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A Cutrell, J Hernandez, C Brothers , J Yeo, W Burkle, W Spreen.

Is abacavir (ABC)-containing combination antiretroviral therapy (CART) associated with myocardial infarction (MI)? No association identified in pooled summary of 54 clinical trials. A Cutrell, J Hernandez, C Brothers , J Yeo, W Burkle, W Spreen.

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A Cutrell, J Hernandez, C Brothers , J Yeo, W Burkle, W Spreen.

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  1. Is abacavir (ABC)-containing combination antiretroviral therapy (CART) associated with myocardial infarction (MI)? No association identified in pooled summary of 54 clinical trials A Cutrell, J Hernandez, C Brothers, J Yeo,W Burkle, W Spreen. XVII International AIDS Conference, 3-8 August 2008, Mexico City Cutrell A, Hernandez J, Brothers C et al. 2008

  2. Background and Objective • The D:A:D study group recently reported an unexpected increase in risk of MI with ABC and ddI in a large, prospective observational cohort(Lancet 2008; 371:1417-26). • To determine whether there is an increase in cardiovascular events associated with ABC containing CART as compared to non-ABC containing CART using GSK-sponsored clinical trials contained in the GSK HIV Data Repository. Cutrell A, Hernandez J, Brothers C et al. 2008

  3. Methods (1) • GSK-sponsored clinical trials with > 24 weeks of follow up with data from 1995-2006 were analyzed. • Data from 54 clinical trials analyzed: • 12/54 adult trials were randomized for ABC vs control • 33/54 trials included ABC in background ART • 8/54 trials did not include ABC • Includes data from 14683 subjects (14174 adults and 509 children) • Descriptive statistics were summarized for naïve and experienced subjects treated with and without ABC. Cutrell A, Hernandez J, Brothers C et al. 2008

  4. Methods (2) • To capture events of interest (myocardial ischemia or infarction) all data were queried for events coded as “Coronary Artery Disorders” and “Ischemic Coronary Artery Disorders”. • Specific preferred terms included: coronary artery atherosclerosis, coronary artery disease, coronary artery occlusion, acute MI, angina pectoris, angina unstable, MI and myocardial ischemia. • All fatal cases (any cause) in the HIV Data Repository were reviewed by an external cardiologist. • Framingham risk not calculated at baseline – not all factors routinely collected. • Rates per 1000 person/years were calculated, and Poisson regression models were used to calculate unadjusted relative rates and 95% confidence intervals using SAS. Cutrell A, Hernandez J, Brothers C et al. 2008

  5. Demographic and HIV-disease Characteristics at Baseline Cutrell A, Hernandez J, Brothers C et al. 2008

  6. Baseline Lipids and Glucose (mmol/L) Cutrell A, Hernandez J, Brothers C et al. 2008

  7. CV Outcomes - Exposure to ABC Compared with No Exposure to ABC Cutrell A, Hernandez J, Brothers C et al. 2008

  8. CV Outcomes - Exposure to ABC or No ABC (12 Adult Randomized Trials) Cutrell A, Hernandez J, Brothers C et al. 2008

  9. Prospective clinical trial data with large number of patients exposed to ABC, consistent data collection Standard and real-time monitoring and follow up of all reported AEs External expert review supportive Post-hoc analysis Duration of exposure on average 24-48 weeks Studies not designed to detect CV risk specifically Low event rate therefore less power Strengths and Limitations Cutrell A, Hernandez J, Brothers C et al. 2008

  10. Conclusion • Overall, among pts in the GSK HIV Data Repository: • the incidence rate of MI and Coronary Artery Disorders was low • there was no difference in incidence of ischemic coronary artery events or myocardial infarction in subjects who received abacavir-containing vs. non-ABC containing CART • Further study is needed to fully evaluate the association of ABC and cardiovascular disease. Cutrell A, Hernandez J, Brothers C et al. 2008

  11. What’s Next to Further Address the Question? • Analysis of Internal Clinical Trial Data • Continued vigilance of spontaneous event data and published literature • In all future studies, incorporate cardiovascular risk factor and biomarker collection • Mechanism research • Analyze inflammatory markers in current and future studies • Support additional cohort collaborations Cutrell A, Hernandez J, Brothers C et al. 2008

  12. HEAT Biomarker Analysis: Geometric Mean (95% CI) by Study Week (ITT-E) High Sensitivity C-Reactive Protein (hsCRP) Interleukin 6 (IL-6) n (obs) ABC/3TC = 243 248 230 256 251 232 TDF/FTC = 249 235 216 252 236 216 Cutrell A, Hernandez J, Brothers C et al. 2008 Adapted from Smith K, et al. IAC 2008. Abstract LBPE1138.

  13. Acknowledgments The authors wish to thank… • Harry Staines, Suki Pabla, Dupe Bassey, Lee Tombs and Pinal Patel at SRG Interesource Satellite Operations for statistical support • Drs. Peter Kowey & Gary Koch for expert input • Investigators who supported the clinical trials • All of the patient volunteers. Cutrell A, Hernandez J, Brothers C et al. 2008

  14. Back up slides Cutrell A, Hernandez J, Brothers C et al. 2008

  15. Percent 0.139% 0.129% 0.125% Non-ABC 7/5043 Total 19/14682 ABC 12/9639 n/N= Cutrell A, Hernandez J, Brothers C et al. 2008 Cutrell A, Hernandez J, Brothers C et al. 2008

  16. Percent 0.169% 0.188% 0.125% Total 14/8265 Non-ABC 3/2406 ABC 11/5859 n/N= Cutrell A, Hernandez J, Brothers C et al. 2008 Cutrell A, Hernandez J, Brothers C et al. 2008

  17. Percent 0.067% 0.177% 0.027% Non-ABC 4/2266 Total 5/5908 ABC 1/3643 n/N= Cutrell A, Hernandez J, Brothers C et al. 2008 Cutrell A, Hernandez J, Brothers C et al. 2008

  18. Abacavir and Risk of MI:Evaluation of potential biologic mechanisms • Review of preclinical, clinical pharmacology and clinical information does not indicate a clear contribution of abacavir therapy to enhanced risk of MI via plausible biologic mechanisms. Rather, the preponderance of data support a conclusion of a generally favorable cardiovascular safety profile. Cutrell A, Hernandez J, Brothers C et al. 2008 Cutrell A, Hernandez J, Brothers C et al. 2008

  19. Safety pharmacology • Isolated cardiac muscle (rat, guinea-pig & cat): • No inotropic, chronotropic or dysrythmic effects. • Concious normotensive rat: • No effect on Arterial BP or heart rate (100mg/Kg). • Anesthetized dog: • Little effect on ABP or HR, no arrhythmia (50 mg/Kg IV) • No effect on 19 receptor binding sites, including: • cholinergic, adrenergic, histaminergic and serotonergic. • No effect in tissue responsiveness to arachidonic acid, bradykinin and angiotensin II Cutrell A, Hernandez J, Brothers C et al. 2008 Cutrell A, Hernandez J, Brothers C et al. 2008

  20. Incidence of Serious CV Events D:A:D Study, VA Study & GSK Data Repository Sabin C, et al. 15th CROI 2008: Abstract. Bozzette S, et al. J Acquir Immune Defic Syndr 2007;0:1-4. Cutrell A, Hernandez J, Brothers C et al. 2008

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