example average - faculty of medicine and health sciences

1

Course: EPIB 679-001 Clinical Epidemiology

Date: May 9 to June 38:35 – 11:40

Session 6: Study Designs (2)

Dr. J. Brophy

Internal Standardization: The Mantel-Haenszel Estimator

• For >2 internal groups, RRMH, comparing group-2 to group-1, is a weighted average of the stratum-specific rate ratios:

RRMH = ∑j (wj RRj) / ∑j wj

where wj = deaths in reference population (group-1) x proportion of P-Y in stratum j for group-2

Mantel-Haenszel as a Weighted Average

2 1

1 2i

1 2

2 1

ii

Assume that the reference group is labeled "1":/

/

The weights are: / and{ / }

and the total number of person-time i

MH i i ii

i i i

i i i i

MH ii

i

RR d n N

d n N

w d n NRR w

w

N

λ λ

=

=

=

=

∑

∑

∑

∑n stratum "i"

Example

0.96710707.3966Total

22012010550>65

210440531526-65

225101110-25

RR (2 vs1)

Rate(10-3)

P-Y(103)

No.Rate(10-3)

P-Y(103 )

NoAge

Cohort-2Cohort-1

Rate ratio

Example

2 1

1 2

/

/

Numerator: 10 1/6+40 3/7+20 5/6=35.48Denominator: 1 5/6+15 4/7+50 1/6=17.74

2

MH i i ii

i i ii

MH

RR d n N

d n N

RR

=

× × ×× × ×

∴ =

∑

∑

M-H

• M-H estimator is an unbiased and efficient estimator of the rate ratio under the conditions of: – No residual confounding– Homogeneity of the relative risks across strata

2

Kaplan-Meier

Product-limit method

Kaplan-Meier Life-Tables

• Order survival times: t1 <t2 <…tm – n observations – N failures– m<N failures – Number at risk denoted by ni and number of

deaths at ti is di

Data Layout

cN

…

c2

c1

Number censored (ci)

N

…

2

1

Order

dNnNtN

………

d2n2t2

d1n1t1

Number of deaths (di)

Number at risk (ni)

Survival time (ti)

Example

0.040.67213[58,60)

….….….….….….

0.690.8621073[4,5)

0.800.945583[2,4)

0.850.85215100[1,2)

1.01.000100[0,1)

S(n-d)/nNo. censored

No. deaths (d)

No at risk(n)

Interval

Survival = 1 before 1st failure, by definition

[0=include 01)=exclude 1

NB: These curves are step-functions

Log-rank test used to compare survival curves

Estimating Survival

• Kaplan-Meier estimator of survival by time is:

1

^

^

if 1)(

where

/)()(

tttS

ndntS iitt

ii

<=

−=∏≤

3

Assumptions

• Assume that each set of subsequent events is independent of the previous ones– This is a fundamental assumption of all analyses

of cohort data• Therefore, we can multiply probabilities,

according to the independence law

Assumptions

• If rates depend on calendar year, then this method may be biased– Can use “proportional hazards model” instead

• Short-term studies should not be affected

Case - control Case - control

Case - control Case – control (DES study)

4

Nested Case-Control Studies

• Sub-study that is based on an explicit cohort• Motivation:

– Computational ease for large datasets– Require additional information not already

collected• To reduce costs, a sample of subjects from the original

cohort is taken

Synonyms

• Case-control-within-cohort studies• Incidence density sampling studies• Synthetic case-control studies

• Case-control studies are also referred to as case-referent studies

Incidence Density Sampling

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Time

No.12345678

Time for 1st failure

Time for 2nd failureRisk set for 1st failure

Risk set for 2nd failureIncidence Density Sampling

1. For each failure time (T) of each case, define all subjects who at that time are still at risk of developing the outcome

– The complete set of such subjects is called the risk set for the case

– Will exclude all subjects who before T were:• Censored• Failed


2. Randomly select without replacement a sample of “controls” from the risk set

• These subjects are therefore “matched” to the case by time of event

• Other matching variables can be used so that the sampling is stratified; e.g., select only a random sample of women

• If a potential control eventually becomes a case, he is still at-risk at the time of the event

• A fixed number of controls can be selected; that number can vary from risk set to risk set


3. The analysis of these data is similar to the stratified analysis used in the M-H procedure for rates

4. The strata are now defined as each selected risk set.

5


5. The measure of association is the odds ratio. With this sampling strategy and a matched analysis, it provides an unbiased estimate of the rate ratio.

• A matched analysis is one that accounts explicitly for the matching during the fieldwork


6. The estimated OR will have more variability than the full M-H cohort analysis because fewer subjects are included

7. There is no need to calculate person-years in this analysis. It is subsumed automatically in the sampling.


8. Odds ratios in each risk set are not calculated; rather a summary estimate across all risk sets is obtained.

• This assumes that the rate ratio does not vary by time (proportional hazards assumption). Equivalently, the OR across strata (matched subjects) are ~ equal (homogeneous).

9. Only risk sets that are discordant on exposure contribute information

Globe and Mail, October 1 2004

6

Our Coxib Research Project

• February 2002 – CIHR protocol submitted• September 2002 – CIHR re-submission• March 2003 – CIHR Funding approved• May 2003 – Approval from CAI• July & October 2003 – Data from RAMQ and

MedEcho• January 2004 – Corrected data from MedEcho• February 2004 – Death data from ISQ• September 29 2004 – Analyses completed

NY Times Nov 14 2004

The Economic Fallout

• Estimated 20 million patients• Estimated 80 million prescriptions• Estimated yearly sales $2.5 billion USD• Merck stock fell $12 /share or 26% in 1 day• Total Merck fall 40% or $ 50 billion• Estimated legal liability $10-18 billion• Pfizer stock down 21% since Vioxx

withdrawal (collateral damage?)

The Final Straw - APPROVe

• Randomized trial (n=2600)– Placebo-controlled, multicentre– Individuals with colon polyps & no CVD– Rofecoxib 25mg/day vs placebo

• Primary endpoint:– Recurrence of colorectal polyp

• 18 month interim analysis:– ↑ risk of serious cardiovascular events RR=1.84

(P<0.001)

More News, More Questions

More News, More Questions More News, More Questions

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Questions

• What is the strength of the evidence against Vioxx?

• Is this a class effect of Cox –2 inhibitors?• How transparent have both manufactures and

researchers been been?• What about naproxyn?• What about “real patients”?• What about aspirin?• What about the FDA?

Back to the Beginning

• Synthesis of aspirin (1899)• Mainstay of therapy

– Pain– Inflammation

• Wide clinical application• Among most widely prescribed class• Last 30 years found to be cardioprotective

Gastrointestinal Effects of NSAIDs

• Minor gastrointestinal toxicity– Nausea, dyspepsia, abdominal pain, heartburn,

diarrhea, and constipation– Affect approximately 20-30% of users

• Serious gastroduodenal toxicity– Result from erosions, gastric or duodenal ulcers,

upper GI bleed, perforations– Rate of serious GI toxicity → 20-40 per 1000

person-years

Mechanism of Action of NSAIDs

Membrane-bound phospholipids

Phospholipase A2

COXASA,

NSAIDs

Tissue-specific isomerases

O2

PGG2

PGH2

PGF2αPGE2PGD2 PGI2 TxA2

X

Stimuli

Arachidonic acid

Fever, pain, inflammationX

Mechanism of Action of NSAIDs


Phospholipase A2

COXASA,

NSAIDs


O2

PGG2

PGH2

PGF2αPGE2PGD2 PGI2 TxA2

X

Stimuli

Arachidonic acid

Fever, pain, inflammationX

Discovery of two cyclooxygenases

Phospholipase A2


Arachidonic acidO2

PGG2

PGH2

PGE2Pain & inflammation

PGsRenal homostasis

PGI2↓ Platelet aggregation

TxA2↑ Platelet aggregation


X

Stimuli

COX-1

COX-2

ASA,NSAIDs

X

PGE1GI cytoprotection

X XXX X COX-1COX-2 COX-2

X

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The COX-2 Hypothesis

PGsPGs

COX-1(constitutive)

COX-2(inducible)

• Pain & inflammation• Fever• ↓ Platelet aggregation• Carcinogenesis

• GI cytoprotection• ↑ Platelet aggregation• Renal function

(homeostasis)

Arachidonic acid

Effects of NSAIDs on Thromboxane and Prostacyclin

McAdam et al. Proc. Natl. Acad Sci. USA . 1999;96:272.

Thromboxane (TxA2)

Platelet AggregationVasoconstriction

Platelets

Inhibits Platelet AggregationVasodilatation

Endothelial cells

Prostacyclin (PGI2)

COX-2COX-2 Inhibitors


COX-1 Nonselective NSAIDs/ASA

Nonselective Aspirin

Effects of NSAIDs on Thrombotic State

COX-1

Platelet aggregation

COX-2

Antiplateletfactor


COX-1


COX-2

Antiplateletfactor

Nonselective NSAIDs


COX-1


COX-2

Antiplateletfactor

COX-2 Inhibitors


COX-1


COX-2

Antiplateletfactor

COX-2 Inhibitors

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Degree of inhibition of COX-2 relative to COX-1 for various NSAIDs

NSAID type COX-2 selectivity *

COX-2 selective inhibitors Rofecoxib 80 Etodolac 23 Meloxicam 11 Celecoxib 9

Nonselective NSAIDs Diclofenac 4 Sulindac 3 Piroxicam 2 Ibuprofen 0.4 Naproxen 0.3 Indomethacin 0.2 Ketorolac 0.003

* The 80% inhibitory concentration ratios of COX-2 relative to COX-1 in human whole blood assays.

NEJM November 2000

VIGOR - Summary of GI Endpoints

†p < 0.001. * p = 0.005.

0

1

2

3

4

5

Confirmed ClinicalUpper GI Events

ConfirmedComplicated

Upper GI Events

All ClinicalGI Bleeding

RR: 0.46†

(0.33, 0.64)

RR: 0.43*(0.24, 0.78)

RR: 0.38†

(0.25, 0.57)

Rat

es p

er 1

00 P

atie

nt-Y

ears

RofecoxibNaproxen

( ) = 95% CI.Bombardier et al. N Engl J Med. 2000 Nov 23;343(21):1520-1528.

* Not including hemorrhagic stroke.

Event CategoryRofecoxib(n=4047)

Naproxen(n=4029)

Relative Risk(95% CI)

Cardiac 28 (1.0) 10 (0.4)

Cerebrovascular* 11 (0.4) 8 (0.3)

Peripheral vascular 6 (0.2) 1 (0.04)

Confirmed CV 45 (1.7) 19 (0.7)

Patients With Events (Rates per 100 Patient-Years)

0.36

0.73

0.17

0.420 1 2

FDA Advisory Committee Meeting, 2001.

CV Adverse Events: VIGOR

VIGOR CV Results

• Naproxen is cardioprotective?– Antiplatelet activity

• Aspirin use was not permitted?– RR asa indicated = 4.89 (95% CI: 1.41-16.88)– RR asa non-indicated = 1.89 (95% CI: 1.03-3.45)

• Unique population• Play of chance?

– Small number of events

Descriptive Statistics

Canadian Prescriptions and Sales Statistics: The first 3 months

$ 4,189,000N/AMarch 1997Lipitor

$ 9,071,00050,000†August 1998Zyban

$ 13,306,000178,400March 1999Viagra

$ 20,736,000428,400April 1999Celebrex

Total salesPrescriptionsLaunch dateDrug

Source: IMS Health Canada† Approximation

10

0

10

20

30

40

50

60

70

80

90

100

Jan-9

9Apr-9

9Ju

l-99

Oct-99

Jan-0

0Apr-0

0Ju

l-00

Oct-00

Jan-0

1Apr-0

1Ju

l-01

Oct-01

Jan-0

2Apr-0

2

Coxibs

Naproxen

NSAIDs

Meloxicam

Prop

ortio

n (%

) of i

ndiv

idua

ls in

itiat

ing

trea

tmen

t

Time trend analysis in Quebec

0

10

20

30

40

50

60

70

80

90

Jan-9

9Apr-9

9Ju

l-99

Oct-99

Jan-0

0Apr-0

0Ju

l-00

Oct-00

Jan-0

1Apr-0

1Ju

l-01

Oct-01

Jan-0

2Apr-0

2

NSAIDs

Naproxen

Celecoxib

Rofecoxib

Meloxicam

Prop

ortio

n (%

) of i

ndiv

idua

ls in

itiat

ing

trea

tmen

t

Time trend analysis

VIGOR

Direct-to-Consumer Advertising

• Launched in 2001 (US)• $100 million per year• Exceeding medical advertising

The Debate Begins

Mukherjee, D. et al. JAMA 2001;286:954-959.

Time to Cardiovascular Adverse Event in the VIGOR Trial


MI Rates Among Subjects Receiving Placebo vsRofecoxib or Celecoxib (Different Studies)

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MI, Stroke, and Death in the CLASS Trial, Stratified by Aspirin Use CV Adverse Events: CLASS

% of Patients With EventsCelecoxib Diclofenac Ibuprofen

Event (n=3988) (n=1996) (n=1985)

MI 20 (0.5) 6 (0.3) 10 (0.5)Angina 24 (0.6) 10 (0.5) 12 (0.6)Unstable angina 12 (0.3) 4 (0.2) 2 (0.1)Any event 100 (2.5) 42 (2.1) 44 (2.2)Withdrawals 32 (0.8) 14 (0.7) 16 (0.8)

FDA Arthritis Advisory Committee Meeting, 2001.

JAMA Conclusions (2001)

“Our findings suggest a potential increase in cardiovascular event rates for the presently available COX-2 inhibitors. It is possible that concomitant use of aspirin may not fully offset the risk of selective COX-2 inhibitors. However, definitive evidence of such an adverse effect will require a prospective randomized clinical trial”.

Merck Replies

Cardiovascular Thrombotic Events in Controlled,Clinical Trials of Rofecoxib

Circulation. 2001;104:2280-2288

Merck Replies

• 23 RCTs of > 28,000 patients, > 14,000 pt. yrs• Mortality, non-fatal MI & stroke• Placebo 3482 vs. rofecoxib 6290 pts.

32/1678 (1.91%) vs. 33/2189 (1.51%)• Non-naproxen NSAIDs 2755 vs. rofecoxib 4549 pts.

14/984 (1.42%) vs. 21/1934 (1.09%)• Naproxen 7870 pts. vs. rofecoxib 9083 pts.

27/3742 (0.72%) vs. 57/4622 (1.23%)

Merck Replies

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Merck Replies

Conclusions—No evidence for an excess of CV events for rofecoxib relative to either placebo or the non-naproxen NSAIDs. Differences observed between rofecoxib and naproxen are likely the result of the antiplatelet effects of the latter agent.

(Circulation. 2001;104:2280-2288.)

But CAD is an Inflammatory Disease

Circulation. 2004;110:934-939

Effect of Rofecoxib on Inflammation Our Coxib Research Project

• February 2002 – CIHR protocol submitted• September 2002 – CIHR re-submission• March 2003 – CIHR Funding approved• May 2003 – Approval from CAI• July & October 2003 – Data from RAMQ and

MedEcho• January 2004 – Corrected data from MedEcho• February 2004 – Death data from ISQ• September 29 2004 – Analyses completed

Objective

• To assess whether and to what extent the use of individual NSAIDs changes the risk of a first myocardial infarction

• To assess if this risk is modified by– Dose– Concomitant use of low dose aspirin– Both factors simultaneously

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Study Population

• Cohort formation– Random sample (n=125,000) of all residents ≥ 66 years of age

newly treated with an NSAID between January 1st, 1999 and June 30th, 2002

– Excluded:• Health care coverage <1 year• NSAIDs in the year preceding cohort entry• Rx from ≥2 NSAID categories on day of cohort entry• Prior MI (ICD-9 codes 410 and 412)

• Cohort entry• Date of first Rx during study period

• Cohort exit:• Date of first hospitalization for AMI (index date)• Date of death, termination of health coverage, or end of study

(December 31, 2002)

Study Endpoint

• Outcome– AMI (ICD-9 code 410), fatal and non-fatal

• Provided length of stay ≥3 days or,• Transferred from another institution or,• Had undergone angioplasty

• Only the first endpoint in a given subject was used in the analysis– Date of first hospitalization taken as index date

Exposure

• NSAID drug categories:1. Nonselective, non-aspirin NSAIDs2. Partially selective (naproxen)3. COX-2 selective inhibitors

– Celecoxib and rofecoxib4. Preferentially selective COX-2 inhibitors

– Meloxicam

• Exposure time windows:– Current use: Rx preceding the event and overlapping with

the index date– Past use: Rx in the year preceding the index date but not

currently exposed– Ever use: 1 year preceding the index date

Exposure

• NSAID dosage categories– Low dose

• Celecoxib ≤200mg/day• Rofecoxib ≤25mg/day

– High dose• Celecoxib >200mg/day• Rofecoxib >25mg/day

• Effect modification with aspirin– Low dose ≤325mg/day– Current use + 30 day grace period

Statistical Analysis

• Time-matched, nested case-control approach• Up to 20 controls matched on:

– Month and year of cohort entry– Age (within 1 year)

• Comparator group = no use in the year preceding the index date

• Conditional logistic regression

Statistical Analysis

• Covariates– Conventional risk factors

• Age, sex, hypertension, pre-existing coronary artery disease, cerebrovascular disease, peripheral vascular disease, congestive heart failure, diabetes, use of antilipemics, antigoagulants, and low dose aspirin.

– Presence of other comorbid conditions, use of other medications, measures of health care utilization and measures of comorbidity

• Tested as potential confounders using the change-in-estimate method

– Interaction term for current use of low dose aspirin

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Study Population302,964

Individuals with at least 1 year of enrolment initiating treatment with an NSAID between

January 1st, 1999 and June 30th, 2002(Identified by the RAMQ)

125,000Random sample of above subjects selected

by the RAMQ prior to data transfer

113,934Subjects

113,927Study population

2,844First AMI

10,355Deaths

(non-AMI)

100,728Alive on

Dec 31/02

Exclusions

2,283Non-fatal AMI

561Fatal AMI

• 1,552 subjects received aspirin but not other NSAIDS

• 1,193 subjects received an NSAID in the year preceding cohort entry

• 8,168 had a previous MI (5.390 for ICD9 code 412 and 2,778 for ICD9 code 410)

• 153 subject received an NSAID from ≥2 categories on the day of cohort entry

• 7 subjects had duration of follow-up <0 days (possible data errors)

Table 1. Characteristics of cases and controls

Cases

(N = 2,844)

Controls

(N = 56,880)

Age†, years, mean (± SD) 78.1 (± 5.4) 78.1 (± 5.4)

Sex (%) Female Male

53.5 46.5

68.0 32.0

Comorbid conditions (%) ‡ Hypertension Coronary artery disease Cerebrovascular disease Peripheral vascular disease Congestive heart failure Diabetes Respiratory illness Gastrointestinal ulcer disease Thyroid disorders Depression/psychiatric illness Cancer

57.0 30.1 1.4 3.5 13.5 23.1 24.0 26.6 16.5 14.7 2.9

49.8 16.5 0.7 1.2 6.7 11.0 18.5 23.6 17.1 14.4 2.7

Use of concomitant therapy (%) ‡ Use of antilipemic agent Use of anticoagulants Use of low dose ASA Use of oral corticosteroids

22.3 5.5 35.7 8.8

19.3 4.2 21.8 6.4

Health care utilization § Hospitalizations (%) None ≥ 1

62.3 37.7

76.4 23.6

Outpatient medical visits All physician visits (%) ≤ 12 > 12 Cardiologist visits (%) None ≥ 1

63.0 37.0

75.5 24.5

72.5 27.5

85.2 14.8

Co-morbidity indices § No. of different drugs, mean (±SD) Chronic disease score, mean (±SD) Charlson index, mean (±SD)

10.9 (± 6.2) 7.2 (± 4.2) 0.73 (± 1.6)

8.3 (± 5.2) 5.4 (± 3.9) 0.33 (± 1.1)

† At index date ‡ In the year preceding initiation of an anti-inflammatory agent (i.e., cohort entry) § In the year preceding the index date

Table 2. Crude and adjusted rate ratios of AMI for the use of various anti-inflammatory agentsdispensed in the year preceding the index date

Cases (n =2,844 )

Controls (n =56,880 )

Crude rate ratio

Adjusted † rate ratio 95% CI

No use ‡ (%) 793 (27.9) 16,680 (29.3) 1.00 1.00 Reference

Any use * (%) NSAIDs 271 (9.5) 5532 (9.7) 1.07 0.91 0.77-1.09 Naproxen 106 (3.7) 2017 (3.5) 1.15 0.98 0.78-1.24 Celecoxib 751 (26.4) 14,898 (26.2) 1.09 1.00 0.88-1.13

Rofecoxib 544 (19.1) 10,990 (19.3) 1.06 0.97 0.85-1.10

Meloxicam 13 (0.5) 312 (0.6) 0.89 0.76 0.43-1.36 Combined use ¥ 366 (12.9) 6451 (11.4) 1.23 0.99 0.86-1.15

AMI = acute myocardial infarction; NSAIDs = Non-steroidal Anti-inflammatory drugs; CI = confidence interval. † Adjusted for age at index (continuous variable); sex, hypertension, coronary artery disease, cerebrovascular disease, peripheral vascular disease, congestive heart failure, diabetes, respiratory illness, gastrointestinal ulcer disease, thyroid disorders, depression/psychiatric illness and cancer, in the year preceding cohort entry; use of concomitant therapy including antilipemic agents, anticoagulants and low dose aspirin in the year preceding cohort entry; health care utilization including hospitalizations, outpatient vis its to any physician and outpatient cardiologist visits, in the year preceding the index date and; number of different drugs taken, chronic disease score and charlson index in the year preceding the index date. ‡ No use in the year preceding the index date. * Any use is defined as the dispensing of at least one prescription in the year preceding the index date. ¥ Combined use represents the dispensing of two or more categories of NSAIDs in the year preceding the index date. § Past users are those who were currently unexposed but had received at least one prescription for an NSAID in the year preceding the index date.

Table 3. Crude and adjusted rate ratios of AMI for the current use of various anti-inflammatory agents

Cases(n =2,844 )


Crude rate ratio

Adjusted † rate ratio 95% CI

No use ‡ (%) 793 (27.9) 16,680 (29.3) 1.00 1.00 Reference

Current use (%) NSAIDs 51 (1.8) 962 (1.7) 1.17 1.00 0.73-1.37 Naproxen 23 (0.8) 336 (0.6) 1.52 1.17 0.75-1.84 Celecoxib 287 (10.1) 5598 (9.9) 1.11 0.99 0.85-1.16 Rofecoxib 239 (8.4) 3708 (6.5) 1.41 1.24 1.05-1.46 Meloxicam 7 (0.2) 132 (0.2) 1.15 1.06 0.49-2.30

Past use (%) § 1,444 (50.8) 29,464 (51.8) 1.05 0.93 0.84-1.04

AMI = acute myocardial infarction; NSAIDs = Non-steroidal Anti-inflammatory drugs; CI = confidence interval. † Adjusted for age at index (continuous variable); sex, hypertension, coronary artery disease, cerebrovascular disease, peripheral vascular disease, congestive heart failure, diabetes, respiratory illness, gastrointestinal ulcer disease, thyroid disorders, depression/psychiatric illness and cancer, in the year preceding cohort entry; use of concomitant therapy including antilipemic agents, anticoagulants and low dose aspirin in the year preceding cohort entry; health care utilization including hospitalizations, outpatient visits to any physician and outpatient cardiologist visits, in the year preceding the index date and; number of different drugs taken, chronic disease score and charlson index in the year preceding the index date. ‡ No use in the year preceding the index date. * Any use is defined as the dispensing of at least one prescription in the year preceding the index date. ¥ Combined use represents the dispensing of two or more categories of NSAIDs in the year preceding the index date. § Past users are those who were currently unexposed but had received at least one prescription for an NSAID in the year preceding the index date.

Table 4. Crude and adjusted rate ratios of AMI for current use of celecoxib and rofecoxib according to dose

Cases Controls Adjusted † rate ratio 95% CI

No use ‡ 793 16,680 1.00 Reference

Celecoxib N 287 5598 Low dose § 208 (72.5%) 4176 (74.6%) 0.98 0.83-1.17 High dose * 79 (27.5%) 1422 (25.4%) 1.00 0.78-1.29 Rofecoxib N 239 3708 Low dose § 218 (91.2%) 3485 (94.0%) 1.21 1.02-1.43 High dose * 21 (9.8%) 223 (6.0%) 1.73 1.09-2.76

AMI = acute myocardial infarction; CI = confidence interval. † Adjusted for age at index (continuous); sex, hypertension, coronary artery disease, cerebrovascular disease, peripheral vascular disease, congestive heart failure, diabetes, respiratory illness, gastrointestinal ulcer disease, thyroid disorders, depression/psychiatric illness and cancer, in the year preceding cohort entry; use of concomitant therapy including antilipemic agents, anticoagulants and low dose aspirin in the year preceding cohort entry; health care utilization including hospitalizations, outpatient visits to any physician and outpatient cardiologist visits, in the year preceding the index date; number of different drugs taken, chronic disease score and charlson index in the year preceding the index date and; past use of NSAID. ‡ No use in the year preceding the index date. § ≤200mg/day and ≤25mg/day for celecoxib and rofecoxib respectively. * >200mg/day and >25mg/day for celecoxib and rofecoxib respectively.

Table 5. Crude and adjusted rate ratios of AMI for current use of anti-inflammatory agents according to the concomitant use of low dose aspirin † and dose of Cox-2 selective inhibitors

No concomitant use of aspirin Concomitant use of aspirin

Cases Controls Adjusted RR ‡ (95% CI) Cases Controls Adjusted RR ‡ (95% CI)

NSAIDs 32 724 1.04 (0.71-1.54) 19 238 0.94 (0.57-1.54)

Naproxen 18 249 1.59 (0.95-2.65) 5 87 0.60 (0.24-1.50)

Celecoxib 176 4043 1.07 (0.89-1.30) 111 1555 0.88 (0.70-1.10) Low dose § 126 3021 1.04 (0.84-1.28) 82 1155 0.91 (0.70-1.17) High dose* 50 1022 1.16 (0.85-1.57) 29 400 0.80 (0.54-1.20)

Rofecoxib 143 2586 1.37 (1.12-1.68) 96 1122 1.07 (0.84-1.36) Low dose § 135 2432 1.38 (1.12-1.69) 83 1053 1.00 (0.77-1.28) High dose* 8 154 1.23 (0.59-2.54) 13 69 2.36 (1.27-4.39)

Meloxicam 2 92 0.59 (0.14-2.41) 5 40 1.59 (0.61-4.14)

AMI = acute myocardial infarction; RR= rate ratio; CI = confidence interval. † Low dose aspirin defined as ≤325mg/day. ‡ Adjusted for age at index; sex, hypertension, coronary artery disease, cerebrovascular disease, peripheral vascular disease, congestive heart failure, diabetes, respiratory illness, gastrointestinal ulcer disease, thyroid disorders, depression/psychiatric illness and cancer, in the year preceding cohort entry; use of concomitant therapy including antilipemic agents, anticoagulants and low dose aspirin in the year preceding cohort entry; health care utilization including hospitalizations, outpatient visits to any physician and outpatient cardiologist visits, in the year preceding the index date; number of different drugs taken, chronic disease score and charlson index in the year preceding the index date and; past use of NSAID. Rate ratios are for current users compared to non-users. § ≤200mg/day and ≤25mg/day for celecoxib and rofecoxib respectively. * >200mg/day and >25mg/day for celecoxib and rofecoxib respectively.

15

Discussion

• Our findings are consistent with:– risk of AMI with rofecoxib– 1st to show risk is dose dependent– 1st to demonstrate effect modification of aspirin– No increase in risk observed for celecoxib or

nonselective NSAIDs– Acute risk consistent with reversible nature of COX-2

inhibition– Do not require long term exposure or previous AMI– Likely increase risk of 2-8 MI / 1000 exposed (small

individual risk but large public health impact)

Limitations

• Limited power for naproxen and meloxicam• Valdecoxib (Bextra) not studied• Only cases admitted to hospital included• Misclassification of exposure• Use of OTC aspirin and NSAIDs• Missing information

– Smoking– Obesity

Conclusion

• Current use of rofecoxib, particularly at doses of >25mg/day, is associated with an increased risk of myocardial infarction

• Risk is increased even for those receiving usual doses of this agent

• Risk is restricted to exposure immediately preceding the event consistent with an acute effect

• Concomitant use of aspirin mitigates risk in those receiving low doses

• Risk extends to younger and healthier elderly persons• No increased risk found for celecoxib

– Evidence for a broad class-effect for cox-2 mediated cardiotoxicity is unclear

In the meantime…

1. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease Lancet Oct 2002; 360: 1071-73

2. Effect of Selective Cyclooxygenase 2 Inhibitors and Naproxen on Short-term Risk of Acute Myocardial Infarction in the Elderly Arch Intern Med. 2003;163:481-486

3. Relationship Between Selective Cyclooxygenase-2 Inhibitors and Acute Myocardial Infarction in Older Adults Circulation. 2004;109:2068-2073

Lancet 2002

• Tendency for increase risk with high dose• No increase with low dose

Archives 2003

• No increased risk• Several methodological limitations

16

Circulation 2004

• Very elderly population• Increased rofecoxib risk depends on controls

Lancet 2004; 364: 2021-29

A 2004 Meta-analysis

Lancet 2004; 364: 2021-29

Naproxen Meta-analysis APPROVe Published online Feb 15 2005

APPROVe

• Hypothesis rofecoxib reduces risk of recurrent adenomatous polyps

• Main results regarding principal hypothesis still not published

• Generally no pre-existing heart disease• 20% ASA use for higher risk subjects

APPROVe Exclusions

• HBP, moderate angina or CHF, previous MI, revascularization within the preceding year, or stroke / TIA within two years before screening were excluded.

17

APPROVe APPROVe

APPROVe

• BP increased more with rofecoxib• No statistically interactions with age, sex,

heart disease, BP • CAD - RR 9.59 (95 %CI 1.36 to 416) to RR

1.58 (95 %CI 0.95 to 2.64) without.• Diabetics - RR 6.10 (95 %CI 1.36 to 56.1) to

RR 1.55 (95 %CI, 0.92 to 2.61) without

APPROVe

Published online Feb 15 2005 APC

• Randomized trial (n=2035)– Placebo-controlled, multicentre– Individuals with colonic polyps & no CVD– Celecoxib 400 or 800 mg/day vs placebo

• Primary endpoint:– Recurrence of colorectal polyp

• Generally free of CVD • Report of independent safety group

18

APC APC

APC APC

So, is the evidence clear for celecoxib?

• Randomized Clinical Trials• Observational Studies

Celecoxib RCTs

CAESAR 13/458 9/458 0.70 (0.28 to 1.58)

IQ5-97-02-001 3/140 11/285 1.65 (0.56 to 7.46)

CLASS 46/3981 48/3987 1.04 (0.69 to 1.57)

APC 6/679 35/1356 2.78 (1.32 to 7.53)

PreSAP 11/628 16/933 0.97 (0.46 to 2.16)

ADAPT 52/1759 18/704 0.88 (0.49 to 1.46)

Trial

Placebo/NSAIDsn/N

Celecoxibn/N

Odds Ratio (95% CrI)

0.2 1 5

Total 1.11 (0.78 to 1.58)131/7645 137/7723

19

Celecoxib Observational Studies

Cardiovascular risks with Celecoxib (Observational Studies)

0.990.9 0.93

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What about high risk patients?

THE CORONARY RISK OF CYCLOOXYGENASE-2 (COX-2) INHIBITORS IN SUBJECTS WITH A PREVIOUS

MYOCARDIAL INFARCTIONJames M. Brophy1,2 MD, PhD; Linda E. Lévesque1 BScPhm, MSc; Bin Zhang1 MSc

Submitted JAMA April 14 2005

High Risk Patients

Cases(n =3,423 )


Unadjusted rate ratio

Adjusted † rate ratio (95%CI) P Value *

No use ‡ (%) 932 (27.2) 19,647 (28.7) 1.00 1.00 (reference) Reference

Current use (%)

NSAIDs 59 (1.7) 1,191 (1.7) 1.10 1.00 (0.75-1.34) No previous MI 51 1,123 1.01 (0.74-1.38) Previous MI 8 68 0.95 (0.44-2.04)

0.87

Rofecoxib 297 (8.7) 4,603 (6.7) 1.43 1.28 (1.10-1.49) No previous MI 239 4,295 1.23 (1.05-1.45) Previous MI 58 308 1.59 (1.15-2.18)

0.14

Celecoxib 369 (10.8) 6,793 (9.9) 1.19 1.08 (0.94-1.25)

No previous MI 287 6,321 1.03 (0.88-1.20)

Previous MI 82 472 1.40 (1.06-1.84)

0.04

Past use (%) § 1,728 (50.5) 35,591 (52.0) 1.05 0.95 (0.86-1.05)

Effect of Dose in High Risk Patients

No previous myocardial infarction Previous myocardial infarction

Cases Controls Adjusted RR † (95% CI) Cases Controls Adjusted RR † (95% CI)

No use ‡ 793 18,502 1.00 (reference) 139 1,145 1.00 (reference)

Celecoxib 287 6,321 1.03 (0.88-1.20) 82 472 1.40 (1.06-1.84) Low dose § 208 4,704 1.01 (0.86-1.20) 57 349 1.32 (0.96-1.82) High dose * 79 1,617 1.06 (0.83-1.36) 25 123 1.60 (1.00-2.54)

Rofecoxib 239 4,295 1.23 (1.05-1.45) 58 308 1.59 (1.15-2.18) Low dose § 218 4,010 1.20 (1.02-1.42) 50 287 1.48 (1.06-2.07) High dose * 21 285 1.66 (1.04-2.63) 8 21 2.99 (1.25-7.14)

Published online Feb 15 2005

March 17

20

Valdecoxib Risk What do you think?

• Should Cox-2 inhibitors be banned?

Rofecoxib yes noCelecoxib yes noValdecoxib yes no

15 171 3113 17

FDA advisory vote Feb 18 2005

The FDA (Re)Acts

Pfizer Takes Painkiller Bextra Off Market

April 7, 2005Associated Press

WASHINGTON -- The blockbuster painkiller Bextra was yanked off the market Thursday, and the government ordered that 19 other popular prescription competitors -- fromCelebrex to Mobic to high-dose naproxen -- carry tough new warnings that they, too, may increase the risk of heart attacks and strokes.

Conclusions (1)

• Difficult to evaluate rare side effects from RCTs• Clear, consistent evidence risk with rofecoxib• Higher risk with dose• risk with celecoxib in high risk situations• risk of valdecoxib in high risk patients• Aspirin and individual risk profile may modulate• Small individual risk but large public health

Conclusions (2)

• Interpretation of scientific data is not absolute• Need more transparency

– Drug companies– Researchers– Media

• Easy to criticize retrospectively• Earlier investigation of harm by diverting advertising

money to post-marketing pharmacovigilence• FDA responds more to political pressure than science

example average - faculty of medicine and health sciences

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