The cumulative evidence base informing almost every aspect of myocardial infarction acute coronary syndrome (ACS) care is expansive and has been associated with a decline in the rate of mortality. Within the context of current-era clinical trials of ST-segment-elevation myocardial infarction, 30-day mortality rates of 4–5% have now been reported for high-risk individuals,1,2 with similar rates reported among the non-ST-segmente-levation ACS populations.3,4 However, large observational studies still report substantially higher rates of in-hospital death than observed in these studies.5,6 Furthermore, recent clinical trials with novel treatment approaches have not provided further reductions in mortality or recurrent ischaemic outcomes, and have seen a shift in focus towards improved alternative outcomes such as bleeding.7,8 Have we reached a ceiling in mortality reduction with modern pharmacological and invasive approaches? Do we need to look beyond the questions of therapeutic innovation to provide further reductions in mortality from myocardial infarction?
While early clinical studies evaluating the efficacy of aspirin, reperfusion therapy and angiotensin-converting enzyme inhibition demonstrated the substantial clinical benefits of these agents in terms of mortality, more modest reductions in events observed in recent trials have led to a greater reliance on non-fatal clinical events and composite end-points. For example, placebo-controlled studies of fibrinolysis and percutaneous coronary intervention (PCI) provided approximately 5% absolute risk reductions in 30-day death, while more recent attempts to refine approaches to reperfusion with bolus fibrinolytic agents and improved antiplatelet and antithrombin therapies have not led to mortality reductions. Also, attempts to couple a fibrinolytic and emergent PCI within a facilitated PCI strategy have not been associated with further reductions in mortality despite the hope for both earlier and more sustained reperfusion. The Assessment of the Safety and Efficacy of a New Thrombolytic Agent (ASSENT-4) study randomised 1,667 patients to receive tenecteplase or tenecteplase and emergent PCI. Patients randomised to receive tenecteplase and emergent PCI experienced greater in-hospital mortality than those receiving tenecteplase alone (6 versus 3%; p=0.0105), with associated higher rates of intracerebral bleeding, re-infarction and urgent revascularisation.4 More novel approaches aimed at reducing mortality following myocardial infarction, such as suppressing the inflammatory response via the compliment pathway, have also failed to reduce mortality. In the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX) study of 5,745 patients, those randomised to pexelizumab had no benefit for 30-day death (pexelizumab 4.06% versus placebo 3.92%; p = not significant).2
- Stone GW, McLaurin BT, Cox DA, et al. for the ACUITY Investigators, N Engl J Med, 2006;355:2203–16.
- Armstrong PW, Granger CB, Adams PX, et al., JAMA, 2007;297:43–51.
- Ferguson JJ, Califf RM, Antman EM, et al., JAMA, 2004;292: 45–54.
- Anonymous, Lancet, 2006;367:569–78.
- Peterson ED, Roe MT, Mulgund J, et al., JAMA, 2006;295: 1912–20.
- Bradley EH, Herrin J, Elbel B, et al., JAMA, 2006;296:72–8.
- Lincoff AM, Bittl JA, Harrington RA, et al., JAMA, 2003;289: 853–63.
- Manoukian SV, Feit F, Mehran R, et al., J Am Coll Cardiol, 2007;49:1362–8.
- Hochman JS et al., N Engl J Med, 2006;355:2395–2407.
- Lagerqvist B, James SK, Stenestrand U, et al., N Engl J Med, 2007;356:1009–19.
- White HD, Willerson JT, Circulation, 2004;109:698–700.
- Mukherjee D, Fang J, Chetcuti S, et al., Circulation, 2004;109: 745–9.
- Ho PM, Spertus JA, Masoudi FA, et al., Arch Intern Med, 2006;166:1842–7.
- Steg PG, Lopez-Sendon J, Lopez DS, et al., Arch Intern Med, 2007;167:68–73.
- Sonel AF, Good CB, Mulgund J, et al., Circulation, 2005;111: 1225–32.
- Stone PH, Thompson B, Anderson HV, et al., JAMA, 1996;275: 1104–12.
- Scott IA, Harper CM, Med J Aust, 2002;177:26–31.
- Roe MT, Peterson ED, Newby LK, et al., Am Heart J, 2006;151: 1205–13.
- Mehta RH, Montoye CK, Gallogly M, et al., JAMA, 2002;287: 1269–76.
- LaBresh KA, Ellrodt AG, Gliklich R, et al., Arch Intern Med, 2004;164:203–9.
- Eagle KA, Montoye CK, Riba AL, et al., J Am Coll Cardiol, 2005;46:1242–8.
- White HD, Lancet, 2005;366:1989–91.
- Granger BB, Swedberg K, Ekman I, et al., Lancet, 2005;366: 2005–11.
- Pfeffer MA, Swedberg K, Granger CB, et al., Lancet, 2003;362: 759–66.
- Eagle KA, Goodman SG, Avezum A, et al., Lancet, 2002;359: 373–7.
- Foley KA, Denke MA, Kamal-Bahl S, et al., Med Care, 2006;44: 421–8.
- Fox KA, Goodman SG, Anderson FA Jr, et al., Eur Heart J, 2003;24:1414–24.
- Fox KA, Goodman SG, Klein W, et al., Eur Heart J, 2002;23: 1177–89.