-
Goldstein RE et al. Clinical and circulatory effects of isosorbide dinitrate. Comparison with nitroglycerin. Circulation 1971;43(5):629-40. PubMed
| Level of Evidence |
1b |
| Study Design |
Prospective, Randomized, Placebo Controlled, Single-Center Study |
| Sample Size |
N = 23 |
| Groups |
Adults with stable angina for at least 6 months who underwent exercise stress testing and randomly received either sublingual nitroglycerin, isosorbide dinitrate (ISDN), or placebo, with the medications in doses enough to produce either a 10 mm Hg decrease in the mean arterial blood pressure, or a 10 beat per minute rise in the heart rate. |
| Results |
- Ten minutes after ISDN 21 of 23 patients exercised longer (average 2.7 min, P < 0.001) vs placebo.
- There was a lower mean blood pressure (average 13 mm Hg, P < 0.001), higher heart rate (average 10 beats/min, P < 0.001), and shorter ejection time (average 0.04 second, P < 0.001) after ISDN. Similar changes were seen after nitroglycerin.
|
| Conclusions |
ISDN resembles nitroglycerin in effects on changing circulatory function during exercise as well as improved duration exercise and overall exercise capacity. |
| Location |
National Hearth and Lung Institute, Bethesda, MD |
| Comments |
This is one of the primary references cited by the NSTEMI Guidelines to support the use of nitroglycerin in the early or acute management NSTEMI even though the patients in this study had stable angina and were undergoing exercise stress testing. |
-
Chiche P et al. A randomized trial of prolonged nitroglycerin infusion in acute myocardial infarction. Circulation (Suppl II) 1979;165:59-60.
| LOE |
1b |
| Study Design |
Prospective, Single-Center, Randomized, Open-Label |
| Sample Size |
n = 95 with signs and symptoms of AMI within 12 hrs onset |
| Treatment |
- Nitroglycerin IV 10-15 mg/min with adjustments to achieve nor more than a 20 mm Hg reduction in blood pressure x 7 days vs.
- Placebo
|
| Follow Up |
28 days |
| Results |
Morality at nitroglycerin was 6%; 3/50 vs placebo 18%; 8/45 |
| Conclusion |
IV nitroglycerin may have beneficial effect on mortality compared to placebo. |
| Location |
France |
| Funding |
Not reported |
| Comments |
The study is not listed in PubMed and is from a supplement. |
-
Bussman WD et al. Reduction of CK and CK-MB indexes of infarct size by intravenous nitroglycerin. Circulation 1981;63(3):615-22. PubMed
| LOE |
1b |
| Study Design |
Prospective, Single-Center Study |
| Sample Size |
N = 60 |
| Population |
Adults with STEMI and pathologic Q-waves |
| Groups |
- IV nitroglycerin infusion (n = 31) at 0.75, 1.5, or 3 mg/hr x up to 48 hrs.
- This group was further divided into early intervention (i.e., within 8 hrs; n = 9) vs late intervention (i.e., after 8 hrs; n = 18) Placebo (controls; n = 29)
|
| Other Treatments |
Lidocaine, digitalis, furosemide, morphine, atropine |
| Results |
Early intervention subgroup (< 8 hrs from onset of symptoms):
- The peak CK activity for the nitroglycerin-treated patients (n = 9) in this subgroup was 544 U/1 vs 871 U/1 for the controls (n = 13) (p less than 0.05).
- The rate of CK release was reduced from 79 to 33 U/1.hr (58%), as was total CK and CK-MB release (p < 0.02).
- Calculated infarct size was 69 gEq in the controls and 48 gEq in patients receiving nitroglycerin (CK-MB: 69 vs 43 gEq, p < 0.05).
Late intervention subgroup (> 8 hrs from onset of symptoms):
- Nitroglycerin therapy was begun > 8 hours (mean 12.8 hours) after the onset of symptoms. Nitroglycerin was associated with lower peak CK and CK-MB levels as well as a reduction in calculated infarct size (p < 0.05).
- Hemodynamic measurements, recorded every 4 hours, showed that nitroglycerin also reduced left ventricular filling pressure significantly and cardiac output increased. Blood pressure fell slightly, and systemic vascular resistance declined.
- Mortality differences: For nitroglycerin group (10d = 6.4%; 2/31 and 30d = 19%; 6/31) vs. control (10d = 17%; 5/29 and 30d = 41%; 12/29). Note: this was reported in another paper in 1983.
|
| Conclusion |
The early (within 8 hrs) and late (after 8 hrs) administration of IV nitroglycerin in adults with STEMI and pathologic Q-waves reduced CK, CK-MB, calculated infarct size. |
| Location |
University Clinic Frankfurt/Main, West Germany |
| Comments |
It is important to recognize that this study was only in patients with STEMI and with the use of IV nitroglycerin (not sublingual). |
-
Flaherty JT et al. A randomized prospective trial of intravenous nitroglycerin in patients with acute myocardial infarction. Circulation 1983;68(3):576-588. PubMed
| LOE |
1b |
| Study Design |
Prospective, Single-Center, Randomized, Single-Blind Study |
| Sample Size |
N = 104 |
| Population |
AMI within 12 hrs of onset of chest pain |
| Groups |
- Nitroglycerin IV initial dose of 5 mcg/min titrated at 3-5 min to reduce MAP by 10% x 48 hrs (n = 56; patients were further divided in early (<10 hrs) compared to late (≥ 10 hrs) vs
- Placebo (n = 48)
|
| Other Treatments |
Patients with Killip class I or II got lidocaine at 1 mg/kg bolus then 20 mcg/kg/min x 24 hrs. Others: heparin infusion, morphine, digitalis |
| Follow-Up |
15 months (average; range 4 - 44 months) |
| Results |
- Mortality at 10 days was 7% (4/56) for those getting nitroglycerin vs 14.5% (7/48) getting placebo. At 3 months it was 15% for those getting nitroglycerin vs 25% placebo (p = NS).
- No significant differences were found in peak creatine kinase (CK) blood levels, creatine kinase infarct size, or preservation of precordial R waves by serial ECG mapping.
- 35% of patients getting early nitroglycerine had greater improvements in LVEF vs 6% of those treated late with TNG, 11% of those treated early with placebo, and 0% of those treated late with placebo (p = .004).
- Similarly, in 68 patients in whom paired thallium scintigrams were taken, a decrease of greater than 75% in the computer determined thallium defect score was seen in 48% of patients getting early nitroglycerin vs 14% treated late, 33% of placebo patients treated early and 0% of placebo patients treated late (p = .039).
|
| Conclusion |
Larger studies are needed to determine if nitroglycerin can reduce mortality and further define the population who would benefit most from nitroglycerin. |
| Location |
Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD |
-
Jaffe AS et al. Reduction of infarct size in patients with inferior infarction with intravenous glyceryl trinitrate. A randomized study. Br Heart J 1983;49(5):452-60. PubMed
| LOE |
1b |
| Study Design |
Prospective, Randomized, Open-Label, Single-Center Study |
| Sample Size |
N = 114 |
| Population |
MI within 12 hrs of onset of symptoms and SBP > 100 mm Hg and pulse < 120 bpm |
| Groups |
Nitroglycerin (as glyceryl trinitrate; n = 57) IV with initial dose of 10 mcg/min to adjust to a reduction of SBP of 10% or achieve SBP < 95 mmHg or a max dose of 200 mcg/min for at least 24 hrs vs. Placebo (n = 57) |
| Other Treatments |
Morphine, then after first 24 hrs digitalis, oral or SL nitrates, and propranolol |
| Results |
- Out of the 114 admitted, only 85 were found to have AMI (thus 43 were treated with IV nitroglycerin and 42 placebo) with mean time to treatment being 10 hrs.
- For patients with an inferior MI, infarct size estimated by enzymes in the treated was only 12.2 +/- 1.8 in nitrate group vs 19.1 +/- 3.6 CK gram equivalents per meter squared in the placebo group.
- No differences in rate of ventricular arrhythmias or morphine requirement.
- Mortality was not reported.
|
| Conclusion |
IV glyceryl trinitrate can be given safely during an evolving infarction. |
| Location |
Washington University School of Medicine, St Louis, Missouri |
| Funding |
National Institutes of Health |
-
Lis Y et al. A preliminary double-blind study of intravenous nitroglycerin in acute myocardial infarction. Intensive Care Med 1984;10(4):179-84. PubMed
| LOE |
1b |
| Study Design |
Prospective, Randomized, Multi-Center, Double-Blind, Study |
| Sample Size |
N = 140 |
| Population |
ECG evidence of MI within 24 hrs of admission |
| Groups |
- Nitroglycerin (n = 64) IV infusion at 10 mcg/min (adjusted to a change in BP based on baseline reading) x 48 hrs vs
- Placebo (n = 76)
|
| Follow-Up |
4 months |
| Results |
- There was reduction in diamorphine usage in the first 24 h.
- More patients in the placebo arm had cardiac dysrhythmias and need for antiarrhythmic medications but this was not significant.
- Mortality rate in the placebo group was 13% vs 7.8% with IV nitrates, but was not significant.
- At the 3-month follow-up, more patients getting IV nitrates (83%) vs placebo (60%) were able to resume normal or near-normal activities.
|
| Conclusion |
IV nitrates appear to be useful in acute MI but should be studied in a larger trial. |
| Location |
St. George's Hospital and Greenwich District Hospital, London, UK |
-
Fitzgerald LJ et al. The effects of oral isosorbide 5-mononitrate on morality following acute myocardial infarction: a multicenter study. Eur Heart J 1990;11:120-126. PubMed
| LOE |
1b |
| Study Design |
Prospective, Randomized, Multi-Centered, Double-Blind Study |
| Sample Size |
N = 360 |
| Population |
• AMI onset with 8 hrs of onset of symptoms |
| Groups |
- Isosorbide 5 mono-nitrate (ISMN; n = 184) as 40 mg if the SBP was > 110 mm Hg or 20 mg if < 110 mm Hg x 5 days vs
- Placebo (n = 176)
|
| Other Treatments |
Lignocaine, IV nitrates, diamorphine |
| Follow-Up |
6 months |
| Results |
- Overall mortality was 4.9% in the ISMN group vs 4.0% with placebo at 5 days, and 14.1% vs 10.5% at 6 months (NS).
- A reduction in mortality in the ISMN group with heart failure was seen (7.9%) vs placebo (12.9%), at 5 days but was not significant. This was contrasted with an increase in mortality in patients without heart failure treated with ISMN (4.1% vs placebo 2.1%) at 5 days, but was also NS.
- Lignocaine was used in twice as many patients in the ISMN group vs in the placebo group (P less than 0.01), both with and without heart failure.
- Diamorphine usage was similar in both groups.
|
| Conclusion |
Oral nitrates can result in similar hemodynamic effects as IV nitrates in patients having an MI and could be effective for patients also with heart failure. However those without heart failure should be investigated further. |
| Location |
9 locations in England. |
| Comment |
Isosorbide mononitrate (marketed as Imdur) is a metabolite of isosorbide dinitrate and does not undergo first pass metabolism. |
-
Jugdutt BI et al. Intravenous nitroglycerin therapy to limit myocardial infarct size, expansion, and complications. Effect of timing, dosage, and infarct location. Circulation 1988;78)4):906-19. PubMed
| LOE |
1b |
| Study Design |
Prospective, Single-Center, Single-Blinded, Randomized Study |
| Sample Size |
N = 310 |
| Population |
AMI to include STEMI or other MI within 12 hours of onset |
| Groups |
- Nitroglycerin (NTG) by IV Infusion to a response to reduce the blood pressure (BP by 10% in normotensive or 30% in hypertensive patients but to keep mean blood pressure > 80 mm Hg x 48 hrs (n = 154). There were subgroups of < 4 hrs or ≥ 4 hrs of onset of set of pain.
- Control (no nitroglycerin; n = 156)
|
| Other Treatments |
Supplemental O2, IV morphine, lidocaine infusion at 1 mg/min. |
| Follow-Up |
10 days and 43 months |
| Results |
- The creatine kinase (CK) infarct size was less in those getting NTG (41 vs. 55 geq, p < 0.001), in anterior (44 vs. 58 geq, p < 0.05), and inferior (39 vs. 53 geq, p < 0.025) NG subgroups, and in early than late NTG subgroups (43% vs. 22% decrease).
- By day 10, LV asynergy was 40% less, LVEF was 22% more, and Killip class score was 41% less in those getting NTG.
- When the mean blood pressure < 80 mm Hg with NTG there were negative effects.
- Infarct-related major complications were less frequent in the NTG vs control groups: infarct expansion syndrome (2% vs. 15%, p < 0.0005), LV thrombus (5% vs. 22%, p < 0.0005), cardiogenic shock (5% vs. 15%, p < 0.005), and infarct extension (11% vs. 22%, p < 0.025).
- NTG reduce the mortality vs control groups in-hospital (14% vs. 26%, p < 0.01), at 3 months (16% vs. 28%, p < 0.025) and 12 months (21% vs. 31%, p < 0.05), but this advantage was only found in the anterior subgroups.
|
| Conclusions |
Overall, the use of IV nitroglycerin during AMI reduced the infarct size, expansion, and infarct related complications. These effects were also independent of the location of infarction. However, when the mean blood pressure fell below 80 mm Hg, these benefits were lost and worsened. |
| Location |
University of Alberta, Canada |
| Funding |
Canadian Heart Foundation, Alberta Heritage Foundation for Medical Research, Special Services of the University of Alberta Hospital |
| Comments |
While the current guidelines do not recommend that we specifically dose nitroglycerin to specific changes in the blood pressure, this study is cited by the guidelines for possible advantages to using NTG acutely and if the pain is not resolved after the 3rd sublingual dose then moving on to a NTG infusion is recommended. It is also one of the only studies showing a possible benefit on mortality. |
-
Anonymous. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico. Lancet 1994;343(8906):1115-22. PubMed
| LOE |
1b |
| Study Design |
Prospective, Randomized, Multi-Center, Open-Label 2 x 2 Factorial Design Trial |
| Sample Size |
N = 19,318 |
| Population |
Adults with onset of AMI within 24 hrs |
| Groups |
- Only reflects the arms with nitrates: Glyceryl trinitrate (n = 9,453) IV 5 mcg/min titrated every 5 min by 5-20 mcg/min to achieve a SBP of at least 10% but not lower than 90 mm Hg x 24 hrs, then transdermal patch providing 10 mg of nitrate daily X 6 weeks vs.
- Placebo (n = 9,655)
|
| Other Treatments |
Mainly: IV beta-blockers (30%), thrombolytics (71%), aspirin (83%). |
| Follow-Up |
6 months |
| Results |
- Patients getting transdermal GTN did not show any independent effect on mortality or severe ventricular dysfunction (0.94 [0.84-1.05] and 0.94 [0.87-1.02]).
- Only when combined with lisinopril did the nitrate therapy show a significant reduction in mortality.
|
| Location |
200 centers with most in Italy |
| Funding |
Zeneca Pharmaceutical and Schwarz Pharma |
-
Anonymous. ISIS-4: A randomized factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58050 patients with suspected myocardial infarction. Lancet 1995;345(8951):669-685. PubMed
| LOE |
1b |
| Study Design |
Prospective, Randomized, Multi-Center, Double-Blind Study |
| Sample Size |
N = 58,050 |
| Population |
Adults with onset of AMI within 24 hrs |
| Groups |
- Captopril and IV magnesium groups are not reported here.
- Isosorbide mononitrate (ISMN; n = 29,018) initially as 30 mg, then 12 hrs later another 30 mg, then maintenance dose of 60 mg daily x 28 days vs.
- Placebo (n = 29,032)
|
| Other Treatments |
IV nitrates (47%), anti-platelet drug (93%), thrombolytics (68%), IV beta-blockers (9%) |
| Follow-Up |
1-year |
| Results |
- There was no significant reduction in 5-week mortality in those receiving ISMN overall (2129 [7.34%] vs 2190 [7.54%] placebo or in any subgroup examined.
- Additional further follow-up also did not indicate any later survival advantage.
- The main side effect with ISMN was an increased risk of 15 (SD 2) per 1000 in hypotension.
- Those allocated active treatment had somewhat fewer deaths on days 0-1, which is reassuring about the safety of using nitrates early in acute MI.
|
| Conclusion |
While oral nitrate therapy was overall safe it did not show a clear reduction in mortality. |
| Locations |
1,086 locations internationally |
-
Nicolini FA et al. Concurrent nitroglycerin therapy impairs tissue-type plasminogen activator-induced thrombolysis in patients with acute myocardial infarction. Am J Cardiol 1994;74(7):662-6. PubMed
| Study Design |
Prospective, Single-Center Study |
| Sample Size |
N = 47 |
| Population |
Adults with AMI |
| Groups |
- t-PA + saline (n = 11) vs.
- t-PA + nitroglycerin (n = 36)
|
| Results |
- More patients getting t-PA (without nitro) had stable coronary artery reperfusion assessed by continuous ST-segment monitoring in 2 ECG as well as release of CK; 91% of vs 44% in patients getting t-PA ++ nitro (95% CI, 14% to 82%; p < 0.02).
- t-PA antigen in the plasma was also consistently higher (p < 0.005) in those only getting t-PA 6 hours after t-PA infusion.
- Plasminogen activator inhibitor-1 (PAI-1) levels were slightly higher in patients getting t-PA + nitro.
|
| Conclusion |
The combination of t-PA and nitroglycerin not only decreased the plasma concentrations of t-PA, but also impaired the thrombolytic effects of t-PA. |
-
Charvat J et al. Beneficial effect of intravenous nitroglycerin in patients with non-Q myocardial infarction. Cardiologia 1990;35(1):49-54. PubMed
| LOE |
1b |
| Study Design |
Prospective, Open-label, Single-Centered, Single-Blinded, Placebo-Controlled Study |
| Sample Size |
N = 129 |
| Groups |
- Nitroglycerin IV (n = 62) x 48 hrs (if BP was <160/105 then 10 mcg/min and increased every 5 min by 10 mcg/min until SBP decreased by 20 mm Hg but > 100 mm HG (or) if BP was > 160/105 then 40 mcg/min and titrated every 5 min by 10 mcg/min until SBP decreased by 20 mm Hg and DBP was < 90 mmHg) vs.
- Placebo (n = 67)
|
| Results |
- Only when mortality, extension of MI or occurrence of left ventricular failure were combined was there a benefit seen, but not individually. Mortality for nitroglycerin group at 10d = 8%; 5/62 vs placebo at 10d = 7.5%; 5/67.
- The size of MI (per peak of creatine kinase (CK) levels) was similar in both groups. However, if Q-wave and non Q-wave MI were analyzed separately, the peak CK was significantly lower in non Q-wave MI patients receiving nitroglycerin (523 +/- 161 IU/l compared to 1049 +/- 583 IU/l for placebo, p = 0.002).
- Although there was no difference in the final occurrence of Q-wave MI, non Q-wave MI patients had lower peak CK than Q MI patients (770 +/- 491.9 to 2783 +/- 1720.9, p = 0.001) and this peak CK was observed earlier for non Q MI patients (16.2 +/- 5.41 hours compared to 22.6 +/- 6.86 hours for Q MI patients, p = 0.001).
|
| Conclusion |
The use of IV nitroglycerin may have a beneficial effect in non-Q-wave MI per CK levels. |
| Location |
Sabah Hospital, Safat, Kuwait |
-
Gobel EJ et al. Randomised, double-blind trial of intravenous diltiazem versus glyceryl trinitrate for unstable angina pectoris. Lancet 1995;346(899-18992):1653-7. PubMed
| LOE |
1b |
| Study Design |
Prospective, Randomized, Double-Blind, Single Center Study |
| Sample Size |
N = 121 |
| Population |
Adults with unstable angina |
| Groups |
- Diltiazem 25 mg IV over 5 mins loading dose, then 5 mg/h infusion titrated as need up to a max dose of 25 mg/hr (n = 60)
- Glyceryl trinitrate given as a IV saline bolus over 5 mins for blinding purposes, then infusion at 1 mg/h titrated every 5 min to a max dose of 5 mg/h (n = 61)
|
| Other Treatments |
Aspirin and IV heparin infusion |
| Primary Endpoint |
Refractory angina or myocardial infarction, both individually and as a composite |
| Results |
- Refractory angina occurred in 6 (10%) on diltiazem vs 17 (28%) in the glyceryl trinitrate group (RR 0.36, p = 0.02).
- Those with refractory angina plus a MI were 9 (15%) vs 23 (38%) (RR 0.40, p = 0.007).
- At 48 h the number of refractory angina was 8 (13%) vs 18 (30%), RR 0.45, p = 0.03, and refractory angina plus an MI was 12 (20.0%) vs 25 (41%), RR 0.49, p = 0.02.
- Patients receiving diltiazem group had better (p < 0.05) event-free survival and the heart-rate pressure product was reduced significantly (p < 0.05).
- The incidence of bradyarrhythmias did not differ significantly, but AV conduction disturbances occurred in 5 (8%) patients in the diltiazem group vs none in the glyceryl trinitrate group (p = 0.03). These disturbances could be reversed by decreasing the dose of the drug or withdrawing it. No temporary pacemakers were required.
- Headache requiring an analgesic or dose adjustment occurred significantly less in the diltiazem group: 3 (5%) versus 15 (25%), relative risk 0.20 (p < 0.004).
|
| Conclusions |
The results indicate that IV diltiazem can reduce ischemic events compared to glyceryl trinitrate and can be safely used in patients with unstable angina. |
| Location |
University Hospital Groningen, The Netherlands |
| Comments |
The number of patients with heart failure is unknown and would be limitation to the use of diltiazem. |
|
