Unstable angina: nifedipine should not be used alone.

Clinical bottom line (level 1b)

  1. Nifedipine given alone increased the number of MI (NNH = 8 at 48 hours) . The effect on recurrent ischaemia was unclear.
  2. Oral metoprolol reduced recurrent ischaemia in patients with unstable angina (NNT = 9 at 48 hours) not already on beta-blockers. The effect on MI was unclear.
  3. Nifedipine and metoprolol together were not clearly better than metoprolol alone.
  4. Adding in nifedipine if the patient is already taking a beta-blocker reduced recurrent ischaemia (NNT = 7 at 48 hours) . The effect on MI was unclear.
Holland Interuniversity Nifedipine/ Metoprolol Trial (HINT) Research Group : British Heart Journal 1986; 56: 400-413
Expires June 2003

The study

Double-blinded concealed randomised trial without intention-to-treat
Setting: eight university and three non-university hospitals, Holland

515 patients (aged range 55 to 65 years; mean ~50, 75% male) chest pain with any of:
  • varying reversible pattern of ST-T changes
  • typical angina chest pain within 12 hours of admission lasting more than 15 minutes with: ST-T changes, prior history of MI or unstable angina or >50% stenosis of coronary artery at earlier angiography


Excluded if
  • >70 years
  • CK-MB > two times upper limit, intractable chest pain, new Q-wave on ECG, or acute MI <within one month
  • maintenance therapy on nifedipine
  • heart rate <50 or >120 bpm, systolic blood pressure <100 or >170 mmHg, diastolic blood pressure >110 mmHg
  • anaemia (Hb <6.5 mmol/l)
  • conduction abnormalities (not bundle branch block)
  • congestive heart failure, congenital or valvular heart disease, cardiomyopathy or serious pulmonary or other non-cardiac disease


    • Control Group: (n = 84, 84 analysed): patients on no prior beta-blocker for >3 days: placebo for at least 48 hours; patients on beta-blockers therapy- control (n=81; 81 analysed)- placebo for at least 48 hours
    Experimental Group: (n = 89, 89 analysed): no prior beta-blocker for >3 days: nifedipine , 60 mg per day for at least 48 hours; on beta-blockers- (n=96; 96 analysed) nifedipine 60 mg per day for at least 48 hours
    Experimental Group: (n = 79, 79 analysed): no prior beta-blockers: metoprolol , 100 mg twice daily po for at least 48 hours
    Experimental Group: (n = 86, 86 analysed): no prior beta-blockers: nifedipine and metoprolol for at least 48 hours
    All patients had iv nitrates and fentanyl patches and anticoagulants, anti-arrhythmics, digitalis, diuretics and hypertensives, if required for at least 48 hours. CK and 12-lead ECGs obtained every six hours. Cardiac catheterisation and angiography >54 hours post-admission and pre-discharge.
    100% followed for 48 hours
    Outcome notes:
    • MI : chest pain with ST-T changes and serial enzyme changes (with one >upper limit of normal within 54 hours)
    • recurrent ischaemia : chest pain with ST-T changes

    The evidence

    not on beta-blockers: nifedipine vs placebo
    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    MI 48 hours 13
    (15.5%)    		 25
    (28.1%)    		 -82%
    (-231% to 0%)    		 -12.6%
    (-24.7% to -0.49%)    		 -8
    (-210 to -4)
    recurrent ischaemia 48 hours 18
    (12.4%)    		 17
    (19.1%)    		 11%
    (-61% to 51%)    		 2.33%
    (-9.66% to 14.3%)    		 43
    (NNT = 10 to infinity;
    NNH = 7 to infinity)

    not on beta-blockers: metoprolol vs placebo
    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    MI 48 hours 13
    (15.5%)    		 13
    (16.5%)    		 -6%
    (-115% to 47%)    		 -0.98%
    (-12.2% to 10.3%)    		 -100
    (NNT = 8 to infinity;
    NNH = 10 to infinity)
    recurrent ischaemia 48 hours 18
    (21.4%)    		 9
    (11.4%)    		 47%
    (-11% to 75%)    		 10.0%
    (-1.19% to 21.3%)    		 10
    (NNT = 84 to infinity;
    NNH = 5 to infinity)

    not on beta-blockers: nifedipine plus metoprolol vs metoprolol
    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    MI 48 hours 13
    (16.5%)    		 12
    (14.0%)    		 15%
    (-75% to 59%)    		 2.50%
    (-8.47% to 13.5%)    		 40
    (NNT = 12 to infinity;
    NNH = 7 to infinity)
    recurrent ischaemia 48 hours 9
    (11.4%)    		 14
    (16.3%)    		 -43%
    (-212% to 34%)    		 -4.89%
    (-15.4% to 5.60%)    		 -20
    (NNT = 7 to infinity;
    NNH = 18 to infinity)

    on beta-blocker: nifedipine vs placebo
    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    MI 48 hours 16
    (19.8%)    		 13
    (13.5%)    		 31%
    (-34% to 65%)    		 6.21%
    (-4.84% to 17.3%)    		 10
    (NNT = 21 to infinity;
    NNH = 6 to infinity)
    recurrent ischaemia 48 hours 25
    (30.9%)    		 16
    (16.7%)    		 46%
    (6% to 69%)    		 14.2%
    (1.68% to 26.7%)    		 7
    (4 to 60)

    Comments

    1. Today the baseline risks would not nearly approach this study's results with beta blockers,ACEI,AT1 blockers,urgent coronary angiography with angioplasty or bypass surgery,etc.
    2. Study was too small to comment on effect of combination of nifedipine and beta-blocker therapy. Follow-up very short- medications are typically given for longer than this. Benefits consequently may have been missed.
    3. Given the difficulty of differentiating between MI and unstable angina in the acute setting, and the proven benefit of beta-blockers in acute MI, they should be considered in chest pain unless there are absolute contraindications.
    4. Short-acting calcium antagonists have been associated with an increased risk for cancer.

    Citation

    1. Holland Interuniversity Nifedipine/ Metoprolol Trial (HINT) Research Group , : Early treatment of unstable angina in the coronary care unit: a randomised, double-blind, placebo controlled comparison of recurrent ischaemia in patients treated with nifedipine or metoprolol or both. British Heart Journal 1986; 56: 400-413
    Search Terms: angin* and beta-blocker in Cochrane
    Contributor: Nick Shenker, Chris Ball and Clare Wotton, June 2000
    Reviewer: Dwight Peretz

    Clinical Question.
    Patient chest pain
    Intervention or Exposure nifedipine, metoprolol or both
    Comparison placebo
    Outcome MI, recurrent ischaemia