Unstable angina: intravenous diltiazem was more effective than iv nitrate.

Clinical bottom line (level 1b)

  1. Patients with unstable angina who received iv diltiazem compared with iv nitrate, had fewer episodes of refractory angina or MI in the next 48 hours (NNT = 5 at 48 hours) .
  2. More patients had atrioventricular conduction abnormalities (NNH = 12 at 48 hours) , but fewer had headaches bad enough to require analgesia (NNT = 5 at 48 hours) .
Gobel et al: Lancet 1995; 346: 1653-1657
Expires July 2003

The study

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

121 patients (aged range 40 to 80 years; mean 64, 71% male) unstable angina, defined as one of:
  • crescendo angina superimposed on a pre-existing pattern of stable, exertion-related angina
  • angina of new onset (within one month) brought on by slight exertion
  • angina at rest or during light activity occurring within 12 hours of admission and lasting >15 minutes
AND one of, on ECG:
  • 0.1 mV or more ST depression in two limb or three precordial leads
  • abnormal ST segments followed by inverted T-waves in two or more inferior or precordial leads
  • ST elevation <0.1 mV in two or more limb leads or <0.2 mV in two or more precordial leads


Excluded if
  • MI- presence of typical angina >30 minutes and either rise in CK:CK-MB ratio more than twice upper limit of normal or ST elevation 0.1 mV or more in one or more limb leads or 0.2 mV or more in two or more precordial leads
  • heart rate <50 bpm
  • systolic blood pressure <90 mmHg
  • second or third degree heart block
  • severe heart failure
  • sick sinus syndrome, atrial fibrillation, atrial flutter, intraventricular conduction disturbances (QRS >100 ms)
  • use drugs affecting ST segment
  • known intolerance to calcium channel blockers or nitrates


    • Control Group: (n = 61, 61 analysed): iv nitroglycerin - initially saline bolus for 5 minutes, then continuous infusion at 1 mg/hour increased to 3 mg/hr over 10 minutes. If patients still had angina, increased to maximum of 5 mg/hr
    Experimental Group: (n = 60, 60 analysed): iv diltiazem - loading dose of 25 mg over 5 minutes, followed by continuous infusion at 5 mg/hr; increased to 15 mg/hr over 10 minutes. If patients still had angina, increased to a maximum of 25 mg/hr
    All patients had calcium channel blockers and long acting nitrates stopped on admission, but continued on beta-blockers and ACE inhibitors. All patients received iv heparin (5000 units bolus followed by infusion so that aPTT was 2-3 for 48 hours, followed by aspirin. Patients continued on infusion for 48 hours or until angina was refractory (when medication was stopped and anti-ischaemic drugs or invasive procedures were performed)
    100% followed for 48 hours

    The evidence

    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    MI or refractory angina 48 hours 25
    (41.0%)    		 12
    (20.0%)    		 51%
    (12% to 73%)    		 21.0%
    (5.02% to 36.9%)    		 5
    (3 to 20)
    refractory angina 48 hours 18
    (29.5%)    		 8
    (13.3%)    		 55%
    (4% to 79%)    		 16.2%
    (1.86% to 30.5%)    		 6
    (3 to 54)
    MI 48 hours 15
    (24.6%)    		 8
    (13.3%)    		 46%
    (-18% to 75%)    		 11.3%
    (-2.56% to 25.1%)    		 9
    (NNT = 39 to infinity;
    NNH = 4 to infinity)
    serious headache requiring analgesia 48 hours 15
    (24.6%)    		 3
    (5.00%)    		 80%
    (33% to 94%)    		 19.6%
    (7.46% to 31.7%)    		 5
    (3 to 13)
    pulse <50 bpm 48 hours 2
    (3.28%)    		 7
    (11.7%)    		 -256%
    (-1544% to 23%)    		 -8.39%
    (-17.7% to 0.88%)    		 -12
    (NNT = 6 to infinity;
    NNH = 110 to infinity)
    AV conduction abnormalities 48 hours 0
    (0.00%)    		 5
    (8.33%)    		 100%
    (% to %)    		 -8.33%
    (-15.3% to -1.34%)    		 -12
    (-75 to -7)

  • Cardiac arrhythmias were terminated by lowering the infusion rate of the study medication.

    • Comments

    1. Short follow-up so difficult to comment on outcomes like revascularisation and mortality. Indeed, no patients died during the study. No studies have yet shown that calcium channel blockers or nitrates have any effect on mortality in patients with unstable angina.
    2. Patients did not have current optimal management- aspirin was given late, and none had beta-blockers started. Most clinicians would now give combination therapy of nitrates and a beta-blocker or diltiazem. How does iv diltiazem compare with iv beta-blockers (shown to be beneficial in MI), and is combining medication beneficial?
    3. Consequently, it is difficult to know how to apply this study practically.

    Citation

    1. Gobel EJ, Hautvast RW, van Gilst WH, et al: Randomised, double-blind trial of intravenous diltiazem versus glycerol trinitrate for unstable angina pectoris. Lancet 1995; 346: 1653-1657
    Search Terms: angin* and (nitriglyc* or nitrat* or trinitr*) in Cochrane
    Contributor: Chris Ball and Clare Wotton, July 2000
    Reviewer: Dwight Peretz

    Clinical Question.
    Patient unstable angina
    Intervention or Exposure i/v diltiazem
    Comparison i/v nitrate
    Outcome pain, death, infarction