Unstable angina: stopping heparin without aspirin caused recurrent angina and increased urgent interventions.

Clinical bottom line (level 1b)

  1. Abruptly stopping heparin without aspirin in patients being treated for unstable angina caused rebound angina and an increase in urgent intervention within the next 96 hours.
  2. Problems occured sooner in patients who were on heparin alone.
  3. Patients who had been on heparin and aspirin had less recurrent angina, MI or death (NNT = 12 at 4 days) , and fewer urgent interventions (NNT = 10 at 4 days) than those just on heparin.
  4. There was no clear difference in mortality.
Theroux et al: New England Journal of Medicine 1992; 327 (3): 141-145
Expires July 2003

The study

Double-blinded concealed randomised trial without intention-to-treat
Setting: continuation of RCT, two teaching hospitals, Canada

403 patients (aged mean 57 years, 72% male) hospitalised with unstable angina (history of accelerating pattern of chest pain occurring at rest or with minimal exercise, or chest pain >20 minutes with serum CK< twice upper limit of normal, and ECG changes compatible with ischaemia) who completed six days of therapy

Excluded if
  • died, had refractory angina or MI during first six days of study
  • regular use of aspirin or other anticoagulant
  • prior PTCA <6 months
  • CABG <12 months
  • age >75
  • identifiable precipitating causes


    • Control Group: (n = 87, 87 analysed): placebo (large number of patients excluded with 'events' during initial 6 day period)
    Experimental Group: (n = 101, 101 analysed): aspirin 325 mg bd po daily and placebo "heparin"
    Experimental Group: (n = 107, 107 analysed): heparin 5000 units of bolus iv then at a rate 1000 units/hour; adjusted by pharmacist to keep aPTT 1.5-2.0, with placebo "aspirin"
    Experimental Group: (n = 108, 108 analysed): heparin and aspirin together
    All patients continued pre-admission medications; dosage was increased or another antianginal added. Patients had all study medication stopped abruptly following coronary angioography and followed for 96 hours. Patients continued antianginal medication.
    100% followed for 4 days
    Outcome notes:
    • reactivation events : refractory angina, new MI or death

    The evidence

    heparin vs placebo
    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    reactivation events 4 days 5
    (5.75%)    		 14
    (13.0%)    		 -126%
    (-502% to 15%)    		 -7.22%
    (-15.2% to 0.79%)    		 -14
    (NNT = 127 to infinity;
    NNH = 7 to infinity)
    recurrent unstable angina 4 days 4
    (4.60%)    		 14
    (13.0%)    		 -182%
    (-726% to 4%)    		 -8.37%
    (-16.1% to -0.65%)    		 -12
    (-153 to -6)
    urgent reintervention 4 days 1
    (1.15%)    		 11
    (10.2%)    		 -786%
    (-6631% to -17%)    		 -9.04%
    (-15.2% to -2.91%)    		 -11
    (-34 to -7)

    aspirin vs heparin
    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    reactivation event 4 days 14
    (13.1%)    		 5
    (4.95%)    		 62%
    (-1% to 86%)    		 8.13%
    (0.47% to 15.8%)    		 12
    (6 to 210)
    recurrent unstable angina 4 days 14
    (13.1%)    		 4
    (3.96%)    		 70%
    (11% to 90%)    		 9.12%
    (1.69% to 16.6%)    		 11
    (6 to 59)
    urgent reintervention 4 days 11
    (10.3%)    		 1
    (0.99%)    		 90%
    (27% to 99%)    		 9.29%
    (3.22% to 15.4%)    		 11
    (7 to 31)

    aspirin and heparin vs heparin
    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    reactivation event 4 days 14
    (13.1%)    		 5
    (4.95%)    		 65%
    (5% to 87%)    		 8.45%
    (0.94% to 16.0%)    		 12
    (6 to 110)
    recurrent unstable angina 4 days 14
    (13.1%)    		 5
    (4.95%)    		 65%
    (5% to 87%)    		 8.45%
    (0.94% to 16.0%)    		 12
    (6 to 107)
    urgent reintervention 4 days 11
    (10.3%)    		 0
    (0.00%)    		 100%
    (% to %)    		 10.3%
    (4.53% to 16.0%)    		 10
    (6 to 22)

    Outcome Control Group
    (SD)    		 Experimental Group
    (SD)    		 Mean Difference
    (95% CI)
    reactivation of pain (hours) heparin- 9.5
    ()     		all other groups- 28
    ()     		p<0.05
    ( to )

    Comments

    1. There are many other studies confirming the benefit of aspirin inunstable coronary artery disease. More recently, the low molecular weight heparin, enoxaparin, plus aspirin, has been shown to be superior to intravenous standard heparin plus aspirin. (Cohen M et al. A comparison of low molecular weight heparin with unfractionated heparin for unstable coronary artery disease. New Engl JMed 1997;337:447-452)
    2. No studies have shown a clear benefit from taking aspirin in combination with heparin compared with alone.

    Citation

    1. Theroux P, Waters D, Lam J, et al: Reactivation of unstable angina after the discontinuation of heparin. New England Journal of Medicine 1992; 327 (3): 141-145
    Contributor: Nick Shenker and Chris Ball, July 2000
    Reviewer:

    Clinical Question.
    Patient unstable angina
    Intervention or Exposure aspirin and heparin
    Comparison placebo
    Outcome recurrence and urgent intervention