Unstable angina: dalteparin was probably as effective as unfractionated heparin.

Clinical bottom line (level 1b-)

  1. Low-molecular-weight heparin was probably as good as unfractionated heparin in preventing deaths, MI and recurrent angina in patients with unstable angina or non-Q-wave MI. There was no clear effect on major bleeds or need for revascularisation.
  2. Patients on dalteparin and aspirin compared with aspirin alone did not clearly have a reduction in deaths, MI or unstable angina. There was no clear effect on major bleeds or the need for revascularisation.
Klein et al: Circulation 1997; 96 (1): 61-68
Expires July 2002

The study

Unblinded concealed randomised trial with intention-to-treat
Setting: 81 acute hospitals, North America and Europe

1482 patients (aged range 25 to 92 years; mean 65, 64% male) unstable angina or non-Q-wave MI, defined as chest pain within 72 hours and ECG on admission showing at least one of:
  • temporary or persistent ST segment depression of 0.1 mV or more
  • temporary or persistent T-wave inversion of 0.1 mV or more without corresponding Q-waves


Excluded if
  • newly developed Q-waves
  • left bundle branch block
  • indication for thrombolysis
  • pacemaker
  • known primary myocardial disease, septic endocarditis, pericarditis or aortic valvular disease or haemodynamic significance
  • any known haemostasis deficit, ongoing treatment with anticoagulants or heparin
  • diastolic blood pressure >120 mmHg or systolic blood pressure <90 mmHg
  • fever 39 ° C or more
  • haemoglobin <11 g/dl if female; <12.5 g/dl if male
  • known renal or liver insufficiency
  • history of a cerebrovascular accident, peptic ulceration or GI bleeding within three months of admission
  • surgery of any type within one week, or eye, ear or neurosurgery within one month of admission
  • malignancy or other disease with unfavourable prognosis
  • known hypersensitivity to aspirin, unfractionated heparin or LMWH
  • CABG or PTCA planned within three weeks
  • pregnant or lactating


    • Control Group: (n = 731, 731 analysed): unfractionated heparin iv bolus 5000 units, then 1000 units/hr adjusted so aPTT 1.5 normal for 6 days. This could be replaced with subcutaneous heparin 12500 units every 12 hours after 48 hours if desired
    Experimental Group: (n = 751, 751 analysed): dalteparin 120 IU/kg subcutaneously every 12 hours for 6 days
    All patients had aspirin 75 to 165 mg po once daily, and other anti-anginal medication as given by the study centre. 1132 patients (64% male; aged 25 to 89; mean 65) who were still eligible were than entered into double-blind randomised control trial with intention-to-treat: control group (565; 565)- saline s/c od for 39 days; experimental group (567; 567)- dalteparin s/c 7500 IU od for 39 days (followed for 39 days)
    100% followed for 6 days
    Outcome notes:
    • death, MI, recurrent angina : MI- on serial ECGs or two of: prolonged ischaemic pain, ECG evolution suggestive of MI, elevation of cardiac enzymes
    • major bleeding : fall in Hb 2.0 g/dl or more, or transfused, or intracranial or caused death or cessation of study treatment

    The evidence

    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    death, MI, recurrent angina 6 days 55
    (7.52%)    		 69
    (9.19%)    		 -22%
    (-71% to 13%)    		 -1.66%
    (-4.48% to 1.15%)    		 -60
    (NNT = 87 to infinity;
    NNH = 22 to infinity)
    revascularisation 6 days 39
    (5.34%)    		 36
    (4.79%)    		 10%
    (-40% to 42%)    		 0.54%
    (-1.69% to 2.78%)    		 185
    (NNT = 36 to infinity;
    NNH = 59 to infinity)
    major bleeding 6 days 7
    (0.96%)    		 8
    (1.07%)    		 -11%
    (-205% to 59%)    		 -0.11%
    (-1.13% to 0.91%)    		 -930
    (NNT = 110 to infinity;
    NNH = 89 to infinity)

    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    death, MI, recurrent angina 39 days 69
    (12.21%)    		 69
    (12.17%)    		 0%
    (-36% to 27%)    		 0.04%
    (-3.77% to 3.86%)    		 2300
    (NNT = 26 to infinity;
    NNH = 27 to infinity)
    revascularisation 39 days 76
    (13.45%)    		 76
    (13.40%)    		 0%
    (-34% to 26%)    		 0.05%
    (-3.92% to 4.02%)    		 2100
    (NNT = 25 to infinity;
    NNH = 25 to infinity)
    major bleeding 39 days 2
    (0.35%)    		 3
    (0.53%)    		 -49%
    (-791% to 75%)    		 -0.18%
    (-0.95% to 0.60%)    		 -570
    (NNT = 167 to infinity;
    NNH = 106 to infinity)

    Comments

    1. Study too small to demonstrate small differences between dalteparin and heparin or placebo. Cohen et al showed LMWH to reduce deaths and revascularisation in a larger double-blinded study.

    Citation

    1. Klein W, Buchwald A, Hillis SE, et al: Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease: fragmin in unstable coronary artery disease study (FRIC). Circulation 1997; 96 (1): 61-68
    Search Terms: unstable angina and LMWH in Cochrane
    Contributor: Chris Ball and Clare Wotton, July 2000
    Reviewer:

    Clinical Question.
    Patient unstable angina
    Intervention or Exposure unfractionated heparin
    Comparison dalteparin, LMWH
    Outcome death, MI, recurrent angina