Cardiovascular and Renal Implications of Myocardial Infarction in the ISCHEMIA-CKD Trial

Abstract

Background: ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) reported an initial invasive treatment strategy did not reduce the risk of death or nonfatal myocardial infarction (MI) compared with a conservative treatment strategy in patients with advanced chronic kidney disease, stable coronary disease, and moderate or severe myocardial ischemia. The cumulative frequency of different MI type after randomization and subsequent prognosis have not been reported.

Methods: MI classification was based on the Third Universal Definition for MI. For procedural MI, the primary MI definition used creatine kinase-MB as the preferred biomarker, whereas the secondary MI definition used cTn (cardiac troponin); both definitions included elevated biomarker-only events with higher thresholds than nonprocedural MIs. The cumulative frequency of MI type according to treatment strategy was determined. The association of MI with subsequent all-cause death and new dialysis initiation was assessed by treating MI as a time-dependent covariate.

Results: The 3-year incidence of type 1 or 2 MI with the primary MI definition was 11.2% in invasive treatment strategy and 13.6% in conservative treatment strategy (hazard ratio [HR], 0.66 [95% CI, 0.42-1.02]). Procedural MIs were more frequent in invasive treatment strategy and accounted for 9.8% and 28.3% of all MIs with the primary and secondary MI definitions, respectively. Patients had an increased risk of all-cause death after type 1 MI (adjusted HR, 4.35 [95% CI, 2.73-6.93]) and after procedural MI with the primary (adjusted HR, 2.75 [95% CI, 0.99-7.60]) and secondary MI definitions (adjusted HR, 2.91 [95% CI, 1.73-4.88]). Dialysis initiation was increased after a type 1 MI (HR, 6.45 [95% CI, 2.59-16.08]) compared with patients without an MI.

Conclusions: In ISCHEMIA-CKD, the invasive treatment strategy had higher rates of procedural MIs, particularly with the secondary MI definition, and lower rates of type 1 and 2 MIs. Procedural MIs, type 1 MIs, and type 2 MIs were associated with increased risk of subsequent death. Type 1 MI increased the risk of dialysis initiation.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT01985360.

Keywords: epidemiology; mortality; myocardial infarction; myocardial ischemia; myocardial revascularization; renal insufficiency, chronic.

Figure 1.. Frequency distribution of first myocardial infarction (MI) by type and definition according to treatment strategy.

A) Primary MI Definition; B) Secondary MI Definition. Spontaneous type 1 (dark blue) and type 2 (red) MIs were less frequent in the invasive strategy regardless of which MI definition was used. Procedural MIs (type 4a-green; type 5- olive) were more common in the invasive strategy and with the secondary MI definition. Stent related type 4b (stent thrombosis-related and 4c MIs (in-stent restenosis–related) shown in brown/violet were more frequent in the invasive strategy. Silent MIs were infrequent (n=5) and are not shown.

Figure 2.. Cumulative incidence of primary and secondary outcomes by randomized treatment group and by MI definition.

A) All-cause Death or MI (Primary MI Definition). B) All-cause Death or MI (Secondary MI Definition). C) All-cause Death, MI, or Hospitalization for UA, HF, or RCA (Primary MI Definition). D) All-cause Death, MI, or Hospitalization for UA, HF, or RCA (Secondary MI Definition). There were no treatment differences observed using the primary MI definition (Panel A) or secondary MI definition (Panel B). The results were similar for the major secondary composite endpoint of death, nonfatal myocardial infarction (MI), hospitalization for unstable angina (UA), heart failure (HF), or resuscitated cardiac arrest (RCA) (Panels C, D).

Figure 3.. MI type and relationship with subsequent all-cause death.

A) Cumulative incidence of subsequent all-cause death after types 1,2 MI and no MI for the primary MI definition; B) Cumulative incidence of subsequent all-cause death after types 1,2 MI and no MI for the secondary MI definition; C) All-cause Death (Primary MI Definition); D) All-cause Death (Secondary MI Definition). Procedural MIs were associated with an increased risk of death compared with those without an MI during follow-up regardless of MI definition.

Figure 4.. Forest Plots for Death/Hospitalization for Heart Failure.

CV=cardiovascular; MI=myocardial infarction. Multivariate adjusted risks of MI on subsequent all-cause death, cardiovascular death, or cardiovascular death or heart failure admission, according to MI definition. A) Prognosis of MI Types in ISCHEMIA CKD (Primary MI Definition); B) Prognosis of MI Types in ISCHEMIA CKD (Secondary MI Definition). Total number of MI events and subsequent deaths are shown in the second column. The adjusted risk of subsequent all-cause death, cardiovascular death, or cardiovascular death or admission for heart failure was increased for patients that had a type 1 MI and type 2 MI and no procedural MI compared with patients that had no MI during follow-up. The risk for all 3 endpoints was increased for patients with a procedural MI (p=0.001) using the secondary MI definition. There were a limited number of procedural MIs using the primary MI definition.

Figure 5.. Relationship between Type 1 MI and Procedural MI vs No MI and all-cause death in the ISCHEMIA and ISCHEMIA-CKD trials.

Main refers to the ISCHEMIA trial. CKD refers to the ISCHEMIA-CKD trial. A) All-cause Death (Primary MI Definition); B) All-cause Death (Secondary MI Definition). Top Panel: The cumulative incidence of all-cause death was greater in patients that had a type 1 MI compared with those that did not during follow-up in both trials regardless of MI definition used. The higher risk population in the ISCHEMIA-CKD trial is illustrated by the fact that the cumulative incidence of death in patients without an MI during follow-up exceeded that observed in the ISCHEMIA population with a type 1 MI. Bottom Panel: The cumulative incidence of all-cause death after procedural MI was greater compared with those that did not have an MI during follow-up, regardless of MI definition used. In contrast, in the ISCHEMIA trial which enrolled a lower-risk population, the cumulative incidence of all-cause death after procedural MI was similar compared with those that did not have an MI during follow-up, regardless of MI definition used.

Figure 5.. Relationship between Type 1 MI and Procedural MI vs No MI and all-cause death in the ISCHEMIA and ISCHEMIA-CKD trials.

Main refers to the ISCHEMIA trial. CKD refers to the ISCHEMIA-CKD trial. A) All-cause Death (Primary MI Definition); B) All-cause Death (Secondary MI Definition). Top Panel: The cumulative incidence of all-cause death was greater in patients that had a type 1 MI compared with those that did not during follow-up in both trials regardless of MI definition used. The higher risk population in the ISCHEMIA-CKD trial is illustrated by the fact that the cumulative incidence of death in patients without an MI during follow-up exceeded that observed in the ISCHEMIA population with a type 1 MI. Bottom Panel: The cumulative incidence of all-cause death after procedural MI was greater compared with those that did not have an MI during follow-up, regardless of MI definition used. In contrast, in the ISCHEMIA trial which enrolled a lower-risk population, the cumulative incidence of all-cause death after procedural MI was similar compared with those that did not have an MI during follow-up, regardless of MI definition used.