Kari Saunamäki

Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction.

AIMS Exenatide, a glucagon-like-peptide-1 analogue, increases myocardial salvage in experimental settings with coronary occlusion and subsequent reperfusion. We evaluated the cardioprotective effect of exenatide at the time of reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). METHODS AND RESULTS A total of 172 patients with STEMI and Thrombolysis in Myocardial Infarction flow 0/1 were randomly assigned to exenatide or placebo (saline) intravenously. Study treatment was commenced 15 min before intervention and maintained for 6 h after the procedure. The primary endpoint was salvage index calculated from myocardial area at risk (AAR), measured in the acute phase, and final infarct size measured 90 ± 21 days after pPCI by cardiac magnetic resonance (CMR). In 105 patients evaluated with CMR, a significantly larger salvage index was found in the exenatide group than in the placebo group (0.71 ± 0.13 vs. 0.62 ± 0.16; P= 0.003). Infarct size in relation to AAR was also smaller in the exenatide group (0.30 ± 0.15 vs. 0.39 ± 0.15; P= 0.003). In a regression analysis, there was a significant correlation between the infarct size and the AAR for both treatment groups and an analysis of covariance showed that datapoints in the exenatide group lay significantly lower than for the placebo group (P= 0.011). There was a trend towards smaller absolute infarct size in the exenatide group (13 ± 9 vs. 17 ± 14 g; P= 0.11). No difference was observed in left ventricular function or 30-day clinical events. No adverse effects of exenatide were observed. CONCLUSION In patients with STEMI undergoing pPCI, administration of exenatide at the time of reperfusion increases myocardial salvage.

Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3—PRIMULTI): an open-label, randomised controlled trial.

BACKGROUND Patients with acute ST-segment elevation myocardial infarction (STEMI) and multivessel coronary disease have a worse prognosis compared with individuals with single-vessel disease. We aimed to study the clinical outcome of patients with STEMI treated with fractional flow reserve (FFR)-guided complete revascularisation versus treatment of the infarct-related artery only. METHODS We undertook an open-label, randomised controlled trial at two university hospitals in Denmark. Patients presenting with STEMI who had one or more clinically significant coronary stenosis in addition to the lesion in the infarct-related artery were included. After successful percutaneous coronary intervention (PCI) of the infarct-related artery, patients were randomly allocated (in a 1:1 ratio) either no further invasive treatment or complete FFR-guided revascularisation before discharge. Randomisation was done electronically via a web-based system in permuted blocks of varying size by the clinician who did the primary PCI. All patients received best medical treatment. The primary endpoint was a composite of all-cause mortality, non-fatal reinfarction, and ischaemia-driven revascularization of lesions in non-infarct-related arteries and was assessed when the last enrolled patient had been followed up for 1 year. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01960933. FINDINGS From March, 2011, to February, 2014, we enrolled 627 patients to the trial; 313 were allocated no further invasive treatment after primary PCI of the infarct-related artery only and 314 were assigned complete revascularization guided by FFR values. Median follow-up was 27 months (range 12–44 months). Events comprising the primary endpoint were recorded in 68 (22%) patients who had PCI of the infarct-related artery only and in 40 (13%) patients who had complete revascularisation (hazard ratio 0∙56, 95% CI 0∙38–0∙83; p=0∙004). INTERPRETATION In patients with STEMI and multivessel disease, complete revascularisation guided by FFR measurements significantly reduces the risk of future events compared with no further invasive intervention after primary PCI. This effect is driven by significantly fewer repeat revascularisations, because all-cause mortality and non-fatal reinfarction did not differ between groups. Thus, to avoid repeat revascularisation, patients can safely have all their lesions treated during the index admission. Future studies should clarify whether complete revascularization should be done acutely during the index procedure or at later time and whether it has an effect on hard endpoints. FUNDING Danish Agency for Science, Technology and Innovation and Danish Council for Strategic Research.

Randomized evaluation of polytetrafluoroethylene-covered stent in saphenous vein grafts: the Randomized Evaluation of polytetrafluoroethylene COVERed stent in Saphenous vein grafts (RECOVERS) Trial.

Background Treatment of lesions located in saphenous vein grafts (SVGs) is associated with increased procedural risk and a high rate of restenosis. Methods and Results We conducted a randomized, multicenter trial to evaluate the usefulness of a polytetrafluoroethylene (PTFE)‐covered stent compared with a bare stainless steel (SS) stent for prevention of restenosis and major adverse cardiac events (MACE) in patients undergoing SVG treatment. The primary end point was angiographic restenosis at 6 months. Secondary end points were 30‐day and 6‐month MACE rates, defined as the cumulative of death, myocardial infarction (MI), and target lesion revascularization. Between September 1999 and January 2002, 301 patients with SVG lesions were randomized to either the PTFE‐covered JoStent coronary stent graft (PTFE group, n=156) or the SS JoFlex stent (control group, n=145). Angiographic and procedural success rates were similar between the 2 groups (97.4% versus 97.9% and 87.3% versus 93.8%, respectively). The incidence of 30‐day MACE was higher in the PTFE group (10.9% versus 4.1%, P=0.047) and was mainly attributed to MI (10.3% versus 3.4%, P=0.037). The primary end point, the restenosis rate at 6‐month follow‐up, was similar between the 2 groups (24.2% versus 24.8%, P=0.237). Although the 6‐month non‐Q‐wave MI rate was higher in the PTFE group (12.8% versus 4.1%, P=0.013), the cumulative MACE rate was not different (23.1% versus 15.9%, P=0.153). Conclusions The study did not demonstrate a difference in restenosis rate and 6‐month clinical outcome between the PTFE‐covered stent and the SS stent for treatment of SVG lesions. However, a higher incidence of nonfatal myocardial infarctions was found in patients treated with the PTFE‐covered stent. (Circulation. 2003;108:37‐42.)

Comparison of Paclitaxel- and Sirolimus-Eluting Stents in Everyday Clinical Practice: The SORT OUT II Randomized Trial

CONTEXT Approval of drug-eluting coronary stents was based on results of relatively small trials of selected patients; however, in routine practice, stents are used in a broader spectrum of patients. OBJECTIVE To compare the first 2 commercially available drug-eluting stents-sirolimus-eluting and paclitaxel-eluting-for prevention of symptom-driven clinical end points, using a study design reflecting everyday clinical practice. DESIGN, SETTING, AND PATIENTS Randomized, blinded trial conducted August 2004 to January 2006 at 5 university hospitals in Denmark. Patients were 2098 men and women (mean [SD] age, 63.6 [10.8] years) treated with percutaneous coronary intervention (PCI) and randomized to receive either sirolimus-eluting (n = 1065) or paclitaxel-eluting (n = 1033) stents. Indications for PCI included ST-segment elevation myocardial infarction (STEMI), non-STEMI or unstable angina pectoris, and stable angina. MAIN OUTCOME MEASURES The primary end point was a composite clinical end point of major adverse cardiac events, defined as either cardiac death, acute myocardial infarction, target lesion revascularization, or target vessel revascularization. Secondary end points included individual components of the composite end point, all-cause mortality, and stent thrombosis. RESULTS The sirolimus- and the paclitaxel-eluting stent groups did not differ significantly in major adverse cardiac events (98 [9.3%] vs 114 [11.2%]; hazard ratio, 0.83 [95% confidence interval, 0.63-1.08]; P = .16) or in any of the secondary end points. The stent thrombosis rates were 27 (2.5%) and 30 (2.9%) (hazard ratio, 0.87 [95% confidence interval, 0.52-1.46]; P = .60), respectively. CONCLUSION In this practical randomized trial, there were no significant differences in clinical outcomes between patients receiving sirolimus- and paclitaxel-eluting stents. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00388934.

Exenatide Reduces Final Infarct Size in Patients With ST-Segment–Elevation Myocardial Infarction and Short-Duration of Ischemia

Background— Exenatide has been demonstrated to be cardioprotective as an adjunct to primary percutaneous coronary intervention in patients with ST-segment–elevation myocardial infarction (STEMI). The aim of the post hoc analysis study was to evaluate the effect of exenatide in relation to system delay, defined as time from first medical contact to first balloon. Methods and Results— Patients with STEMI and Thrombolysis In Myocardial Infarction flow 0/1 were randomly assigned to intravenous exenatide or placebo continuous infusion. Study treatment was commenced 15 minutes before intervention and maintained for 6 hours after the procedure. The patients were stratified according to median system delay (132 minutes). Final infarct size and myocardial area at risk were measured by cardiovascular magnetic resonance. Among patients with a system delay ⩽132 minutes (n=74), treatment with exenatide resulted in a smaller infarct size (9 grams [interquartile range (IQR), 4–13] versus 13 grams [IQR, 8–24], P=0.008, corresponding to 8% [IQR, 4–12] versus 11% [IQR, 7–17] of the left ventricle, P=0.015). In a regression analysis adjusting for myocardial area at risk the data points of the exenatide group lay significantly lower than for the placebo group (P=0.006). In the patients with system delay >132 minutes (n=74) no difference was observed in infarct size expressed as grams (P=0.49) or percentage (P=0.46). There was significant interaction between system delay (less than or equal to median versus greater than median) and treatment allocation in terms of infarct size (P=0.018). Conclusions— In this post hoc analysis, exenatide treatment was associated with a 30% decrease in final infarct size in patients with short system delay, whereas no cardioprotective effect in patients with long system delay was seen. However, this finding must be confirmed in larger studies. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00835848.

Randomized comparison of distal protection versus conventional treatment in primary percutaneous coronary intervention: the drug elution and distal protection in ST-elevation myocardial infarction (DEDICATION) trial.

OBJECTIVES The purpose of this study was to evaluate the use of distal protection during percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) in native coronary vessels. BACKGROUND Embolization of material from the infarct-related lesion during PCI may result in impaired myocardial perfusion and worsen the prognosis. Previous attempts to protect the microcirculation during primary PCI have had conflicting results. METHODS We randomly assigned 626 patients with STEMI referred within 12 h to have PCI performed with (n = 312) or without (n = 314) distal protection. The primary end point was complete (>or=70%) ST-segment resolution detected by continuous ST-segment monitoring. Blood levels of troponin-T and creatine kinase-MB were monitored before and after the procedure, and echocardiographic determination of the left ventricular wall motion index (WMI) was performed before discharge. RESULTS Patients were well matched in terms of demographic and angiographic baseline characteristics. There was no significant difference in the occurrence of the primary end point (76% vs. 72%, p = 0.29), no difference in maximum troponin-T (4.8 microg/l and 5.0 microg/l, p = 0.87) or maximum creatine kinase-MB (185 microg/l and 184 microg/l, p = 0.99), and no difference in median WMI (1.70 vs. 1.70, p = 0.35). The rate of major adverse cardiac and cerebral events (MACCE) 1 month after PCI was 5.4% with distal protection and 3.2% with conventional treatment (p = 0.17). CONCLUSIONS The routine use of distal protection by a filterwire system during primary PCI does not seem to improve microvascular perfusion, limit infarct size, or reduce the occurrence of MACCE.

Long-Term Outcome After Drug-Eluting Versus Bare-Metal Stent Implantation in Patients With ST-Segment Elevation Myocardial Infarction: 5 Years Follow-Up From the Randomized DEDICATION Trial (Drug Elution and Distal Protection in Acute Myocardial Infarction)

OBJECTIVES This study sought to compare the long-term effects of drug-eluting stent (DES) compared with bare-metal stent (BMS) implantation in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. BACKGROUND The randomized DEDICATION (Drug Elution and Distal Protection in Acute Myocardial Infarction) trial evaluated the outcome after DES compared with BMS implantation in patients with STEMI undergoing primary percutaneous coronary intervention. METHODS Patients with a high-grade stenosis/occlusion of a native coronary artery presenting with symptoms <12 h and ST-segment elevation were enrolled after giving informed consent. Patients were randomly assigned to receive a DES or a BMS in the infarct-related lesion. Patients were followed for at least 5 years, and clinical endpoints were evaluated from population registries and hospital charts. The main endpoint was the occurrence of the first major adverse cardiac event (MACE), defined as cardiac death, nonfatal recurrent myocardial infarction, and target lesion revascularization. RESULTS Complete clinical status was available in 623 patients (99.5%) at 5 years follow-up. The combined MACE rate was insignificantly lower in the DES group (16.9% vs. 23%), mainly driven by a lower need of repeat revascularization (p = 0.07). Whereas the number of deaths from all causes tended to be higher in the DES group (16.3% vs. 12.1%, p = 0.17), cardiac mortality was significantly higher (7.7% vs. 3.2%, p = 0.02). The 5-year stent thrombosis rates were generally low and similar between the DES and the BMS groups. No cardiac deaths occurring within 1 month could be clearly ascribed to stent thrombosis, whereas stent thrombosis was involved in 78% of later-occurring deaths. CONCLUSIONS The 5-year MACE rate was insignificantly different, but the cardiac mortality was higher after DES versus BMS implantation in patients with STEMI. Stent thrombosis was the main cause of late cardiac deaths.

Randomized double-blind Scandinavian trial of angiopeptin versus placebo for the prevention of clinical events and restenosis after coronary balloon angioplasty

Angiopeptin, a somatostatin analogue, inhibits intimal hyperplasia after percutaneous transluminal coronary artery balloon angioplasty (PTCA) in several animal models. This pilot study sought to determine the effect of subcutaneous infusion of angiopeptin on clinical events and restenosis in patients undergoing successful PTCA. One hundred twelve patients were randomized to receive continuous subcutaneous angiopeptin (750 micrograms/day) or placebo infusion from the day before PTCA and for the following 4 days in a double-blind study. An additional subcutaneous injection of 375 micrograms of angiopeptin or saline was given immediately before PTCA. Eighty patients had a successful PTCA, and 75 of these patients with 94 lesions underwent angiography 6 +/- 2 months after PTCA. All 112 patients underwent a 12-month clinical follow-up examination. Age, sex, smoking, diabetes, hypertension, hyperlipidemia, and morphologic features of stenosis were similar in both groups. The hierarchical 12-month event rate (death, myocardial infarction, coronary artery bypass grafting, and repeated PTCA) was reduced from 34% to 25% (p = 0.30) by angiopeptin by intention-to-treat analysis. Restenosis (> or = 50% diameter stenosis) was significantly reduced in lesions treated with angiopeptin (12% vs 40%; p = 0.003). Late lumen loss also was significantly reduced after angiopeptin treatment (0.12 +/- 0.46 mm vs 0.52 +/- 0.64 mm; p = 0.003). In conclusion, continuous subcutaneous angiopeptin infusion for 5 days tended to decrease clinical events and restenosis after PTCA.

Significance and management of early graft failure after coronary artery bypass grafting. Feasibility and results of acute angiography and re-re-vascularization

UNLABELLED Perioperative ischaemia and infarction after CABG are associated with increased morbidity and mortality. OBJECTIVE To study causes of perioperative ischaemia and infarction by acute re-angiography and to treat incomplete re-vascularization caused by graft failure or any other cause. METHODS Between 1990 and 1995, 2003 patients underwent an isolated CABG operation. Myocardial ischaemia was suspected if one or more of the following criteria were present: New changes in the ST-segment in the ECG; a CKMB value greater than 80 U/L; new Q-waves in the ECG; recurrent episodes of, or sustained ventricular tachyarrhythmia; ventricular fibrillation; haemodynamic deterioration and left ventricular failure. Acute coronary angiography was performed in stable patients, while haemodynamically severely compromised patients were rushed to the operating room. RESULTS A total of 71 (3.5%) patients of all CABGs with suspected graft failure were identified and included in the study. Patients were grouped according to whether they had an acute re-angiography (n = 59; group 1) or an immediate re-operation (n = 12; group 2) performed. In group 1, the acute re-angiography demonstrated graft failure/incomplete re-vascularization in 43 patients (73%). The angiographic findings were: Occluded vein graft(s) in 19 (32%); poor distal run-off to the grafted coronary artery in ten (17%); internal mammary artery stenosis in four (7%); internal mammary artery occlusion in three (5%); vein graft stenoses in three (5%); left mammary artery subclavian artery steal in two (3%); and the wrong coronary artery grafted in one (2%). Based on the angiography findings, 27 patients were re-operated and re-grafted. At the time of re-operation, 18 patients (67%) had evolving infarction documented by ECG or CKMB. Two patients (3%) experienced stroke in immediate relation to the re-angiography. The 30-day mortality was three (7%). In group 2, graft occlusions were found in 11 patients (92%). The 30-day mortality was six (50%). CONCLUSION An acute re-angiography demonstrated graft failure or incomplete re-vascularization in the majority of patients with myocardial ischaemia early after CABG. Re-operation for re-re-vascularization was performed with low risk. Few patients with circulatory collapse could be saved by an immediate re-operation without preceding angiography.

Final infarct size measured by cardiovascular magnetic resonance in patients with ST elevation myocardial infarction predicts long-term clinical outcome: an observational study

AIMS Tailored heart failure treatment and risk assessment in patients following ST-segment elevation myocardial infarction (STEMI) is mainly based on the assessment of the left ventricular (LV) ejection fraction (EF). Assessment of the final infarct size in addition to the LVEF may improve the prognostic evaluation. To evaluate the prognostic importance of the final infarct size measured by cardiovascular magnetic resonance (CMR) in patients with STEMI. METHODS AND RESULTS In an observational study the final infarct size was measured by late gadolinium enhancement CMR 3 months after initial admission in 309 patients with STEMI. The clinical endpoint was a composite of all-cause mortality and admission for heart failure. During the follow-up period of median 807 days (IQR: 669-1117) 35 events (5 non-cardiac deaths, 3 cardiac deaths, and 27 admissions for heart failure) were recorded. Patients with a final infarct size ≥ median had significantly higher event rates than patients with a final infarct size <median (17 vs. 6%; Log rank P = 0.002). In a multivariable Cox regression analysis, including age, peak troponin T, LVEF, LV volume index, and heart rate, the final infarct size remained significantly associated with the occurrence of subsequent events (adjusted hazard ratio 1.13 per 1% increase (95% CI: 1.05-1.21; P = 0.001). The overall Wald χ(2) value of a model including known risk factors was 47.3, which increased to 57.9 when the final infarct size was added (P = 0.001 for the difference). CONCLUSION Assessment of the final infarct size by CMR 3 months after a STEMI provides strong independent prognostic information incremental to known risk factors including the LVEF, and may help to improve the risk stratification of STEMI patients.