Unstable angina: topical nitroglycerin and oral N-acetylcysteine reduced revascularisation interventions, but cause severe headaches.

Clinical bottom line (level 1b)

  1. In patients with unstable angina, topical nitroglycerin and oral n-acetylcysteine reduced the number of patients with persistent angina requiring revascularisation (NNT = 5 at 4 months) , and the total number of cardiac events (NNT = 4 at 4 months) .
  2. However, severe headaches were common (NNH = 4 at 4 months) , and many patients had to stop the medication (NNH = 4 at 4 months) .
  3. The effect of topical nitroglycerin and oral n-acetylcysteine alone was unclear.
Ardissino et al: Journal of the American College of Cardiology 1997; 29 (5): 941-947
Expires July 2003

The study

Double-blinded concealed randomised trial with intention-to-treat
Setting: university hospital, Italy

200 patients (aged mean 57 years, 76% male) unstable angina (chest pain of recent onset/sudden worsening of stable angina/ angina developing >12 weeks post-MI, and transient ECG changes)

Excluded if
  • age >75 years
  • required emergency coronary revascularisation (left main artery stenosis >50%; failure of maximal medical therapy)
  • previous CABG or angioplasty
  • valvular heart disease
  • systolic blood pressure <100 mmHg
  • congenital heart disease
  • symptomatic cerebrovascular disease
  • extra-cardiac conditions that may affect the prognosis over the 4 months
  • extra-cardiac conditions that intensify angina (anaemia, fever, infections, uncontrolled hypertension, tachyarrhythmias, unusual emotional stress, thyrotoxicosis and hypoxemia secondary to respiratory failure)


    • Control Group: (n = 46, 46 analysed): nitroglycerin placebo plus n-acetylcysteine placebo
    Experimental Group: (n = 54, 54 analysed): nitroglycerin (10 mg patches, changed daily) plus n-acetylcysteine placebo
    Experimental Group: (n = 45, 45 analysed): nitroglycerin placebo plus n-acetylcysteine (600 mg tablets)
    Experimental Group: (n = 55, 55 analysed): nitroglycerin plus n-acetylcysteine
    All patients had: aspirin 300 to 325 mg po once daily; metoprolol 100 to 200 mg po once daily; nifedipine 40 to 80 mg po once daily. If aspirin was contraindicated, it was replaced by ticlodipine. All nitrates had to be stopped >4 days before entering the study.
    100% followed for 4 months

    The evidence

    placebo vs nitroglycerin tablets
    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    death 4 months 1
    (2.17%)    		 0
    (0.00%)    		 100%
    (% to %)    		 2.17%
    (-2.04% to 6.39%)    		 46
    (NNT = 49 to infinity;
    NNH = 16 to infinity)
    MI 4 months 2
    (4.35%)    		 3
    (5.56%)    		 -28%
    (-632% to 78%)    		 -1.21%
    (-9.70% to 7.28%)    		 -83
    (NNT = 10 to infinity;
    NNH = 14 to infinity)
    persistent angina requiring revascularisation 4 months 15
    (32.6%)    		 14
    (25.9%)    		 20%
    (-47% to 57%)    		 6.68%
    (-11.2% to 24.6%)    		 15
    (NNT = 9 to infinity;
    NNH = 4 to infinity)
    any event 4 months 18
    (39.1%)    		 17
    (31.5%)    		 20%
    (-47% to 57%)    		 7.65%
    (-11.1% to 26.4%)    		 13
    (NNT = 9 to infinity;
    NNH = 4 to infinity)
    severe headache 4 months 2
    (4.35%)    		 10
    (18.5%)    		 -326%
    (-1746% to 2%)    		 -14.2%
    (-26.1% to 2.25%)    		 -7
    (NNT = 4 to infinity;
    NNH = 44 to infinity)
    study drug discontinued 4 months 4
    (8.70%)    		 12
    (22.2%)    		 -156%
    (-638% to 12%)    		 -13.5%
    (-27.3% to 0.23%)    		 -7
    (NNT = 4 to infinity;
    NNH = 433 to infinity)

    placebo vs n-acetylcysteine
    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    death 4 months 1
    (2.17%)    		 0
    (0.00%)    		 100%
    (% to %)    		 2.17%
    (-2.04% to 6.39%)    		 46
    (NNT = 49 to infinity;
    NNH = 16 to infinity)
    MI 4 months 2
    (4.35%)    		 1
    (2.22%)    		 49%
    (-444% to 95%)    		 2.13%
    (-5.17% to 9.42%)    		 47
    (NNT = 19 to infinity;
    NNH = 11 to infinity)
    persistent angina requiring revascularisation 4 months 15
    (32.6%)    		 18
    (40.0%)    		 -23%
    (-112% to 29%)    		 -7.39%
    (-27.1% to 12.3%)    		 -14
    (NNT = 4 to infinity;
    NNH = 8 to infinity)
    any event 4 months 18
    (39.1%)    		 19
    (42.2%)    		 -8%
    (-77% to 34%)    		 -3.09%
    (-23.3% to 17.1%)    		 -32
    (NNT = 4 to infinity;
    NNH = 6 to infinity)
    severe headache 4 months 2
    (4.35%)    		 1
    (2.22%)    		 49%
    (-444% to 95%)    		 2.13%
    (-5.17% to 9.42%)    		 47
    (NNT = 19 to infinity;
    NNH = 11 to infinity)
    study drug discontinued 4 months 4
    (8.70%)    		 8
    (17.8%)    		 -104%
    (-531% to 34%)    		 -9.08%
    (-22.9% to 4.74%)    		 -11
    (NNT = 4 to infinity;
    NNH = 21 to infinity)

    placebo vs n-acetylcysteine and nitrate
    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    death 4 months 1
    (2.17%)    		 0
    (0.00%)    		 100%
    (% to %)    		 2.17%
    (-2.04% to 6.39%)    		 46
    (NNT = 49 to infinity;
    NNH = 16 to infinity)
    MI 4 months 2
    (4.35%)    		 1
    (1.82%)    		 58%
    (-347% to 96%)    		 2.53%
    (-4.34% to 9.40%)    		 40
    (NNT = 23 to infinity;
    NNH = 11 to infinity)
    persistent angina requiring revascularisation 4 months 15
    (32.6%)    		 6
    (10.9%)    		 67%
    (29% to 85%)    		 21.7%
    (5.84% to 37.6%)    		 5
    (3 to 17)
    any event 4 months 18
    (39.1%)    		 7
    (12.7%)    		 67%
    (29% to 85%)    		 26.4%
    (9.77% to 43.0%)    		 4
    (2 to 10)
    severe headache 4 months 2
    (4.35%)    		 17
    (30.9%)    		 -611%
    (-2817% to -73%)    		 -26.6%
    (-40.1% to 13.0%)    		 -4
    (-8 to -2)
    study drug discontinued 4 months 4
    (8.70%)    		 18
    (32.7%)    		 -276%
    (-934% to -37%)    		 -24.0%
    (-38.9% to -9.20%)    		 -4
    (-11 to -3)

    Comments

    1. The study was too small to demonstrate benefit or harm for topical nitrates or n-acetylcysteine individually.

    Citation

    1. Ardissino D, Merlini PA, Savonitto S, et al: Effect of transdermal nitroglycerin or N-acetylcysteine, or both in the long-term treatment of unstable angina pectoris. Journal of the American College of Cardiology 1997; 29 (5): 941-947
    Contributor: Nick Shenker and Chris Ball, July 2000
    Reviewer: Greg Flaker

    Clinical Question.
    Patient unstable angina
    Intervention or Exposure N-acetyl cysteine, nitroglycerin
    Outcome death, revascularisation, cardiac events, adverse events