23)

1.72(0.71-4.18)

Renal diseases

1.99(1.58-2.50)

1.47(1.16-1.88)

diabetes

1.69(1.43-1.98)

1.51(1.27-1.78)

 

Table 2-1:  Crude and adjusted odds ratios (reference group=using clopidogrel alone) 

Variable

Crude OR (95% CI)

Adjusted OR (95% CI)

Exposure:

 

 

Both PPI use and clopidogrel use

0.99(0.81-1.22)

0.92(0.74-1.14)

PPI use alone

1.36(0.92-1.99)

1.29(0.87-1.91)

Neither PPI use nor clopidogrel use

1.17(0.96-1.42)

1.18(0.97-1.44)

Clopidogrel use alone

1

1

 

 

 

Comorbid conditions

 

 

hypertension

1.31(1.12-1.53)

1.15(0.97-1.35)

Disorders of lipoid metabolism

1.11(0.96-1.29)

1.02(0.88-1.19)

Heart failure

1.68(1.43-1.96)

1.46(1.23-1.72)

ischemic heart disease

1.00(0.78-1.29)

0.89(0.69-1.14)

cerebrovascular disease

2.21(1.72-2.84)

1.83(1.40-2.39)

peripheral vascular disease

1.83(1.53-2.20)

1.45(1.20-1.76)

Conduction disorders & Cardiac dysrhythmias

1.17(0.99-1.37)

0.99(0.83-1.17)

Glaucoma

0.91(0.57-1.47)

0.88(0.54-1.43)

Blindness and low vision

1.77(0.74-4.23)

1.72(0.71-4.18)

Renal diseases

1.99(1.58-2.50)

1.47(1.16-1.88)

diabetes

1.69(1.43-1.98)

1.51(1.27-1.78)


 

Table 3: Sensitivity analysis-1 (time-dependent Cox -model)

Exposure

Crude OR (95% CI)

Adjusted OR (95% CI)

 

 

 

Ref: Neither PPI use nor clopidogrel use

 

 

Both PPI use and clopidogrel use

0.57 (0.43, 0.75)

0.53(0.40, 0.69)

PPI use alone

1.07(0.80,1.42)

0.99(0.74,1.33)

Clopidogrel use alone

0.66(0.54,0.80)

0.66(0.54,0.80)

Neither PPI use nor clopidogrel use

1

1

 

 

 

Ref: Clopidogrel use alone

 

 

Both PPI use and clopidogrel use

0.87(0.67, 1.12)

0.80(0.62,1.04)

PPI use alone

1.63(1.19, 2.23)

1.51 (1.10, 2.07)

Neither PPI use nor clopidogrel use

1.53(1.25, 1.86)

1.52(1.25, 1.85)

Clopidogrel use alone

1

1

 

 

 

 

 

Table 4:  Sensitivity analysis-2 ( 5 outcomes individually)

 

Table 4-1: AMI 

Exposure

Crude OR (95% CI)

Adjusted OR (95% CI)

 

 

 

Ref: Neither PPI use nor clopidogrel use

 

 

Both PPI use and clopidogrel use

0.81(0.49, 1.34)

0.76(0.45-1.28)

PPI use alone

0.93(0.38, 2.28)

0.84(0.34-2.10)

Clopidogrel use alone

0.88(0.60, 1.28)

0.90(0.61-1.33)

Neither PPI use nor clopidogrel use

1

1

 

 

 

Ref: Clopidogrel use alone

 

 

Both PPI use and clopidogrel use

0.92(0.61, 1.38)

0.84(0.55-1.29)

PPI use alone

1.05(0.44, 2.50)

0.93(0.39-2.24)

Neither PPI use nor clopidogrel use

1.14(0.78, 1.66)

1.11(0.75-1.63)

Clopidogrel use alone

1

1

 

 

 

 

 

Table 4-2: Stroke 

Exposure

Crude OR (95% CI)

Adjusted OR (95% CI)

 

 

 

Ref: Neither PPI use nor clopidogrel use

 

 

Both PPI use and clopidogrel use

0.91(0.35, 2.33)

1.05(0.36-3.08)

PPI use alone

0.45(0.06, 3.63)

0.53(0.05-5.31)

Clopidogrel use alone

1.11(0.58, 2.12)

1.28(0.62-2.65)

Neither PPI use nor clopidogrel use

1

1

 

 

 

Ref: Clopidogrel use alone

 

 

Both PPI use and clopidogrel use

0.82(0.38, 1.76)

0.82(0.34-1.96)

PPI use alone

0.40(0.05, 3.06)

0.41(0.04-3.79)

Neither PPI use nor clopidogrel use

0.90(0.47, 1.73)

0.78(0.38-1.62)

Clopidogrel use alone

1

1

 

 

 

 

 

Table 4-3: PCI 

Exposure

Crude OR (95% CI)

Adjusted OR (95% CI)

 

 

 

Ref: Neither PPI use nor clopidogrel use

 

 

Both PPI use and clopidogrel use

0.88(0.62, 1.25)

0.82(0.58-1.17)

PPI use alone

0.92(0.51, 1.64)

0.90(0.50-1.60)

Clopidogrel use alone

0.83(0.64, 1.08)

0.81(0.62-1.06)

Neither PPI use nor clopidogrel use

1

1

 

 

 

Ref: Clopidogrel use alone

 

 

Both PPI use and clopidogrel use

1.05(0.79, 1.40)

1.01(0.76-1.35)

PPI use alone

1.10(0.64, 1.91)

1.10(0.63-1.91)

Neither PPI use nor clopidogrel use

1.20(0.92, 1.56)

1.23(0.94-1.60)

Clopidogrel use alone

1

1

 

 

 

 

 

Table 4-4: CABG 

Exposure

Crude OR (95% CI)

Adjusted OR (95% CI)

 

 

 

Ref: Neither PPI use nor clopidogrel use

 

 

Both PPI use and clopidogrel use

0.78(0.37, 1.67)

0.74(0.34-1.61)

PPI use alone

1.85(0.68, 5.06)

1.60(0.57-4.52)

Clopidogrel use alone

0.46(0.25, 0.82)

0.41(0.22-0.74)

Neither PPI use nor clopidogrel use

1

1

 

 

 

Ref: Clopidogrel use alone

 

 

Both PPI use and clopidogrel use

1.72(0.91, 3.27)

1.81(0.92-3.56)

PPI use alone

4.07(1.55, 10.69)

3.94(1.46-10.60)

Neither PPI use nor clopidogrel use

2.20(1.23, 3.94)

2.46(1.35-4.48)

Clopidogrel use alone

1

1

 

 

 

  

 

Table 4-5: Death  

Exposure

Crude OR (95% CI)

Adjusted OR (95% CI)

 

 

 

Ref: Neither PPI use nor clopidogrel use

 

 

Both PPI use and clopidogrel use

1.17(0.68, 2.01)

0.93(0.51-1.67)

PPI use alone

1.33(0.61, 2.86)

1.13(0.49-2.61)

Clopidogrel use alone

0.90(0.59, 1.37)

0.87(0.55-1.36)

Neither PPI use nor clopidogrel use

1

1

 

 

 

Ref: Clopidogrel use alone

 

 

Both PPI use and clopidogrel use

1.30(0.84, 1.99)

1.07(0.67-1.69)

PPI use alone

1.47(0.72, 3.00)

1.30(0.60-2.83)

Neither PPI use nor clopidogrel use

1.11(0.73, 1.70)

1.15(0.73-1.81)

Clopidogrel use alone

1

1