• Documented coronary atherothrombosis as the cause of death in post-discharge patients after coronary revascularization

    Abstract

    Background

    The contemporary medications for secondary prevention like statins and antithrombotic agents are targeting to delay the progression of atherothrombosis. However, there is limited data on the relation between death and progressive coronary atherothrombosis. This study sought to evaluate what proportion of death after coronary revascularization is related to documented progressive coronary atherothrombosis.

    Methods

    We reviewed the detailed causes of death among 15,231 patients receiving their first coronary revascularization enrolled in the CREDO-Kyoto PCI/CABG registry cohort-2, dividing into two groups; 13,839 patients with clinical success and without major complication (uncomplicated) and the other 1392 patients (complicated). Documented progressive coronary atherothrombosis as the cause of death was defined as preceding coronary revascularization within 30 days before death or irreversible brain damage and/or proof of coronary thrombus by autopsy.

    Results

    During the median follow-up of 5.4 years, 2837 patients died with cumulative 5-year incidence of 17.5%. The proportions of cardiac/non-cardiovascular death among all-cause death in uncomplicated patients and complicated patients were 36.6%/51.5% and 74.2%/17.4%, respectively. The numbers of patients died with documented progressive coronary atherothrombosis were 41 (1.9% of all-cause death) and 304 (47.3%). The number was only 51 (2.1%) among all post-discharge patients. Dominant causes of cardiac death in post-discharge patients included heart failure (10.0%) and sudden cardiac death (9.1%), both without apparent relation with progressive coronary atherothrombosis.

    Conclusions

    Only about one-third of deaths were cardiac in origin during 5-year follow-up in post-discharge patients after coronary revascularization. Cardiac death after discharge was very infrequently related to documented progressive coronary atherothrombosis.

    Highlights

     

    •  

      This study demonstrated the causes of death after first coronary revascularization in Japanese cohort data.

    •  

      Cardiac death inpost-discharge patients was only 37.5% in all-cause death, while non-cardiovascular cause was dominant.

    •  

      Documented progressive coronary atherothrombosis as coronary revascularization within 30-day before death was only 2.1%.

    •  

      Frequent causes of cardiac death were heart failure or sudden cardiac arrest without progressive coronary atherothrombosis.

     

    Introduction

    Coronary artery disease (CAD) and cerebral vascular disease (CVD) are the two leading causes of death all over the world. CAD, CVD and peripheral artery disease (PAD) are caused primarily by atherosclerosis and thrombosis and commonly referred as “atherothrombosis”  . Pharmacologic interventions such as aspirin and statins to prevent progression of atherothrombosis have been successful in reducing cardiovascular (CV) events  . Moreover, recent studies reported there remains a residual risk for CV events even after aggressive lipid lowering with intensive statins therapy in conjunction with other contemporary evidence-based medications to prevent CV events  . Therefore, various novel pharmacologic anti-atherothrombotic interventions to further reduce CV events have been explored extensively  . However, there seem to be many CV events actually not related to the progression of atherothrombosis. Anti-atherothrombotic agents could at least theoretically prevent death caused by progression of atherothrombosis, but most likely could not prevent death unrelated to it. Currently, there is a paucity of information regarding the relation between progressive atherothrombosis and mortality. Therefore, we sought to explore the actual causes of death and their relation with progressive coronary atherothrombosis documented by coronary angiography or autopsy in a large Japanese observational database of patients undergoing first coronary revascularization.

    Methods

    Study population

    The Coronary REvascularization Demonstrating Outcome study in Kyoto (CREDO-Kyoto) percutaneous coronary intervention (PCI)/coronary artery bypass grafting (CABG) registry cohort-2 is a physician-initiated multicenter registry enrolling a total of 15,939 consecutive patients undergoing first coronary revascularization procedures at 26 centers in Japan (Online Appendix 1) from January 2005 to December 2007, when the first generation drug-eluting stents (DES) began to be broadly used instead of bare-metal stents (BMS) in Japan. The design and patient enrollment of the registry has been described previously  . The ethics committees in all participating centers approved the research protocol. Because of retrospective enrollment, written informed consents from the patients were waived; however, we excluded those patients who refused participation in the study when contacted for follow-up.

    The current study population was 15,231 patients who underwent first PCI or isolated CABG after excluding 99 patients who refused study participation and 609 CABG patients who underwent combined surgical procedures. In analysis, we divided the population into two groups; first, 13,839 patients who had clinical success and discharged without major in-hospital complications including death, Q-wave myocardial infarction (MI), stent thrombosis, and emergent PCI/CABG and second, 1392 patients consisting of 1109 patients with major in-hospital complications and 283 patients without clinical success ( Fig. 1 ). 

    Fig. 1
    Study flow.
    *Major in-hospital complications included death, Q-wave myocardial infarction, stent thrombosis, and emergent PCI/CABG.
    CREDO-Kyoto = The Coronary REvascularization Demonstrating Outcome study in Kyoto, PCI = percutaneous coronary intervention, and CABG = coronary artery bypass grafting.

     

    Data collection and definitions

    As described in previous reports, demographic, angiographic, and procedural data were collected from the hospital charts or hospital databases according to the pre-specified definitions by the independent clinical research coordinators in a clinical research organization (Research Institute for Production Development, Kyoto, Japan; Online Appendix 2)  . Follow-up data were also obtained by the clinical research coordinators from hospital charts or by contacting patients or referring physicians.

    Death was classified with cardiac, vascular, and non-cardiovascular death by its cause. Regarding the causes of death, one most influencing and primary cause of death was selected under the concept of underlying cause stated by the World Health Organization (WHO). Those deaths without obvious non-cardiac causes or without sufficient information on their causes were classified into cardiac death. Sudden death was defined as unexplained death in previously stable patients. Stent thrombosis was defined according to the Academic Research Consortium definition  . MI was defined with definition of the Arterial Revascularization Therapy Study  . Within 1 week of the index procedure, only Q-wave myocardial infarction was adjudicated as myocardial infarction. Stroke during follow-up was defined as ischemic or hemorrhagic stroke requiring hospitalization with symptoms lasting > 24 h. Death, MI and stroke were adjudicated by an independent clinical event committee (Online Appendix 3).

    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.).

    Statistical analysis

    Categorical variables were expressed as number and percentages. Continuous variables were expressed as mean ± SD or median and interquartile range (IQR). The cumulative incidence of event was estimated by the Kaplan-Meier method. Analysis was made by using JMP 10.0. (SAS Institute Inc., Cary, NC, USA). All the statistical analyses were two-tailed. value < 0.05 was considered statistically significant.

    Results

    Patient demographics

    The current study population represented the typical Japanese CAD patients including a high prevalence of elderly patients with preponderance of men and with small body mass index. In comparison of uncomplicated and complicated patients, complicated patients more often had high risk features like higher age, lower BMI, heart failure, cardiogenic shock, left main disease, atrial fibrillation, renal failure, anemia, or thrombocytopenia ( Table 1). 

    Table 1
    Baseline clinical characteristics.
     All patientsUncomplicated patientsComplicated patientsPvalue
     N = 15,231N = 13,839 (90.9%)N = 1392 (9.1%) 
    Age (years) 68.2 ± 10.8 68.0 ± 10.7 71.0 ± 11.2 < 0.001
    Age ≥ 75 years 4699 (31%) 4108 (30%) 591 (42%) < 0.001
    Male 11,009 (72%) 10,061 (73%) 948 (68%) < 0.001
    BMI (kg/m ) 23.7 ± 3.4 23.7 ± 3.4 23.2 ± 3.7 < 0.001
    BMI < 25.0 kg/m 2 10,493 (69%) 9439 (68%) 1054 (75%) < 0.001
    Acute myocardial infarction 4892 (32%) 4318 (31%) 574 (41%) < 0.001
    Hyperlipidemia 10,507 (69%) 9626 (70%) 881 (63%) < 0.001
    Hypertension 12,512 (82%) 11,414 (82%) 1098 (79%) 0.001
    Diabetes mellitus 5999 (39%) 5459 (39%) 540 (39%) 0.63
    Insulin therapy 1353 (9%) 1232 (9%) 121 (9%) 0.79
    Current smoking 4709 (31%) 4333 (31%) 376 (27%) < 0.001
    Heart failure 3134 (21%) 2561 (19%) 573 (41%) < 0.001
    Shock at presentation 840 (6%) 558 (4%) 282 (20%) < 0.001
    Multivessel disease 9191 (60%) 8225 (59%) 966 (69%) < 0.001
    LMCA disease 1290 (8%) 1087 (8%) 203 (15%) < 0.001
    Mitral regurgitation grade 3/4 591 (4%) 506 (4%) 85 (6%) < 0.001
    LVEF (%) 58.4 ± 13.4 58.7 ± 13.0 54.2 ± 16.3 < 0.001
    LVEF ≤ 40% 1419 (11%) 1191 (10%) 228 (30%) < 0.001
    Prior myocardial infarction 1817 (12%) 1610 (12%) 207 (15%) < 0.001
    Prior stroke 1688 (11%) 1491 (11%) 197 (14%) < 0.001
    Peripheral artery disease 1225 (8%) 1108 (8%) 117 (8%) 0.6
    ESRD (eGFR < 30 mL/min/1.73 m ) not on dialysis 682 (4%) 560 (4%) 122 (9%) < 0.001
    Dialysis 600 (4%) 510 (4%) 90 (6%) < 0.001
    Atrial fibrillation 1493 (10%) 1306 (9%) 187 (13%) < 0.001
    Anemia (hemoglobin < 11 g/dL) 1927 (13%) 1676 (12%) 251 (18%) < 0.001
    Thrombocytopenia (platelets < 10^11/L) 247 (2%) 192 (1%) 55 (4%) < 0.001
    Chronic obstructive pulmonary disease 529 (3%) 473 (3%) 56 (4%) 0.25
    Liver cirrhosis 404 (3%) 369 (3%) 35 (3%) 0.73
    Malignancy 1402 (9%) 1275 (9%) 127 (9%) 0.91
    BMI = body mass index, eGFR = estimated glomerular filtration rate, ESRD = end-stage renal disease, LMCA = left main coronary artery, and LVEF = left ventricular ejection fraction.

     

    Study population including 86% of PCI patients and 14% of CABG patients, and the percentages were not different between uncomplicated group and complicated group. Complicated patients showed lower rate of use of stent and DES, higher rate of procedure involving left main, longer stent use, higher rate of saphenous vein grafting and on-pump CABG ( Table 2 ). Regarding the medications at hospital discharge, aspirin was prescribed in almost all patients both after PCI and CABG, while thienopyridines were prescribed in almost all PCI patients and in very few CABG patients. Fewer patients with complication received appropriate antiplatelet therapy. The rate of clopidogrel use was quite low because this agent was available in Japan only from 2006. Especially in complicated patients, the prescription rates of so called evidence-based medications such as statins, beta-blockers, and blockers of renin-angiotensin system were not so high ( Table 2 ). 

    Table 2
    Procedural characteristics and medications.
     Uncomplicated (N = 13,839)Complicated (N = 1392)value a
     PCICABGPCICABGUncomplicated vs Complicated
     N = 11,867 (86%)N = 1972 (14%)N = 1191 (86%)N = 201 (14%)
    (A) Procedural characteristics          
    PCI          
    Stent use 11,356 (96%)   824 (69%)   < 0.001
    DES use 6414 (54%)   374 (31%)   < 0.001
    Number of target vessels 1.3 ± 0.6   1.4 ± 0.6   0.67
    Number of target lesions 1.5 ± 0.8   1.4 ± 0.8   0.052
    Target of proximal LAD 6845 (58%)   624 (52%)   < 0.001
    Target of unprotected LMCA 377 (3%)   101 (8%)   < 0.001
    Total number of stents 1.8 ± 1.2   2.2 ± 1.6   < 0.001
    Total stent length (mm) 39.1 ± 28.6   47.2 ± 37.5   < 0.001
    CABG          
    Number of bypassed vessels   2.5 ± 0.6   2.6 ± 0.6 0.44
    LITA graft   1894 (96%)   183 (91%) 0.003
    RITA graft   563 (29%)   56 (28%) 0.84
    GEA graft   431 (22%)   36 (18%) 0.19
    Radial artery graft   443 (22%)   39 (19%) 0.31
    Saphenous vein graft   1290 (65%)   154 (77%) 0.001
    On-pump CABG   714 (36%)   104 (52%) < 0.001
    (B) Medication at hospital discharge          
    Thienopyridines 11,645 (98%) 180 (9%) 1040 (87%) 26 (13%) < 0.001
    Ticlopidine 10,505 (89%) 173 (9%) 935 (79%) 21 (10%) < 0.001
    Clopidogrel 1113 (9%) 7 (0.3%) 102 (9%) 5 (2%) 0.59
    Cilostazole 2243 (19%) 144 (7%) 269 (23%) 22 (11%) < 0.001
    Aspirin 11,743 (99%) 1944 (99%) 1123 (94%) 189 (94%) < 0.001
    Statins 6257 (53%) 594 (30%) 437 (37%) 42 (21%) < 0.001
    Beta-blockers 3663 (31%) 501 (25%) 311 (26%) 49 (24%) < 0.001
    ACE-I/ARB 7059 (59%) 616 (31%) 557 (47%) 49 (24%) < 0.001
    ACE-I 2550 (21%) 154 (8%) 225 (19%) 12 (6%) 0.02
    ARB 4757 (40%) 490 (25%) 350 (29%) 37 (18%) < 0.001
    Nitrates 4268 (36%) 673 (34%) 380 (32%) 71 (35%) 0.01
    Calcium channel blockers 4861 (41%) 1009 (51%) 386 (32%) 72 (36%) < 0.001
    Nicorandil 2853 (24%) 789 (40%) 273 (23%) 76 (38%) 0.31
    Warfarin 973 (8%) 726 (37%) 100 (8%) 78 (39%) 0.58
    Proton pump inhibitors 3056 (26%) 804 (41%) 314 (26%) 70 (35%) 0.81
    H2-blockers 3140 (26%) 678 (34%) 255 (21%) 48 (24%) < 0.001
    ACE-I = angiotensin converting enzyme inhibitors, ARB = angiotensin II receptor blockers, CABG = coronary artery bypass grafting, DES = drug-eluting stents, GEA = gastroepiploic artery, LAD = left anterior descending coronary artery, LITA = left internal thoracic artery, LMCA = left main coronary artery, LVEF = left ventricular ejection fraction, PCI = percutaneous coronary intervention, and RITA = right internal thoracic artery.

    a Indicates -value in comparison between uncomplicated and complicated patients as two groups combining PCI patients with CABG patients.

     

    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 ). 

    Fig. 2
    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.
    Fig. 3
    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%, = 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).

    Mortality and cause of death in complicated patients

    On the other hand, among 1392 complicated patients, 643 patients died during the entire follow-up with cumulative 5-year incidence of 45.7% ( Fig. 2 C). The number of patients with in-hospital death was 399 (28.7%) and the cause of death in almost all the patients was classified into cardiac cause. The Kaplan-Meier curves indicated sharp rise of all-cause and cardiac death just after index procedure, and after that gradually increase of all-cause death and non-CV death in parallel ( Fig. 2 C). The proportion of cardiac death was occupied in 74.2% of all-cause death, while the corresponding proportions of vascular death and non-cardiovascular death were as low as 8.4%, and 17.4%, respectively ( Fig. 3 B).

    The number of cardiac death related to documented coronary atherothrombosis was 304 (47.3%), quite higher than uncomplicated patients, and the major cause was myocardial infarction at index procedure (272, 42.3%, Fig. 3 B). The Kaplan-Meier curve of cardiac death related to documented coronary atherothrombosis indicated almost all the event was adjudicated during index hospitalization and thereafter the event seldom happened ( Fig. 2 D). Actually, when subjects were limited to complicated patients with discharge alive, the proportion of type A cardiac death among all-cause death was only 4.1%. And cardiac death, comprising 46.3% of all-cause death, included type B heart failure (12.7%), unknown cardiac death (12.3%) and sudden cardiac death (8.6%) as dominant causes (Supplementary Fig. 2).

    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 ). 

    Fig. 4
    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).

    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  . 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.

    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.

    Author bio

    Cardiovascular Revascularization Medicine, 2018-07-01, Volume 19, Issue 5, Pages 597-606, Copyright © 2017 Elsevier Inc.

    Source:

    1. [1]Viles-Gonzalez J.F., Fuster V., and Badimon J.J.: Atherothrombosis: a widespread disease with unpredictable and life-threatening consequences. Eur Heart J 2004; 25: pp. 1197-1207
    2. [2]Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: pp. 71-86
    3. [3]Lièvre M., and Cucherat M.: Aspirin in the secondary prevention of cardiovascular disease: an update of the APTC meta-analysis. Fundam Clin Pharmacol 2010; 24: pp. 385-391
    4. [4]Lancet 1994; 344: pp. 1383-1389
    5. [5]Baigent C., Keech A., Kearney P.M., Blackwell L, Buck G., Pollicino C., et al: Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366: pp. 1267-1278
    6. [6]Baigent C., Blackwell L., Emberson J., Holland L.E., Reith C., Bhala N., et al: Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376: pp. 1670-1681
    7. [7]Cannon C.P., Braunwald E., McCabe C.H., Rader D.J., Rouleau J.L., Belder R., et al: Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350: pp. 1495-1504
    8. [8]LaRosa J.C., Grundy S.M., Waters D.D., Shear C., Barter P., Fruchart J.C., et al: Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352: pp. 1425-1435
    9. [9]Schwartz G.G., Olsson A.G., Abt M., Ballantyne C.M., Barter P.J., Brumm J., et al: Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012; 367: pp. 2089-2099
    10. [10]Mauri L., Kereiakes D.J., Yeh R.W., Driscoll-Shempp P., Cutlip D.E., Steg P.G., et al: Twelve or 30 . N Engl J Med 2014; 371: pp. 2155-2166
    11. [11]Bonaca M.P., Bhatt D.L., Cohen M., Steg P.G., Storey R.F., Jensen E.C., et al: Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372: pp. 1791-1800
    12. [12]Cannon C.P., Blazing M.A., Giugliano R.P., McCagg A., White J.A., Theroux P., et al: Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372: pp. 2387-2397
    13. [13]Sabatine M.S., Giugliano R.P., Keech A.C., Honarpour N., Wiviott S.D., Murphy S.A., et al: Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376: pp. 1713-1722
    14. [14]Kimura T., Morimoto T., Furukawa Y., Nakagawa Y., Kadota K., Iwabuchi M., et al: Long-term safety and efficacy of sirolimus-eluting stents versus bare-metal stents in real world clinical practice in Japan. Cardiovasc Interv Ther 2011; 26: pp. 234-245
    15. [15]Natsuaki M., Morimoto T., Furukawa Y., Nakagawa Y., Kadota K., Yamaji K., et al: Late adverse events after implantation of sirolimus-eluting stent and bare-metal stent: long-term (5–7 . Circ Cardiovasc Interv 2014; 7: pp. 168-179
    16. [16]Cutlip D.E., Windecker S., Mehran R., Boam A., Cohen D.J., van Es G.A., et al: Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115: pp. 2344-2351
    17. [17]Serruys P.W., Unger F., Sousa J.E., Jatene A., Bonnier H.J., Schönberger J.P., et al: Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med 2001; 344: pp. 1117-1124
    18. [18]Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015; 385: pp. 117-171
    19. [19]Nichols M., Townsend N., Scarborough P., and Rayner M.: Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J 2014; 35: pp. 2950-2959
    20. [20]Spoon D.B., Psaltis P.J., Singh M., Holmes D.R., Gersh B.J., Rihal C.S., et al: Trends in cause of death after percutaneous coronary intervention. Circulation 2014; 129: pp. 1286-1294
    21. [21]Pedersen F., Butrymovich V., Kelbæk H., Wachtell K., Helgvist S., Kastrup J., et al: Short- and long-term cause of death in patients treated with primary PCI for STEMI. J Am Coll Cardiol 2014; 64: pp. 2101-2108
    22. [22]Annual health, labour and welfare report 2016, references no. 1 general welfare and labour. http://www.mhlw.go.jp/english/wp/wp-hw10/dl/01e.pdf
    23. [23]Zinman B., Wanner C., Lachin J.M., Fitchett D., Bluhmki E., Hantel S., et al: Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: pp. 2117-2128
    24. [24]Huikuri H.V., Castellanos A., and Myerburg R.J.: Sudden death due to cardiac arrhythmias. N Engl J Med 2001; 345: pp. 1473-1482
    25. [25]Chugh S.S., Reinier K., Teodorescu C., Evanado A., Kehr E., Al Samara M., et al: Epidemiology of sudden cardiac death: clinical and research implications. Prog Cardiovasc Dis 2008; 51: pp. 213-228
    26. [26]Maekawa K., Tanno K., Hase M., Mori K., and Asai Y.: Extracorporeal cardiopulmonary resuscitation for patients with out-of-hospital cardiac arrest of cardiac origin: a propensity-matched study and predictor analysis. Crit Care Med 2013; 41: pp. 1186-1196
    27. [27]Kjekshus J., Apetrei E., Barrios V., Böhm M., Cleland J.G., Cornel J.H., et al: Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007; 357: pp. 2248-2261

This site uses cookies. By continuing to browse the site you are agreeing to our use of cookies. Review our Privacy Policy for more details