Relation of Bleeding Events to Mortality in Patients With ST-Segment Elevation Myocardial Infarction Treated by Percutaneous Coronary Intervention (a DANAMI-3 Substudy).

Bleeding events in relation to treatment of ST-segment elevation myocardial infarction (STEMI) have previously been associated with mortality. In this study, we investigated the incidence and prognosis of, and variables associated with serious bleedings within 30 days after primary percutaneous coronary intervention in patients from The Third Danish Study of Optimal Acute Treatment of Patients with ST-Segment Elevation Myocardial Infarction (DANAMI-3) (n = 2,217). Hospital charts were read within 30 days postadmission to assess bleeding events using thrombolysis in myocardial infarction (TIMI) and Bleeding Academic Research Consortium criteria. TIMI minor/major bleeding (TMMB) occurred in 59 patients (2.7%). Variables associated with TMMB were female gender (hazard ratio [HR] 3.9, 95% confidence interval [CI] 2.2 to 6.7, p <0.0001), symptom-to-catheterization time >3 hours (HR 1.9, 95% CI 1.1 to 3.3, p = 0.02), use of glycoprotein IIb/IIIa inhibitor (HR 2.1, 95% CI 1.2 to 3.7, p = 0.01), and increasing S-creatinine (HR 1.1, 95% CI 1.0 to 1.2, p = 0.001). Undergoing 2 in-hospital procedures were not associated with increased risk of TMMB. TMMB was strongly associated with 30-day mortality in multivariable analysis (HR 4.8, 95% CI 2.2 to 10.4, p <0.0001) but not with mortality days 31 to 365. When excluding fatal bleedings from the analysis, a TMMB was no longer associated with 30-day mortality. In conclusion, we found that in a contemporary STEMI-population, the incidence of 30-day TMMB was low. A TMMB was strongly associated with 30-day mortality but not with mortality days 31 to 365. If patients survived a serious bleeding, their short- and long-term prognoses were not affected.

Quality assurance of the Western Denmark Heart Registry, a population-based healthcare register.

INTRODUCTION: During the past decade, the mandatory population-based healthcare database, the Western Denmark Heart Registry (WDHR), has provided the data for several research projects. As in most clinical registries, the data quality has not been validated thoroughly. This study was undertaken to evaluate the quality of registrations in the WDHR. METHODS: The audit supervised procedures from involved departments that were performed in 2013. An experienced research nurse completed data collection, and an experienced consultant evaluated the agreement between the WDHR and patient records. Indistinct data from patient records were determined after consulting a specialist from the department in question. Patient files were double-checked in case of disagreements between the involved systems. RESULTS: The total proportion of errors in the referral date was 16.4% in surgery, 9.8% in percutaneous invasive procedures (PCI), 16.1% in coronary angiography (CAG) and 19.5% in computed tomography (CT)-CAG, while the errors in inhospital dates were slightly lower. In the cardiac surgery registries, the proportion of errors was 3.3% in the history and EuroSCORE module, 1.0% in the procedure module and 2.8% in the discharge module. For PCI procedures, the errors were 3.8% in the history module, 2.2% in the procedure module and 1.6% in the discharge module. CAG and CT-CAG had slightly more errors. CONCLUSIONS: The quality control of the WDHR revealed that overall data errors were lower than 3% and for procedure-specific registrations including indications and complications, the error rate was below 1.5%. The WDHR is valid and may be used in contemporary epidemiological studies. FUNDING: none. TRIAL REGISTRATION: not relevant.

Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial.

BACKGROUND: Coronary artery bypass grafting (CABG) is the standard treatment for revascularisation in patients with left main coronary artery disease, but use of percutaneous coronary intervention (PCI) for this indication is increasing. We aimed to compare PCI and CABG for treatment of left main coronary artery disease. METHODS: In this prospective, randomised, open-label, non-inferiority trial, patients with left main coronary artery disease were enrolled in 36 centres in northern Europe and randomised 1:1 to treatment with PCI or CABG. Eligible patients had stable angina pectoris, unstable angina pectoris, or non-ST-elevation myocardial infarction. Exclusion criteria were ST-elevation myocardial infarction within 24 h, being considered too high risk for CABG or PCI, or expected survival of less than 1 year. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary revascularisation, and stroke. Non-inferiority of PCI to CABG required the lower end of the 95% CI not to exceed a hazard ratio (HR) of 1·35 after up to 5 years of follow-up. The intention-to-treat principle was used in the analysis if not specified otherwise. This trial is registered with ClinicalTrials.gov identifier, number NCT01496651. FINDINGS: Between Dec 9, 2008, and Jan 21, 2015, 1201 patients were randomly assigned, 598 to PCI and 603 to CABG, and 592 in each group entered analysis by intention to treat. Kaplan-Meier 5 year estimates of MACCE were 29% for PCI (121 events) and 19% for CABG (81 events), HR 1·48 (95% CI 1·11-1·96), exceeding the limit for non-inferiority, and CABG was significantly better than PCI (p=0·0066). As-treated estimates were 28% versus 19% (1·55, 1·18-2·04, p=0·0015). Comparing PCI with CABG, 5 year estimates were 12% versus 9% (1·07, 0·67-1·72, p=0·77) for all-cause mortality, 7% versus 2% (2·88, 1·40-5·90, p=0·0040) for non-procedural myocardial infarction, 16% versus 10% (1·50, 1·04-2·17, p=0·032) for any revascularisation, and 5% versus 2% (2·25, 0·93-5·48, p=0·073) for stroke. INTERPRETATION: The findings of this study suggest that CABG might be better than PCI for treatment of left main stem coronary artery disease. FUNDING: Biosensors, Aarhus University Hospital, and participating sites.

Deferred versus conventional stent implantation in patients with ST-segment elevation myocardial infarction (DANAMI 3-DEFER): an open-label, randomised controlled trial.

BACKGROUND: Despite successful treatment of the culprit artery lesion by primary percutaneous coronary intervention (PCI) with stent implantation, thrombotic embolisation occurs in some cases, which impairs the prognosis of patients with ST-segment elevation myocardial infarction (STEMI). We aimed to assess the clinical outcomes of deferred stent implantation versus standard PCI in patients with STEMI. METHODS: We did this open-label, randomised controlled trial at four primary PCI centres in Denmark. Eligible patients (aged >18 years) had acute onset symptoms lasting 12 h or less, and ST-segment elevation of 0·1 mV or more in at least two or more contiguous electrocardiographic leads or newly developed left bundle branch block. Patients were randomly assigned (1:1), via an electronic web-based system with permuted block sizes of two to six, to receive either standard primary PCI with immediate stent implantation or deferred stent implantation 48 h after the index procedure if a stabilised flow could be obtained in the infarct-related artery. The primary endpoint was a composite of all-cause mortality, hospital admission for heart failure, recurrent infarction, and any unplanned revascularisation of the target vessel within 2 years' follow-up. Patients, investigators, and treating clinicians were not masked to treatment allocation. We did analysis by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01435408. FINDINGS: Between March 1, 2011, and Feb 28, 2014, we randomly assigned 1215 patients to receive either standard PCI (n=612) or deferred stent implantation (n=603). Median follow-up time was 42 months (IQR 33-49). Events comprising the primary endpoint occurred in 109 (18%) patients who had standard PCI and in 105 (17%) patients who had deferred stent implantation (hazard ratio 0·99, 95% CI 0·76-1·29; p=0·92). Procedure-related myocardial infarction, bleeding requiring transfusion or surgery, contrast-induced nephopathy, or stroke occurred in 28 (5%) patients in the conventional PCI group versus 27 (4%) patients in the deferred stent implantation group, with no significant differences between groups. INTERPRETATION: In patients with STEMI, routine deferred stent implantation did not reduce the occurrence of death, heart failure, myocardial infarction, or repeat revascularisation compared with conventional PCI. Results from ongoing randomised trials might shed further light on the concept of deferred stenting in this patient population. FUNDING: Danish Agency for Science, Technology and Innovation, and Danish Council for Strategic Research.

Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3­PRIMULTI): 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 12­44 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∙38­0∙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.

Long-term outcome of sirolimus-eluting and zotarolimus-eluting coronary stent implantation in patients with and without diabetes mellitus (a Danish organization for randomized trials on clinical outcome III substudy).

We compared 5-year clinical outcomes in diabetic and nondiabetic patients treated with Endeavor zotarolimus-eluting stents (ZESs; Endeavor Sprint, Medtronic, Santa Rosa, California) or Cypher sirolimus-eluting stents (SESs; Cordis, Johnson & Johnson, Warren, New Jersey) coronary implantation. We randomized 2,332 patients to either ZESs (n = 1,162, n = 169 diabetic patients) or SESs (n = 1,170, n = 168 diabetic patients) stratified according to presence or absence of diabetes mellitus. End points included major adverse cardiac event (MACE), a composite of cardiac death, myocardial infarction, target vessel revascularization (TVR), and definite stent thrombosis. Among diabetic patients, MACE occurred more frequently in patients treated with ZESs than SESs (48 [28.4%] vs 31 [18.5%]; odds ratio [OR] 1.75, 95% confidence interval [CI] 1.05 to 2.93, p = 0.032) because of a higher rate of TVR (32 [18.9%] vs 14 [8.3%]; OR 2.57, 95% CI 1.32 to 5.02, p = 0.006). Among nondiabetic patients, ZES and SES had similar MACE rates at 5-year follow-up but SES was associated with a significantly higher risk of definite stent thrombosis (10 [1.0%] vs 23 [2.3%]; OR 0.43, 95% CI 0.20 to 0.91, p = 0.028). Moreover, during the last 4 years, ZES had fewer MACE, TVR, and stent thrombosis events among nondiabetic patients. In conclusion, SES remains superior to ZES in patients with diabetes throughout the 5-year follow-up, however, among nondiabetic patients, SES demonstrated a highly dynamic performance with favorable initial results followed by a late catch-up that included an overall higher risk of stent thrombosis.

Prevention of contrast-induced nephropathy with N-acetylcysteine or sodium bicarbonate in patients with ST-segment-myocardial infarction: a prospective, randomized, open-labeled trial.

BACKGROUND: Contrast-induced nephropathy (CIN) is a serious condition in patients with ST-segment-elevation myocardial infarction treated with primary percutaneous coronary intervention. We compared the risk of acute CIN and the influence of preventive strategies in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. METHODS AND RESULTS: A total of 720 patients were randomized in the Prevention of Contrast-induced Nephropathy in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention (CINSTEMI) trial. Patients were randomly assigned in a 1:1:1:1 ratio to receive hydration with sodium chloride together with 1 of 4 prophylactic regimes (1) N-acetylcysteine (NAC), (2) sodium bicarbonate (NaHCO3) infusion, (3) NAC in combination with NaHCO3, or (4) hydration with sodium chloride infusion alone. Patients in cardiogenic shock were excluded. Acute CIN was defined as an increase in serum creatinine concentration >25% from the baseline value within a 3-day period. Overall, CIN occurred in 141 (21.9%) patients. The prevention treatment with NAC, NaHCO3, or the combined NAC and NaHCO3 did not reduce the rate of CIN significantly compared with hydration with intravenous sodium chloride infusion alone (20.1% versus 20.1% versus 20.8% versus 26.5%; P=NS). However, an increase in serum creatinine >25% from the baseline value to 30 day was significantly lower in patients treated with combined NAC and NaHCO3 (18.7% versus 19.1% versus 9.2% versus 21.3%; P=0.033). CONCLUSIONS: Treatment with NAC or NaHCO3 did not reduce the rate of acute CIN significantly. Combined treatment with NAC and NaHCO3 may reduce the risk of renal dysfunction after 30 days. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01160627.

Graft patency after off-pump coronary artery bypass surgery is inferior even with identical heparinization protocols: results from the Danish On-pump Versus Off-pump Randomization Study (DOORS).

OBJECTIVE: To determine whether graft patency after on-pump and off-pump coronary artery bypass surgery is similar when performed using the same heparinization protocol. METHODS: In a randomized, controlled, multicenter trial, 900 patients more than 70 years of age received either on-pump or off-pump coronary artery bypass surgery. Heparin was given to achieve an activated clotting time of 400 seconds before arteriotomy in both groups. After the procedure, protamine sulfate was given to revert the activated clotting time to less than 120 seconds. Coronary angiography was performed 6 months after the operation and graft patency was assessed by independent blinded observers. RESULTS: A total of 481 patients underwent angiography. In the off-pump group, 561 (79%) of 710 grafts were open, 65 (9%) were stenotic, and 84 (12%) were occluded. In the on-pump group, 549 (86%) of 650 grafts were open, 38 (5%) were stenotic, and 63 (9%) were occluded. The difference between the proportion of open grafts was statistically significant in favor of on-pump surgery (P=.01). The proportion of open left internal thoracic artery grafts was 95% in both groups. Perioperative use of intracoronary shunts did not increase the risk of stenosis of the coronary artery distal to the anastomosis. CONCLUSIONS: Despite comparable heparinization, graft patency after off-pump surgery was inferior to that after on-pump surgery.

Future biomarkers for detection of ischemia and risk stratification in acute coronary syndrome.

BACKGROUND: Evaluation of patients who present to the hospital with a complaint of chest pain or other signs or symptoms suggestive of acute coronary syndrome (ACS) is time-consuming, expensive, and problematic. Recent investigations have indicated that increases in biomarkers upstream from biomarkers of necrosis (cardiac troponins I and T), such as inflammatory cytokines, cellular adhesion molecules, acute-phase reactants, plaque destabilization and rupture biomarkers, biomarkers of ischemia, and biomarkers of myocardial stretch may provide earlier assessment of overall patient risk and aid in identifying patients with higher risk of an adverse event. APPROACH AND CONTENT: The purpose of this review is to provide an overview of the pathophysiology and clinical and analytical characteristics of several biomarkers that may have potential clinical utility to identify ACS patients. These biomarkers (myeloperoxidase, metalloproteinase-9, soluble CD40 ligand, pregnancy-associated plasma protein A, choline, ischemia-modified albumin, unbound free fatty acids, glycogen phosphorylase isoenzyme BB, and placental growth factor) have demonstrated promise and need to be more thoroughly evaluated for commercial development for implementation into routine clinical and laboratory practice. SUMMARY: Specifications that have been addressed for cardiac troponins and natriuretic peptides will need to be addressed with the same scrutiny for the biomarkers discussed in this review. They include validating analytical imprecision and detection limits, calibrator characterization, assay specificity and standardization, pre-analytical issues, and appropriate reference interval studies. Crossing boundaries from research to clinical application will require replication in multiple settings and experimental evidence supporting a pathophysiologic role and, ideally, interventional trials demonstrating that monitoring single or multiple biomarkers improves outcomes.

Randomized comparison of deliverability and in-hospital complications in implantation of BxSonic(R), Express(R), and Flexmaster(R) coronary stents.

AIMS: To compare deliverability and in-hospital complications in implantation of BxSonic(R), Express(R), and Flexmaster(R) coronary stents in a randomized multicenter trial in five Danish interventional centres. METHODS AND RESULTS: Patients with planned stenting of at least one stenotic lesion in a native coronary artery were included in the study. There were 494 (664) patients (treated lesions) in the BxSonic(R), 499 (657) in the Express(R) and 500 (658) in the Flexmaster(R) groups. The groups were well matched with regard to age, sex, diabetes, smoking, hypercholesterolemia, hypertension, indication for PCI and coronary artery lesion complexity. The study stents were implanted with or without predilatation according to ordinary -clinical practice.Rates of successful stent implantation and in-hospital stent thrombosis, re-intervention, non-fatal myocardial infarction or death. The BxSonic(R), Express(R) and Flexmaster(R) stents were successfully implanted in 92,2%, 89,3% and 91,6% of all lesions (ns). There were no in-hospital deaths and the rates of in-hospital complications were similar in the three stent groups. CONCLUSION: We found similar deliverability and in-hospital complication rates of the BxSonic(R), Express(R) and Flexmaster(R) stents.