The main findings in this study were the following; (1) only one-third of deaths in uncomplicated patients and 46% even in complicated patients were cardiac in origin during follow-up after coronary revascularization; (2) death related to progressive coronary atherothrombosis documented by coronary angiography or autopsy constituted only 2.1% of all-cause death among post-discharged patients; and (3) dominant causes of cardiac death were heart failure, and sudden cardiac death without apparent relation with progressive coronary atherothrombosis.
During the recent decades, there has been a notable decrease in CV mortality in the developed countries owing to the improved pharmacologic and interventional treatments together with favorable life style modification . Furthermore, the causes of death after PCI were reported to be shifting from cardiac causes to non-cardiac causes . A report suggested that the risk of non-cardiac death was much greater than the risk of cardiac death beyond the acute phase in patients who underwent primary PCI for ST-segment elevation myocardial infarction . In the present study, the proportion of CV death among all-cause death during follow-up after coronary revascularization was slightly < 50%, and only one-third of deaths were cardiac in origin. Though these numbers were higher when compared with the proportion of cardiac or CV death in Japanese general population , the focus of prevention should be not only on cardiac death, but also on non-cardiac death to improve the survival of patients who underwent coronary revascularization.
Aspirin and statins to prevent progression of atherothrombosis are the established secondary prevention regimen in patients with established CV disease. Both aspirin and statins have demonstrated survival benefit in the meta-analyses of the placebo-controlled randomized clinical trials . However, only 1.9% of all-cause deaths were definitely related to progressive coronary atherothrombosis in the present study, in which aspirin and statins were prescribed at hospital discharge in 99% and 50%, respectively. MI definitely related to progressive coronary atherothrombosis was the cause of all-cause death in only 1.0% of patients, which was related to the low rates of MI during follow-up, and improved survival outcome after MI. Therefore, it seems unrealistic for a novel pharmacologic agent solely with anti-atherothrombosis effect to show mortality benefit during a relatively short follow-up period of clinical trials. Indeed, in the Dual Antiplatelet Therapy (DAPT) trial, prolonged DAPT did not confer any positive effect on cardiac death despite > 50% relative risk reduction for MI .
In the present study, dominant causes of cardiac death were heart failure, and sudden cardiac death. As the prevention of cardiac death after PCI or CABG, we should focus more on developing effective interventions to prevent heart failure and/or arrhythmic events that are probably unrelated to progressive coronary atherothrombosis. In this context, it was noteworthy that the EMPA-REG OUTCOME trial demonstrated significant 38% reduction of CV death as well as 35% reduction of hospitalization for heart failure without impacting on MI and stroke by empagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT-2), in patients with diabetes and established cardiovascular disease .
The present study has several important limitations. First, due to the retrospective study design, there were a significant proportion of patients with undetermined death, who were regarded as having cardiac death despite insufficient information to adjudicate the causes of death. Although we made an effort to identify the cause of death by collecting information from not only medical record but letters for referred doctors or patients, total 264 patients died from undetermined causes and were adjudicated as cardiac death. Therefore, the proportion of death related to progressive coronary atherothrombosis might be underestimated. Second, the definition for documented progressive coronary atherothrombosis required proof by coronary angiography or autopsy in this study, which might lead to underestimate its incidence. In the case of heart failure, only a very small proportion of patients had angiographic or autopsy evaluation for progressive coronary atherothrombosis. However, in the Japanese clinical practice, it seems very unlikely that a heart failure patient with signs and/or symptoms suggestive of myocardial ischemia did not undergo coronary angiographic evaluation. In the case of sudden cardiac death, cardiac rhythm was documented in only about 3% of diseased patients, and about 97% of patients, we did not have enough information to know whether sudden death was related to the primary arrhythmic event or undiagnosed fatal myocardial infarction. Although some review described about 80% of sudden cardiac death was attributed to coronary artery disease, the percentage included both acute coronary ischemia and chronic myocardial scar caused by prior myocardial infarction and did not indicate the pure proportion of patients having progressive coronary artery disease . A previous study reported that primary PCI was performed in only 16.7% among the 162 consecutive adult patients with witnessed cardiac arrest of cardiac origin who had received cardiopulmonary resuscitation > 20 min and undergone emergency coronary angiography . Sudden cardiac death often occurs in patients with depressed left ventricular function with or without chronic heart failure and lethal arrhythmia caused by myocardial scar is theoretically unpreventable by anti-atherothrombotic agents. In the CORONA trial that enrolled patients with ischemic systolic heart failure, the risk of sudden death was not reduced by rosuvastatin therapy, which is the established treatment to prevent cardiovascular events related to atherothrombotic progression . Therefore, sudden cardiac death might more often be related to primary arrhythmia rather than to acute myocardial infarction. Third, the source of data in current study becomes outdated and there are several different points from today's clinical practice. The rate of DES use was about 50% and the prescription rate of statins or clopidogrel was also low. Furthermore, the first-generation DES predominantly used in this study is no longer used in the contemporary clinical practice. Therefore, these data are thought to be not a true representation under the current standard of care. However, the proportion of cardiac death, MI, and stroke related to progressive coronary atherothrombosis might further be reduced, if we had implemented contemporary standard therapy more widely. Finally, because the current study results might be related to the low rates of MI in patients undergoing PCI and CABG in Japan, generalizing the results to populations outside Japan should be done with caution.