Antithrombotic Treatment and the Incidence of Angina Pectoris

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Antithrombotic Treatment and the Incidence of
Angina Pectoris

• Gloria Wu, M.D.
• 5/15/02

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Why study Warfarin as a treatment for Angina
Pectoris?

• Warfarin is known to have beneficial effect on
  IHD
• The PCABG trial found that effect of warfarin was
  only seen on long term follow-up, suggesting that
  it may act by reducing the formation of atheroma
• delaying onset of angina may be associated with
  reduced risk of future IHD events

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Thrombosis Prevention Trial

• -1983-92, Great Britain
• -low-dose antithrombotic treatment in preventing
  angina and major CHD
• -Prevention of CHD- results published in 1998

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Study Design

• 45-69 year-old men recruited from 108 general
  practices in Britain.
• 25 highest risk patients eligible to enter study
  (BMI, total cholesterol, BP, plasma fibrinogen,
  factor VII activity)
• Excluded patients with angina, risk factors for
  bleeding
• Mean INR1.5 ASA dose 75mg

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Prefactorial Phase(1983-89)
1427 Patients
706 Warfarin
721 Placebo
Factorial Phase (1989-92)
221 Withdrew
193 Refused Factorial
1013 Entered Factorial Stage
4072 entered Factorial Stage directly
1268 warfarin placebo
1277 warfarin aspirin
1268 placebo aspirin
1272 placebo placebo
751 withdrew
735 withdrew
735 withdrew
748 withdrew
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Study Design cont

• Follow up 6.8 yrs for major outcomes (MI or
  coronary death) and 5.0 yrs for angina
• Diagnosis of angina definite Vs probable Vs
  doubtful (table 1)
• Annual medical exam, reports by research nurses
  in between annual exams, patients withdrawing
  from trial secondary to angina

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Is this a good study?

• Randomization
• Double-blinded and placebo
• Similarities among groups
• Groups treated equally
• Intention to treat

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Randomization and similarities among groups

• Random allocation through computer-generated
  numbers
• Similar characteristics among treatment groups

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Characteristics at trial entry
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Double-blind and placebo controlled

• Prolonged bleeding led some practice staff and
  men in the trial to assume they were on active tx
• Treatment code was broken in emergencies (such as
  major bleed), medication incompatible with trial
  tx.

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Are the groups treated equally?

• Dosage changes made for those on placebo as on
  active treatment
• Equal testing among groups

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Results- major CHD

• Prevention of major CHD warfarin and ASA each
  reduced the incidence of CHD by 20(p0.02)
• Warfarin reduces fatal episodes by 39(p0.003),
  while ASA reduces nonfatal episodes by
  32(p0.004)
• Combined tx reduces fatal or nonfatal by 34
• major CHD defined as coronary death and fatal
  and nonfatal MI
• results published in Lancet, 1998

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Results- incidence of all angina

• Total 128 definite cases, 76 probable cases, 15
  doubtful cases
• Warfarin reduces all angina(definite and
  probable) by 11(p0.42), NNT200
• ASA increases all angina (definite and
  probable)by 33(p0.05)

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Results stable angina

• Warfarin reduces the incidence of stable angina
  by 16(p0.26)
• ASA increases the incidence of stable angina by
  39(p0.05)

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Discussion

• No significant reduction in angina but
  significant reduction in major CHD. Why?
• -was follow-up time sufficient? (gt85 of onset
  of angina occurred gt12months)
• -was diagnosis of angina made correctly?
• - is there a poor correlation between symptom
  and severity of disease?

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Discussion cont

• How about combining ASA and warfarin in
  preventing angina?- 27 increase in all angina
• Why did ASA increase the incidence of angina?
• Comparison with other studies- unclear if ASA has
  any effect on the incidence of angina

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Aspirin and Incident Angina
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Are the results applicable to our patients?

• Are our patients different?
• Is the treatment feasible in our setting?
• What are our patients potential benefits and
  harms from the therapy

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Patient Population

• 45-69 y.o. men recruited from 108 practices in
  Great Britain
• Demographics not reported, but most likely
  Caucasian
• High risk patients

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Is the treatment feasible?

• Requires monitoring of INR at least once every 6
  months
• Study was conducted in a controlled environment
  and only 5 noncompliance
• Maybe more feasible if home-monitoring becomes
  available

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Risk of bleeding
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Conclusion

• 1. Is incidence of angina lowered by warfarin?
  More evidence needed
• 2. Low dose warfarin prevents CHD in high risk
  patients- must weigh risks and benefits.
• 3. ASA increases incidence of angina
  significantly