Faculty Bibliography

Cardiogenic shock is a life-threatening condition that occurs in response to reduced cardiac output in the presence of adequate intravascular volume and results in tissue hypoxia. Cardiogenic shock has several underlying aetiologies, with the most common being acute myocardial infarction (AMI). Refractory cardiogenic shock presents as persistent tissue hypoperfusion despite administration of adequate doses of two vasoactive medications and treatment of the underlying aetiology. Investigators of the SHOCK trial reported a long-term mortality benefit of emergency revascularization for shock complicating AMI. Since the publication of the SHOCK trial and subsequent guideline recommendations, the increase in community-based use of percutaneous coronary intervention for this condition has resulted in a significant decline in mortality. Despite these successes in the past 15 years, mortality still remains exceptionally high, particularly in patients with refractory cardiogenic shock. In this Review, we discuss the aetiology and pathophysiology of cardiogenic shock and summarize the data on the available therapeutics and their limitations. Although new mechanical circulatory support devices have been shown to improve haemodynamic variables in patients with shock complicating AMI, they did not improve clinical outcomes and are associated with high costs and complications.

BACKGROUND: Few studies have assessed treatment effects on health-related quality of life (HRQoL) in patients with acute coronary syndrome (ACS) treated without revascularization. The TRILOGY ACS trial randomized patients with ACS to either prasugrel or clopidogrel therapy plus aspirin. Outcomes showed a complex pattern suggestive of late benefits with respect to repeat clinical events and benefits confined to patients who underwent angiography. Here, we examine the HRQoL correlates of these patterns. METHODS: HRQoL was measured at baseline and 3, 12, and 24 months or end of study (EOS) in 7243 patients aged <75 years using the EuroQol 3-level, group 5-dimension index (EQ-5D). Linear mixed effects models for repeated measures were used to examine treatment differences in HRQoL overall, stratified by angiography status, and among patients who did and did not have non-fatal events. RESULTS: No baseline differences in HRQoL were seen between patients randomized to prasugrel (n=3620) or clopidogrel (n=3623). At 24 months, remaining patients assigned to prasugrel (n=1450) vs. clopidogrel (n=1443) had higher EQ-5D index scores (86.4 vs. 84.9, P=.01). Mixed effects models found no difference in EQ-5D scores among prasugrel and clopidogrel patients overall across subgroups stratified by angiography status. However, among patients with non-fatal clinical events, patients on clopidogrel reported a larger decrement in HRQoL than patients on prasugrel (79.5+/-18.1 vs. 80.6+/-18.0; P=.02). CONCLUSIONS: Overall, there was no difference in HRQoL outcomes among patients receiving prasugrel vs. clopidogrel. However, the differential effects of the treatments among patients with non-fatal events require further investigation.

BACKGROUND: We evaluated lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp-PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial. METHODS AND RESULTS: Plasma Lp-PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp-PLA2 activity levels and outcomes. At baseline, the median Lp-PLA2 level was 172.4 mumol/min per liter (interquartile range 143.1-204.2 mumol/min per liter). Comparing the highest and lowest Lp-PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23-1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29-2.93) for hospitalization for heart failure, 1.42 (1.07-1.89) for cardiovascular death, and 1.37 (1.03-1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a approximately 65% persistent reduction in median Lp-PLA2 activity. There were no associations between on-treatment Lp-PLA2 activity or changes of Lp-PLA2 activity and outcomes, and there were no significant interactions between baseline and on-treatment Lp-PLA2 activity or changes in Lp-PLA2 activity levels and the effects of darapladib on outcomes. CONCLUSIONS: Although high Lp-PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp-PLA2 activity by approximately 65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp-PLA2 activity. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00799903.

AIMS: Little is known regarding consequences of frailty in patients with acute coronary syndrome (ACS). We assessed the associations of frailty and outcomes in ACS patients who were participating in a clinical trial. METHODS AND RESULTS: The TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial randomized 9326 patients planned for medical management to prasugrel or clopidogrel. The primary endpoint was a composite of cardiovascular death, myocardial infarction (MI), or stroke over a period of 30 months. A frailty score based upon the Fried score was self-reported at baseline in patients aged 65 years. Five frailty questions were recorded for 4996/5102 (97.9%) patients: 72.3% were classified as not-frail (0 items), 23.0% as pre-frail (1-2 items), and 4.7% as frail (3 items). Increasing frailty score was associated with older age, diabetes, and higher Global Registry of Acute Coronary Events (GRACE) scores. Frailty was associated with a higher unadjusted incidence of the primary endpoint (pre-frail vs not-frail: 29.2% vs 23.1%; hazard ratio [HR]: 1.39; 95% confidence interval [CI]: 1.19-1.61; p<0.001; frail vs not-frail: 39.7% vs 23.1%; HR: 1.76; 95% CI: 1.36-2.28; p<0.001), and all-cause mortality (pre-frail vs not-frail: 21.7% vs 15.0%; HR: 1.45; 95% CI: 1.22-1.73; p<0.001; frail vs not-frail: 30.2% vs 15.0%; HR: 1.98; 95% CI: 1.47-2.68; p<0.001). After adjustment for baseline characteristics and GRACE covariates, frailty remained independently associated with the primary endpoint: pre-frail vs not-frail, HR: 1.33; 95% CI: 1.15-1.54; p<0.001; frail vs not-frail, HR: 1.52; 95% CI: 1.18-1.98; p=0.002. There was no association of frailty with bleeding. CONCLUSION: Frailty is associated with the composite of cardiovascular death, MI, or stroke. Frailty assessment contributes to risk prediction and adds to the GRACE score.

BACKGROUND: Among patients presenting with ST-segment elevation myocardial infarction (STEMI) for primary percutaneous coronary intervention (PCI), the associations between clinical outcomes and both baseline renal function and the development of acute kidney injury (AKI) have not been reported in a trial population with unselected baseline renal function. METHODS: Patients enrolled in the APEX-AMI trial who underwent primary PCI for the treatment of STEMI were categorized according to (a) baseline renal function and (b) the development of AKI. Patient characteristics, clinical outcomes, and treatment patterns were analyzed according to baseline renal function and the development of AKI. A prediction model for AKI after primary PCI for STEMI was also developed. RESULTS: A total of 5,244 patients were included in this analysis and stratified according to baseline estimated glomerular filtration rate (eGFR) (milliliters per minute per 1.73 m(2)) of >90, 60 to 90, 30 to 59, or <30 or as dialysis dependent. Patients with lower eGFR were older, more often female, and less often treated with evidence-based medicines and had worse angiographic outcomes and higher mortality. The rates of AKI for patients with a baseline eGFR of >90, 60 to 90, 30 to 59, and <30 were 2.5%, 4.1%, 8.1%, and 1.6%, respectively (P < .0001). The strongest predictors of AKI were age and presenting in Killip class III or IV. CONCLUSIONS: Among patients undergoing primary PCI for STEMI, impaired renal function at presentation and development of post-PCI AKI were highly associated with worse clinical and angiographic outcomes, including death. The risk of developing AKI was low and only modestly associated with baseline renal function.

BACKGROUND: The relationship between culprit vessel, infarct size, and outcomes in non-ST-segment elevation acute coronary syndromes (NSTE ACS) is unclear. In some reports, the left circumflex artery (LCX) was more often the culprit at angiography than the right coronary artery (RCA) or left anterior descending artery (LAD), and infarcts were larger with LCX culprits. METHODS: We determined culprit vessel frequency and initial patency (TIMI flow grade), median fold elevation of peak troponin above the upper limit of normal, and outcomes (30-day death or myocardial infarction [MI] and 1-year mortality) by culprit vessel in high-risk NSTE ACS patients in the EARLY ACS trial. RESULTS: Of 9406 patients, 2066 (22.0%) had angiographic core laboratory data. We evaluated 1774 patients for whom the culprit artery was not the left main, a bypass graft, or branch vessel. The culprit was the LCX in 560 (31.6%), LAD in 653 (36.8%), and RCA in 561 (31.6%) patients. There were fewer women (24.1%) and more prior MI (25.5%) among patients with a culprit LCX compared with those with a culprit LAD or RCA. Patients with LCX (21.2%) and RCA (27.5%) culprits more often had an occluded artery (TIMI 0/1) than did those with LAD (11.3%). Peak troponin elevation was significantly higher for LCX than RCA or LAD culprits. LCX culprit vessels were not associated with worse 30-day or 1-year outcomes in adjusted models. CONCLUSIONS: Among patients with NSTE ACS, the frequencies of LCX, LAD, and RCA culprits were similar. Although LCX lesions were associated with higher peak troponin levels, there was no difference in short- or intermediate-term outcomes by culprit artery.

All patients with stable ischemic heart disease (SIHD) should be managed with guideline-directed medical therapy (GDMT), which reduces progression of atherosclerosis and prevents coronary thrombosis. Revascularization is also indicated in patients with SIHD and progressive or refractory symptoms, despite medical management. Whether a strategy of routine revascularization (with percutaneous coronary intervention or coronary artery bypass graft surgery as appropriate) plus GDMT reduces rates of death or myocardial infarction, or improves quality of life compared to an initial approach of GDMT alone in patients with substantial ischemia is uncertain. Opinions run strongly on both sides, and evidence may be used to support either approach. Careful review of the data demonstrates the limitations of our current knowledge, resulting in a state of community equipoise. The ongoing ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) is being performed to determine the optimal approach to managing patients with SIHD, moderate-to-severe ischemia, and symptoms that can be controlled medically. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).