Comparative Effectiveness Research

1. The use of administrative data and
natural language processing to
estimate the incidence of statin-
related rhabdomyolysis
James Floyd, MD, MS
HMORN Conference
May 3, 2012

2. Background: Statins and Rhabdomyolysis
• Statins
– Reduce the risk of cardiovascular events and death
– Can cause a spectrum of muscle injury
• Rhabdomyolysis
– Other causes: immobility, arterial ischemia, surgery
– Rhabdomyolysis related to statin use occurs about
once per 10,000 person-years of statin use

3. Background: Simvastatin
• SEARCH:1 Secondary prevention trial
comparing simvastatin 80mg/day vs 20mg/day
– Rhabdomyolysis RR 26
• FDA safety announcement: June 8, 2011
1. Lancet. 2010;376:1658.

4. Background: Study of Rare ADRs
• Spontaneous adverse event reports: FDA
AERS1
– Incomplete reporting of cases
– No information about denominators
• Administrative data in large health plans2
– Difficult to identify “statin-related” cases
– Among statin users in 11 health plans, only 24/194
(12%) of potential cases were validated
• Rhabdomyolysis ICD-9 code introduced in 2006
1. Staffa JA. NEJM. 2002;346:539.
2. Graham DJ. JAMA. 2004;292:2585.

5. Aims
• Aim #1: Evaluate use of the new ICD-9 code for
rhabdomyolysis as a method of identifying cases
of statin-related rhabdomyolysis
• Aim #2: Determine whether the markedly
increased risk of rhabdomyolysis associated with
high-dose simvastatin use can be detected
using these methods

6. Methods
• Setting: Group Health Cooperative, 2006-2010
– Electronic medical record introduced in 2005
• Statin use estimated from computerized
prescription data
• Statin-related rhabdomyolysis: Muscle
symptoms with peak creatine kinase (CK) level ≥
10x ULN, no other cause

7. Methods
• Rhabdomyolysis ICD-9 code (728.88)
• Other methods:
– ICD-9 code for adverse event of a lipid agent
– CK level > 5x ULN in GHC laboratory database
– Natural language processing (NLP)
• Incidence rates estimated from cases divided by
person-years of statin use
– One set of cases identified only by rhabdo ICD-9
code
– Second set of cases validated by EMR review

8. Results: Case Identification
Validated
Reviewed Cases
Case identification method N N %
Rhabdomyolysis ICD-9 292 22 8%
Other criteria
AE of lipid agent ICD-9 30 1 3%
CK > 1000 IU/L 39 1 3%
Natural language processing 438 5 1%
Total, all methods 799 29

9. Results: Characteristics of Cases
Validated
Cases
N=29
Age, median (range) 73 (53-87)
Female 18 (62%)
Hospitalized 26 (90%)
Renal failure 8 (29%)
Hemodialysis 2 (7%)
Death 0 (0%)
Creatine kinase, median (range) 7,450 (1,477-150,510)

10. Results: Incidence Rates
Validated Person-Years Incidence
Statin Cases Statin Use Rate* 95% CI
Simvastatin 23 170,605 14 9-20
<20 mg/day 0 21,832 0 0-17
20-39 mg/day 4 75,082 5 2-14
40-79 mg/day 8 56,703 14 6-28
≥80 mg/day 11 18,876 65 32-117
Other statins** 6 116,154 5 2-11
*Cases per 100,000 person-years statin use
**Non-simvastatin use primarily lovastatin (69%) and atorvastatin (24%)

11. Results: Incidence Rate Ratios
Comparison Rhabdo ICD-9 Cases Validated Cases
Simvastatin vs other statins 1.0 2.6
(95% CI) (0.8 - 1.3) (1.0 - 7.8)
Simvastatin 80mg vs 20mg 1.8 12.2
(95% CI) (1.1 - 2.9) (3.6 - 52)

12. Summary of Findings
• Poor positive predictive value of rhabdomyolysis
ICD-9 code: 8%
• NLP detected additional cases
• Use of administrative data without medical
record review may fail to detect important harms
• Confirmed in a community setting the increased
risk with high dose simvastatin in SEARCH trial

13. Acknowledgements
Cardiovascular Health Research Unit, University of Washington
Bruce Psaty
Susan Heckbert
Noel Weiss
Group Health Research Institute, Group Health Cooperative
David Carrell
Eric Larson
NHLBI T32 Training Grant
PI David Siscovick
NHLBI grants HL078888 and HL085251
PI Bruce Psaty

14. THANK YOU

15. Potential Confounding
Simvastatin dose Mean age Fibrate use
20-39 mg/day 75 25%
80+ mg/day 68 27%

16. Diffusion of rhabdo ICD-9 code
Cases: Cases:
Rhabdo Other Simvastatin Other Simvastatin Other
Year ICD9 methods P-Y P-Y Cases Cases
2006 2 0 13,750 36,758 0 2
2007 2 2 22,034 31,082 2 2
2008 4 2 41,709 15,827 5 1
2009 8 1 45,171 15,755 8 1
2010 6 2 47,940 16,732 8 0