Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden.

Inflammatory Differences in Plaque Erosion and Rupture in Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Plaque erosion causes 30% of ST-segment elevation myocardial infarctions, but the underlying cause is unknown. Inflammatory infiltrates are less abundant in erosion compared with rupture in autopsy studies. We hypothesized that erosion and rupture are associated with significant differences in intracoronary cytokines in vivo. METHODS AND RESULTS: Forty ST-segment elevation myocardial infarction patients with <6 hours of chest pain were classified as ruptured fibrous cap (RFC) or intact fibrous cap (IFC) using optical coherence tomography. Plasma samples from the infarct-related artery and a peripheral artery were analyzed for expression of 102 cytokines using arrays; results were confirmed with ELISA. Thrombectomy samples were analyzed for differential mRNA expression using quantitative real-time polymerase chain reaction. Twenty-three lesions were classified as RFC (58%), 15 as IFC (38%), and 2 were undefined (4%). In addition, 12% (12 of 102) of cytokines were differentially expressed in both coronary and peripheral plasma. I-TAC was preferentially expressed in RFC (significance analysis of microarrays adjusted P<0.001; ELISA IFC 10.2 versus RFC 10.8 log2 pg/mL; P=0.042). IFC was associated with preferential expression of epidermal growth factor (significance analysis of microarrays adjusted P<0.001; ELISA IFC 7.42 versus RFC 6.63 log2 pg/mL, P=0.036) and thrombospondin 1 (significance analysis of microarrays adjusted P=0.03; ELISA IFC 10.4 versus RFC 8.65 log2 ng/mL, P=0.0041). Thrombectomy mRNA showed elevated I-TAC in RFC (P=0.0007) epidermal growth factor expression in IFC (P=0.0264) but no differences in expression of thrombospondin 1. CONCLUSIONS: These results demonstrate differential intracoronary cytokine expression in RFC and IFC. Elevated thrombospondin 1 and epidermal growth factor may play an etiological role in erosion.

Safety of short-term dual antiplatelet therapy after drug-eluting stents: An updated meta-analysis with direct and adjusted indirect comparison of randomized control trials.

BACKGROUND: Duration of dual antiplatelet therapy (DAPT) following drug-eluting stents (DES) remains controversial and is a topic of ongoing research. METHODS: Direct and adjusted indirect comparisons of all the recent randomized control trials (RCTs) were performed to evaluate the safety of short-term versus long-term DAPT following DES. RESULTS: 8 RCTs were identified and 7 (16,318 subjects) were included. 4 groups of 3 vs 12 months, 6 vs 12 months, 6 vs 24 months and 12 vs 24 months of DAPT were used for direct comparison. There was no significant difference in stent thrombosis, myocardial infarction (MI), stroke and revascularization, cardiovascular and all-cause mortality between the different durations in all 4 groups. Pooling trials of 3-6 months of DAPT against 12 months, we found a significant reduction in the risk of total bleeding (RR 0.61, 95% CI 0.43-0.87). Adjusted indirect comparison between 3 vs 6 months, 3 vs 24 months and 6 vs 24 month duration of DAPT showed no significant differences in risk of death or MI, or revascularization between 3 or 6 months and 24 months. However, 24months of DAPT was associated with significantly more bleeding than 3 or 6 months. CONCLUSIONS: 3 to 6 months of DAPT following second generation DES and above is safe with no increased risk of thrombotic complications and mortality, and lower bleeding risk. However a tailored approach may be more appropriate for high-risk patients.

Benefits and harms of extending the duration of dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stents: a meta-analysis.

BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) is unclear. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials evaluating risk of adverse events in participants receiving different durations of DAPT following insertion of drug-eluting stents. RESULTS: Five trials were included, but only four had data suitable for meta-analysis (n = 8,231 participants). No significant increase in the composite endpoint of death and nonfatal myocardial infarction was observed with earlier cessation of DAPT in any instance when compared to longer durations of DAPT (RR 0.64 95% CI 0.25-1.63 for 3 versus 12 months, RR 1.09 95% CI 0.84-1.41 for 6 versus 12 months and, RR 0.64 95% CI 0.35-1.16 for 12 versus 24 months). Pooled results showed a significantly lower risk of major bleeding (RR 0.48 95% CI 0.25-0.93) and total bleeding (RR 0.30 95% CI 0.16-0.54) for shorter compared to longer duration of DAPT. Subgroup analysis based on age, prior diabetes, and prior ACS failed to show any group where longer durations were consistently better than shorter ones. CONCLUSIONS: There are no cardiovascular or mortality benefits associated with extended duration of DAPT, but the risk of major bleeding was significantly lower with shorter lengths of therapy.

Predictive value of ST resolution analysis performed immediately versus at ninety minutes after primary percutaneous coronary intervention.

ST segment resolution (STR) predicts epicardial and microvascular reperfusion after primary percutaneous coronary intervention (PPCI) or thrombolysis for ST-elevation myocardial infarction. Immediate restoration of epicardial coronary flow, with improved microvascular perfusion, is much more likely with PPCI. However, the predictive value of immediate STR compared to 90 minutes after PPCI remains unknown. In 622 consecutive patients with ST-elevation myocardial infarction (mean age 59 +/- 13 years), 217 had complete STR immediately after PPCI (group A), 188 had complete STR only at 90 minutes (group B), and 217 had incomplete STR at either point (group C). The primary end point was mortality and adverse cardiovascular events ([MACE] death, nonfatal repeat myocardial infarction, and heart failure). Group A had a greater left ventricular ejection fraction (53%, 47%, and 46%, p <0.001) and lower all-cause mortality (1.8%, 3.2%, and 6%, p = 0.07), lower heart failure (1.8%, 4.3%, and 7.8%, p <0.001), and MACE (5.1%, 9.6%, and 16.1%, p = 0.001) at 30 days compared to groups B and C, respectively. The rate of MACE at 1 year was 7.6%, 17.1%, and 20.2% in groups A, B, and C, respectively (p <0.001). Immediate STR independently predicted MACE (adjusted hazard ratio 0.36, 95% confidence interval 0.21 to 0.61, p = 0.001, group A vs C), and STR at 90 minutes did not. In conclusion, STR analysis performed immediately after PPCI provided superior differentiation for adverse cardiovascular events compared to STR at 90 minutes. Immediate STR should be the contemporary goal of reperfusion with PPCI.

Prognostic impact of Q waves on presentation and ST resolution in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention.

Q waves can develop early in infarction and indicate infarct progression better than symptom duration. ST resolution (STR) is a predictor of reperfusion success. Our aim was to assess the prognostic impact of Q waves on presentation and STR after primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction. The combined end point was of mortality and adverse cardiovascular events (MACE; death, repeat myocardial infarction, or heart failure). Q waves on presentation (Q wave, n = 332; no Q wave, n = 337) was associated with significantly less mean STR, greater incidence of akinetic, dyskinetic, or aneurysmal regional wall motion, lower left ventricular ejection fraction, and worse in-hospital and 1-year MACEs (1 year 24% vs 8.2%, p <0.001). In addition, Q waves on presentation compared to no Q waves were associated with worse 1-year MACE regardless of infarct presentation in < or =3 hours, infarct location, and adequate STR (> or =70%). Q waves on presentation and inadequate STR (<70%), but not symptom duration, were independent predictors of MACE by multivariable analysis (adjusted hazard ratios of 2.7 and 2.4 for Q waves and STR, respectively). Compared to group A (no Q waves on presentation with STR), patients in group B (no Q waves with inadequate STR), group C (Q waves with STR), and group D (Q waves with inadequate STR) had hazard ratios of 3.0, 3.6, and 7.7, respectively (p <0.05) for the occurrence of MACE. In conclusion, assessment of Q-wave status on presentation and STR immediately after PPCI provides a simple and early clinical predictor of outcomes in ST-elevation myocardial infarction.

Prognostic value of brain natriuretic peptide in noncardiac surgery: a meta-analysis.

BACKGROUND: The prognostic role of brain natriuretic peptide (BNP) measurement before noncardiac surgery is unclear. The authors therefore performed a meta-analysis of studies in patients undergoing noncardiac surgery to assess the prognostic value of elevated BNP or N-terminal pro-BNP (NT-proBNP) levels in predicting mortality and major adverse cardiovascular events (MACE) (cardiac death or nonfatal myocardial infarction). METHODS: Unrestricted searches of MEDLINE and EMBASE bibliographic databases were performed using the terms "brain natriuretic peptide," "b-type natriuretic peptide," "BNP," "NT-proBNP," and "surgery." In addition, review articles, bibliographies, and abstracts of scientific meetings were manually searched. The meta-analysis included prospective studies that reported on the association of BNP or NT-proBNP and postoperative major adverse cardiovascular event (MACE) or mortality. The study endpoints were MACE, all-cause mortality, and cardiac mortality at short-term (less than 43 days after surgery) and longer-term (more than 6 months) follow-up. A random-effects model was used to pool study results; funnel-plot inspection was done to evaluate publication bias; Cochrane chi-square test and I testing was used to test for heterogeneity. RESULTS: Data from 15 publications (4,856 patients) were included in the analysis. Preoperative BNP elevation was associated with an increased risk of short-term MACE (OR 19.77; 95% confidence interval [CI] 13.18-29.65; P < 0.0001), all-cause mortality (OR 9.28; 95% CI 3.51-24.56; P < 0.0001), and cardiac death (OR 23.88; 95% CI 9.43-60.43; P < 0.00001). Results were consistent for both BNP and NT-proBNP. Preoperative BNP elevation was also associated with an increased risk of long-term MACE (OR 17.70; 95% CI 3.11-100.80; P < 0.0001) and all-cause mortality (OR 4.77; 95% CI 2.99-7.46; P < 0.00001). CONCLUSIONS: Elevated BNP and NT-proBNP levels identify patients undergoing major noncardiac surgery at high risk of cardiac mortality, all-cause mortality, and MACE.