The Death of MONA in ACS: Part III – Nitroglycerin

Background: Nitroglycerin is a first line agent in the treatment of ACS. The physiologic basis for it’s use rests on it’s ability to promote coronary vasodilation resulting in increased blood flow to the coronary arteries . Nitroglycerin, is typically given as sublingual tablets or sublingual spray of 0.3 – 0.4mg q5min x3 for ischemic chest pain and only after this is IV NTG given for persistent pain.

The last AHA/ACC guidelines for the management of patients with Non-ST-Elevation Acute Coronary Syndromes was published in 2014 [3].  The majority of the studies included in these recommendations were published between 1979 – 1995. The strength of recommendations are listed below:

Clinical Question: Nitroglycerin may be first line therapy in ACS, but what is the actual evidence to defend its role?

Lancet 1988 Review [2]

What They Did:

• Systematic review of RCTs or IV nitroglycerin or nitroprusside in acute myocardial infarction

Outcomes:

• Primary: Mortality
• Secondary: “Early” Mortality (Within 1^st week) and “Late” Mortality (Subsequent Months)

Exclusion:        

• RCTs of oral nitrates
• “Very old” – not defined in paper
• Pulmonary Edema
• Cardiogenic Shock
• Systolic BP ≤90mmHg (some trials 95 – 100mmHg)
• SBP ≥200mmHg
• COPD
• Non-cardiac life-threatening disease

Results:

• 10 Trials with approximately 2000 patients
  • 3 Trials IV Nitroprusside
    • Initial Dose 10 – 33 ug/min
  • 7 Trials IV Nitroglycerin
    • Initial Dose: 5 – 50 ug/min

Critical Results:

Overall Mortality

“Early” vs “Late” Mortality

Strengths:

• All treatment started within 24hr of the onset of pain
• 7/10 studies had placebo

Limitations:

• Number of Patients in Trials: 30 – 800 (Mean: Just over 200)
• Dose and duration of nitrate infusions varied in studies
• Quality of methods not reported

Author Conclusion: “Both nitroglycerin and nitroprusside reduced mortality, the reduction being non-significantly greater with nitroglycerin than with nitroprusside.  The greatest reduction in mortality occurred during the first week or so of follow-up, with a non-significant further reduction after this early period.  This suggests that the early benefit is not rapidly lost.”

2009 Cochrane Review [1]

What They Did:

• Systematic review and meta-analysis of RCTs comparing anti-hypertensive drugs with placebo or no treatment within 24 hrs of onset of an acute cardiovascular event

Outcomes:

• All-cause mortality (0 – 48hrs)
• All-cause mortality (0 – 10 days)
• All-cause mortality (≥ 30 days)

Inclusion:

• RCTs with parallel design comparing an anti-hypertensive drug with placebo or no treatment in patients with an acute cardiovascular event
• Intervention must have been started within 24hours of the onset of the acute cardiovascular event
• Patients followed for at least 24 hours and mortality or serious adverse events data provided at least one of the prespecified times (2 days, 10 days, or ≥30 days)

Exclusion:

• Mortality not reported or not reported in a form or time period that could be used
• Uncertain time of patient inclusion following acute event
• Follow-up of <24 hours

Results:

• 65 Total RCTS (N = 166,206) of which 18 trials evaluated nitrates
• All-cause mortality (2d): 6 Trials (N = 82624)
  • RR 0.81 (0.74 – 0.89)

• All-cause mortality (10d): 6 Trials (N = 78178)
  • RR 0.91 (0.86 – 0.97)
• All-cause mortality (≥30d): 3 trials (N = 570)
  • RR 0.72 (0.48 – 1.10)

Strengths:

• 40 trials (60%) were double-blind placebo-controlled trials, involving 75% (N=125,487) or the entire studied population

Limitations:

• None of the trials reported non-fatal serious adverse events
• 75% of trials in this review had incomplete data or did not report all-cause mortality at 2 days

Discussion:

• In the paper the authors state that the benefit of nitrates in the first 48 hours was, “Highly significant benefit was achieved. 125 or 250 patients, with high or low risk, need to be treated to prevent one death.” They go on to state in the in the 0 – 10 day sub-cohort of patients, “Significant benefit is demonstrated, but this is the same absolute magnitude as day 2.  Thus, likely reflects the mortality benefit at day 2.”
• The largest trial included in this review had 58,050 patients (ISIS-4) published in 1995. The authors used controlled released isosorbide starting with 30mg BID for day 1 and then followed by 60mg qD for 28 days.  Only 47% of patients in this study received IV nitrates.
• The second largest trial included in this review had 19,394 patients (GISSI-3) published in 1994. The authors used IV nitroglycerin initiated at 5 – 20 ug/min to achieve a 10% SBP reduction during the 1^st 24 hours.
• Isolating the 2 trials above the mortality benefit for nitrates at day two were the same for both both trials (RR 0.82; 95% CI 0.73 – 0.92 and RR 0.82; 95% CI 0.68 – 0.99 respectively)

Author Conclusion: “Nitrates reduce mortality (4-8 deaths prevented per 1000) at 2 days when administered within 24 hours of symptom onset of an acute myocardial infarction. No mortality benefit was seen when treatment continued beyond 48 hours. Mortality benefit of immediate treatment with ACE inhibitors post MI at 2 days did not reach statistical significance but the effect was significant at 10 days (3-5 deaths prevented per 1000). There is good evidence for lack of a mortality benefit with immediate or short-term treatment with beta- blockers and calcium channel blockers for acute myocardial infarction.”

Nitroglycerin Preparations:

• SL NTG: 0.3 – 0.6mg (Can be repeated every 5 min up to a max of 3x)
  • Onset of Action: 2 – 5min
  • Duration of Action: 10 – 30 min
• Spray/Mist/Aerosol NTG: 0.4mg (1 – 2 sprays as needed, up to 3 doses 5 min apart)
  • Onset of Action: 2 – 5 min
  • Duration of Action: 10 – 30 min

Clinical Take Home Points:

• The evidence for SL NTG in acute coronary syndromes appears to be extrapolated from IV nitrate dosing
• Nitrates studied in most of these trials were IV nitrates and oral long acting nitrates (i.e. isosorbide dinitrate) not SL nitroglycerin
• In patients with ischemic chest pain, IV nitroglycerin initiated within the first 24 hours of symptom onset reduces overall mortality.

References:

1. Perez MI et al. Effect of Early Treatment with Anti-Hypertensive Drugs on Short and Long-Term Mortality in Patients with an Acute Cardiovascular Event (Review). Cochrane Database Syst Rev 2009. PMID: 19821384
2. Yusuf S et al. Effect of Intravenous Nitrates on Mortality in Aute Myocardial Infarction: An Overview of the Randomised Trials. Lancet 1988. PMID: 2896919
3. Amsterdam EA et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: A Report of the American college of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am coll Cardiol 2014. PMID: 25260718

Post Peer Reviewed By: Anand Swaminathan (Twitter: @EMSwami)

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