3

Results

3.2

Mortality and cause of death in uncomplicated patients

The median clinical follow-up duration of overall patients was 5.1 (IQR: 4.2–5.9) years. Among 15,231 patients, 2837 patients died during the entire follow-up with cumulative 5-year incidence of 17.5%.

Among 13,839 uncomplicated patients, 2194 patients died during the entire follow-up with cumulative 5-year incidence of 14.6%. The cumulative incidence of mortality and its components (cardiac, vascular, or non-CV death) increased proportional to time ( Fig. 2 A ). The proportion of cardiac death was only 36.6% of all-cause death, while the corresponding proportions of vascular death and non-cardiovascular death were 11.9%, and 51.5%, respectively ( Fig. 3 A ). 

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Kaplan-Meier curves for mortality.

(A) and (B) indicate Kaplan-Meier curves for mortality and its components in uncomplicated patients and (C) and (D) indicate the curves in complicated patients. (A) and (C) show all cause death (blue), cardiac death (red), vascular death (orange) and non-CV death (gray), and (B) and (D) show all cardiac death (blue), and cardiac death related to documented progressive coronary atherothrombosis (red).

CV = cardiovascular, PCI = percutaneous coronary intervention.

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Detailed causes of death after coronary revascularization.

Circles indicate the proportions of detailed causes in all-cause death among (A) 13,839 uncomplicated patients, (B) 1392 patients without clinical success or with complication, and (C) 14,832 patients who were alive at discharge regardless of clinical success or complications.

Inner zones colored in red, orange, and gray indicated cardiac death, vascular death, and non-cardiovascular death, respectively. Percentages in the parenthesis were proportion in all-cause death. In the present analysis, we carefully reviewed the original source documents in patients with cardiac death and classified the cardiac death into 3 types according to the presence of documented progressive coronary atherothrombosis as the specific cause of death; Type A: death with documented progressive coronary atherothrombosis (preceding coronary revascularization within 30 days before death or irreversible brain damage and/or proof of coronary thrombus by autopsy); Type B: death without documented progressive coronary atherothrombosis by coronary angiography, autopsy, or clinical inference; and Type C: death without enough information to infer the presence or absence of progressive coronary atherothrombosis (e.g. sudden death without coronary angiography or autopsy, undefined death, etc.).

CV = cardiovascular, MI = myocardial infarction, HF = heart failure, SCD = sudden cardiac death, and PAD = peripheral artery disease.

 

Among 802 patients with cardiac death, only 41 patients had cardiac death related to documented progressive coronary atherothrombosis (type A events: 1.9% of all-cause death), including MI (1.0%), heart failure (0.2%), arrhythmia (0.2%), and coronary revascularization procedure (0.6%) ( Fig. 3 A). The cumulative 5-year incidence of such cardiac death was as low as 0.3% ( Fig. 2 B). The causes of death were undetermined in 10.6% of all-cause death, which were adjudicated as cardiac death. Similarly, MI was adjudicated as the cause of death in 2.6% of cases without sufficient information to infer its relation with progressive coronary atherothrombosis. Dominant causes of cardiac death included heart failure (9.7%), and sudden cardiac death (9.2%), both without apparent relation with progressive coronary atherothrombosis ( Fig. 3 A). Among the 270 cardiac deaths adjudicated as not related to documented progressive coronary atherothrombosis, absence of progressive coronary atherothrombosis was actually demonstrated by coronary angiography or autopsy only in 37 events (13.7%), which comprised 3 for MI, 19 for heart failure, and 15 for arrhythmia.

Among 262 patients with vascular death, 132 patients were adjudicated as death related to stroke (6.1% of all-cause death; ischemic stroke: 3.0%, and hemorrhagic stroke: 3.1%) ( Fig. 3 A). Dominant cause of death in this population was non-CV death (1130 patients, 51.5%) with malignancy (25.2%), and infection (14.7%) as the majorities ( Fig. 3 A).

When dividing uncomplicated patients into aged group (≥ 75 years old) or others, the proportion of cardiac death was similar (about 36%), although that of cardiac death related to documented progressive coronary artery atherothrombosis was slightly but significantly lower in aged patients group (1.3% vs 2.5%, P = 0.043, Supplemental Fig. 1). Otherwise, the proportion of type B heart failure, unknown cardiac death, infection, and malnutrition or senility were higher in aged patients group and the proportion of type B arrhythmia, type C sudden cardiac death, peripheral artery disease, and malignancy were higher in younger patients group with significance (Supplemental Fig. 1).

3.4

Other findings across two patient groups

When focused on all discharged patients regardless of clinical success or complications, CV death and cardiac death accounted for 50% and 38% of all-cause death ( Fig. 3 C). The cardiac death related to documented progressive coronary atherothrombosis account for 2.1%, 4.2%, and 5.6% of all-cause death, CV death and cardiac death, respectively ( Fig. 4 ). 

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Proportion of cardiac death related to documented coronary atherothrombosis in all-cause death, cardiovascular death, and cardiac death among post-discharge patients.

Post-discharge patients comprise 13,839 uncomplicated patients and 993 complicated patients with discharge alive. Definitions for type A, type B, and type C events were described in the legends for Fig. 3 .

CD = cardiac death, CVD = cardiovascular death, VD = vascular death, and NCVD = non-cardiovascular death.

 

Among 40 patients with arrhythmic death (type B) and 225 with sudden cardiac death (type C) in Fig. 2 A and B, the numbers and percentages of patients with documented shockable rhythm (ventricular tachycardia or ventricular fibrillation, VT/VF) were respectively 24 (60.0%) and 4 (1.8%) (Supplementary Table 1).

4

Discussion

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 [1819] . Furthermore, the causes of death after PCI were reported to be shifting from cardiac causes to non-cardiac causes [20] . 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 [21] . 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[22] , 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 [356] . 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 [10] .

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 [23] .

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 [2425] . 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 [26] . 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 [27] . 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.

5

Conclusion

Only one-third of deaths were cardiac in origin during 5-year follow-up after coronary revascularization. Cardiac death was very infrequently related to documented progressive coronary atherothrombosis, but frequently related to heart failure or sudden cardiac arrest without apparent relation with progressive coronary atherothrombosis.