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.

Short- and long-term cause of death in patients treated with primary PCI for STEMI.

BACKGROUND: Short-term mortality has been studied thoroughly in patients undergoing primary percutaneous coronary intervention (PCI), whereas long-term cause of death in patients with ST-segment elevation myocardial infarction (STEMI) remains unknown. OBJECTIVES: The goal of this study was to describe the association between time and cause of death in patients with STEMI undergoing primary PCI. METHODS: A centralized civil registration system, patient files, and public disease and death cause registries with an accurate record linkage were used to trace time and cause of death in 2,804 consecutive patients with STEMI (age 63 ± 13 years, 72% males) treated with primary PCI. RESULTS: Patients were followed up for a median of 4.7 years. During a total of 13,447 patient-years, 717 patients died. Main causes of death within the first 30 days were cardiogenic shock and anoxic brain injury after cardiac arrest. Age, culprit vessel size and flow, and the presence of heart failure and diabetes were independent predictors of mortality. After 30 days, the annual cardiac mortality rate was <1.5%. Causes of death beyond 30 days were noncardiac in 65% of cases (mainly malignancies and pulmonary diseases). The 30-day, 1-year, and 5-year all-cause (and cardiac) mortality rates were 7.9% (7.3%), 11.4% (8.4%), and 23.3% (13.8%), respectively. CONCLUSIONS: Patients who survive the first month after an STEMI treated with primary PCI have an excellent prognosis, with a <1.5% annual risk of successive cardiac death. Noncardiac causes are responsible for the majority of later deaths in these patients.

Copy number variation in glutathione S-transferases M1 and T1 and ischemic vascular disease: four studies and meta-analyses.

BACKGROUND: Glutathione S-transferases (GSTs) M1 and T1 detoxify products of oxidative stress and may protect against atherosclerosis and ischemic vascular disease (IVD). We tested the hypothesis that copy number variation (CNV) in GSTM1 and GSTT1 genes, known to be associated with stepwise decreases in catalytic activity, predict risk of IVD. METHODS AND RESULTS: We included 23 059 Danes from 2 general population studies and 2 case-control studies, of whom 4930 had ischemic heart disease (IHD) and 2086 had ischemic cerebrovascular disease. A real-time polymerase chain reaction method genotyped for the exact number of GSTM1 and GSTT1 gene copies. We also performed meta-analyses, including our own and former studies, totaling 13 196 IHD cases and 33 228 controls. CNV in GSTM1 or GSTT1 or genotype combinations were not associated with an increased risk of IHD, myocardial infarction, ischemic cerebrovascular disease, ischemic stroke, or any ischemic vascular event in studies individually or combined or in the meta-analyses. Furthermore, genotypes did not interact with smoking on risk of disease end points. Finally, GST genotypes did not associate with markers of inflammation and oxidation or interact with smoking on markers of inflammation in the general population. In contrast, we observed the well-established association between CNV in GSTM1 and risk of bladder cancer. CONCLUSIONS: In studies including 6557 IVD cases and 16 502 controls and in meta-analyses of 13 196 cases and 33 228 controls, CNV in GSTM1 and GSTT1 genes did not associate with risk of IVD or with markers of inflammation. These observations were independent of smoking exposure.

TRIB1 and GCKR polymorphisms, lipid levels, and risk of ischemic heart disease in the general population.

OBJECTIVE: The goal of this study was to test whether TRIB1-rs2954029 and GCKR-rs1260326 associate with lipid levels and risk of ischemic heart disease (IHD) and myocardial infarction (MI) in the general population. METHODS AND RESULTS: We genotyped >71 000 individuals. Lipid levels were studied cross-sectionally. Risk of IHD and MI was examined prospectively, cross-sectionally, and in a case-control study, and a metaanalysis was performed. TRIB1 TA (50%) and AA (27%) versus TT (23%) genotypes were associated with increased levels of triglycerides (total increase, +0.16 mmol/L; trend, P<0.001), remnant cholesterol (+0.07 mmol/L; P<0.001), apolipoprotein B (+5.7 mg/dL; P<0.001), and low-density lipoprotein cholesterol (+0.11 mmol/L; P<0.001) and with decreased levels of high-density lipoprotein cholesterol (-0.04 mmol/L; P<0.001). In metaanalyses of the 3 studies combined, TRIB1 TA and AA versus TT genotypes were associated with 13% (95% CI, 5% to 20%) and 15% (7% to 23%) increased risk of IHD, and 11% (1% to 21%) and 17% (6% to 30%) increased risk of MI, respectively. Although GCKR CT (46%) and TT (14%) versus CC (40%) genotypes had effects on triglycerides (+0.17 mmol/L; trend, P<0.001), remnant cholesterol (+0.07 mmol/L; P<0.001), and apolipoprotein B (+4.6 mg/dL; P<0.001) similar to those of TRIB1, GCKR did not influence low-density lipoprotein cholesterol levels or risk of IHD or MI. Risks of IHD were similar after stratification for gender, age, body mass index, hypertension, diabetes mellitus, smoking, statin use, alcohol intake, and physical activity. CONCLUSIONS: In the general population, both TRIB1-rs2954029 and GCKR-rs1260326 were associated with lipid levels, whereas TRIB1 was also associated with increased risk of IHD and MI.

Long-term effects of invasive treatment in patients with a post-thrombolytic Q-wave myocardial infarction.

OBJECTIVES: The aim of the present study was to assess the effect of a deferred invasive treatment strategy on long-term outcome in patients with a post-thrombolytic Q-wave myocardial infarction and inducible myocardial ischemia. DESIGN: Patients (N=751) with post-thrombolytic Q-wave myocardial infarction and inducible ischemia (angina pectoris or silent myocardial ischemia) were randomized to a deferred invasive treatment (balloon angioplasty or coronary bypass surgery) or medical treatment. Vital status and non-fatal cardiac events defined as hospitalization caused by acute cardiac events were recorded for a median of 11.4 years. RESULTS: Survival was significantly improved in patients receiving invasive treatment compared to patients treated medically (hazard ratio 0.85 (95% confidence limits 0.73-0.99), p=0.034). Subgroup analysis showed a reduction of non-fatal cardiac events and improved survival among the patients with post-infarction angina pectoris and not among the patients with silent myocardial ischemia. CONCLUSIONS: A deferred invasive treatment strategy improves survival compared to medical treatment in patients with inducible myocardial ischemia after a post-thrombolytic Q-wave myocardial infarction.

Pre-discharge exercise test for evaluation of patients with complete or incomplete revascularization following primary percutaneous coronary intervention: a DANAMI-2 sub-study.

OBJECTIVES: It is unclear whether the completeness of revascularization impacts on the prognostic value of an exercise test after primary percutaneous coronary intervention (PCI). METHODS: The DANAMI-2 trial included patients with ST elevation acute myocardial infarction randomized to primary PCI or fibrinolysis. Of the 790 patients randomized to primary PCI, 572 performed an exercise test. Prospectively, 310 patients were classified as having complete and 216 as having incomplete revascularization. Primary endpoint was a composite of reinfarction and/or death. RESULTS: Patients with incomplete revascularization had lower exercise capacity [6.5 (95% CI: 1.9-12.8) vs. 7.0 (95% CI: 2.1-14.0) METs, p = 0.004] and more frequently ST depression [43 (20%) vs. 39 (13%), p = 0.02] compared to patients with complete revascularization. ST depression was not predictive of outcome in either groups, while multivariable analyses showed that exercise capacity was predictive of reinfarction and/or death in patients with incomplete revascularization [hazard ratio = 0.71 (95% CI: 0.54-0.93), p = 0.012] or of death alone [hazard ratio = 0.56 (95% CI: 0.41-0.77), p = 0.0003], which was not found in patients with complete revascularization. CONCLUSIONS: Exercise capacity was prognostic of reinfarction and/or death in patients with incomplete revascularization, but not in completely revascularized patients. ST segment depression alone did not predict residual coronary stenosis or dismal prognosis.

Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes.

OBJECTIVES: In a substudy of DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non-ST-segment Elevation myocardial infarction)-2, we compared the antiplatelet effects of AZD6140 and clopidogrel and assessed the effects of AZD6140 in clopidogrel-pretreated patients. BACKGROUND: Clopidogrel, in combination with aspirin, reduces cardiovascular events in patients with acute coronary syndromes (ACS). However, patients with poor inhibition of platelet aggregation with clopidogrel may be less well protected. AZD6140 is a reversible oral P2Y(12) receptor antagonist that has been studied in ACS patients in comparison with clopidogrel (DISPERSE-2 study). METHODS: Patients were randomized to receive either AZD6140 90 mg twice a day, AZD6140 180 mg twice a day, or clopidogrel 75 mg once a day for up to 12 weeks in a double-blind, double-dummy design. One-half the patients allocated AZD6140 received a 270-mg loading dose. Patients randomized to receive clopidogrel were given a 300-mg loading dose unless they had already been treated with clopidogrel. Adenosine diphosphate-induced platelet aggregation was assessed by optical aggregometry on day 1 and at 4-week intervals. RESULTS: AZD6140 inhibited platelet aggregation in a dose-dependent fashion and both doses achieved greater levels of inhibition than clopidogrel (e.g., 4 weeks, 4-h postdose [mean (+/-SD)]: clopidogrel 64% [+/-22%], AZD6140 90 mg 79% [+/-22%], AZD6140 180 mg 95% [+/-8%]. AZD6140 also produced further suppression of platelet aggregation in patients previously treated with clopidogrel. CONCLUSIONS: AZD6140 exhibited greater mean inhibition of platelet aggregation than a standard regimen of clopidogrel in ACS patients. In addition, AZD6140 further suppressed platelet aggregation in clopidogrel pretreated patients.

Estrogen receptor alpha polymorphism and risk of cardiovascular disease, cancer, and hip fracture: cross-sectional, cohort, and case-control studies and a meta-analysis.

BACKGROUND: We hypothesized that the estrogen receptor alpha (ESR1) IVS1-397T/C polymorphism affects high-density lipoprotein cholesterol response to hormone replacement therapy and risk of cardiovascular disease (CVD), cancer of reproductive organs, and hip fracture. METHODS AND RESULTS: We studied cross-sectionally 9244 individuals from the Danish general population and followed them up for 23 to 25 years. End points were CVD (ischemic heart disease, myocardial infarction, angina pectoris, ischemic cerebrovascular disease, ischemic stroke, other ischemic cerebrovascular disease, venous thromboembolism, deep vein thrombosis, and pulmonary embolism), cancer of reproductive organs (breasts, ovaries, uterus, and prostate), and hip fracture. We also studied patients with ischemic heart disease (n=2495), ischemic cerebrovascular disease (n=856), and breast cancer (n=1256) versus general population controls. The CC, CT, and TT genotypes had general population frequencies of 21%, 50%, and 29%, respectively. Cross-sectionally, genotype did not influence high-density lipoprotein cholesterol response to hormone replacement therapy. In the cohort study, there were no differences in risks of CVD, cancer of reproductive organs, or hip fracture between genotypes. In case-control studies, risk of CVD did not differ between genotypes; however, the odds ratio for breast cancer in women with TT versus CC genotypes was 1.4 (95% CI, 1.1 to 1.7). Meta-analysis in men of 6 previous and the present 2 studies, including 4799 cases and 12,190 controls, showed odds ratios in CC versus CT and TT genotypes for fatal and nonfatal myocardial infarction of 0.81 (95% CI, 0.59 to 1.12) and 1.08 (95% CI, 0.97 to 1.21). CONCLUSIONS: ESR1 IVS1-397T/C polymorphism does not influence high-density lipoprotein cholesterol response to hormone replacement therapy or risk of CVD, most cancers of reproductive organs, or hip fracture.

Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial.

BACKGROUND: Phase 1 clinical trials of granulocyte-colony stimulating factor (G-CSF) treatment after myocardial infarction have indicated that G-CSF treatment is safe and may improve left ventricular function. This randomized, double-blind, placebo-controlled trial aimed to assess the efficacy of subcutaneous G-CSF injections on left ventricular function in patients with ST-elevation myocardial infarction. METHODS AND RESULTS: Seventy-eight patients (62 men; average age, 56 years) with ST-elevation myocardial infarction were included after successful primary percutaneous coronary stent intervention <12 hours after symptom onset. Patients were randomized to double-blind treatment with G-CSF (10 microg/kg of body weight) or placebo for 6 days. The primary end point was change in systolic wall thickening from baseline to 6 months determined by cardiac magnetic resonance imaging (MRI). An independent core laboratory analyzed all MRI examinations. Systolic wall thickening improved 17% in the infarct area in the G-CSF group and 17% in the placebo group (P=1.0). Comparable results were found in infarct border and noninfarcted myocardium. Left ventricular ejection fraction improved similarly in the 2 groups measured by both MRI (8.5 versus 8.0; P=0.9) and echocardiography (5.7 versus 3.7; P=0.7). The risk of severe clinical adverse events was not increased by G-CSF. In addition, in-stent late lumen loss and target vessel revascularization rate in the follow-up period were similar in the 2 groups. CONCLUSIONS: Bone marrow stem cell mobilization with subcutaneous G-CSF is safe but did not lead to further improvement in ventricular function after acute myocardial infarction compared with the recovery observed in the placebo group.

In-stent neo-intimal hyperplasia after stem cell mobilization by granulocyte-colony stimulating factor Preliminary intracoronary ultrasound results from a double-blind randomized placebo-controlled study of patients treated with percutaneous coronary intervention for ST-elevation myocardial infarction (STEMMI Trial).

OBJECTIVE: The influence of treatment with granulocyte-colony stimulating factor (G-CSF) on the development of in-stent intimal hyperplasia is not known. We aimed to study this phenomenon in patients who had stents implanted in the course of an acute ST-elevation infarction and successively were treated with G-CSF. METHOD: We performed angiography and intracoronary ultrasound follow-up after 5 months in 41 consecutive patients in the STEMMI trial, which is a randomized double-blind placebo-controlled study on the effect of G-CSF injections on the myocardial function following acute myocardial infarction in patients treated with primary percutaneous coronary stent implantation. The intracoronary ultrasound images were analyzed by a blinded and independent core laboratory. RESULTS: There were no differences in in-stent neo-intimal hyperplasia determined by intracoronary ultrasound between patients treated with G-CSF compared to patients treated with placebo. Neo-intimal hyperplasia per mm of stent was 1.87 (+/-1.41) and 1.89 (+/-1.39), respectively (p = 0.97). Angiographic in-segment restenosis (>50% diameter stenosis) was found in 28% of patients (24% in the G-CSF group and 33% in the placebo group; p = 0.55). CONCLUSION: G-CSF treatment following coronary stent implantation in primary PCI treated AMI patients does not increase in-stent restenosis excessively and it does not seem warranted to limit further study of effects of G-CSF for that reason.

Extended follow-up of patients randomly assigned in the Angiotensin-converting enzyme inhibition Post-Revascularization Study (APRES).

BACKGROUND: We hypothesized that the benefit from ramipril on cardiac events and on left ventricular end-systolic volume (ESVI) in the Angiotensin-converting enzyme inhibition Post-revascularization Study (APRES) randomized controlled trial (RCT) was associated with long-term improvement. METHODS: For the 3.2 years after the end of the RCT, we obtained information from a national database regarding date and cause of death and hospitalization for the 159 enrolled patients. RESULTS: Assignment to ramipril in the RCT resulted in a lower rate of cardiac death or hospitalization with heart failure up to the time of complete follow-up of all patients at 4.3 years (relative risk [RR], 0.28; P =.018) and up to 1.5 years after the end of the RCT (RR, 0.35; P =.042) but not up to the complete extended follow-up time at 6.9 years (RR, 0.65; P =.27). Independent predictors for risk of future cardiac death or hospitalization with heart failure were (a) left ventricular dilation (LVD) (RR, 2.84; P =.031), defined as an increase in ESVI greater than the reproducibility coefficient, and (b) composite event of acute myocardial infarction or development of heart failure or LVD (RR, 12.44; P <.001). Ramipril significantly reduced events (a) (P =.046) and (b) (P =.015) during the RCT. CONCLUSIONS: There is congruence between the beneficial effect of ramipril on LVD, acute myocardial infarction, or heart failure and the prognostic importance of these factors and on cardiac death and hospitalization with heart failure. This observation supports and reinforces conclusions from previous APRES reports that ramipril benefits non-high-risk patients after revascularization.

Methylenetetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinemia, and risk of ischemic cardiovascular disease and venous thromboembolism: prospective and case-control studies from the Copenhagen City Heart Study.

Hyperhomocysteinemia is associated with ischemic cardiovascular disease (ICD) and venous thromboembolism (VTE). We tested the hypothesis that methylenetetrahydrofolate reductase (MTHFR) C677T homozygosity with hyperhomocysteinemia is associated with ICD and VTE. First, 9238 randomly selected whites from the general population were followed for 23 years. Second, 2125 whites with ischemic heart disease and 836 whites with ischemic cerebrovascular disease were compared with 7568 controls from the general population. Plasma homocysteine was elevated 25% in homozygotes versus noncarriers (P < .001) and 19% in ICD/VTE cases versus controls (P < .001). In prospective studies adjusted hazard ratios for ICD and VTE for homozygotes versus noncarriers did not differ from 1.0. Furthermore, MTHFR C677T homozygosity was not associated with increased risk of ICD or VTE in subgroups after stratification for sex, age, cholesterol, high-density lipoprotein cholesterol, lipoprotein(a), fibrinogen, triglycerides, body mass index, smoking, diabetes mellitus, hypertension, and factor V Leiden genotype. Finally, in case-control studies odds ratios for ischemic heart disease and ischemic cerebrovascular disease in homozygotes versus noncarriers did not differ from 1.0. In conclusion, MTHFR C677T homozygosity with hyperhomocysteinemia is not associated with ICD or VTE; however, ICD/VTE is associated with hyperhomocysteinemia. Therefore, ICD and VTE may cause hyperhomocysteinemia, rather than vice versa.

Use of biochemical markers of infarction for diagnosing perioperative myocardial infarction and early graft occlusion after coronary artery bypass surgery.

STUDY OBJECTIVES: Perioperative myocardial infarction (PMI) during coronary artery bypass grafting (CABG) is an important clinical problem because it is closely associated with increased morbidity and mortality. The diagnosis of PMI is, however, associated with several problems. Due to the surgical trauma, the usual indicators of myocardial infarction (pain, ECG changes, and elevated biochemical markers of infarction) have uncertain diagnostic value. The primary aim of this study was to illustrate the levels of the biochemical markers after uncomplicated bypass surgery defined as no clinical or ECG evidence of PMI, and no graft occlusion at 7 days by repeat angiography; and secondarily, to establish biochemical diagnostic discrimination limits for detection of in-hospital graft occlusion. METHODS AND RESULTS: One hundred three patients undergoing elective CABG were closely monitored by serial measurements of creatine kinase (CK)-MB mass, myoglobin, troponin T, and troponin I, and underwent a repeat angiography before discharge. Seven patients had ECG evidence of PMI. Peak troponin T and CK-MB values were significantly higher in these seven patients, although the diagnostic performances of the optimally chosen cutoff levels for diagnosing AMI were fair. Twelve patients had at least one occluded graft shown by repeat angiography. Peak values of CK-MB and troponin T were significantly higher in patients with graft occlusion (52.2 microg/L vs 24.7 microg/L, p = 0.01; and 3.7 microg/L vs 1.0 microg/L, p = 0.05, respectively). By multivariate analysis, a diagnostic discrimination level of 30 microg/L for CK-MB did not reach statistical significance; however, the independent diagnostic value of a cutoff level for troponin T at 3 microg/L reached a level of significance (p = 0.06). DISCUSSION: We have suggested normal values of four different biochemical markers of infarction after uncomplicated coronary bypass surgery. Patients with in-hospital graft occlusion had higher peak CK-MB and troponin T values. However, the overlap with patients without graft occlusion is substantial, and the patency status in the individual cannot be reliably predicted from these noninvasive tests.