# Presentation: 670345

## Review of Epidemiologic Studies on Cardiovascular Risk with Selected NSAIDs

- David J. Graham, MD, MPH
- Office of Drug Safety
- Center for Drug Evaluation and Research
- February 17, 2005

## Purpose and Methods

- To evaluate epidemiologic data from the published literature plus 2 currently unpublished studies evaluated by this reviewer
- Focus:  studies providing estimates of risk of acute myocardial infarction in the setting of use of COX-2 selective NSAIDs or naproxen
- PubMed search by specific NSAID, with cross-checking of cited references

## Comments on Estimation of Excess Cases of AMI

- Tomorrow, FDA will present its estimation of the number harmed by rofecoxib, modeling RCT survival curves
- Assumes “grace period” based on VIGOR & APPROVe
- Unreliable due to extremely low statistical power
- Based on total of small # MI events over duration of trial
- Epi studies based on 3- to 50-fold more events: more power
- Based on epi data, rofecoxib risk begins early in therapy
- No “grace period”
- Patients enrolled in RCTs are generally healthier than “real-world”
- Therefore, RCTs will underestimate true risk and population impact because their background rate is lower

## Overview of Epidemiologic Studies on COX-2 AMI Risk (1)

-                         Source                            Ref            Popln     Person-Yrs
- _Study_               _Popln_          _Design_      _Group_          _Size_       _Observed_      _Age_
- Ray                Medicaid       Cohort      Nonuse       454 K        428 K         50-84
- Graham            HMO           NCC        Remote        1.4 M        2.3 M         18-84                                                    			             Celecoxib
- Solomon        Medicare        CC          Multiple         54 K           -               65
- Mamdani        Ontario         Cohort      Nonuse       167 K         76 K           66
- Kimmel        Community       CC          Remote           -               -              40-75
- Ingenix	         MCO           Cohort      Ibu/Diclo      424 K        177 K        40-64
- Medi-Cal	      Medicaid         NCC        Remote       651 K         2.4 M        18-84

## Overview of Epidemiologic Studies on COX-2 AMI Risk (2)

-                                                                      Number of Cases
-                      Case 		              Rofecoxib                    Celecoxib
- _Study_            _Defn_        _Cases_       _All doses_     ___25 mg_     _>25 mg_      _All doses_
- Ray 	      +SCD       5,316            68               55             13	            74
- Graham       +SCD        8,143           68               58             10             126
- Solomon      HAMI       10,895         225             202             23             425
- Mamdani      HAMI           701           58	      -	         -	            75
- Kimmel         HAMI*       1,718           27               25              2               18
- Ingenix         +SCD          628*         124*             83*              9*            139*
- Medi-Cal      HAMI      15,343       1,117	  960	     157	       1,862

## Overview of Epidemiologic Studies on COX-2 AMI Risk (3)

-                                                      Special
- _Study_        _Aspirin_   _Smoking_       _Features_                        _Limitations_
- Ray              No          No       New-user analysis       Low rofecoxib use; no med recs
-                                                                                   possible dose misclassification
- Graham       No*         No*       Inception cohort          Low rofecoxib use;
-                                                *Survey of controls
- Solomon      No          No       Duration analysis         No SCD; multiple comparisons;
-                                               Beneficiary survey       no med recs; possible dose misclassification
- Mamdani     No          No                   -                       Low rofecoxib use; prevalence cohort;
-                                                                                   excluded < 30 d users; no SCD;
-                                                                                   no dose/duration analysis; no med recs
- Kimmel        Yes        Yes      Direct interview            Low rofecoxib use, very low high dose use;
-                                                                                   55% case/50% control participation;
-                                                                                   no fatal AMI or SCD; self-report-?recall bias
- Ingenix	    No	  No        NDI search	  Identified 1798 cases; included only 628;
- 		              New-user analysis	  no non-user reference; low high-dose use;
- 		              Med record review	  possible dose misclassification
- Medi-Cal     Yes        No         Inception cohort	  New database for research purposes;
- 					  no med recs; possible dose misclassification

## California Medicaid

- Strengths
- Large sample size – over 7 million persons per year
- OTC aspirin data
- No censoring at age 65 (dual coverage with Medicare)
- Matching with multiple cause-of-death data
- Long durations of follow-up with low drop-out rates
- Sicker population than private-payors, so easier to detect drug safety signals
- Limitations
- No access to medical records (HIPAA)
- Very complicated data – difficult to understand and analyze.  Therefore, not used often for drug safety research.

## Unmeasured CV Risk Factors and NSAID Use

- Graham			_Celecoxib_    _Rofecoxib_    _Naproxen_    _Remote_
-  	Aspirin		     19%             23%             28%           24%
- 	Smoking                         9%               7%             11%           11%
- 	OTC NSAIDs                15%             14%             12%           13%
- Solomon			_Celecoxib_    _Rofecoxib_    _NSAIDs_
- 	BMI		     27.5            27.2           27.7
- 	Aspirin		     8.2%         11.5%        10.2%
- 	Smoking                       8.7%           7.0%          9.8%
- 	College+		   29.6%         31.8%       26.5%
- 	Income                        Same           Same       Lower
- Kimmel			_Celecoxib_    _Rofecoxib_    _NSAIDs_    _Remote_
- 	BMI		     29.7           28.0            27.7         27.2
- 	Aspirin		    27.6%        32.1%         21.7%      28.8%
- 	Smoking
- 	           Current	    17.2%          6.5%         19.9%      21.2%
- 	           Past	    43.7%	      42.9%         31.8%      32.0%
- 	Physical activity	      7.0             7.2             7.4            7.4

## Risk of AMI with Rofecoxib

- _Study_	     _Ref_	           _All doses_                ___25 mg_	           _>25 mg_
- Ray	     Non	                 - 	        1.02 (0.76-1.37)      1.93 (1.09-3.43)
- Graham       Rem         1.34 (0.98-1.82)      1.23 (0.89-1.71)      3.00 (1.09-8.31)
- Solomon      Rem         1.14 (1.00-1.31)               -                             -
- Mamdani      Non	      1.00 (0.80-1.40)               -                             -
- Kimmel        Rem         1.16 (0.70-1.93)               -                             -
- Ingenix        Active       1.41 (1.07-1.84)       1.54 (1.15-2.04)      0.81 (0.41-1.60)*
- Medi-Cal      Rem        1.32 (1.22-1.42)       1.29 (1.19-1.40)      1.56 (1.28-1.90)

## Preliminary Results: Medi-Cal Study Dose Response for AMI Risk with Rofecoxib

**Odds Ratio**

**1.16**

**1.31**

**1.54**

**2.40**

**Singh et al.**

## Risk of AMI for Rofecoxib vs Celecoxib

- 				Rofecoxib
- _Study_	         _All doses_		___25 mg_		    _>25 mg_
- Ray		 -		     -		2.20 (1.17-4.10)
- Graham     1.59 (1.10-2.32)       1.47 (0.99-2.17)	3.58 (1.27-10.11)
- Solomon    1.24 (1.05-1.46)       1.21 (1.01-1.44)	1.70 (1.07-2.71)
- Kimmel	    2.72 (1.24-5.95)                  -                                -
- Medi-Cal    1.22 (1.11-1.33)                  -                                -

## Individual Excess Risk of AMI or SCD per Year from Rofecoxib Use for an Average 65-74 Year Old US Man, based on Epidemiolgic Data

- 		  	   Based on	        Based on
- 			_point estimate_	  _95% upper bound_
- 	___25 mg_
- Ray			       1/2500         	           1/135
- Graham			       1/217           	           1/70
- Ingenix			       1/93		           1/48
- Medi-Cal			       1/172	           1/125
- 	_>25 mg_
- Ray			       1/54	          	           1/21
- Graham 			       1/25	          	           1/7
- Medi-Cal			       1/89		           1/56

## Excess Population Risk of AMI or SCD in 1 Million US Men 65-74 Years Old Treated with Rofecoxib per Year, Based on Epidemiolgic Data

- 			   Based on	     Based on
- 			_point estimate_	_upper 95% bound_
- 	___25 mg_
- Ray			         400	          7,400
- Graham			      4,600	        14,200
- Ingenix			    10,800	        20,800
- Medi-Cal		      5,800	          8,000
- 	_>25 mg_
- Ray 			    18,600	        48,000
- Graham			    40,000	      146,200
- Medi-Cal		    11,200	        18,000

## AMI Risk with Rofecoxib and Duration of Use

- Graham et al.            _50%_       _75%_     _95%_
- 	  25 mg      <2 m       5 m     13 m
- 	  >25 mg      <3 m       6 m       9 m
- Solomon et al.		    _Days 1-90_
- 	   25 mg	1.37 (1.15-1.63)
- 	   >25 mg	1.38 (0.80-2.37)
- Kimmel et al.                   25/27 cases 25 mg
- 		         102/105 patients 12 m
- 			   _Days 1-30_
- Solomon et al.       	1.43 (1.12-1.83)
- Ingenix             		1.51 (0.98-2.34)

## Risk of AMI with Celecoxib

**Relative Risk**

## Risk of AMI with Celecoxib – the effect of dose

**Relative Risk**

## Preliminary DataRisk of AMI with Valdecoxib

- 		_# cases_		_OR (95% CI)_
- Medi-Cal                54                0.99 (0.72-1.37)
- Mostly 10 and 20 mg.  Medi-Cal only reimburses 10 mg tabs

## Overview of Epidemiologic Studies on Naproxen AMI Risk (1)

- 	             Source                              Ref            Person-Yrs
- _Study_                    _Popln_           _Design_        _Group_         _Observed_       _Age_
- Ray	            Medicaid        Cohort        Nonuse         428 K         50-84
- Graham                HMO             NCC          Remote          2.3 M        18-84
- G Rodriguez        GPRD            NCC          Nonuse             -             50-84
- Rahme               Quebec            NCC        Other NSAIDs      -               65
- Mamdani            Ontario           Cohort        Nonuse            76 K          66
- Schlienger          GPRD              NCC         Nonuse             -             18-75
- Kimmel            Community          CC           Remote             -             40-75
- Solomon      **Medicaid/Medicare**      CC           Remote	   -                -
- Watson              GPRD               NCC         Nonuse             -             40-79
- Ingenix               MCO               Cohort       Ibu/Diclo         177 K        40-64
- Medi-Cal	         Medicaid             NCC         Remote	  52 K       18-84

## Overview of Epidemiologic Studies on Naproxen AMI Risk (2)

-                                Case                                                    Naproxen
- _Study_                 _Defn_            _Aspirin_       _Smoking_          _Cases_
- Ray                   +SCD              No               No                201
- Graham             +SCD              No*              No*              367
- G Rodriguez      +SCD              No              Yes               49
- Rahme               HAMI             Yes*              No              397
- Mamdani           HAMI               No               No                15
- Schlienger         HAMI               No              Yes               19
- Kimmel              HAMI*             Yes              Yes                ?
- Solomon            HAMI               No               No	               ?
- Watson          Composite  	     No*             Yes              26*
- Ingenix              +SCD               No               No             179*
- Medi-Cal            HAMI              Yes               No	            368

## Overview of Epidemiologic Studies on Naproxen AMI Risk (3)

- _Study _                   _Limitations_
- Ray	             Poisson assumption of constant hazard
- G Rodriguez         Definition of current exposure included potentially
- 	             unexposed time (Rx ended within 30d of index date)
- Rahme                 Excluded past AMI; relied on current exposure to
-                              another NSAID as reference; no external reference
- Schlienger            Small # events;
- 	             excluded patients with underlying CV disease
- Kimmel                 2o or 3o analysis; small # events
- Solomon	             Misclassified exposure (any exposure in past 6 mos);
- 	             excluded patients with CV risk; adjustment based on
- 	             diagnoses rather than Rxs
- Watson                 Small # events; excluded prior CV disease & Rxs;
- 	             composite outcome (AMI, CVA, SAH, SDH);
- 	             failed to adjust, or poorly adjusted for CV risk

## Risk of AMI with Naproxen

**Relative Risk**

## A Closer Look at 4 “Positive” Naproxen Studies

- Solomon
-       _Any use_              _Current use_              _Recent use_             _Remote use_
-  0.84 (0.72-0.98)    0.86  (0.64-1.16)      0.84 (0.63-1.12)     0.76 (0.56-1.03)

-            Watson
-                                _ __Age_  _Sex_  _Yr_  _DM_  _CVrisk_  _Comorb_  _Smoke_  _DMARDs_  _Steroids_
-    0.61 (0.39-0.94)      +      +     +     +                     +                                            +
-    0.57 (0.31-1.06)      +      +     +               +           +                                            +
-    0.53 (0.22-1.28)      +      +                      +                         +             +               +

- Rahme
- Current naproxen *vs* _other NSAIDs_: 0.79 (0.63-0.99)
- Reanalyzed, current naproxen *vs* _nonuse_: 1.28 (1.10-1.49), p=.001

- Kimmel
- 0.48 (0.32-0.73)
- Small #s; 50% participation rate; mixing of Rx & OTC use; “reverse” recall bias

## Preliminary Data: Medi-Cal StudyOther NSAIDs

- 		            _# cases_		_OR (95% CI)_
- Ibuprofen	               719	           1.11 (1.01-1.22)
- Indomethacin	               109	           1.71 (1.35-2.17)
- Meloxicam	                 81	           1.37 (1.05-1.78)
- Nabumetone	                 51                0.83 (0.60-1.14)
- Sulindac                             56                1.41 (1.01-1.96)
- Non-coxib NSAIDs        2,006                1.12 (1.06-1.19)

## Dose-Response Relationship of AMI risk with NSAIDs

**Odds Ratio**

## Preliminary Data: Medi-Cal StudyRisk of AMI Compared to Non-Coxib NSAIDs

- 		  _OR (95% CI)_
- Celecoxib	0.97 (0.90-1.05)
- Rofecoxib	1.18 (1.07-1.29)
- Valdecoxib	0.88 (0.64-1.22)

## Conclusions Regarding Risk of Acute MI:COX-2 Selective NSAIDs

- Celecoxib
-  200 mg: no apparent effect
- > 200 mg: probable increased risk
- Rofecoxib
-  25 mg: probable increased risk
- >25 mg: definite increased risk
- Risk begins early in therapy, and is apparent during days 1-30 of use
- Valdecoxib
-  20 mg: no apparent effect

## Conclusions Regarding Risk of Acute MI:“Non-selective” NSAIDs

- As a class, non-coxib NSAIDs may increase risk
- Differences exist between non-coxib NSAIDs with respect to risk
- Naproxen is not cardio-protective

## Open Questions

- Differential NSAID risk
- Dose response
- Duration effect
- Persistency of risk
- Actual benefit in the population
- CHF
- Stroke