Acute coronary syndrome: adding clopidogrel to aspirin reduced myocardial infarction and heart failure, but increased major bleeding

Clinical bottom line (level 1b)

  1. Patients admitted to hospital with acute coronary syndrome and no ST-elevation who received clopidogrel and aspirin compared with placebo and aspirin were less likely to have a myocardial infarction (NNT = 68 at 12 months) , develop heart failure (NNT = 130 at 12 months) or require a revascularisation procedure (NNT = 53 at 12 months) .
  2. Patients on clopidogrel and aspirin were less likely to develop refractory ischaemia in hospital (NNT = 110 at 12 months) but not following discharge.
  3. Patients on clopidogrel and aspirin were at increased risk of having major bleeding (NNH = 99 at 12 months) .
  4. There was no difference in mortality between the two groups.
CURE trial investigators : N Eng J Med 2001; 345 : 494-502
Expires January 2004

The study

Double-blinded concealed randomised trial with intention-to-treat
Setting: 482 acute hospitals in 28 countries in the Americas, Europe, Africa and Australasia

12562 patients (aged mean 64, 61% male) with acute coronary syndrome, admitted to hospital within 24 hours of onset of symptoms and no ST-segment elevation

Excluded if
  • taking oral anticoagulants
  • undergone coronary revascularisation in previous 3 months or received glycoprotein IIb/IIIa receptor inhibitors in the previous 3 days
  • no ECG changes or no elevation in cardiac enzymes
  • contraindications to antithrombotic or antiplatelet therapy
  • at high risk of bleeding or heart failure

Control Group: (n = 6303, 6303 analysed): placebo
Experimental Group: (n = 6259, 6259 analysed): clopidogrel 300 mg loading dose, followed by 75 mg daily for 3 to 12 months
All patients received aspirin 75 mg to 325 mg started with study drug. Patients could also receive other cardiac medication as required.
99.9% followed for 12 months
Outcome notes:
  • cardiovascular event : death from cardiovascular causes, nonfatal myocardial infarction or stroke
  • refractory ischaemia in hospital : further chest pain with ECG changes requiring additional intervention
  • heart failure : confirmed on radiology
  • major bleeding : substantially disabling bleeding, intraocular bleeding leading to loss of vision or bleeding requiring a transfusion of at least 2 units of blood

The evidence

Outcome Time to outcome CER EER RRR
(95% CI)		 ARR
(95% CI)		 NNT
(95% CI)
cardiovascular event 12 months 719
(11.4%)		 582
(9.30%)		 18%
(10% to 27%)		 2.11%
(1.04% to 3.17%)		 47
(32 to 96)
myocardial infarction 12 months 419
(6.65%)		 324
(5.18%)		 22%
(10% to 32%)		 1.47%
(0.647% to 2.30%)		 68
(44 to 160)
death from any cause 12 months 390
(6.19%)		 359
(5.74%)		 7%
(-7% to 19%)		 0.45%
(-0.38% to 1.28%)		 220
(NNT = 260 to infinity;
NNH = 78 to infinity)
refractory ischaemia in hospital 12 months 185
(2.94%)		 126
(2.01%)		 31%
(14% to 45%)		 0.92%
(0.38% to 1.46%)		 110
(68 to 260)
refractory ischaemia after discharge 12 months 461
(7.31%)		 459
(7.33%)		 0%
(-14% to 11%)		 -0.0195%
(-0.93% to 0.892%)		 -5200
(NNT = 110 to infinity;
NNH = 110 to infinity)
heart failure 12 months 280
(4.44%)		 229
(3.66%)		 18%
(2% to 31%)		 0.78%
(0.0943% to 1.47%)		 130
(68 to 1100)
revascularisation procedure 12 months 1431
(22.7%)		 1302
(20.8%)		 8%
(2% to 14%)		 1.90%
(0.46% to 3.34%)		 53
(30 to 220)
major bleeding 12 months 169
(2.68%)		 231
(3.69%)		 -38%
(-67% to -13%)		 -1.01%
(-1.62% to -0.40%)		 -99
(-250 to -62)

Comments

  1. Patients were stratified by centre before randomisation.
  2. No significant increase in haemorrhagic strokes or fatal haemorrhage was noted.

Citation

  1. CURE trial investigators , : effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Eng J Med 2001; 345 : 494-502
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Contributor: Chris Ball, January 2002
Reviewer:

Clinical Question.
Patient acute coronary syndrome
Intervention or Exposure clopidogrel and aspirin
Comparison placebo and aspirin
Outcome myocardial infarction, death, revascularisation, heart failure