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Chenxiong (Charles) Le, Ph.D. OBI/OB/OPaSS/CDER, FDA Cardiovascular and Renal Drugs

Issues with the statistical analyses in the citizen’s petition for aspirin on reduction of the risk of 1 st MI. Chenxiong (Charles) Le, Ph.D. OBI/OB/OPaSS/CDER, FDA Cardiovascular and Renal Drugs Advisory Committee Meeting December 8, 2003. Outline. Background

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Chenxiong (Charles) Le, Ph.D. OBI/OB/OPaSS/CDER, FDA Cardiovascular and Renal Drugs

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  1. Issues with the statistical analyses in the citizen’s petition for aspirin on reduction of the risk of 1st MI Chenxiong (Charles) Le, Ph.D. OBI/OB/OPaSS/CDER, FDA Cardiovascular and Renal Drugs Advisory Committee Meeting December 8, 2003

  2. Outline • Background • Sponsor’s ‘meta-analysis’ • HOT study issues • Pooled analysis issues • Exploratory benefit-risk analysis • Summary

  3. Background • The Sponsor requested amendment to the Professional Labeling for aspirin • Indication: Low dose aspirin (75 mg – 325 mg) reduces the risk of a 1st myocardial infarction (MI) in patients with a CHD risk of 10% or greater over 10 years, or there is a positive benefit-risk as assessed by their health care provider • Five studies were selected to support this citizen’s petition

  4. Background • Five studies • (BDT) British Doctor’s Trial (N=5139) • (PHS) Physician’s Health Study (N=22071) • (TPT) Thrombosis Prevention Trial (N=5085) • (HOT) Hypertension Optimal Treatment Study (N=18790) • (PPP) Primary Prevention Project (N=4495) • Total # of subjects = 55580

  5. Background • The agency considered aspirin (BDT and PHS) for this indication before and did not approve it • PHS showed that some patients had a prior MI and aspirin is already known to reduce the risk of recurrent MI • PHS did not achieve statistical significance when all deaths as well as nonfatal MI and stroke were combined • BDT, despite its similarity to PHS, was neutral on the effect of aspirin on MI

  6. Background • What is new in this petition? • Three new studies (TPT, HOT, PPP) were included • HOT (N = 18790) is the largest among the three studies (TPT, N = 5085, PPP, N = 4495) • Sponsor’s ‘Meta-analysis’ of the five studies was submitted to support the petition

  7. Sponsor’s ‘meta-analysis’ Nonfatal MI

  8. Sponsor’s ‘meta-analysis’ Composite of MI, stroke and CV death

  9. Sponsor’s ‘meta-analysis’ Cardiovascular death

  10. The HOT study Silent MI matters • Primary endpoint was major CV events (non-fatal and silent MI, non-fatal stroke, and cardiovascular death) • Silent MIs were obtained by comparing the ECGs at baseline and final visit • n=9399 in aspirin and n=9391 in placebo

  11. The HOT study Silent MI matters • There were 48% and 31% silent MIs in the aspirin group and placebo group, respectively Note: 14% of the patients’ ECGs were not available .

  12. The HOT study Silent MI matters Source: Final report of the HOT study, THE LANCET, 1755-1762, Vol 351, 1998

  13. The HOT study issues • The published paper reported that statistical significance was achieved for the composite endpoint of non-fatal MI, non-fatal stroke, and CV death, and for MI alone. This is misleading • Silent MIs should be included in both efficacy endpoints according to the study protocol • When silent MIs are included, both the primary endpoint (non-fatal & silent MI, non-fatal stroke, and CV death) and MI alone are not statistically significant

  14. Pooled analysis Studies’ summary Source: FDA’s clinical review by Dr. Juan Carlos Pelayo.

  15. Pooled analysis • The patient populations were quite different among the 5 studies (ranging from apparently healthy physicians to patients at high risk of CV disease) • Aspirin doses vary from 75 mg daily to 500 mg daily, including 325 mg every other day

  16. Pooled analysis Primary Efficacy Endpoints Source: FDA’s clinical review by Dr. Juan Carlos Pelayo. NS: Not significant. NA: Not Available

  17. Pooled analysis MI (fatal and nonfatal) (Individual studies) *Silent MIs included. The relative risk, p-value and 95% CI are from Mantel-Haenszel method.

  18. Pooled analysis MI (fatal and nonfatal) *Silent MIs included. #The relative risk, p-value and 95% CI are from Mantel-Haenszel method.

  19. Pooled analysis issues • Some issues associated with the pooled analysis • Why and how the 5 studies were selected • Patient populations are very different among the 5 studies • Aspirin doses are quite different

  20. Overall evidence for MI • MI is only a secondary endpoint in all 5 studies Silent MI is an issue • PHS suggested potential benefit • TPT had a nominal p-value = 0.04 • HOT is not clear • BDT and PPP failed to show statistical significance • The pooled analysis did not provide any additional information beyond those provided by the individual studies

  21. Exploratory benefit-risk analysis • The new indication will expand the risk population • Bleeding is one of the known adverse events for aspirin • Benefit-risk ratios should be considered

  22. Exploratory benefit-risk analysis MI and major bleeding (HOT) Silent MIs included. Multiple Bleeds in the same patient counted only once.

  23. Exploratory benefit-risk analysis Let PT and PS be the probability of MI-free in aspirin group and placebo group, respectively. Let QT and QS be the probability of major bleeding in aspirin group and placebo group, respectively. A possible measure of benefit-risk ratio: R = (PT – PS) / (QT – QS) Ref: Andrew R. Willan etc. Benefit-Risk Ratios in the Assessment of the Clinical Evidence of a New Therapy. Controlled Clinical Trials 1997; 18:121-130

  24. Exploratory benefit-risk analysis • R measures how many MIs can be prevented at the cost of one major bleeding by using aspirin. CI can be obtained as well • From the HOT study (CIs are wide) Definition of major bleedings can be found in the final report of the HOT study, THE LANCET, 1755-1762, Vol 351, 1998

  25. Exploratory benefit-risk analysis • Overall, 54 MIs may be prevented at the cost of 100 major bleeds by using aspirin • For male, 85 MIs may be prevented at the cost of 100 major bleeds by using aspirin • For female, 14 MIs may be prevented at the cost of 100 major bleeds by using aspirin

  26. Summary • MI is only a secondary endpoint in all 5 studies. Silent MI is an issue • For primary prevention of MI, • PHS suggested potential benefit • TPT had a nominal p-value = 0.04 • HOT failed to show statistical significance when silent MIs were included (protocol specified) • BDT failed to show statistical significance • PPP failed to show statistical significance

  27. Summary • Some issues with the pooled analysis • Studies selection (how and why) • Risk factor of the patient population • Aspirin doses • The pooled analysis does not provide any additional information beyond those provided by the individual studies • The benefit and risk should be considered

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