Pre-AMI Ischemia May Reduce Early Mortality

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Patients who report angina symptoms or are diagnosed with ischemia shortly before an acute myocardial infarction (AMI) are less likely to die within the first week, although they face higher long-term mortality risk, according to a large prospective study published online July 19, 2014, ahead of print in the European Heart Journal. The early benefit likely reflects natural ischemic preconditioning, the authors say. 

Investigators led by Emily Herrett, PhD, of the London School of Hygiene and Tropical Medicine (London, England), analyzed the clinical presentation and mortality of 16,439 first-MI patients by linking data from the Myocardial Ischaemia National Audit Project (MINAP) registry, hospital discharge and primary care records, and the Office of National Statistics. About half of patients (50.9%) had no prior history of ischemia and showed no ischemia in the 90 days before the index event, while 12.9% presented with new chest pain or a new CAD diagnosis, and 36.2% had longstanding atherosclerotic disease but no new ischemia within 90 days.
Framingham risk before AMI was highest in patients with existing ischemic disease, intermediate in those with new ischemic presentations, and lowest in those with no prior ischemia. Among the MINAP patients, those who presented with new ischemia in the 90 days before AMI or existing ischemic disease were more likely to have NSTEMI than patients with no ischemia. In addition, infarct size was smaller in patients with new or existing ischemia compared with those with no prior ischemia regardless of whether they had NSTEMI or STEMI.

Over a median follow-up of 2.6 years, 5,283 patients (32.1%) died of coronary heart disease (CHD), the primary endpoint. 

Early Mortality Benefit Lost After 3 Months

Patients with ischemic presentations in the 90 days before AMI had lower CHD mortality in the first 7 days after the event compared with those without such presentations, even after adjustment for age, sex, cardiovascular risk factors, and cardiovascular medicine prescriptions. The relationship between pre-AMI ischemia and mortality was borderline among those with existing ischemic disease.

However, between 7 and 90 days after AMI, the protective effect was lost and mortality was greater in those with established ischemia. Beyond 90 days, patients with new angina also experienced higher mortality, while the adverse impact of existing ischemia was exacerbated (table 1).

Table 1. CHD Mortality for Patients With vs Without Ischemia, by Presentation Type


Adjusted HR 

95% CI 

New Symptoms/CAD Diagnosis 
0-7 Days After AMI 
7-90 Days After AMI 
90+ Days After AMI 





Existing Ischemic Diseases 
0-7 Days After AMI 
7-90 Days After AMI 
90+ Days After AMI 






The strength of the mortality benefit during the first week was strongest when ischemia occurred within a few days of the AMI and diminished with more remote presentations.

Prior Ischemia a Double-Edged Sword 

The authors suggest that “the early beneficial association of ischemic presentations in the 2 days prior to AMI with mortality may be a result of ischemic preconditioning,” while the positive effects observed for earlier presentations may reflect the opening of collateral vessels. On the other hand, the longer-term increased mortality in ischemic patients is likely “attributable to a higher atherosclerotic burden,” they add. 

Dr. Herrett and colleagues observe that the mortality differences between ischemic and nonischemic patients were not explained by faster time to hospital admission or reperfusion, health-seeking behavior, prescription of cardiovascular medications, or differences in baseline cardiovascular risk.

“This study is unique in that the data were collected prospectively,” Jay H. Traverse, MD, of Abbott Northwestern Hospital (Minneapolis, MN), told TCTMD in a telephone interview. 

In addition, while most studies of the angina effect have looked only at STEMI, this one included many patients with NSTEMI and even small troponin rises, he noted. And in spite of the likelihood that many patients with angina never visited a doctor and so were not captured in the data, the researchers still found a decrease in early mortality. 

However, he observed, “once you start including all [ischemic] comers you start to see the importance of CAD, and in the long-term that’s going to catch up with you—the bad effect of CAD is much stronger than the protective effect of preinfarction angina.” 

While acknowledging the value of this large database study, Dr. Traverse lamented the lack of clinical granularity. Knowing the exact cause of death—for example, whether it was due to arrhythmia or pump failure, which speak to infarct size and LV function, respectively—and total ischemic time would go a long way toward parsing the mechanisms involved, he commented. 

Incentive to Pursue Therapy for Reperfusion Injury

Dr. Traverse said the findings suggest a possible explanation for the failure of most studies testing treatments for reperfusion injury. About 30% to 40% of the study populations likely had preinfarction angina, and “the benefit of any drug you give is going to be much smaller than the protective effect it imparts,” he explained.

It would be a stretch to suggest that these data have immediate clinical application, Dr. Traverse acknowledged, but they should encourage ongoing research into ischemic preconditioning. “We’ve maxed out reduction in door-to-balloon time,” he observed, “so to me the next important target is reperfusion injury. We just need to determine the mechanisms and come up with pharmacologic ways of treating it.”


Herrett E, Bhaskaran K, Timmis A, et al. Association between clinical presentations before myocardial infarction and coronary mortality: a prospective population-based study using linked electronic records. Eur Heart J. 2014;Epub ahead of print.

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Pre-AMI Ischemia May Reduce Early Mortality

  • Drs. Herrett and Traverse report no relevant conflicts of interest.